Title 21—Food and Drugs

(This book contains parts 300 to 499)

Part

CHAPTER I—Food and Drug Administration, Department of Health and Human Services (Continued) ...... 300

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EDITORIAL NOTE: Nomenclature changes to chapter I appear at 59 FR 14366, Mar. 28, 1994, and 69 FR 13717, Mar. 24, 2004.

SUBCHAPTER D—DRUGS FOR HUMAN USE

Part Page 300 General ...... 5 310 New drugs...... 5 312 Investigational new drug application ...... 52 314 Applications for FDA approval to market a new drug ...... 94 315 Diagnostic radiopharmaceuticals...... 191 316 Orphan drugs...... 193 317 Qualifying pathogens...... 205 320 Bioavailability and bioequivalence requirements ... 206 328 Over-the-counter drug products intended for oral ingestion that contain alcohol ...... 221 329 Nonprescription human drug products subject to section 760 of the Federal food, drug, and cosmetic act ...... 222 330 Over-the-counter (OTC) human drugs which are generally recognized as safe and effective and not misbranded ...... 223 331 Antacid products for over-the-counter (OTC) human use ...... 243 332 Antiflatulent products for over-the-counter human use ...... 247 333 Topical antimicrobial drug products for over-the- counter human use ...... 248 335 Antidiarrheal drug products for over-the-counter human use ...... 256 336 Antiemetic drug products for over-the-counter human use ...... 258 338 Nighttime sleep-aid drug products for over-the- counter human use ...... 260 3

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Part Page 340 Stimulant drug products for over-the-counter human use ...... 261 341 Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use ...... 262 343 Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use .... 286 344 Topical otic drug products for over-the-counter human use ...... 293 346 Anorectal drug products for over-the-counter human use ...... 295 347 Skin protectant drug products for over-the-counter human use ...... 300 348 External analgesic drug products for over-the- counter human use ...... 308 349 Ophthalmic drug products for over-the-counter human use ...... 309 350 Antiperspirant drug products for over-the-counter human use ...... 315 352 Sunscreen drug products for over-the-counter human use [stayed indefinitely] ...... 317 355 Anticaries drug products for over-the-counter human use ...... 327 357 Miscellaneous internal drug products for over-the- counter human use ...... 332 358 Miscellaneous external drug products for over-the- counter human use ...... 336 361 Prescription drugs for human use generally recognized as safe and effective and not misbranded: Drugs used in research ...... 345 369 Interpretative statements re warnings on drugs and devices for over-the-counter sale ...... 350 370–499 [Reserved]

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PART 300—GENERAL presented for it, then formulation, labeling, or dosage changes may be pro- Subpart A [Reserved] posed and any resulting formulation may meet the appropriate criteria list- Subpart B—Combination Drugs ed in paragraph (a) of this section. (c) A fixed-combination prescription Sec. 300.50 Fixed-combination prescription drugs drug for humans that has been deter- for humans. mined to be effective for labeled indications by the Food and Drug Adminis- Subpart C—Substances Generally tration, based on evaluation of the Prohibited From Drugs NAS-NRC report on the combination, is considered to be in compliance with 300.100 Chlorofluorocarbon propellants. the requirements of this section. AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 360b, 361, 371. [40 FR 13496, Mar. 27, 1975, as amended at 64 FR 401, Jan. 5, 1999] Subpart A [Reserved] Subpart C—Substances Generally Subpart B—Combination Drugs Prohibited From Drugs § 300.50 Fixed-combination prescrip- § 300.100 Chlorofluorocarbon propel- tion drugs for humans. lants. The Food and Drug Administration’s The use of chlorofluorocarbons in policy in administering the new-drug, human drugs as propellants in self- antibiotic, and other regulatory provi- pressurized containers is generally pro- sions of the Federal Food, Drug, and hibited except as provided by § 2.125 of Cosmetic Act regarding fixed combina- this chapter. tion dosage form prescription drugs for [43 FR 11317, Mar. 17, 1978] humans is as follows: (a) Two or more drugs may be combined in a single dosage form when PART 310—NEW DRUGS each component makes a contribution to the claimed effects and the dosage of Subpart A—General Provisions each component (amount, frequency, Sec. duration) is such that the combination 310.3 Definitions and interpretations. is safe and effective for a significant 310.4 Biologics; products subject to license patient population requiring such con- control. current therapy as defined in the label- 310.6 Applicability of ‘‘new drug’’ or safety ing for the drug. Special cases of this or effectiveness findings in drug efficacy general rule are where a component is study implementation notices and no- added: tices of opportunity for hearing to iden- (1) To enhance the safety or effec- tical, related, and similar drug products. tiveness of the principal active compo- Subpart B—Specific Administrative Rulings nent; and and Decisions (2) To minimize the potential for abuse of the principal active compo- 310.100 New drug status opinions; statement nent. of policy. (b) If a combination drug presently 310.103 New drug substances intended for the subject of an approved new-drug hypersensitivity testing. application has not been recognized as effective by the Commissioner of Food Subpart C—New Drugs Exempted From and Drugs based on his evaluation of Prescription-Dispensing Requirements the appropriate National Academy of 310.200 Prescription-exemption procedure. Sciences-National Research Council 310.201 Exemption for certain drugs limited panel report, or if substantial evidence by new drug applications to prescription of effectiveness has not otherwise been sale.

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Subpart D—Records and Reports 310.537 Drug products containing active ingredients offered over-the-counter (OTC) 310.303 Continuation of long-term studies, for oral administration for the treatment records, and reports on certain drugs for of fever blisters and cold sores. which new drug applications have been 310.538 Drug products containing active in- approved. gredients offered over-the-counter (OTC) 310.305 Records and reports concerning ad- for use for ingrown toenail relief. verse drug experiences on marketed pre- 310.540 Drug products containing active in- scription drugs for human use without gredients offered over-the-counter (OTC) approved new drug applications. for use as stomach acidifiers. 310.306 Notification of a permanent dis- 310.541 Over-the-counter (OTC) drug prod- continuance or an interruption in manu- ucts containing active ingredients of- facturing of marketed prescription drugs fered for use in the treatment of hypo- for human use without approved new phosphatemia. drug applications. 310.542 Over-the-counter (OTC) drug products containing active ingredients of- Subpart E—Requirements for Specific New fered for use in the treatment of hyper- Drugs or Devices phosphatemia. 310.543 Drug products containing active in- 310.501 Patient package inserts for oral con- gredients offered over-the-counter (OTC) traceptives. for human use in exocrine pancreatic in- 310.502 Certain drugs accorded new drug sta- sufficiency. tus through rulemaking procedures. 310.544 Drug products containing active in- 310.503 Requirements regarding certain ra- gredients offered over-the-counter (OTC) dioactive drugs. for use as a smoking deterrent. 310.509 Parenteral drug products in plastic 310.545 Drug products containing certain ac- containers. tive ingredients offered over-the-counter 310.515 Patient package inserts for estro- (OTC) for certain uses. gens. 310.546 Drug products containing active in- 310.517 Labeling for oral hypoglycemic gredients offered over-the-counter (OTC) drugs of the sulfonylurea class. for the treatment and/or prevention of 310.518 Drug products containing iron or nocturnal leg muscle cramps. iron salts. 310.547 Drug products containing quinine of- 310.519 Drug products marketed as over-the- fered over-the-counter (OTC) for the counter (OTC) daytime sedatives. treatment and/or prevention of malaria. 310.527 Drug products containing active in- 310.548 Drug products containing colloidal gredients offered over-the-counter (OTC) silver ingredients or silver salts offered for external use as hair growers or for over-the-counter (OTC) for the treatment hair loss prevention. and/or prevention of disease. 310.528 Drug products containing active ingredients offered over-the-counter (OTC) AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, for use as an aphrodisiac. 355, 360b–360f, 360j, 360hh–360ss, 361(a), 371, 374, 310.529 Drug products containing active in- 375, 379e, 379k–l; 42 U.S.C. 216, 241, 242(a), 262. gredients offered over-the-counter (OTC) for oral use as insect repellents. Subpart A—General Provisions 310.530 Topically applied hormone-containing drug products for over-the- § 310.3 Definitions and interpretations. counter (OTC) human use. 310.531 Drug products containing active in- As used in this part: gredients offered over-the-counter (OTC) (a) The term act means the Federal for the treatment of boils. Food, Drug, and Cosmetic Act, as 310.532 Drug products containing active in- amended (secs. 201–902, 52 Stat. 1040 et gredients offered over-the-counter (OTC) seq., as amended; 21 U.S.C. 321–392). to relieve the symptoms of benign prostatic hypertrophy. (b) Department means the Department 310.533 Drug products containing active in- of Health and Human Services. gredients offered over-the-counter (OTC) (c) Secretary means the Secretary of for human use as an anticholinergic in Health and Human Services. cough-cold drug products. (d) Commissioner means the Commis- 310.534 Drug products containing active in- sioner of Food and Drugs. gredients offered over-the-counter (OTC) (e) The term person includes individ- for human use as oral wound healing uals, partnerships, corporations, and agents. 310.536 Drug products containing active in- associations. gredients offered over-the-counter (OTC) (f) The definitions and interpreta- for use as a nailbiting or thumbsucking tions of terms contained in section 201 deterrent. of the act shall be applicable to such

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terms when used in the regulations in manufactured by other manufacturers: this part. and any other drug containing a com- (g) New drug substance means any ponent so related by chemical struc- substance that when used in the manu- ture or known pharmacological prop- facture, processing, or packing of a erties that, in the opinion of experts drug, causes that drug to be a new qualified by scientific training and ex- drug, but does not include intermedi- perience to evaluate the safety and ef- ates used in the synthesis of such sub- fectiveness of drugs, it is prudent to as- stance. sume or ascertain the liability of simi- (h) The newness of a drug may arise lar side effects and contraindications. by reason (among other reasons) of: (l) Special packaging as defined in sec- (1) The newness for drug use of any tion 2(4) of the Poison Prevention substance which composes such drug, Packaging Act of 1970 means packaging in whole or in part, whether it be an that is designed or constructed to be active substance or a menstruum, ex- significantly difficult for children cipient, carrier, coating, or other com- under 5 years of age to open or obtain ponent. a toxic or harmful amount of the sub- (2) The newness for a drug use of a stance contained therein within a rea- combination of two or more sub- sonable time and not difficult for nor- stances, none of which is a new drug. mal adults to use properly, but does (3) The newness for drug use of the not mean packaging which all such proportion of a substance in a combina- children cannot open or obtain a toxic tion, even though such combination or harmful amount within a reasonable containing such substance in other pro- time. portion is not a new drug. (m) [Reserved] (4) The newness of use of such drug in (n) The term radioactive drug means diagnosing, curing, mitigating, treat- any substance defined as a drug in sec- ing, or preventing a disease, or to af- tion 201(g)(1) of the Federal Food, fect a structure or function of the Drug, and Cosmetic Act which exhibits body, even though such drug is not a new drug when used in another disease spontaneous disintegration of unstable or to affect another structure or func- nuclei with the emission of nuclear tion of the body. particles or photons and includes any (5) The newness of a dosage, or meth- nonradioactive reagent kit or nuclide od or duration of administration or ap- generator which is intended to be used plication, or other condition of use pre- in the preparation of any such sub- scribed, recommended, or suggested in stance but does not include drugs such the labeling of such drug, even though as carbon-containing compounds or po- such drug when used in other dosage, tassium-containing salts which contain or other method or duration of admin- trace quantities of naturally occurring istration or application, or different radionuclides. The term ‘‘radioactive condition, is not a new drug. drug’’ includes a ‘‘radioactive biologi- (i) [Reserved] cal product’’ as defined in § 600.3(ee) of (j) The term sponsor means the per- this chapter. son or agency who assumes responsi- [39 FR 11680, Mar. 29, 1974, as amended at 39 bility for an investigation of a new FR 20484, June 11, 1974; 40 FR 31307, July 25, drug, including responsibility for com- 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. pliance with applicable provisions of 22, 1985] the act and regulations. The ‘‘sponsor’’ may be an individual, partnership, cor- § 310.4 Biologics; products subject to poration, or Government agency and license control. may be a manufacturer, scientific in- (a) If a drug has an approved license stitution, or an investigator regularly under section 351 of the Public Health and lawfully engaged in the investiga- Service Act (42 U.S.C. 262 et seq.) or tion of new drugs. under the animal virus, serum, and (k) The phrase related drug(s) includes toxin law of March 4, 1913 (21 U.S.C. 151 other brands, potencies, dosage forms, et seq.), it is not required to have an ap- salts, and esters of the same drug moi- proved application under section 505 of ety, including articles prepared or the act.

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(b) To obtain marketing approval for plicable. Any product not in compli- radioactive biological products for ance with an applicable drug efficacy human use, as defined in § 600.3(ee) of notice is in violation of section 505 this chapter, manufacturers must com- (new drugs) and/or section 502 (mis- ply with the provisions of § 601.2(a) of branding) of the act. this chapter. (b)(1) An identical, related, or similar drug includes other brands, potencies, [64 FR 56448, Oct. 20, 1999, as amended at 70 FR 14981, Mar. 24, 2005] dosage forms, salts, and esters of the same drug moiety as well as of any § 310.6 Applicability of ‘‘new drug’’ or drug moiety related in chemical struc- safety or effectiveness findings in ture or known pharmacological prop- drug efficacy study implementation erties. notices and notices of opportunity (2) Where experts qualified by sci- for hearing to identical, related, entific training and experience to and similar drug products. evaluate the safety and effectiveness of (a) The Food and Drug Administra- drugs would conclude that the findings tion’s conclusions on the effectiveness and conclusions, stated in a drug effi- of drugs are currently being published cacy notice or notice of opportunity for in the FEDERAL REGISTER as Drug Effi- hearing, that a drug product is a ‘‘new cacy Study Implementation (DESI) No- drug’’ or that there is a lack of evi- tices and as Notices of Opportunity for dence to show that a drug product is Hearing. The specific products listed in safe or effective are applicable to an these notices include only those that identical, related, or similar drug prod- were introduced into the market uct, such product is affected by the no- through the new drug procedures from tice. A combination drug product con- 1938–62 and were submitted for review taining a drug that is identical, re- by the National Academy of Sciences- lated, or similar to a drug named in a National Research Council (NAS-NRC), notice may also be subject to the find- Drug Efficacy Study Group. Many ings and conclusions in a notice that a products which are identical to, related drug product is a ‘‘new drug’’ or that to, or similar to the products listed in there is a lack of evidence to show that these notices have been marketed a drug product is safe or effective. under different names or by different (3) Any person may request an opin- firms during this same period or since ion on the applicability of such a no- 1962 without going through the new tice to a specific product by writing to drug procedures or the Academy re- the Food and Drug Administration at view. Even though these products are the address shown in paragraph (e) of not listed in the notices, they are cov- this section. ered by the new drug applications re- (c) Manufacturers and distributors of viewed and thus are subject to these drugs should review their products as notices. All persons with an interest in drug efficacy notices are published and a product that is identical, related, or assure that identical, related, or simi- similar to a drug listed in a drug effi- lar products comply with all applicable cacy notice or a notice of opportunity provisions of the notices. for a hearing will be given the same op- (d) The published notices and sum- portunity as the applicant to submit mary lists of the conclusions are of data and information, to request a particular interest to drug purchasing hearing, and to participate in any hear- agents. These agents should take paring. It is not feasible for the Food and ticular care to assure that the same Drug Administration to list all prod- purchasing policy applies to drug products which are covered by an NDA and ucts that are identical, related, or thus subject to each notice. However, similar to those named in the drug effi- it is essential that the findings and cacy notices. The Food and Drug Ad- conclusions that a drug product is a ministration applies the same regu- ‘‘new drug’’ or that there is a lack of latory policy to all such products. In evidence to show that a drug product is many instances a determination can safe or effective be applied to all iden- readily be made as to the applicability tical, related, and similar drug prod- of a drug efficacy notice by an indi- ucts to which they are reasonably ap- vidual who is knowledgeable about

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drugs and their indications for use. (Public Law 87–781; 76 Stat. 788–89). In Where the relationships are more sub- particular, when approval of a new tle and not readily recognized, the pur- drug application is withdrawn under chasing agent may request an opinion provisions of section 505(e) of the Fed- by writing to the Food and Drug Ad- eral Food, Drug, and Cosmetic Act, a ministration at the address shown in drug generally recognized as safe may paragraph (e) of this section. become a ‘‘new drug’’ within the mean- (e) Interested parties may submit to ing of section 201(p) of said act as the Food and Drug Administration, amended by the Kefauver-Harris Act on Center for Drug Evaluation and Re- October 10, 1962. This is of special im- search, Office of Compliance, 10903 New Hampshire Ave., Silver Spring, MD portance by reason of proposed actions 20993–0002, the names of drug products, to withdraw approval of new drug ap- and of their manufacturers or distribu- plications for lack of substantial evi- tors, that should be the subject of the dence of effectiveness as a result of re- same purchasing and regulatory poli- ports of the National Academy of cies as those reviewed by the Drug Effi- Sciences—National Research Council cacy Study Group. Appropriate action, on its review of drug effectiveness; for including referral to purchasing offi- example, see the notice published in cials of various government agencies, the FEDERAL REGISTER of January 23, will be taken. 1968 (33 FR 818), regarding rutin, quer- (f) This regulation does not apply to cetin, et al. OTC drugs identical, similar, or related (c) Any marketed drug is a ‘‘new to a drug in the Drug Efficacy Study drug’’ if any labeling change made unless there has been or is notification after October 9, 1962, recommends or in the FEDERAL REGISTER that a drug suggests new conditions of use under will not be subject to an OTC panel re- which the drug is not generally recog- view pursuant to §§ 330.10, 330.11, and nized as safe and effective by qualified 330.5 of this chapter. experts. Undisclosed or unreported side [39 FR 11680, Mar. 29, 1974, as amended at 48 effects as well as the emergence of new FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; knowledge presenting questions with 55 FR 11578, Mar. 29, 1990; 74 FR 13113, Mar. 26, 2009] respect to the safety or effectiveness of a drug may result in its becoming a Subpart B—Specific Administrative ‘‘new drug’’ even though it was previously considered ‘‘not a new drug.’’ Rulings and Decisions Any previously given informal advice § 310.100 New drug status opinions; that an article is ‘‘not a new drug’’ statement of policy. does not apply to such an article if it (a) Over the years since 1938 the Food has been changed in formulation, man- and Drug Administration has given in- ufacture control, or labeling in a way formal advice to inquirers as to the that may significantly affect the safety new drug status of preparations. These of the drug. drugs have sometimes been identified (d) For these reasons, all opinions only by general statements of composi- previously given by the Food and Drug tion. Generally, such informal opinions Administration to the effect that an were incorporated in letters that did article is ‘‘not a new drug’’ or is ‘‘no not explicitly relate all of the nec- longer a new drug’’ are hereby revoked. essary conditions and qualifications This does not mean that all articles such as the quantitative formula for that were the subjects of such prior the drug and the conditions under opinions will be regarded as new drugs. which it was prescribed, recommended, The prior opinions will be replaced by or suggested. This has contributed to opinions of the Food and Drug Admin- misunderstanding and misinterpreta- istration that are qualified and current tion of such opinions. on when an article is ‘‘not a new drug,’’ (b) These informal opinions that an as set forth in this subchapter. article is ‘‘not a new drug’’ or ‘‘no longer a new drug’’ require reexamina- [39 FR 11680, Mar. 29, 1974] tion under the Kefauver-Harris Act

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§ 310.103 New drug substances in- (c) This section does not apply to tended for hypersensitivity testing. drugs or their components that are (a) The Food and Drug Administra- subject to the licensing requirements tion is aware of the need in the prac- of the Public Health Service Act of tice of medicine for the ingredients of 1944, as amended. (See subchapter F— a new drug to be available for tests of Biologics, of this chapter.) hypersensitivity to such ingredients [39 FR 11680, Mar. 29, 1974, as amended at 55 and therefore will not object to the FR 11578, Mar. 29, 1990; 67 FR 4907, Feb. 1, shipment of a new drug substance, as 2002] defined in § 310.3(g), for such purpose if all of the following conditions are met: Subpart C—New Drugs Exempted (1) The shipment is made as a result From Prescription-Dispensing of a specific request made to the manu- Requirements facturer or distributor by a practitioner licensed by law to administer § 310.200 Prescription-exemption pro- such drugs, and the use of such drugs cedure. for patch testing is not promoted by (a) Duration of prescription require- the manufacturer or distributor. ment. Any drug limited to prescription (2) The new drug substance requested use under section 503(b)(1)(B) of the act is an ingredient in a marketed new remains so limited until it is exempted drug and is not one that is an ingre- as provided in paragraph (b) or (e) of dient solely in a new drug that is le- this section. gally available only under the inves- (b) Prescription-exemption procedure for tigational drug provisions of this part. drugs limited by a new drug application. (3) The label bears the following Any drug limited to prescription use prominently placed statements in lieu under section 503(b)(1)(B) of the act of adequate directions for use and in shall be exempted from prescription- addition to complying with the other dispensing requirements when the labeling provisions of the act: Commissioner finds such requirements (i) ‘‘Rx only’’; and are not necessary for the protection of (ii) ‘‘For use only in patch testing’’. the public health by reason of the (4) The quantity shipped is limited to drug’s toxicity or other potentiality an amount reasonable for the purpose for harmful effect, or the method of its of patch testing in the normal course use, or the collateral measures nec- of the practice of medicine and is used essary to its use, and he finds that the solely for such patch testing. drug is safe and effective for use in (5) The new drug substance is manu- self-medication as directed in proposed factured by the same procedures and labeling. A proposal to exempt a drug meets the same specifications as the from the prescription-dispensing re- component used in the finished dosage quirements of section 503(b)(1)(B) of the form. act may be initiated by the Commis- (6) The manufacturer or distributor sioner or by any interested person. Any maintains records of all shipments for interested person may file a petition this purpose for a period of 2 years seeking such exemption, which petition after shipment and will make them may be pursuant to part 10 of this available to the Food and Drug Admin- chapter, or in the form of a supplement istration on request. to an approved new drug application. (b) When the requested new drug sub- (c) New drug status of drugs exempted stance is intended for investigational from the prescription requirement. A drug use in humans or the substance is le- exempted from the prescription re- gally available only under the inves- quirement under the provisions of tigational drug provisions of part 312 of paragraph (b) of this section is a ‘‘new this chapter, the submission of an ‘‘In- drug’’ within the meaning of section vestigational New Drug Application’’ 201(p) of the act until it has been used (IND) is required. The Food and Drug to a material extent and for a material Administration will offer assistance to time under such conditions except as any practitioner wishing to submit an provided in paragraph (e) of this sec- Investigational New Drug Application. tion.

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(d) Prescription legend not allowed on (v) The preparation is labeled with exempted drugs. The use of the prescrip- adequate directions for use in minor tion caution statement quoted in sec- conditions as a simple analgesic. tion 503(b) (4) of the act, in the labeling (vi) The dosages of N-acetyl-p-amino- of a drug exempted under the provi- phenol recommended or suggested in sions of this section, constitutes mis- the labeling do not exceed: For adults, branding. Any other statement or sug- 0.65 gram (10 grains) per dose or 2.6 gestion in the labeling of a drug ex- grams (40 grains) per 24-hour period: for empted under this section, that such children 6 to 12 years of age, one-half of drug is limited to prescription use, the maximum adult dose or dosage; for may constitute misbranding. children 3 to 6 years of age, one-fifth of (e) Prescription-exemption procedure of the maximum adult dose or dosage. OTC drug review. A drug limited to pre- (vii) The labeling bears, in juxtaposi- scription use under section 503(b)(1)(B) tion with the dosage recommendations, of the act may also be exempted from a clear warning statement against ad- prescription-dispensing requirements ministration of the drug to children by the procedure set forth in § 330.13 of under 3 years of age and against use of this chapter. the drug for more than 10 days, unless such uses are directed by a physician. [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, (viii) If the article is offered for use 1977; 42 FR 15674, Mar. 22, 1977; 72 FR 15043, in arthritis or rheumatism, the label- Mar. 30, 2007] ing prominently bears a statement that the beneficial effects claimed are § 310.201 Exemption for certain drugs limited to the temporary relief of limited by new-drug applications to minor aches and pains of arthritis and prescription sale. rheumatism and, in juxtaposition with (a) The prescription-dispensing re- directions for use in such conditions, a quirements of section503(b)(1)(B) of the conspicuous warning statement, such Federal Food, Drug, and Cosmetic Act as ‘‘Caution: If pain persists for more are not necessary for the protection of than 10 days, or redness is present, or the public health with respect to the in conditions affecting children under following drugs subject to new drug ap- 12 years of age, consult a physician implications: mediately’’. (1) N-Acetyl-p-aminophenol (acetami- (2) Sodium gentisate (sodium-2, 5-di- nophen, p-hydroxy-acetanilid) prepara- hydroxybenzoate) preparations meet- tions meeting all the following condi- ing all the following conditions: tions: (i) The sodium gentisate is prepared, (i) The N-acetyl-p-aminophenol is with or without other drugs, in tablet prepared, with or without other drugs, or other dosage form suitable for oral in tablet or other dosage form suitable use in self-medication, and containing for oral use in self-medication, and no drug limited to prescription sale containing no drug limited to prescrip- under the provisions of section 503(b)(1) tion sale under the provisions of sec- of the act. tion 503(b)(1) of the act. (ii) The sodium gentisate and all (ii) The N-acetyl-p-aminophenol and other components of the preparation all other components of the prepara- meet their professed standards of iden- tion meet their professed standards of tity, strength, quality, and purity. identity, strength, quality, and purity. (iii) If the preparation is a new drug, (iii) If the preparation is a new drug, an application pursuant to section an application pursuant to section 505 505(b) of the act is approved for it. (b) of the act is approved for it. (iv) The preparation contains not (iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhy- more than 0.325 gram (5 grains) of N- drous sodium gentisate per dosage acetyl-p-aminophenol per dosage unit, unit. or if it is in liquid form not more than (v) The preparation is labeled with 100 milligrams of N-acetyl-p-amino- adequate directions for use in minor phenol per milliliter. conditions as a simple analgesic.

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(vi) The dosages of sodium gentisate case of rectal bleeding, as this may in- recommended or suggested in the label- dicate serious disease. ing do not exceed: For adults, 0.5 gram (4) Phenyltoloxamine dihydrogen cit- (7.7 grains) per dose of 2.0 grams (31 rate (N,N-dimethyl-(a-phenyl-O-toloxy) grains) per 24-hour period; for children ethylamine dihydrogen citrate), prep- 6 to 12 years of age, one-half of the arations meeting all the following con- maximum adult dose or dosage. ditions: (vii) The labeling bears, in juxtaposi- (i) The phenyltoloxamine dihydrogen tion with the dosage recommendations, citrate is prepared, with or without a clear warning statement against ad- other drugs, in tablet or other dosage ministration of the drug to children form suitable for oral use in self-medi- under 6 years of age and against use of cation, and containing no drug limited the drug for a prolonged period, except to prescription sale under the provi- as such uses may be directed by a phy- sions of section 503(b)(1) of the act. sician. (ii) The phenyltoloxamine dihydro- (3) Isoamylhydrocupreine and zola- gen citrate and all other components of mine hydrochloride (N, N-dimethyl-N′- the preparation meet their professed 2-thiazolyl-N′-p-methoxybenzyl-ethyl- standards of identity, strength, qual- enediamine hydrochloride) prepara- ity, and purity. tions meeting all the following condi- (iii) If the preparation is a new drug, tions: an application pursuant to section (i) The isoamylhydrocupreine and zo- 505(b) of the act is approved for it. lamine hydrochloride are prepared in (iv) The preparation contains not dosage form suitable for self-medica- more than 88 milligrams of phenyl- tion as rectal suppositories or as an toloxamine dihydrogen citrate (equiva- ointment and containing no drug lim- lent to 50 milligrams of phenyltolox- ited to prescription sale under the pro- amine) per dosage unit. visions of section 503(b)(1) of the act. (v) The preparation is labeled with adequate directions for use in the tem- (ii) The isoamylhydrocupreine, zola- porary relief of the symptoms of hay amine hydrochloride, and all other fever and/or the symptoms of other components of the preparation meet minor conditions in which it is indi- their professed standards of identity, cated. strength, quality, and purity. (vi) The dosages recommended or (iii) If the preparation is a new drug, suggested in the labeling do not exceed: an application pursuant to section For adults, 88 milligrams of phenyl- 505(b) of the act is approved for it. toloxamine dihydrogen citrate (equiva- (iv) The preparation contains not lent to 50 milligrams of phenyltolox- more than 0.25 percent of isoamyl- amine) per dose or 264 milligrams of hydrocupreine and 1.0 percent of zola- phenyltoloxamine dihydrogen citrate mine hydrochloride. (equivalent to 150 milligrams of phen- (v) If the preparation is in supposi- yltoloxamine) per 24-hour period; for tory form, it contains not more than children 6 to 12 years of age, one-half of 5.0 milligrams of isoamylhydrocupreine the maximum adult dose or dosage. and not more than 20.0 milligrams of (vii) The labeling bears, in juxtaposi- zolamine hydrochloride per supposi- tion with the dosage recommendations: tory. (a) Clear warning statements against (vi) The preparation is labeled with administration of the drug to children adequate directions for use in the tem- under 6 years of age, except as directed porary relief of local pain and itching by a physician, and against driving a associated with hemorrhoids. car or operating machinery while using (vii) The directions provide for the the drug, since it may cause drowsi- use of not more than two suppositories ness. or two applications of ointment in a 24- (b) If the article is offered for tem- hour period. porary relief of the symptoms of colds, (viii) The labeling bears, in jux- a statement that continued adminis- taposition with the dosage rec- tration for such use should not exceed ommendations, a clear warning state- 3 days, except as directed by a physi- ment against use of the preparation in cian.

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(5)–(7) [Reserved] suitable for self-medication by external (8) Dicyclomine hydrochloride (1- application to the skin as a spray, and cyclohexylhexahydrobenzoic acid. b-di- containing no drug limited to prescrip- ethylaminoethyl ester hydrochloride; tion sale under the provisions of sec- diethylaminocarbethoxy-bicyclohexyl tion 503(b)(1) of the act. hydrochloride) preparations meeting (ii) The hexadenol and all other com- all the following conditions: ponents of the preparation meet their (i) The dicyclomine hydrochloride is professed standards of identity, prepared with suitable antacid and strength, quality, and purity. other components, in tablet or other (iii) If the preparation is a new drug, dosage form for oral use in self-medica- an application pursuant to section tion, and containing no drug limited to 505(b) of the act is approved for it. prescription sale under the provisions (iv) The preparation contains not of section 503(b)(1) of the act. more than 5 percent by weight of (ii) The dicyclomine hydrochloride hexadenol. and all other components of the prepa- (v) The preparation is labeled with ration meet their professed standards adequate directions for use by external of identity, strength, quality, and pu- application in the treatment of minor rity. burns and minor skin irritations. (iii) If the preparation is a new drug, (vi) The labeling bears, in juxtaposi- an application pursuant to section tion with the directions for use, clear 505(b) of the act is approved for it. warning statements against: (iv) The preparation contains not (a) Use on serious burns or skin con- more than 5 milligrams of dicyclomine ditions or prolonged use, except as dihydrochloride per dosage unit, or if it rected by a physician. is in liquid form not more than 0.5 mil- (b) Spraying the preparation in the ligram of dicyclomine hydrochloride vicinity of eyes, mouth, nose, or ears. per milliliter. (12) Sulfur dioxide preparations (v) The preparation is labeled with meeting all the following conditions: adequate directions for use only by adults and children over 12 years of (i) The sulfur dioxide is prepared with age, in the temporary relief of gastric or without other drugs, in an aqueous hyperacidity. solution packaged in a hermetic con- (vi) The dosages recommended or tainer suitable for use in self-medica- suggested in the directions for use do tion by external application to the not exceed 10 milligrams of dicyclo- skin, and containing no drug limited to mine hydrochloride per dose or 30 mil- prescription sale under the provisions ligrams in a 24-hour period. of section 503(b)(1) of the act. (vii) The labeling bears, in juxtaposi- (ii) The sulfur dioxide and all other tion with the dosage recommendations, components of the preparation meet clear warning statements against: their professed standards of identity, (a) Exceeding the recommended dos- strength, quality, and purity. age. (iii) If the preparation is a new drug, (b) Prolonged use, except as directed an application pursuant to section by a physician, since persistent or re- 505(b) of the act is approved for it. curring symptoms may indicate a seri- (iv) The preparation contains not ous disease requiring medical atten- more than 5 grams of sulfur dioxide per tion. 100 milliliters of solution. (c) Administration to children under (v) The preparation is labeled with 12 years of age except as directed by a adequate directions for use by external physician. application to the smooth skin in the (9)–(10) [Reserved] prevention or treatment of minor con- (11) Hexadenol (a mixture of tetra- ditions in which it is indicated. cosanes and their oxidation products) (vi) The directions for use rec- preparations meeting all the following ommend or suggest not more than two conditions: applications a day for not more than 1 (i) The hexadenol is prepared and week, except as directed by a physi- packaged, with or without other drugs, cian. solvents, and propellants, in a form (13)–(15) [Reserved]

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(16) Tuaminoheptane sulfate (2-ami- ester) preparations meeting all the fol- noheptane sulfate) preparations meet- lowing conditions. ing all the following conditions: (i) The vibesate is prepared and pack- (i) The tuaminoheptane sulfate is aged, with or without other drugs, sol- prepared, with or without other drugs, vents, and propellants, in a form suit- in an aqueous vehicle suitable for ad- able for self-medication by external ap- ministration in self-medication as nose plication to the skin as a spray, and drops, and containing no drug limited containing no drug limited to prescrip- to prescription sale under the provi- tion sale under the provisions of sec- sions of section 503(b)(1) of the act. tion 503(b)(1) of the act. (ii) The preparation is packaged with (ii) The vibesate and all other compo- a style of container or assembly suited nents of the preparation meet their to self-medication by the recommended professed standards of identity, route of administration, and delivering strength, quality, and purity. not more than 0.1 milliliter of the prep- (iii) If the preparation is a new drug, aration per drop. an application pursuant to section (iii) The tuaminoheptane sulfate and 505(b) of the act is approved for it. all other components of the prepara- (iv) The preparation contains not tion meet their professed standards of more than 13 percent by weight of vi- identity, strength, quality, and purity. besate. (iv) If the preparation is a new drug, (v) The preparation is labeled with an application pursuant to section adequate directions for use by external 505(b) of the act is approved for it. application as a dressing for minor (v) The tuaminoheptane sulfate con- burns, minor cuts, or other minor skin tent of the preparation does not exceed irritations. 10 milligrams per milliliter. (vi) The labeling bears in juxtaposi- (vi) The preparation is labeled with tion with the directions for use clear adequate directions for use in the tem- warning statements against: porary relief of nasal congestion. (a) Use on serious burns and on in- (vii) The dosages recommended or fected, deep, and puncture wounds un- suggested in the directions for use do less directed by a physician. not exceed the equivalent: For adults, 5 (b) Spraying the preparation near the drops of a 1 percent solution per nostril eyes or other mucous membranes. per dose, and 5 doses in a 24-hour pe- (c) Inhaling the preparation. riod; for children 1 to 6 years of age, 3 (d) Use near open flames. drops of a 1 percent solution per nostril (e) Puncturing the container or per dose, and 5 doses in a 24-hour pe- throwing the container into fire. riod; for infants under 1 year of age, 2 (19) Pramoxine hydrochloride (4-N- drops of a 1 percent solution per nostril butoxyphenyl g-morpholinopropyl per dose, and 5 doses in a 24-hour pe- ether hydrochloride) preparations riod. meeting all the following conditions: (viii) The labeling bears, in jux- (i) The pramoxine hydrochloride is taposition with the dosage rec- prepared, with or without other drugs, ommendations: in a dosage form suitable for use in (a) Clear warning statements against self-medication by external application use of more than 5 doses daily, and to the skin, and containing no drug against use longer than 4 days unless limited to prescription sale under the directed by a physician. provisions of section 503(b)(1) of the (b) A clear warning statement to the act. effect that frequent use may cause (ii) The pramoxine hydrochloride and nervousness or sleeplessness, and that all other components of the prepara- individuals with high blood pressure, tion meet their professed standards of heart disease, diabetes, or thyroid dis- identity, strength, quality, and purity. ease should not use the preparation un- (iii) If the preparation is a new drug, less directed by a physician. an application pursuant to section (17) [Reserved] 505(b) of the act is approved for it. (18) Vibesate (a mixture of copoly- (iv) The preparation contains not mers of hydroxy-vinyl chlorideacetate, more than 1.0 percent of pramoxine hy- sebacic acid, and modified maleic rosin drochloride.

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(v) The preparation is labeled with (i) The diphemanil methylsulfate is adequate directions for use by external prepared, with or without other drugs, application to the skin for the tem- in a dosage form suitable for use in porary relief of pain or itching due to self-medication by external application minor burns and sunburn, nonpoi- to the skin, and containing no drug sonous insect bites, and minor skin ir- limited to prescription sale under the ritations. provisions of section 503(b)(1) of the (vi) The directions for use rec- act. ommend or suggest not more than four (ii) The diphemanil methylsulfate applications of the preparation per day, and all other components of the prepa- unless directed by a physician. ration meet their professed standards (vii) The labeling bears, in juxtaposi- of identity, strength, quality, and pu- tion with the directions for use, clear rity. warning statements against: (iii) If the preparation is a new drug, (a) Prolonged use. an application pursuant to section (b) Application to large areas of the 505(b) of the act is approved for it. body. (iv) The preparation contains not (c) Continued use if redness, irrita- more than 2.0 percent of diphemanil tion, swelling, or pain persists or in- methylsulfate. creases, unless directed by a physician. (v) The preparation is labeled with (d) Use in the eyes or nose. adequate directions for use by external application to the skin for the relief of (20) [Reserved] symptoms of mild poison ivy, oak, and (21) Pamabrom (2-amino-2-methyl- sumac and other minor irritations and propanol-1-8-bromotheophyllinate) itching of the skin. preparations meeting all the following (vi) The directions for use rec- conditions: ommend or suggest not more than four (i) The pamabrom is prepared with applications of the preparation per day, appropriate amounts of a suitable an- unless directed by a physician. algesic and with or without other (vii) The labeling bears, in juxtaposi- drugs, in tablet or other dosage form tion with the directions for use, a clear suitable for oral use in self-medication, warning statement, such as: ‘‘Caution: and containing no drug limited to pre- If redness, irritation, swelling, or pain scription sale under the provisions of persists or increases, discontinue use section 503(b)(1) of the act. and consult physician.’’ (ii) The pamabrom and all other com- (23) Dyclonine hydrochloride (4-but- ponents of the preparation meet their oxy-3-piperidinopropiophenone hydro- professed standards of identity, chloride; 4-n-butoxy-b-piperidono- strength, quality, and purity. propiophenone hydrochloride) prepara- (iii) If the preparation is a new drug, tions meeting all the following condi- an application pursuant to section tions: 505(b) of the act is approved for it. (i) The dyclonine hydrochloride is (iv) The preparation contains not prepared, with or without other drugs, more than 50 milligrams of pamabrom in a dosage form suitable for use as a per dosage unit. cream or ointment in self-medication (v) The preparation is labeled with by external application to the skin, or adequate directions for use in the tem- rectally, and contains no drug limited porary relief of the minor pains and to prescription sale under the provi- discomforts that may occur a few days sions of section 503(b)(1) of the act. before and during the menstrual pe- (ii) The dyclonine hydrochloride and riod. all other components of the prepara- (vi) The dosages recommended or tion meet their professed standards of suggested in the labeling do not exceed identity, strength, quality, and purity. 50 milligrams of pamabrom per dose or (iii) If the preparation is a new drug, 200 milligrams per 24-hour period. an application pursuant to section (22) Diphemanil methylsulfate (4-di- 505(b) of the act is approved for it. phenylmethylene-1,1-dimethyl-piper- (iv) The preparation contains not idinium methylsulfate) preparations more than 1.0 percent of dyclonine hy- meeting all the following conditions: drochloride.

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(v) The preparation is labeled with half of the maximum adult dose or dos- adequate directions for use: age. (a) By external application to the (vii) The labeling bears, in juxtaposi- skin for the temporary relief of pain tion with the dosage recommendations: and itching in sunburn, nonpoisonous (a) Clear warning statements against insect bites, minor burns, cuts, abra- administration of the drug to children sions, and other minor skin irritations. under 6 years of age or exceeding the (b) [Reserved] recommended dosage, unless directed (c) In the prevention or treatment of by a physician, and against driving a other minor conditions in which it is car or operating machinery while using indicated. the drug, since it may cause drowsi- (vi) The labeling bears, in juxtaposi- ness. tion with the directions for use, clear (b) If the article is offered for the warning statements against: temporary relief of symptoms of colds, (a) Continued use if redness, irrita- a statement that continued adminis- tion, swelling, or pain persists or in- tration for such use should not exceed creases, unless directed by a physician. 3 days, unless directed by a physician. (b) Use in case of rectal bleeding, as (25) [Reserved] this may indicate serious disease. (26) Methoxyphenamine hydro- (c) Use in the eyes. chloride (b-(o-methoxyphenyl)-iso- (d) Prolonged use. propyl-methylamine hydrochloride; 1- (e) Application to large areas of the (o-methoxyphenyl)- 2-methylamino- body. propane hydrochloride) preparations (f) Use for deep or puncture wounds meeting all the following conditions: or serious burns. (i) The methoxyphenamine hydro- (24) Chlorothen citrate (chlorometha- chloride is prepared with appropriate pyrilene citrate; N,N-dimethyl-N′-(2- amounts of a suitable antitussive, with pyridyl)-N′-(5-chloro-2-thenyl) ethyl- or without other drugs, in a dosage enediamine citrate) preparations meet- form suitable for oral use in self-medi- ing all the following conditions: cation, and containing no drug limited (i) The chlorothen citrate is pre- to prescription sale under the provi- pared, with or without other drugs, in sions of section 503(b)(1) of the act. tablet or other dosage form suitable for (ii) The methoxyphenamine hydro- oral use in self-medication, and con- chloride and all other components of taining no drug limited to prescription the preparation meet their professed sale under the provisions of section standards of identity, strength, qual- 503(b)(1) of the act. ity, and purity. (ii) The chlorothen citrate and all (iii) If the preparation is a new drug, other components of the preparation an application pursuant to section meet their professed standards of iden- 505(b) of the act is approved for it. tity, strength, quality, and purity. (iv) The preparation contains not (iii) If the preparation is a new drug, more than 3.5 milligrams of methoxy- an application pursuant to section phenamine hydrochloride per milli- 505(b) of the act is approved for it. liter. (iv) The preparation contains not (v) The preparation is labeled with more than 25 milligrams of chlorothen adequate directions for use in the tem- citrate per dosage unit. porary relief of cough due to minor (v) The preparation is labeled with conditions in which it is indicated. adequate directions for use in the tem- (vi) The dosages recommended or porary relief of the symptoms of hay suggested in the labeling do not exceed: fever and/or the symptoms of other For adults, 35 milligrams of methoxy- minor conditions in which it is indi- phenamine hydrochloride per dose or cated. 140 milligrams of methoxyphenamine (vi) The dosages recommended or hydrochloride per 24-hour period; for suggested in the labeling do not exceed: children 6 to 12 years of age, one-half of For adults, 25 milligrams of chlorothen the maximum adult dose or dosage. citrate per dose or 150 milligrams of (vii) The label bears a conspicuous chlorothen citrate per 24-hour period; warning to keep the drug out of the for children 6 to 12 years of age, one- reach of children, and the labeling

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bears, in juxtaposition with the dosage afford adequate protection and be suit- recommendations: able for self-medication with a min- (a) A clear warning statement imum risk of contamination of the so- against administration of the drug to lution during use. Any dispensing unit children under 6 years of age, unless di- is sterile and so packaged as to main- rected by a physician. tain sterility until the package is (b) A clear warning statement to the opened. effect that frequent or prolonged use (iii) The tyloxapol, benzalkonium may cause nervousness, restlessness, or chloride, and other ingredients used to drowsiness, and that individuals with prepare the isotonic aqueous solution high blood pressure, heart disease, dia- meet their professed standards of iden- betes, or thyroid disease should not use tity, strength, quality, and purity. the preparation unless directed by a (iv) An application pursuant to sec- physician. tion 505(b) of the act is approved for (c) A clear warning statement the drug. against use of the drug in the presence (v) The preparation contains 0.25 per- of high fever or if cough persists, since cent of tyloxapol and 0.02 percent of persistent cough as well as high fever benzalkonium chloride. may indicate the presence of a serious (vi) The label bears a conspicuous condition. warning to keep the drug out of the (27) Biphenamine hydrochloride (b-di- reach of children and the labeling ethylaminoethyl-3-phenyl-2-hydroxy- bears, in juxtaposition with the dosage benzoate hydrochloride) preparations recommendations, a clear warning that meeting all the following conditions: if irritation occurs, persists, or in- (i) The biphenamine hydrochloride is creases, use of the drug should be dis- prepared in a form suitable for use as a continued and a physician consulted. shampoo and contains no drug limited The labeling includes a statement that to prescription sale under the provi- the dropper or other dispensing tip sions of section 503(b)(1) of the act. should not touch any surface, since (ii) The biphenamine hydrochloride this may contaminate the solution. meets its professed standards of iden- (29) [Reserved] tity, strength, quality, and purity. (b) [Reserved] (iii) If the preparation is a new drug, an application pursuant to section [39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, 505(b) of the act is approved for it. 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, (iv) The preparation contains not Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR more than 1 percent of biphenamine 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; hydrochloride. 60 FR 52507, Oct. 6, 1995; 72 FR 15043, Mar. 30, (v) The preparation is labeled with 2007; 72 FR 67640, Nov. 30, 2007] adequate directions for use for the temporary relief of itching and scaling due Subpart D—Records and Reports to dandruff. (vi) The label bears a conspicuous § 310.303 Continuation of long-term warning to keep the drug out of the studies, records, and reports on cer- reach of children. tain drugs for which new drug ap- (28) Tyloxapol (an alkylarylpolyether plications have been approved. alcohol) and benzalkonium chloride (a) A new drug may not be approved ophthalmic preparations meeting all for marketing unless it has been shown the following conditions: to be safe and effective for its intended (i) The tyloxapol and benzalkonium use(s). After approval, the applicant is chloride are prepared, with other ap- required to establish and maintain propriate ingredients which are not records and make reports related to drugs limited to prescription sale clinical experience or other data or in- under the provisions of section 503(b)(1) formation necessary to make or facili- of the act, as a sterile, isotonic aque- tate a determination of whether there ous solution suitable for use in self- are or may be grounds under section medication on eye prostheses. 505(e) of the act for suspending or with- (ii) The preparation is so packaged as drawing approval of the application. to volume and type of container as to Some drugs, because of the nature of

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the condition for which they are in- the reporting requirements of para- tended, must be used for long periods of graph (c) of this section must also de- time—even a lifetime. To acquire nec- velop written procedures for the sur- essary data for determining the safety veillance, receipt, evaluation, and re- and effectiveness of long-term use of porting of postmarketing adverse drug such drugs, extensive animal and clin- experiences to FDA. ical tests are required as a condition of (b) Definitions. The following defini- approval. Nonetheless, the therapeutic tions of terms apply to this section: or prophylactic usefulness of such Adverse drug experience. Any adverse drugs may make it inadvisable in the event associated with the use of a drug public interest to delay the avail- in humans, whether or not considered ability of the drugs for widespread clin- drug related, including the following: ical use pending completion of such An adverse event occurring in the long-term studies. In such cases, the course of the use of a drug product in Food and Drug Administration may ap- professional practice; an adverse event prove the new drug application on con- occurring from drug overdose whether dition that the necessary long-term accidental or intentional; an adverse studies will be conducted and the re- event occurring from drug abuse; an sults recorded and reported in an orga- adverse event occurring from drug nized fashion. The procedures required withdrawal; and any failure of expected by paragraph (b) of this section will be pharmacological action. followed in order to list such a drug in Disability. A substantial disruption of § 310.304. a person’s ability to conduct normal (b) A proposal to require additional life functions. or continued studies with a drug for Individual case safety report (ICSR). A which a new drug application has been description of an adverse drug experi- approved may be made by the Commis- ence related to an individual patient or sioner on his own initiative or on the subject. petition of any interested person, pur- ICSR attachments. Documents related suant to part 10 of this chapter. Prior to the adverse drug experience de- to issuance of such a proposal, the ap- scribed in an ICSR, such as medical plicant will be provided an opportunity records, hospital discharge summaries, for a conference with representatives of or other documentation. the Food and Drug Administration. Life-threatening adverse drug experi- When appropriate, investigators or ence. Any adverse drug experience that other individuals may be invited to places the patient, in the view of the participate in the conference. All re- initial reporter, at immediate risk of quirements for special studies, records, death from the adverse drug experience and reports will be published in as it occurred, i.e., it does not include § 310.304. an adverse drug experience that, had it occurred in a more severe form, might [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, have caused death. 1977] Serious adverse drug experience. Any adverse drug experience occurring at § 310.305 Records and reports con- any dose that results in any of the fol- cerning adverse drug experiences lowing outcomes: Death, a life-threat- on marketed prescription drugs for ening adverse drug experience, inpa- human use without approved new tient hospitalization or prolongation of drug applications. existing hospitalization, a persistent or (a) Scope. FDA is requiring manufac- significant disability/incapacity, or a turers, packers, and distributors of congenital anomaly/birth defect. Im- marketed prescription drug products portant medical events that may not that are not the subject of an approved result in death, be life-threatening, or new drug or abbreviated new drug ap- require hospitalization may be consid- plication to establish and maintain ered a serious adverse drug experience records and make reports to FDA of all when, based upon appropriate medical serious, unexpected adverse drug expe- judgment, they may jeopardize the pa- riences associated with the use of their tient or subject and may require med- drug products. Any person subject to ical or surgical intervention to prevent

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one of the outcomes listed in this defi- must be accompanied by the current nition. Examples of such medical content of labeling in electronic for- events include allergic bronchospasm mat as an ICSR attachment unless it is requiring intensive treatment in an already on file at FDA. emergency room or at home, blood (ii) A person identified in paragraph dyscrasias or convulsions that do not (c)(1)(i) of this section is not required result in inpatient hospitalization, or to submit a 15-day ‘‘Alert report’’ for the development of drug dependency or an adverse drug experience obtained drug abuse. from a postmarketing study (whether Unexpected adverse drug experience. or not conducted under an investiga- Any adverse drug experience that is tional new drug application) unless the not listed in the current labeling for applicant concludes that there is a rea- the drug product. This includes events sonable possibility that the drug that may be symptomatically and caused the adverse experience. pathophysiologically related to an (2) Postmarketing 15-day ‘‘Alert re- event listed in the labeling, but differ ports’’—followup. Each person identified from the event because of greater se- in paragraph (c)(1)(i) of this section verity or specificity. For example, must promptly investigate all serious, under this definition, hepatic necrosis unexpected adverse drug experiences would be unexpected (by virtue of that are the subject of these post- greater severity) if the labeling only marketing 15-day Alert reports and referred to elevated hepatic enzymes or must submit followup reports within 15 hepatitis. Similarly, cerebral thrombo- calendar days of receipt of new infor- embolism and cerebral vasculitis would mation or as requested by FDA. If addi- be unexpected (by virtue of greater tional information is not obtainable, specificity) if the labeling only listed records should be maintained of the un- cerebral vascular accidents. ‘‘Unex- successful steps taken to seek addi- pected,’’ as used in this definition, re- tional information. fers to an adverse drug experience that (3) Submission of reports. To avoid un- has not been previously observed (i.e., necessary duplication in the submis- included in the labeling) rather than sion of, and followup to, reports re- from the perspective of such experience quired in this section, a packer’s or dis- not being anticipated from the pharma- tributor’s obligations may be met by cological properties of the pharma- submission of all reports of serious ad- ceutical product. verse drug experiences to the manufac- (c) Reporting requirements. Each per- turer of the drug product. If a packer son identified in paragraph (c)(1)(i) of or distributor elects to submit these this section must submit to FDA ad- adverse drug experience reports to the verse drug experience information as manufacturer rather than to FDA, it described in this section. Except as must submit, by any appropriate provided in paragraph (e)(2) of this sec- means, each report to the manufac- tion, 15-day ‘‘Alert reports’’ and fol- turer within 5 calendar days of its re- lowup reports, including ICSRs and any ceipt by the packer or distributor, and ICSR attachments, must be submitted the manufacturer must then comply to the Agency in electronic format as with the requirements of this section described in paragraph (e)(1) of this even if its name does not appear on the section. label of the drug product. Under this (1) Postmarketing 15-day ‘‘Alert re- circumstance, the packer or distributor ports’’. (i) Any person whose name ap- must maintain a record of this action pears on the label of a marketed pre- which must include: scription drug product as its manufac- (i) A copy of each adverse drug expe- turer, packer, or distributor must re- rience report; port to FDA each adverse drug experi- (ii) The date the report was received ence received or otherwise obtained by the packer or distributor; that is both serious and unexpected as (iii) The date the report was sub- soon as possible, but no later than 15 mitted to the manufacturer; and calendar days from initial receipt of (iv) The name and address of the the information by the person whose manufacturer. name appears on the label. Each report (4) [Reserved]

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(5) A person identified in paragraph (5) Manufacturer, packer, or distributor (c)(1)(i) of this section is not required information. to resubmit to FDA adverse drug expe- (i) Manufacturer, packer, or dis- rience reports forwarded to that person tributor name and contact office ad- by FDA; however, the person must sub- dress; mit all followup information on such (ii) Telephone number; reports to FDA. (iii) Report source, such as sponta- (d) Information reported on ICSRs. neous, literature, or study; ICSRs include the following informa- (iv) Date the report was received by tion: manufacturer, packer, or distributor; (1) Patient information. (v) Whether the ICSR is a 15-day (i) Patient identification code; ‘‘Alert report’’; (ii) Patient age at the time of adverse (vi) Whether the ICSR is an initial drug experience, or date of birth; report or followup report; and (iii) Patient gender; and (vii) Unique case identification num- (iv) Patient weight. ber, which must be the same in the ini- (2) Adverse drug experience. tial report and any subsequent fol- (i) Outcome attributed to adverse lowup report(s). drug experience; (e) Electronic format for submissions. (1) (ii) Date of adverse drug experience; Each report required to be submitted (iii) Date of ICSR submission; to FDA under this section, including (iv) Description of adverse drug expe- the ICSR and any ICSR attachments, rience (including a concise medical must be submitted in an electronic for- narrative); mat that FDA can process, review, and (v) Adverse drug experience term(s); archive. FDA will issue guidance on (vi) Description of relevant tests, in- how to provide the electronic submis- cluding dates and laboratory data; and sion (e.g., method of transmission, (vii) Other relevant patient history, media, file formats, preparation and including preexisting medical condi- organization of files). tions. (2) Each person identified in para- (3) Suspect medical product(s). graph (c)(1)(i) of this section may re- (i) Name; quest, in writing, a temporary waiver (ii) Dose, frequency, and route of ad- of the requirements in paragraph (e)(1) ministration used; (iii) Therapy dates; of this section. These waivers will be (iv) Diagnosis for use (indication); granted on a limited basis for good (v) Whether the product is a com- cause shown. FDA will issue guidance bination product as defined in § 3.2(e) of on requesting a waiver of the require- this chapter; ments in paragraph (e)(1) of this sec- (vi) Whether the product is a pre- tion. scription or nonprescription product; (f) Patient privacy. Manufacturers, (vii) Whether adverse drug experience packers, and distributors should not in- abated after drug use stopped or dose clude in reports under this section the reduced; names and addresses of individual pa- (viii) Whether adverse drug experi- tients; instead, the manufacturer, ence reappeared after reintroduction of packer, and distributor should assign a drug; unique code for identification of the (ix) Lot number; patient. The manufacturer, packer, and (x) Expiration date; distributor should include the name of (xi) National Drug Code (NDC) num- the reporter from whom the informa- ber; and tion was received as part of the initial (xii) Concomitant medical products reporter information, even when the and therapy dates. reporter is the patient. The names of (4) Initial reporter information. patients, individual reporters, health (i) Name, address, and telephone care professionals, hospitals, and geo- number; graphical identifiers in adverse drug (ii) Whether the initial reporter is a experience reports are not releasable to health care professional; and the public under FDA’s public informa- (iii) Occupation, if a health care pro- tion regulations in part 20 of this chap- fessional. ter.

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(g) Recordkeeping. (1) Each manufac- make the notifications required under turer, packer, and distributor must § 314.81(b)(3)(iii) of this chapter and oth- maintain for a period of 10 years erwise comply with § 314.81(b)(3)(iii) of records of all adverse drug experiences this chapter. If the manufacturer of a required under this section to be re- product subject to this section fails to ported, including raw data and any cor- provide notification as required under respondence relating to the adverse § 314.81(b)(3)(iii), FDA will send a letter drug experiences, and the records re- to the manufacturer and otherwise fol- quired to be maintained under para- low the procedures set forth under graph (c)(3) of this section. § 314.81(b)(3)(iii)(e). (2) Manufacturers and packers may (c) Drug shortages list. FDA will in- retain the records required in para- clude on the drug shortages list re- graph (f)(1) of this section as part of its quired by § 314.81(b)(3)(iii)(d) drug prod- complaint files maintained under ucts that are subject to this section § 211.198 of this chapter. that it determines to be in shortage. (3) Manufacturers, packers, and dis- For such drug products, FDA will pro- tributors must permit any authorized vide the names of each manufacturer FDA employee, at all reasonable times, rather than the names of each appli- to have access to and copy and verify cant. With respect to information col- the records established and maintained lected under this paragraph, FDA will under this section. observe the confidentiality and disclo- (h) Disclaimer. A report or informa- sure provisions set forth in tion submitted by a manufacturer, § 314.81(b)(3)(iii)(d)(2). packer, or distributor under this section (and any release by FDA of that [80 FR 38938, July 8, 2015] report or information) does not necessarily reflect a conclusion by the Subpart E—Requirements for manufacturer, packer, or distributor, Specific New Drugs or Devices or by FDA, that the report or information constitutes an admission that the § 310.501 Patient package inserts for drug caused or contributed to an ad- oral contraceptives. verse effect. The manufacturer, packer, (a) Requirement for a patient package or distributor need not admit, and may insert. The safe and effective use of oral deny, that the report or information contraceptive drug products requires submitted under this section con- that patients be fully informed of the stitutes an admission that the drug benefits and the risks involved in their caused or contributed to an adverse ef- use. An oral contraceptive drug prod- fect. uct that does not comply with the re- [51 FR 24479, July 3, 1986, as amended at 52 quirements of this section is mis- FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, branded under section 502 of the Fed- 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, eral Food, Drug, and Cosmetic Act. June 25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR Each dispenser of an oral contraceptive 9585, Mar. 4, 2002; 74 FR 13113, Mar. 26, 2009; 79 drug product shall provide a patient FR 33087, June 10, 2014] package insert to each patient (or to § 310.306 Notification of a permanent an agent of the patient) to whom the discontinuance or an interruption product is dispensed, except that the in manufacturing of marketed pre- dispenser may provide the insert to the scription drugs for human use with- parent or legal guardian of a legally in- out approved new drug applica- competent patient (or to the agent of tions. either). The patient package insert is (a) Applicability. Marketed prescrip- required to be placed in or accompany tion drug products that are not the each package dispensed to the patient. subject of an approved new drug or ab- (b) Distribution requirements. (1) For breviated new drug application are sub- oral contraceptive drug products, the ject to this section. manufacturer and distributor shall pro- (b) Notification of a permanent dis- vide a patient package insert in or with continuance or an interruption in manu- each package of the drug product that facturing. The manufacturer of each the manufacturer or distributor in- product subject to this section must tends to be dispensed to a patient.

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(2) Patient package inserts for oral (ii) A statement concerning excretion contraceptives dispensed in acute-care of the drug in human milk and associ- hospitals or long-term care facilities ated risks to the nursing infant; will be considered to have been pro- (iii) A statement about laboratory vided in accordance with this section if tests which may be affected by oral provided to the patient before adminis- contraceptives; and tration of the first oral contraceptive (iv) A statement that identifies ac- and every 30 days thereafter, as long as tivities and drugs, foods, or other sub- the therapy continues. stances the patient should avoid be- (c) Contents of patient package insert. cause of their interactions with oral A patient package insert for an oral contraceptives. contraceptive drug product is required (11) Information about how to take to contain the following: oral contraceptives properly, including (1) The name of the drug. information about what to do if the pa- (2) A summary including a statement tient forgets to take the product, infor- concerning the effectiveness of oral mation about becoming pregnant after contraceptives in preventing preg- discontinuing use of the drug, a state- nancy, the contraindications to the ment that the drug product has been drug’s use, and a statement of the risks prescribed for the use of the patient and benefits associated with the drug’s and should not be used for other condi- use. tions or given to others, and a state- (3) A statement comparing the effec- ment that the patient’s pharmacist or tiveness of oral contraceptives to other practitioner has a more technical leaf- methods of contraception. let about the drug product that the pa- (4) A boxed warning concerning the tient may ask to review. increased risks associated with ciga- (12) A statement of the possible bene- rette smoking and oral contraceptive use. fits associated with oral contraceptive use. (5) A discussion of the contraindications to use, including information (13) The following information about that the patient should provide to the the drug product and the patient pack- prescriber before taking the drug. age insert: (6) A statement of medical conditions (i) The name and place of business of that are not contraindications to use the manufacturer, packer, or dis- but deserve special consideration in tributor, or the name and place of busi- connection with oral contraceptive use ness of the dispenser of the product. and about which the patient should in- (ii) The date, identified as such, of form the prescriber. the most recent revision of the patient (7) A warning regarding the most se- package insert placed prominently im- rious side effects of oral contracep- mediately after the last section of the tives. labeling. (8) A statement of other serious ad- (d) Other indications. The patient verse reactions and potential safety package insert may identify indica- hazards that may result from the use tions in addition to contraception that of oral contraceptives. are identified in the professional label- (9) A statement concerning common, ing for the drug product. but less serious side effects which may (e) Labeling guidance texts. The Food help the patient evaluate the benefits and Drug Administration issues infor- and risks from the use of oral contra- mal labeling guidance texts under ceptives. § 10.90(b)(9) of this chapter to provide (10) Information on precautions the assistance in meeting the requirements patients should observe while taking of this section. A request for a copy of oral contraceptives, including the fol- the guidance texts should be directed lowing: to the Center for Drug Evaluation and (i) A statement of risks to the moth- Research, Division of Reproductive and er and unborn child from the use of Urologic Products, Food and Drug Ad- oral contraceptives before or during ministration, 10903 New Hampshire early pregnancy; Ave., Silver Spring, MD 20993–0002.

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(f) Requirement to supplement approved (13) Thorium dioxide for drug use. application. Holders of approved appli- (14) Timed release dosage forms. cations for oral contraceptive drug (15) Vinyl chloride as an ingredient, products that are subject to the re- including propellant, in aerosol drug quirements of this section are required products. to submit supplements under § 314.70(c) (b) [Reserved] of this chapter to provide for the label- [62 FR 12084, Mar. 14, 1997, as amended at 64 ing required by this section. Such la- FR 401, Jan. 5, 1999; 84 FR 68334, Dec. 16, 2019] beling may be put into use without advance approval by the Food and Drug § 310.503 Requirements regarding cer- Administration. tain radioactive drugs. [54 FR 22587, May 25, 1989, as amended at 74 (a) On January 8, 1963 (28 FR 183), the FR 13113, Mar. 26, 2009] Commissioner of Food and Drugs exempted investigational radioactive new § 310.502 Certain drugs accorded new drugs from part 312 of this chapter pro- drug status through rulemaking vided they were shipped in complete procedures. conformity with the regulations issued (a) The drugs listed in this paragraph by the Nuclear Regulatory Commis- (a) have been determined by rule- sion. This exemption also applied to in- making procedures to be new drugs vestigational radioactive biologics. within the meaning of section 201(p) of (b) It is the opinion of the Nuclear the Federal Food, Drug, and Cosmetic Regulatory Commission, and the Food Act. An approved new drug application and Drug Administration that this ex- under section 505 of the Federal Food, emption should not apply for certain Drug, and Cosmetic Act and part 314 of specific drugs and that these drugs this chapter is required for marketing should be appropriately labeled for uses the following drugs: for which safety and effectiveness can (1) Aerosol drug products for human be demonstrated by new drug applica- use containing 1,1,1-trichloroethane. tions or through licensing under the (2) Aerosol drug products containing Public Health Service Act (42 U.S.C. 262 zirconium. et seq.) in the case of biologics. Contin- (3) Amphetamines (amphetamine, ued distribution under the investiga- dextroamphetamine, and their salts, tional exemption when the drugs are and levamfetamine and its salts) for intended for established uses will not human use. be permitted. (4) Camphorated oil drug products. (c) Based on its experience in regu- (5) Certain halogenated salicyl- lating investigational radioactive anilides (tribromsalan (TBS, 3,4′,5-tri- pharmaceuticals, the Nuclear Regu- bromosalicylanilide), dibromsalan latory Commission has compiled a list (DBS, 4′, 5-dibromosalicylanilide), of reactor-produced isotopes for which metabromsalan (MBS, 3, 5-dibromo- it considers that applicants may rea- salicylanilide), and 3,3′, 4,5′-tetra- sonably be expected to submit ade- chlorosalicylanilide (TC-SA)) as an in- quate evidence of safety and effective- gredient in drug products. ness for use as recommended in appro- (6) Chloroform used as an ingredient priate labeling. Such use may include, (active or inactive) in drug products. among others, the uses in this tabula- (7) Cobalt preparations intended for tion: use by man. (8) Intrauterine devices for human Isotope Chemical form Use use for the purpose of contraception Chromium 51 ... Chromate ...... Spleen scans. that incorporate heavy metals, drugs, Do ...... do ...... Placenta localiza- or other active substances. tion. (9) Oral prenatal drugs containing Do ...... do ...... Red blood cell labeling and survival fluorides intended for human use. studies. (10) Parenteral drug products in plas- Do ...... Labeled human Gastrointestinal pro- tic containers. serum albumin. tein loss studies. (11) [Reserved] Do ...... do ...... Placenta localization. (12) Sweet spirits of nitre drug prod- Do ...... Labeled red blood Do. ucts. cells.

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Isotope Chemical form Use Isotope Chemical form Use

Cobalt 58 or Labeled cyano- Intestinal absorption Krypton 85 ...... Gas ...... Diagnosis of cardiac Cobalt 60. cobalamin. studies. abnormalities. Gold 198 ...... Colloidal ...... Liver scans. Mercury 197 .... Chlormerodrin ...... Kidney scans. Do ...... do ...... Intracavitary treat- Do ...... do ...... Brain scans. ment of pleural ef- Mercury 203 1 ...... do ...... Kidney scans. fusions and/or as- Do ...... do ...... Brain scans. cites. Phosphorus 32 Soluble phosphate .. Treatment of poly- Do ...... do ...... Interstitial treatment cythemia vera. of cancer. Do ...... do ...... Treatment of leu- Iodine 131 ...... Iodide ...... Diagnosis of thyroid kemia and bone functions. metastasis. Do ...... do ...... Thyroid scans. Do ...... Colloidal chromic Intracavitary treat- Do ...... do ...... Treatment of hyper- phosphate. ment of pleural ef- thyroidism and/or fusions and/or as- cardiac dysfunc- cites. tion. Do ...... do ...... Interstitial treatment Do ...... do ...... Treatment of thyroid of cancer. carcinoma. Potassium 42 .. Chloride ...... Potassium space Do ...... Iodinated human Blood volume deter- studies. serum albumin. minations. Selenium 75 .... Labeled methionine Pancreas scans. Do ...... do ...... Cisternography. Strontium 85 .... Nitrate or chloride ... Bone scans on patients with diag- Do ...... do ...... Brain tumor localiza- nosed cancer. tion. Technetium Pertechnetate ...... Brain scans. Do ...... do ...... Placenta localiza- 99m. tion. Do ...... do ...... Thyroid scans. Do ...... do ...... Cardiac scans for Do ...... Sulfur colloid ...... Liver and spleen determination of scans. pericardial effu- Do ...... Pertechnetate ...... Placenta localiza- sions. tion. Do ...... Rose Bengal ...... Liver function stud- Do ...... do ...... Blood pool scans. ies. Do ...... do ...... Salivary gland Do ...... do ...... Liver scans. scans. Do ...... Iodopyracet, sodium Kidney function Do ...... Diethylenetri-amine Kidney scans. iodohippurate, so- studies and kid- pentaacetic acid dium diatrizoate, ney scans. (DTPA). diatrizoate methyl- Xenon 133 ...... Gas ...... Diagnosis of cardia glucamine, so- abnormalities. dium diprotrizoate, Cerebral blood- sodium acetri- flow studies. Pul- zoate, or sodium monary function iothalamate. studies. Muscle Do ...... Labeled fats and/or Fat absorption stud- bloodflow studies. fatty acids. ies. Do ...... Cholografin ...... Cardiac scans for 1 This item has been removed from the AEC list for kidney determination of scans but is included as the requirements of this order are applicable. pericardial effu- sions. (d)(1) In view of the extent of experi- Do ...... Macroaggregated io- Lung scans. dinated human ence with the isotopes listed in para- serum albumin. graph (c) of this section, the Nuclear Do ...... Colloidal micro- Liver scans. Regulatory Commission and the Food aggregated and Drug Administration conclude that human serum albumin. such isotopes should not be distributed Iodine 125 ...... Iodide ...... Diagnosis of thyroid under investigational-use labeling function. when they are actually intended for Do ...... Iodinated human Blood volume deter- serum albumin. minations. use in medical practice. Do ...... Rose Bengal ...... Liver function stud- (2) The exemption referred to in para- ies. graph (a) of this section, as applied to Do ...... Iodopyracet, sodium Kidney function any drug or biologic containing any of iodohippurate, so- studies. dium diatrizoate, the isotopes listed in paragraph (c) of diatrizoate methyl- this section, in the ‘‘chemical form’’ glucamine, so- and intended for the uses stated, is ter- dium diprotrizoate, sodium acetri- minated on March 3, 1972, except as zoate, or sodium provided in paragraph (d)(3) of this sec- iothalamate. tion. Do ...... Labeled fats and/or Fat absorption stud- (3) The exemption referred to in para- fatty acids. ies. Iron 59 ...... Chloride, citrate Iron turnover stud- graph (a) of this section, as applied to and/or sulfate. ies. any drug or biologic containing any of

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the isotopes listed in paragraph (c) of Drug Administration conclude that this section, in the ‘‘chemical form’’ they should not be distributed under and intended for the uses stated, for investigational-use labeling when they which drug a new drug application or a are actually intended for use in med- ‘‘Investigational New Drug Applica- ical practice. tion’’ was submitted prior to March 3, (3) Any manufacturer or distributor 1972, or for which biologic an applica- interested in continuing to ship in tion for product license or ‘‘Investiga- interstate commerce drugs containing tional New Drug Application’’ was sub- the isotopes listed in paragraph (f)(1) of mitted prior to March 3, 1972, is termi- this section for any of the indications nated on August 20, 1976, unless an ap- listed, shall submit, on or before Au- provable notice was issued on or before gust 25, 1975 to the Center for Drug August 20, 1976, in which case the ex- Evaluation and Research, Food and emption is terminated either upon the Drug Administration, 5600 Fishers subsequent issuance of a nonapprovable Lane, Rockville, MD 20857, a new drug notice for the new drug application or application or a ‘‘Investigational New on November 20, 1976, whichever occurs Drug Application’’ for each such drug first. for which the manufacturer or dis- (e) No exemption from section 505 of tributor does not have an approved new the act or from part 312 of this chapter drug application pursuant to section is in effect or has been in effect for ra- 505(b) of the act. If the drug is a bio- dioactive drugs prepared from accel- logic, a ‘‘Investigational New Drug Ap- erator-produced radioisotopes, natu- plication’’ or an application for a li- rally occurring isotopes, or nonradio- cense under section 351 of the Public active substances used in conjunction Health Service Act shall be submitted with isotopes. to the Food and Drug Administration, (f)(1) Based on its experience in regu- Center for Biologics Evaluation and lating investigational radioactive Research, Document Control Center, pharmaceuticals, the Nuclear Regu- latory Commission has compiled a list 10903 New Hampshire Ave., Bldg. 71, of reactor-produced isotopes for which Rm. G112, Silver Spring, MD 20993–0002, it considers that applicants may rea- in lieu of any submission to the Center sonably be expected to submit ade- for Drug Evaluation and Research. quate evidence of safety and effective- (4) The exemption referred to in para- ness for use as recommended in appro- graph (a) of this section, as applied to priate labeling; such use may include, any drug or biologic containing any of among others, the uses in this tabula- the isotopes listed in paragraph (f)(1) of tion: this section, in the ‘‘chemical form’’ and intended for the uses stated, is ter- Isotope Chemical form Use minated on August 26, 1975 except as Fluorine 18 ...... Fluoride ...... Bone imaging. provided in paragraph (f)(5) of this sec- Indium-113m ... Diethylenetriamine Brain imaging; kid- tion. pentaacetic acid ney imaging. (5)(i) Except as provided in paragraph (DTPA). Do ...... Chloride ...... Placenta imaging; (f)(5)(ii) of this section, the exemption blood pool imag- referred to in paragraph (a) of this sec- ing. tion, as applied to any drug containing Technetium Human serum albu- Lung imaging. 99m. min microspheres. any of the isotopes listed in paragraph Do ...... Diethylenetriamine Kidney imaging; kid- (f)(1) of this section, in the ‘‘chemical pentaacetic acid ney function stud- form’’ and intended for the uses stated, (Sn). ies. Do ...... do ...... Brain imaging. for which drug a new drug application Do ...... Polyphosphates ...... Bone imaging. or ‘‘Investigational New Drug Applica- Do ...... Technetated aggre- Lung imaging. tion’’ was submitted to the Center for gated albumin Drug Evaluation and Research on or (human). Do ...... Disodium etidronate Bone imaging. before August 25, 1975 is terminated on August 20, 1976, unless an approvable (2) In view of the extent of experience notice was issued on or before August with the isotopes listed in paragraph 20, 1976, in which case the exemption is (f)(1) of this section, the Nuclear Regu- terminated either upon the subsequent latory Commission and the Food and issuance of a nonapprovable notice for

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the new drug application or on Novem- graphs (d), (f), and (g) of this section, is ber 20, 1976, whichever occurs first. terminated on August 26, 1975. (ii) The exemption referred to in [39 FR 11680, Mar. 29, 1974, as amended at 40 paragraph (a) of this section, as applied FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, to any biologic containing any of the 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, isotopes listed in paragraph (f)(1) of Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR this section in the ‘‘chemical form’’ 11578, Mar. 29, 1990; 64 FR 56449, Oct. 20, 1999; and intended for the uses stated, for 80 FR 18091, Apr. 3, 2015] which biologic an application for product license or ‘‘Investigational New § 310.509 Parenteral drug products in Drug Application’’ was submitted to plastic containers. the Center for Biologics Evaluation (a) Any parenteral drug product and Research on or before August 25, packaged in a plastic immediate con- 1975 is terminated on October 20, 1976, tainer is not generally recognized as unless an approvable notice was issued safe and effective, is a new drug within on or before October 20, 1976, in which the meaning of section 201(p) of the case the exemption is terminated ei- act, and requires an approved new drug ther upon the subsequent issuance of a application as a condition for mar- nonapprovable notice for the new drug keting. An ‘‘Investigational New Drug application or on January 20, 1977, Application’’ set forth in part 312 of whichever occurs first. this chapter is required for clinical in- (g) The exemption referred to in vestigations designed to obtain evi- paragraph (a) of this section, as applied dence of safety and effectiveness. to any drug intended solely for inves- (b) As used in this section, the term tigational use as part of a research ‘‘large volume parenteral drug prod- project, which use had been approved uct’’ means a terminally sterilized on or before July 25, 1975 in accordance aqueous drug product packaged in a with 10 CFR 35.11 (or equivalent regula- single-dose container with a capacity tion of an Agreement State) is termi- of 100 milliliters or more and intended nated on February 20, 1976 if the manu- to be administered or used intra- facturer of such drug or the sponsor of venously in a human. the investigation of such drug submits (c) Until the results of compatibility on or before August 25, 1975 to the Food studies are evaluated, a large volume and Drug Administration, Bureau of parenteral drug product for intra- Drugs, HFD–150, 5600 Fishers Lane, venous use in humans that is packaged Rockville, MD 20857, the following in- in a plastic immediate container on or formation: after April 16, 1979, is misbranded un- (1) The research project title; less its labeling contains a warning (2) A brief description of the purpose that includes the following informa- of the project; tion: (3) The name of the investigator re- (1) A statement that additives may sponsible; be incompatible. (4) The name and license number of (2) A statement that, if additive the institution holding the specific li- drugs are introduced into the paren- cense under 10 CFR 35.11 (or equivalent teral system, aseptic techniques should regulation of an Agreement State); be used and the solution should be (5) The name and maximum amount thoroughly mixed. per subject of the radionuclide used; (3) A statement that a solution con- (6) The number of subjects involved; taining an additive drug should not be and stored. (7) The date on which the administra- (d) This section does not apply to a tion of the radioactive drugs is ex- biological product licensed under the pected to be completed. Public Health Service Act of July 1, (h) The exemption referred to in 1944 (42 U.S.C. 201). paragraph (a) of this section, as applied [62 FR 12084, Mar. 14, 1997] to any drug not referred to in para-

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§ 310.515 Patient package inserts for drug product is required to contain the estrogens. following information: (a) Requirement for a patient package (1) The name of the drug. insert. FDA concludes that the safe and (2) The name and place of business of effective use of drug products con- the manufacturer, packer, or dis- taining estrogens requires that pa- tributor. tients be fully informed of the benefits (3) A statement regarding the bene- and risks involved in the use of these fits and proper uses of estrogens. drugs. Accordingly, except as provided (4) The contraindications to use, i.e., in paragraph (e) of this section, each when estrogens should not be used. estrogen drug product restricted to (5) A description of the most serious prescription distribution, including risks associated with the use of estro- products containing estrogens in fixed gens. combinations with other drugs, shall (6) A brief summary of other side ef- be dispensed to patients with a patient fects of estrogens. package insert containing information (7) Instructions on how a patient may concerning the drug’s benefits and reduce the risks of estrogen use. risks. An estrogen drug product that (8) The date, identified as such, of the does not comply with the requirements most recent revision of the patient of this section is misbranded under sec- package insert. tion 502(a) of the Federal Food, Drug, (d) Guidance language. The Food and and Cosmetic Act. Drug Administration issues informal (b) Distribution requirements. (1) For labeling guidance texts under estrogen drug products, the manufac- § 10.90(b)(9) of this chapter to provide turer and distributor shall provide a assistance in meeting the requirements patient package insert in or with each of paragraph (c) of this section. Re- package of the drug product that the quests for a copy of the guidance text manufacturer or distributor intends to should be directed to the Center for be dispensed to a patient. Drug Evaluation and Research, Divi- (2) In the case of estrogen drug prod- sion of Reproductive and Urologic ucts in bulk packages intended for Products, Food and Drug Administra- multiple dispensing, and in the case of tion, 10903 New Hampshire Ave., Silver injectables in multiple-dose vials, a Spring, MD 20993–0002. sufficient number of patient labeling (e) Exemptions. This section does not pieces shall be included in or with each apply to estrogen-progestogen oral con- package to assure that one piece can be traceptives. Labeling requirements for included with each package or dose dis- these products are set forth in § 310.501. pensed or administered to every pa- (f) Requirement to supplement approved tient. Each bulk package shall be la- application. Holders of approved appli- beled with instructions to the cations for estrogen drug products that dispensor to include one patient label- are subject to the requirements of this ing piece with each package dispensed section must submit supplements or, in the case of injectables, with each under § 314.70(c) of this chapter to pro- dose administered to the patient. This vide for the labeling required by para- section does not preclude the manufac- graph (a) of this section. Such labeling turer or labeler from distributing addi- may be put into use without advance tional patient labeling pieces to the approval by the Food and Drug Admin- dispensor. istration. (3) Patient package inserts for estro- [55 FR 18723, May 4, 1990, as amended at 74 gens dispensed in acute-care hospitals FR 13113, Mar. 26, 2009] or long-term care facilities will be considered to have been provided in ac- § 310.517 Labeling for oral hypo- cordance with this section if provided glycemic drugs of the sulfonylurea to the patient before administration of class. the first estrogen and every 30 days (a) The University Group Diabetes thereafter, as long as the therapy con- Program clinical trial has reported an tinues. association between the administration (c) Patient package insert contents. A of tolbutamide and increased cardio- patient package insert for an estrogen vascular mortality. The Food and Drug

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Administration has concluded that this class, in view of their close similarities in reported association provides adequate mode of action and chemical structure. basis for a warning in the labeling. In [49 FR 14331, Apr. 11, 1984] view of the similarities in chemical structure and mode of action, the Food § 310.518 Drug products containing and Drug Administration also believes iron or iron salts. it is prudent from a safety standpoint Drug products containing elemental to consider that the possible increased iron or iron salts as an active ingre- risk of cardiovascular mortality from dient in solid oral dosage form, e.g., tolbutamide applies to all other sulfo- tablets or capsules shall meet the fol- nylurea drugs as well. Therefore, the lowing requirements: labeling for oral hypoglycemic drugs of (a) Labeling. (1) The label of any drug the sulfonylurea class shall include a in solid oral dosage form (e.g., tablets warning concerning the possible in- or capsules) that contains iron or iron creased risk of cardiovascular mor- salts for use as an iron source shall tality associated with such use, as set bear the following statement: forth in paragraph (b) of this section. (b) Labeling for oral hypoglycemic WARNING: Accidental overdose or iron- drugs of the sulfonylurea class shall in- containing products is a leading cause of clude in boldface type at the beginning fatal poisoning in children under 6. Keep this product out of reach of children. In case of of the ‘‘Warnings’’ section of the label- accidental overdose, call a doctor or poison ing the following statement: control center immediately. (2)(i) The warning statement required SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY by paragraph (a)(1) of this section shall appear prominently and conspicuously The administration of oral hypoglycemic on the information panel of the imme- drugs has been reported to be associated diate container label. with increased cardiovascular mortality as compared to treatment with diet alone or (ii) If a drug product is packaged in diet plus insulin. This warning is based on unit-dose packaging, and if the imme- the study conducted by the University Group diate container bears labeling but not a Diabetes Program (UGDP), a long-term pro- label, the warning statement required spective clinical trial designed to evaluate by paragraph (a)(1) of this section shall the effectiveness of glucose-lowering drugs appear prominently and conspicuously in preventing or delaying vascular complica- on the immediate container labeling in tions in patients with non-insulin-dependent a way that maximizes the likelihood diabetes. The study involved 823 patients who were randomly assigned to one of four that the warning is intact until all of treatment groups (Diabetes, 19 (supp. 2): 747– the dosage units to which it applies are 830, 1970). used. UGDP reported that patients treated for 5 (3) Where the immediate container is to 8 years with diet plus a fixed dose of tol- not the retail package, the warning butamide (1.5 grams per day) had a rate of statement required by paragraph (a)(1) cardiovascular mortality approximately 21⁄2 of this section shall also appear promi- times that of patients treated with diet nently and conspicuously on the infor- alone. A significant increase in total mortality was not observed, but the use of tol- mation panel of the retail package butamide was discontinued based on the in- label. crease in cardiovascular mortality, thus lim- (4) The warning statement shall ap- iting the opportunity for the study to show pear on any labeling that contains an increase in overall mortality. Despite warnings. controversy regarding the interpretation of (5) The warning statement required these results, the findings of the UGDP study by paragraph (a)(1) of this section shall provide an adequate basis for this warning. The patient should be informed of the poten- be set off in a box by use of hairlines. tial risks and advantages of (name of drug) (b) The iron-containing inert tablets and of alternative modes of therapy. supplied in monthly packages of oral Although only one drug in the sulfonylurea contraceptives are categorically ex- class (tolbutamide) was included in this empt from the requirements of para- study, it is prudent from a safety standpoint graph (a) of this section. to consider that this warning may also apply to other oral hypoglycemic drugs in this [68 FR 59715, Oct. 17, 2003]

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§ 310.519 Drug products marketed as § 310.527 Drug products containing ac- over-the-counter (OTC) daytime tive ingredients offered over-the- sedatives. counter (OTC) for external use as hair growers or for hair loss pre- (a) Antihistamines, bromides, and vention. scopolamine compounds, either singly (a) Amino acids, aminobenzoic acid, or in combinations, have been mar- ascorbic acid, benzoic acid, biotin and keted as ingredients in over-the- all other B-vitamins, dexpanthenol, es- counter (OTC) drug products for use as tradiol and other topical hormones, daytime sedatives. The following jojoba oil, lanolin, nucleic acids, poly- claims have been made for daytime sorbate 20, polysorbate 60, sulfa- sedative products: ‘‘occasional simple nilamide, sulfur 1 percent on carbon in nervous tension,’’ ‘‘nervous irrita- a fraction of paraffinic hydrocarbons, bility,’’ ‘‘nervous tension headache,’’ tetracaine hydrochloride, urea, and ‘‘simple nervousness due to common wheat germ oil have been marketed as every day overwork and fatigue,’’ ‘‘a ingredients in OTC drug products for relaxed feeling,’’ ‘‘calming down and external use as hair growers or for hair relaxing,’’ ‘‘gently soothe away the loss prevention. There is a lack of ade- tension,’’ ‘‘calmative,’’ ‘‘resolving that quate data to establish general rec- irritability that ruins your day,’’ ognition of the safety and effectiveness ‘‘helps you relax,’’ ‘‘restlessness,’’ of these or any other ingredients in- ‘‘when you’re under occasional stress . tended for OTC external use as a hair . . helps you work relaxed.’’ Based on grower or for hair loss prevention. evidence presently available, there are Based on evidence currently available, no ingredients that can be generally all labeling claims for OTC hair grower recognized as safe and effective for use and hair loss prevention drug products as OTC daytime sedatives. for external use are either false, misleading, or unsupported by scientific (b) Any OTC drug product that is la- data. Therefore, any OTC drug product beled, represented, or promoted as an for external use containing an ingre- OTC daytime sedative (or any similar dient offered for use as a hair grower or or related indication) is regarded as a for hair loss prevention cannot be con- new drug within the meaning of section sidered generally recognized as safe 201(p) of the Federal Food, Drug, and and effective for its intended use. Cosmetic Act for which an approved (b) Any OTC drug product that is la- new drug application under section 505 beled, represented, or promoted for ex- of the act and part 314 of this chapter ternal use as a hair grower or for hair is required for marketing. loss prevention is regarded as a new (c) Clinical investigations designed drug within the meaning of section to obtain evidence that any drug prod- 201(p) of the Federal Food, Drug, and uct labeled, represented, or promoted Cosmetic Act (the act), for which an as an OTC daytime sedative (or any approved new drug application under similar or related indication) is safe section 505 of the act and part 314 of and effective for the purpose intended this chapter is required for marketing. must comply with the requirements In the absence of an approved new drug and procedures governing the use of in- application, such product is also mis- vestigational new drugs set forth in branded under section 502 of the act. part 312 of this chapter. (c) Clinical investigations designed (d) Any OTC daytime sedative drug to obtain evidence that any drug product labeled, represented, or promoted product introduced into interstate for OTC external use as a hair grower commerce after December 24, 1979, that or for hair loss prevention is safe and is not in compliance with this section effective for the purpose intended must is subject to regulatory action. comply with the requirements and pro- [44 FR 36380, June 22, 1979; 45 FR 47422, July cedures governing the use of investiga- 15, 1980, as amended at 55 FR 11579, Mar. 29, tional new drugs set forth in part 312 of 1990] this chapter. (d) After January 8, 1990, any such OTC drug product initially introduced

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or initially delivered for introduction In the absence of an approved new drug into interstate commerce that is not in application, such product is also mis- compliance with this section is subject branded under section 502 of the act. to regulatory action. (c) Clinical investigations designed to obtain evidence that any drug prod- [54 FR 28777, July 7, 1989] uct labeled, represented, or promoted § 310.528 Drug products containing ac- for OTC use as an aphrodisiac is safe tive ingredients offered over-the- and effective for the purpose intended counter (OTC) for use as an aphro- must comply with the requirements disiac. and procedures governing the use of in- (a) Any product that bears labeling vestigational new drugs set forth in claims that it will arouse or increase part 312 of this chapter. sexual desire, or that it will improve (d) After January 8, 1990, any such sexual performance, is an aphrodisiac OTC drug product initially introduced drug product. Anise, cantharides, don or initially delivered for introduction qual, estrogens, fennel, ginseng, golden into interstate commerce that is not in seal, gotu kola, Korean ginseng, lico- compliance with this section is subject rice, mandrake, methyltestosterone, to regulatory action. minerals, nux vomica, Pega Palo, sar- [54 FR 28786, July 7, 1989] saparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydro- § 310.529 Drug products containing ac- chloride, and yohimbinum have been tive ingredients offered over-the- present as ingredients in such drug counter (OTC) for oral use as insect products. Androgens (e.g., testosterone repellents. and methyltestosterone) and estrogens (a) Thiamine hydrochloride (vitamin are powerful hormones when adminis- B–1) has been marketed as an ingre- tered internally and are not safe for dient in over-the-counter (OTC) drug use except under the supervision of a products for oral use as an insect repel- physician. There is a lack of adequate lent (an orally administered drug prod- data to establish general recognition of uct intended to keep insects away). the safety and effectiveness of any of There is a lack of adequate data to es- these ingredients, or any other ingre- tablish the effectiveness of this, or any dient, for OTC use as an aphrodisiac. other ingredient for OTC oral use as an Labeling claims for aphrodisiacs for insect repellent. Labeling claims for OTC use are either false, misleading, or OTC orally administered insect repel- unsupported by scientific data. The fol- lent drug products are either false, lowing claims are examples of some misleading, or unsupported by sci- that have been made for aphrodisiac entific data. The following claims are drug products for OTC use: ‘‘acts as an examples of some that have been made aphrodisiac;’’ ‘‘arouses or increases for orally administered OTC insect re- sexual desire and improves sexual per- pellent drug products: ‘‘Oral mosquito formance;’’ ‘‘helps restore sexual vigor, repellent,’’ ‘‘mosquitos avoid you,’’ potency, and performance;’’ ‘‘improves ‘‘bugs stay away,’’ ‘‘keep mosquitos performance, staying power, and sexual away for 12 to 24 hours,’’ and ‘‘the new- potency;’’ and ‘‘builds virility and sex- est way to fight mosquitos.’’ Therefore, ual potency.’’ Based on evidence cur- any drug product containing ingredi- rently available, any OTC drug product ents offered for oral use as an insect re- containing ingredients for use as an pellent cannot be generally recognized aphrodisiac cannot be generally recog- as safe and effective. nized as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or promoted for oral beled, represented, or prompted for use use as an insect repellent is regarded as as an aphrodisiac is regarded as a new a new drug within the meaning of sec- drug within the meaning of section tion 201(p) of the Federal Food, Drug 201(p) of the Federal Food, Drug, and and Cosmetic Act for which an ap- Cosmetic Act, (the act), for which an proved new drug application under sec- approved new drug application under tion 505 of the act and part 314 of this section 505 of the act and part 314 of chapter is required for marketing. In this chapter is required for marketing. the absence of an approved new drug

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application, such product is also mis- the labeling indicating that ‘‘hor- branded under section 502 of the act. mones’’ are present in the product, or (c) Clinical investigations designed any statement that features or empha- to obtain evidence that any drug prod- sizes the presence of a hormone ingre- uct labeled, represented, or promoted dient in the product, will be considered OTC for oral use as an insect repellent to be a therapeutic claim for the prod- is safe and effective for the purpose in- uct, or a claim that the product will af- tended must comply with the require- fect the structure or function of the ments and procedures governing the body, and will consequently cause the use of investigational new drugs set product to be a drug. forth in part 312 of this chapter. (b) Any OTC drug product that is la- (d) Any such drug product in inter- beled, represented, or promoted as a state commerce after December 17, topically applied hormone-containing 1985, that is not in compliance with product for drug use, with the excep- this section is subject to regulatory action of those hormones identified in tion. paragraph (e) of this section, is re- [40 FR 25171, June 17, 1985, as amended at 55 garded as a new drug within the mean- FR 11579, Mar. 29, 1990] ing of section 201(p) of the act, for which an approved application or ab- § 310.530 Topically applied hormone- breviated application under section 505 containing drug products for over- of the act and part 314 of this chapter the-counter (OTC) human use. is required for marketing. In the ab- (a) The term ‘‘hormone’’ is used sence of an approved new drug applica- broadly to describe a chemical sub- tion or abbreviated new drug applica- stance formed in some organ of the tion, such product is also misbranded body, such as the adrenal glands or the under section 502 of the act. pituitary, and carried to another organ (c) Clinical investigations designed or tissue, where it has a specific effect. to obtain evidence that any drug prod- Hormones include, for example, estro- uct labeled, represented, or promoted gens, progestins, androgens, anabolic for OTC use as a topically applied hor- steroids, and adrenal corticosteroids, mone-containing drug product is safe and synthetic analogs. Estrogens, pro- and effective for the purpose intended gesterone, pregnenolone, and pregneno- must comply with the requirements lone acetate have been present as in- and procedures governing the use of ingredients in OTC drug products mar- vestigational new drugs set forth in keted for topical use as hormone part 312 of this chapter. creams. However, there is a lack of (d) After March 9, 1994, any such OTC adequate data to establish effective- drug product initially introduced or ness for any OTC drug use of these in- initially delivered for introduction into gredients. Therefore, with the excep- interstate commerce that is not in tion of those hormones identified in compliance with this section is subject paragraph (e) of this section, any OTC to regulatory action. drug product containing an ingredient (e) This section does not apply to hy- offered for use as a topically applied drocortisone and hydrocortisone ace- hormone cannot be considered gen- tate labeled, represented, or promoted erally recognized as safe and effective for OTC topical use in accordance with for its intended use. The intended use part 348 of this chapter. of the product may be inferred from [58 FR 47610, Sept. 9, 1993] the product’s labeling, promotional material, advertising, and any other § 310.531 Drug products containing ac- relevant factor. The use of the word tive ingredients offered over-the- ‘‘hormone’’ in the text of the labeling counter (OTC) for the treatment of or in the ingredient statement is an boils. implied drug claim. The claim implied (a) Aminacrine hydrochloride, benzo- by the use of this term is that the prod- caine, bismuth subnitrate, calomel, uct will have a therapeutic or some camphor, cholesterol, ergot fluid ex- other physiological effect on the body. tract, hexachlorophene, ichthammol, Therefore, reference to a product as a isobutamben, juniper tar (oil of cade), ‘‘hormone cream’’ or any statement in lanolin, magnesium sulfate, menthol,

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methyl salicylate, oxyguinoline sul- ichthammol, sulfur, or triclosan ini- fate, petrolatum, phenol, pine tar, tially introduced or initially delivered rosin, rosin cerate, sassafras oil, sulfur, for introduction into interstate com- thymol, triclosan, and zinc oxide have merce that is not in compliance with been present in OTC boil treatment this section is subject to regulatory ac- drug products. There is a lack of ade- tion. quate data to establish general rec- (f) This section does not apply to ognition of the safety and effectiveness drug products that contain benzocaine of these or any other ingredient for labeled, represented, or promoted for OTC use for the treatment of boils. OTC topical use in accordance with Treatment is defined as reducing the part 348 of this chapter. size of a boil or reducing an infection [58 FR 60336, Nov. 15, 1993] related to a boil. Treatment has involved the use of ‘‘drawing salves’’ for § 310.532 Drug products containing ac- these purposes. These ‘‘drawing salves’’ tive ingredients offered over-the- contained various ingredients. Based counter (OTC) to relieve the symp- on evidence currently available, any toms of benign prostatic hyper- OTC drug product offered for the treat- trophy. ment of boils cannot be considered gen- (a) The amino acids glycine, alanine, erally recognized as safe and effective. and glutamic acid (alone or in com- (b) Any OTC drug product that is la- bination) and the ingredient sabal have beled, represented, or promoted for the been present in over-the-counter (OTC) treatment of boils is regarded as a new drug products to relieve the symptoms drug within the meaning of section of benign prostatic hypertrophy, e.g., 201(p) of the Federal Food, Drug, and urinary urgency and frequency, exces- Cosmetic Act (the act), for which an sive urinating at night, and delayed approved application or abbreviated urination. There is a lack of adequate application under section 505 of the act data to establish general recognition of and part 314 of this chapter is required the safety and effectiveness of these or for marketing. In the absence of an ap- any other ingredients for OTC use in proved new drug application or abbre- relieving the symptoms of benign pros- viated new drug application, such prod- tatic hypertrophy. In addition, there is uct is also misbranded under section no definitive evidence that any drug 502 of the act. product offered for the relief of the (c) Clinical investigations designed symptoms of benign prostatic hyper- to obtain evidence that any OTC boil trophy would alter the obstructive or treatment drug product is safe and ef- inflammatory signs and symptoms of fective for the purpose intended must this condition. Therefore, self-medica- comply with the requirements and pro- tion with OTC drug products might un- cedures governing the use of investiga- necessarily delay diagnosis and treat- tional new drugs set forth in part 312 of ment of progressive obstruction and this chapter. secondary infections. Based on evi- (d) After May 7, 1991, any such OTC dence currently available, any OTC drug product that contains aminacrine drug product containing ingredients of- hydrochloride, bismuth subnitrate, cal- fered for use in relieving the symptoms omel, camphor, cholesterol, ergot fluid of benign prostatic hypertrophy cannot extract, hexachlorophene, isobu- be generally recognized as safe and ef- tamben, juniper tar (oil of cade), lan- fective. olin, magnesium sulfate, menthol, (b) Any OTC drug product that is la- methyl salicylate, oxyguinoline sul- beled, represented, or promoted to re- fate, petrolatum, phenol, pine tar, lieve the symptoms of benign prostatic rosin, rosin cerate, sassafras oil, thy- hypertrophy is regarded as a new drug mol, or zinc oxide initially introduced within the meaning of section 201(p) of or initially delivered for introduction the Federal Food, Drug, and Cosmetic into interstate commerce that is not in Act (the act), for which an approved compliance with this section is subject application under section 505 of the act to regulatory action. and part 314 of this chapter is required (e) After May 16, 1994, any such OTC for marketing. In the absence of an ap- drug product that contains benzocaine, proved application, such product is also

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misbranded under section 502 of the to establish general recognition of the act. safety and/or effectiveness or any of (c) Clinical investigations designed these ingredients, or any other ingre- to obtain evidence that any drug prod- dient, for OTC use as an anticho- uct labeled, represented, or promoted linergic in cough-cold drug products. for OTC use to relieve the symptoms of (b) Any OTC cough-cold drug product benign prostatic hypertrophy is safe that is labeled, represented, or pro- and effective for the purpose intended moted for use as an anticholinergic is must comply with the requirements regarded as a new drug within the and procedures governing the use of in- meaning of section 201(p) of the Fed- vestigational new drugs set forth in eral Food, Drug, and Cosmetic Act, for part 312 of this chapter. which an approved new drug applica- (d) After August 27, 1990, any such tion under section 505 of the act and OTC drug product initially introduced part 314 of this chapter is required for or initially delivered for introduction marketing. In the absence of an ap- into interstate commerce that is not in proved new drug application, such compliance with this section is subject product is also misbranded under sec- to regulatory action. tion 502 of the act. (c) Clinical investigations designed [55 FR 6930, Feb. 27, 1990] to obtain evidence that any cough-cold § 310.533 Drug products containing ac- drug product labeled, represented, or tive ingredients offered over-the- promoted for OTC use as an anticho- counter (OTC) for human use as an linergic is safe and effective for the anticholinergic in cough-cold drug purpose intended must comply with the products. requirements and procedures governing (a) Atropine sulfate, belladonna alka- the use of investigational new drugs loids, and belladonna alkaloids as con- set forth in part 312 of this chapter. tained in Atropa belladonna and Datu- (d) After the effective date of the ra stramonium have been present as in- final regulation, any such OTC cough- gredients in cough-cold drug products cold drug product that is labeled, rep- for use as an anticholinergic. Anticho- resented, or promoted for use as an linergic drugs have been marketed OTC anticholinergic may not be initially in- in cough-cold drug products to relieve troduced or initially delivered for in- excessive secretions of the nose and troduction into interstate commerce eyes, symptoms that are commonly as- unless it is the subject of an approved sociated with hay fever, allergy, rhi- new drug application. nitis, and the common cold. Atropine [50 FR 46587, Nov. 8, 1985, as amended at 55 sulfate for oral use as an anticho- FR 11579, Mar. 29, 1990] linergic is probably safe at dosages that have been used in marketed § 310.534 Drug products containing ac- cough-cold products (0.2 to 0.3 milli- tive ingredients offered over-the- gram); however, there are inadequate counter (OTC) for human use as data to establish general recognition of oral wound healing agents. the effectiveness of this ingredient. (a) Allantoin, carbamide peroxide in The belladonna alkaloids, which con- anhydrous glycerin, water soluble tain atropine (d, dl hyoscyamine) and chlorophyllins, and hydrogen peroxide scopolamine (l- hyoscine), are probably in aqueous solution have been present safe for oral use at dosages that have in oral mucosal injury drug products been used in marketed cough-cold for use as oral wound healing agents. products (0.2 milligram) but there are Oral wound healing agents have been inadequate data to establish general marketed as aids in the healing of recognition of the effectiveness of minor oral wounds by means other these ingredients as an anticholinergic than cleansing and irrigating, or by for cough-cold use. Belladonna alka- serving as a protectant. Allantoin, car- loids for inhalation use, as contained in bamide peroxide in anhydrous glycerin, Atropa belladonna and Datura stramo- water soluble chlorophyllins, and hy- nium, are neither safe nor effective as drogen peroxide in aqueous solution an OTC anticholinergic. There are in- are safe for use as oral wound healing adequate safety and effectiveness data agents, but there are inadequate data

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to establish general recognition of the is regarded as a new drug within the effectiveness of these ingredients as meaning of section 201(p) of the Fed- oral wound healing agents. eral Food, Drug, and Cosmetic Act (the (b) Any OTC drug product that is la- act) for which an approved application beled, represented, or promoted for use or abbreviated application under sec- as an oral wound healing agent is re- tion 505 of the act and part 314 of this garded as a new drug within the mean- chapter is required for marketing. In ing of section 201(p) of the Federal the absence of an approved new drug Food, Drug, and Cosmetic Act, for application or abbreviated new drug which an approved new drug applica- application, such product is also mis- tion under section 505 of the act and branded under section 502 of the act. part 314 of this chapter is required for (c) Clinical investigations designed marketing. In the absence of an ap- to obtain evidence that any drug prod- proved new drug application, such uct labeled, represented, or promoted product is also misbranded under sec- for OTC use as a nailbiting or thumb- tion 502 of the act. sucking deterrent is safe and effective (c) Clinical investigations designed for the purpose intended must comply to obtain evidence that any drug prod- with the requirements and procedures uct labeled, represented, or promoted governing the use of investigational for OTC use as an oral wound healing new drugs set forth in part 312 of this agent is safe and effective for the pur- chapter. pose intended must comply with the re- (d) After March 2, 1994, any such OTC quirements and procedures governing drug product initially introduced or the use of investigational new drugs initially delivered for introduction into set forth in part 312 of this chapter. interstate commerce that is not in (d) After the effective date of the compliance with this section is subject final regulation, any OTC drug product to regulatory action. that is labeled, represented, or pro- [58 FR 46754, Sept. 2, 1993] moted for use as an oral wound healing agent may not be initially introduced § 310.537 Drug products containing ac- or initially delivered for introduction tive ingredients offered over-the- into interstate commerce unless it is counter (OTC) for oral administra- the subject of an approved new drug ap- tion for the treatment of fever blis- plication. ters and cold sores. [51 FR 26114, July 18, 1986, as amended at 55 (a) L-lysine (lysine, lysine hydro- FR 11579, Mar. 29, 1990] chloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been § 310.536 Drug products containing ac- present in orally administered OTC tive ingredients offered over-the- drug products to treat fever blisters counter (OTC) for use as a nail- and cold sores. There is a lack of ade- biting or thumbsucking deterrent. quate data to establish general rec- (a) Denatonium benzoate and sucrose ognition of the safety and effectiveness octaacetate have been present in OTC of these or any other orally adminis- nailbiting and thumbsucking deterrent tered ingredients for OTC use to treat drug products. There is a lack of ade- or relieve the symptoms or discomfort quate data to establish general rec- of fever blisters and cold sores. Based ognition of the safety and effectiveness on evidence currently available, any of these and any other ingredients OTC drug product for oral administra- (e.g., cayenne pepper) for OTC use as a tion containing ingredients offered for nailbiting or thumbsucking deterrent. use in treating or relieving the symp- Based on evidence currently available, toms or discomfort of fever blisters and any OTC drug product containing in- cold sores cannot be generally recog- gredients offered for use as a nailbiting nized as safe and effective. or thumbsucking deterrent cannot be (b) Any OTC drug product for oral ad- generally recognized as safe and effec- ministration that is labeled, rep- tive. resented, or promoted to treat or re- (b) Any OTC drug product that is la- lieve the symptoms or discomfort of beled, represented, and promoted as a fever blisters and cold sores is regarded nailbiting or thumbsucking deterrent as a new drug within the meaning of

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section 201(p) of the Federal Food, for marketing. In the absence of an ap- Drug, and Cosmetic Act (the act), for proved new drug application or abbre- which an approved application under viated new drug application, such prod- section 505 of the act and part 314 of uct is also misbranded under section this chapter is required for marketing. 502 of the act. In the absence of an approved applica- (c) Clinical investigations designed tion, such product is also misbranded to obtain evidence that any drug prod- under section 502 of the act. uct labeled, represented, or promoted (c) Clinical investigations designed for OTC use for ingrown toenail relief to obtain evidence that any drug prod- is safe and effective for the purpose in- uct for oral administration labeled, represented, or promoted for OTC use tended must comply with the require- to treat or relieve the symptoms or dis- ments and procedures governing the comfort of fever blisters and cold sores use of investigational new drugs set is safe and effective for the purpose in- forth in part 312 of this chapter. tended must comply with the require- (d) After March 9, 1994, any such OTC ments and procedures governing the drug product initially introduced or use of investigational new drugs set initially delivered for introduction into forth in part 312 of this chapter. interstate commerce that is not in (d) After December 30, 1992, any such compliance with this section is subject OTC drug product initially introduced to regulatory action. or initially delivered for introduction (e) This section does not apply to so- into interstate commerce that is not in dium sulfide labeled, represented, or compliance with this section is subject promoted for OTC topical use for in- to regulatory action. grown toenail relief in accordance with [57 FR 29173, June 30, 1992] part 358, subpart D of this chapter, after June 6, 2003. § 310.538 Drug products containing active ingredients offered over-the- [58 FR 47605, Sept. 9, 1993, as amended at 68 counter (OTC) for use for ingrown FR 24348, May 7, 2003] toenail relief. (a) Any product that bears labeling § 310.540 Drug products containing active ingredients offered over-the- claims such as for ‘‘temporary relief of counter (OTC) for use as stomach discomfort from ingrown toenails,’’ or acidifiers. ‘‘ingrown toenail relief product,’’ or ‘‘ingrown toenail reliever,’’ or similar (a) Betaine hydrochloride, glutamic claims is considered an ingrown toenail acid hydrochloride, diluted hydro- relief drug product. Benzocaine, chloro- chloric acid, and pepsin have been butanol, chloroxylenol, dibucaine, tan- present as ingredients in over-the- nic acid, and urea have been present as counter (OTC) drug products for use as ingredients in such products. There is stomach acidifiers. Because of the lack lack of adequate data to establish gen- of adequate data to establish the effec- eral recognition of the safety and effectiveness of these or any other ingredi- tiveness of these or any other ingredients for use in treating achlorhydria ents for OTC use for ingrown toenail and hypochlorhydria, and because such relief. Based on evidence currently conditions are asymptomatic, any OTC available, any OTC drug product con- drug product containing ingredients of- taining ingredients offered for use for fered for use as a stomach acidifier ingrown toenail relief cannot be gen- cannot be considered generally recog- erally recognized as safe and effective. nized as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a beled, represented, or promoted for use new drug within the meaning of section as a stomach acidifier is regarded as a 201(p) of the Federal Food, Drug, and new drug within the meaning of section Cosmetic Act (the act), for which an 201(p) of the Federal Food, Drug, and approved application or abbreviated Cosmetic Act, for which an approved application under section 505 of the act new drug application under section 505 and part 314 of this chapter is required of the act and part 314 of this chapter

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is required for marketing. In the ab- drugs set forth in part 312 of his chap- sence of an approved new drug applica- ter. tion, such product is also misbranded (d) After November 12, 1990, any such under section 502 of the act. OTC drug product initially introduced (c) Clinical investigations designed or initially delivered for introduction to obtain evidence that any drug prod- into interstate commerce that is not in uct labeled, represented, or promoted compliance with this section is subject as a stomach acidifier for OTC use is to regulatory action. safe and effective for the purpose intended must comply with the require- [55 FR 19858, May 11, 1990] ments and procedures governing the use of investigational new drugs set § 310.542 Over-the-counter (OTC) drug products containing active ingredi- forth in part 312 of this chapter. ents offered for use in the treat- (d) After the effective date of the ment of hyperphosphatemia. final regulation, any such OTC drug product initially introduced or ini- (a) Hyperphosphatemia is a condition tially delivered for introduction into in which an abnormally high plasma interstate commerce that is not in level of phosphate occurs in the blood. compliance with this section is subject This condition in not amenable to self- to regulatory action. diagnosis or self-treatment. Treatment of this condition should be restricted [53 FR 31271, Aug. 17, 1988] to the supervision of a physician. For this reason, any drug product con- § 310.541 Over-the-counter (OTC) drug products containing active ingredi- taining ingredients offered for OTC use ents offered for use in the treat- in the treatment of hyperphosphatemia ment of hypophosphatemia. cannot be considered generally recog- (a) Hypophosphatemia is a condition nized as safe and effective. in which an abnormally low plasma (b) Any drug product that is labeled, level of phosphate occurs in the blood. represented, or promoted for OTC use This condition is not amenable to self- in the treatment of hyperphosphatemia diagnosis or self-treatment. Treatment is regarded as a new drug within the of this condition should be restricted meaning of section 201(p) of the Fed- to the supervision of a physician. For eral Food, Drug, and Cosmetic Act (the this reason, any drug product con- act), for which an approved application taining ingredients offered for OTC use under section 505 of the act and part 314 in the treatment of hypophosphatemia of this chapter is required for mar- cannot be considered generally recog- keting. In the absence of an approved nized as safe and effective. application, such product is also mis- (b) Any drug product that is labeled, branded under section 502 of the act. represented, or promoted for OTC use (c) Clinical investigations designed in the treatment of hypophosphatemia to obtain evidence that any drug prod- is regarded as a new drug within the uct labeled, represented, or promoted meaning of section 201(p) of the Fed- for use in the treatment of hyper- eral Food, Drug, and Cosmetic Act (the phosphatemia is safe and effective for act), for which an approved application the purpose intended must comply with under section 505 of the act and part 314 the requirements and procedures gov- of this chapter is required for mar- erning use of investigational new drugs keting. In the absence of an approved application, such product is also mis- set forth in part 312 of this chapter. branded under section 502 of the act. (d) After November 12, 1990, any such (c) Clinical investigations designed OTC drug product initially introduced to obtain evidence that any drug prod- or initially delivered for introduction uct labeled, represented, or promoted into interstate commerce that is not in for OTC use in the treatment of hypo- compliance with this section is subject phosphatemia is safe and effective for to regulatory action. the purpose intended must comply with [55 FR 19858, May 11, 1990] the requirements and procedures governing the use of investigational new

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§ 310.543 Drug products containing ac- and procedures governing the use of in- tive ingredients offered over-the- vestigational new drugs set forth in counter (OTC) for human use in part 312 of this chapter. exocrine pancreatic insufficiency. (d) After May 7, 1991, any such OTC (a) Hemicellulase, pancreatin, and drug product that contains hemi- pancrelipase have been present as in- cellulase initially introduced or ini- gredients in exocrine pancreatic insuf- tially delivered for introduction into ficiency drug products. Pancreatin and interstate commerce that is not in pancrelipase are composed of enzymes: compliance with this section is subject amylase, trypsin (protease), and lipase. to regulatory action. Significant differences have been (e) After October 24, 1995, any such shown in the bioavailability of mar- OTC drug product that contains pan- keted exocrine pancreatic insufficiency creatin or pancrelipase initially intro- drug products produced by different duced or initially delivered for intro- manufacturers. These differences raise duction into interstate commerce that a potential for serious risk to patients using these drug products. The bio- is not in compliance with this section availability of pancreatic enzymes is is subject to regulatory action. dependent on the process used to man- [60 FR 20165, Apr. 24, 1995] ufacture the drug products. Informa- tion on this process is not included in § 310.544 Drug products containing ac- an OTC drug monograph. Therefore, tive ingredients offered over-the- the safe and effective use of these en- counter (OTC) for use as a smoking zymes for treating exocrine pancreatic deterrent. insufficiency cannot be regulated ade- (a) Any product that bears labeling quately by an OTC drug monograph. claims that it ‘‘helps stop or reduce the Information on the product’s formula- cigarette urge,’’ ‘‘helps break the ciga- tion, manufacture, quality control pro- rette habit,’’ ‘‘helps stop or reduce cedures, and final formulation effec- smoking,’’ or similar claims is a smok- tiveness testing are necessary in an ap- ing deterrent drug product. Cloves, co- proved application to ensure that a riander, eucalyptus oil, ginger (Ja- company has the ability to manufac- maica), lemon oil (terpeneless), licorice ture a proper bioactive formulation. In root extract, lobeline (in the form of addition, continuous physician moni- lobeline sulfate or natural lobelia alka- toring of patients who take these drug loids or Lobelia inflata herb), menthol, products is a collateral measure nec- methyl salicylate, povidone-silver ni- essary to the safe and effective use of trate, quinine ascorbate, silver acetate, these enzymes, causing such products silver nitrate, and thymol have been to be available by prescription only. present as ingredients in such drug (b) Any drug product that is labeled, products. There is a lack of adequate represented, or promoted for OTC use data to establish general recognition of in the treatment of exocrine pancreatic the safety and effectiveness of these or insufficiency is regarded as a new drug within the meaning of section 201(p) of any other ingredients for OTC use as a the Federal Food, Drug, and Cosmetic smoking deterrent. Based on evidence Act (the act), for which an approved currently available, any OTC drug application under section 505 of the act product containing ingredients offered and part 314 of this chapter is required for use as a smoking deterrent cannot for marketing. In the absence of an ap- be generally recognized as safe and ef- proved application, such product is also fective. misbranded under section 502 of the (b) Any OTC drug product that is la- act. beled, represented, or promoted as a (c) Clinical investigations designed smoking deterrent is regarded as a new to obtain evidence that any drug prod- drug within the meaning of section uct labeled, represented, or promoted 201(p) of the Federal Food, Drug, and for OTC use in the treatment of exo- Cosmetic Act (the act), for which an crine pancreatic insufficiency is safe approved application or abbreviated and effective for the purpose intended application under section 505 of the act must comply with the requirements and part 314 of this chapter is required

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for marketing. In the absence of an ap- Chloroxylenol proved new drug application or abbre- Cloxyquin viated new drug application, such prod- Coal tar uct is also misbranded under section Dibenzothiophene Estrone 502 of the act. Magnesium aluminum silicate (c) Clinical investigations designed Magnesium sulfate to obtain evidence that any drug prod- Phenol uct labeled, represented, or promoted Phenolate sodium for OTC use as a smoking deterrent is Phenyl salicylate safe and effective for the purpose in- Povidone-iodine tended must comply with the require- Pyrilamine maleate ments and procedures governing the Resorcinol (as single ingredient) use of investigational new drugs set Resorcinol monoacetate (as single ingredient) forth in part 312 of this chapter. Salicylic acid (over 2 up to 5 percent) (d) After May 7, 1991, any such OTC Sodium borate drug product containing cloves, cori- Sodium thiosulfate ander, eucalyptus oil, ginger (Ja- Tetracaine hydrochloride maica), lemon oil (terpeneless), licorice Thymol root extract, menthol, methyl salicy- Vitamin E late, quinine ascorbate, silver nitrate, Zinc oxide and/or thymol initially introduced or Zinc stearate initially delivered for introduction into Zinc sulfide interstate commerce that is not in (2) Anticaries drug products—(i) Ap- compliance with this section is subject proved as of May 7, 1991. to regulatory action. After December 1, 1993, any such OTC drug product con- Hydrogen fluoride Sodium carbonate taining lobeline (in the form of lobeline Sodium monofluorophosphate (6 percent sulfate or natural lobelia alkaloids or rinse) Lobelia inflata herb), povidone-silver ni- Sodium phosphate trate, silver acetate, or any other ingredients initially introduced or ini- (ii) Approved as of October 7, 1996. tially delivered for introduction into Calcium sucrose phosphate interstate commerce that is not in Dicalcium phosphate dihydrate compliance with this section is subject Disodium hydrogen phosphate 1 to regulatory action. Phosphoric acid 1 Sodium dihydrogen phosphate [58 FR 31241, June 1, 1993] Sodium dihydrogen phosphate monohydrate Sodium phosphate, dibasic anhydrous rea- § 310.545 Drug products containing gent 1 certain active ingredients offered over-the-counter (OTC) for certain (3) Antidiarrheal drug products—(i) Ap- uses. proved as of May 7, 1991. (a) A number of active ingredients Aluminum hydroxide have been present in OTC drug prod- Atropine sulfate ucts for various uses, as described Calcium carbonate below. However, based on evidence cur- Carboxymethylcellulose sodium rently available, there are inadequate Glycine Homatropine methylbromide data to establish general recognition of Hyoscyamine sulfate the safety and effectiveness of these in- Lactobacillus acidophilus gredients for the specified uses: Lactobacillus bulgaricus (1) Topical acne drug products. Opium, powdered Opium tincture Alcloxa Paregoric Alkyl isoquinolinium bromide Phenyl salicylate Aluminum chlorohydrex Scopolamine hydrobromide Aluminum hydroxide Zinc phenolsulfonate Benzocaine Benzoic acid Boric acid 1 These ingredients are nonmonograph ex- Calcium polysulfide cept when used to prepare acidulated phos- Calcium thiosulfate phate fluoride treatment rinses identified in Camphor § 355.10(a)(3) of this chapter.

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(ii) Approved as of April 19, 2004; April Cedar leaf oil (topical) 18, 2005, for products with annual sales Creosote, beechwood (topical) less than $25,000. Ephedrine (oral) Ephedrine hydrochloride (oral) Attapulgite, activated Ephedrine sulfate (oral) Bismuth subnitrate Racephedrine hydrochloride (oral/topical) Calcium hydroxide Calcium polycarbophil (C) Approved as of April 11, 2007; Oc- Charcoal (activated) tober 11, 2007, for products with annual Pectin sales less than $25,000. Any ingre- Polycarbophil dient(s) labeled with claims or direc- Potassium carbonate tions for use for sinusitis or for relief Rhubarb fluidextract of nasal congestion associated with si- (4) Antiperspirant drug products—(i) nusitis. Ingredients—Approved as of May 7, 1991. (iii) Expectorant drug products. Alum, potassium Ammonium chloride Aluminum bromohydrate Antimony potassium tartrate Aluminum chloride (alcoholic solutions) Beechwood creosote Aluminum chloride (aqueous solution) (aer- Benzoin preparations (compound tincture of osol only) benzoin, tincture of benzoin) Aluminum sulfate Camphor Aluminum sulfate, buffered (aerosol only) Chloroform Sodium aluminum chlorohydroxy lactate Eucalyptol/eucalyptus oil (ii) Approved as of December 9, 2004; Horehound June 9, 2005, for products with annual Iodides (calcium iodide anyhydrous, hydroid- sales less than $25,000. ic acid syrup, iodized lime, potassium iodide) Aluminum sulfate buffered with sodium alu- Ipecac minum lactate Ipecac fluidextract Ipecac syrup (5) [Reserved] Menthol/peppermint oil (6) Cold, cough, allergy, bronchodilator, Pine tar preparations (extract white pine and antiasthmatic drug products—(i) compound, pine tar, syrup of pine tar, com- Antihistamine drug products—(A) Ingre- pound white pine syrup, white pine) dients. Potassium guaiacolsulfonate Sodium citrate Methapyrilene hydrochloride Squill preparations (squill, squill extract) Methapyrilene fumarate Terpin hydrate preparations (terpin hydrate, Thenyldiamine hydrochloride terpin hydrate elixir) (B) Ingredients. Tolu preparations (tolu, tolu balsam, tolu balsam tincture) Phenyltoloxamine dihydrogen citrate Turpentine oil (spirits of turpentine) Methapyrilene hydrochloride Methapyrilene fumarate (iv) Bronchodilator drug products—(A) Thenyldiamine hydrochloride Approved as of October 2, 1987. (ii) Nasal decongestant drug products— Aminophylline (A) Approved as of May 7, 1991. Belladonna alkaloids Euphorbia pilulifera Allyl isothiocyanate Metaproterenol sulfate Camphor (lozenge) Methoxyphenamine hydrochloride Creosote, beechwood (oral) Pseudoephedrine hydrochloride Eucalyptol (lozenge) Pseudoephedrine sulfate Eucalyptol (mouthwash) Theophylline, anhydrous Eucalyptus oil (lozenge) Theophylline calcium salicylate Eucalyptus oil (mouthwash) Menthol (mouthwash) Theophylline sodium glycinate Peppermint oil (mouthwash) (B) Approved as of January 29, 1996. Thenyldiamine hydrochloride Any combination drug product con- Thymol Thymol (lozenge) taining theophylline (e.g., theophylline Thymol (mouthwash) and ephedrine, or theophylline and Turpentine oil ephedrine and phenobarbital). (C) Approved as of June 19, 1996. Any (B) Approved as of August 23, 1995. ingredient(s) in a pressurized metered- Bornyl acetate (topical) dose inhaler container.

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(D) Approved as of October 29, 2001. Alcohol Any oral bronchodilator active ingre- Aluminum hydroxide dient (e.g., ephedrine, ephedrine hydro- Amylase Anise seed chloride, ephedrine sulfate, Aromatic powder racephedrine hydrochloride, or any Asafetida other ephedrine salt) in combination Aspergillus oryza enzymes (except lactase with any analgesic(s) or analgesic-anti- enzyme derived from Aspergillus oryzae) pyretic(s), anticholinergic, antihis- Bacillus acidophilus tamine, oral antitussive, or stimulant Bean active ingredient. Belladonna alkaloids (7) Dandruff/seborrheic dermatitis/psori- Belladonna leaves, powdered extract Betaine hydrochloride asis drug products. Bismuth subcarbonate Alkyl isoquinolinium bromide Bismuth subgallate Allantoin Black radish powder Benzalkonium chloride Blessed thistle (cnicus benedictus) Benzethonium chloride Buckthorn Boric acid Calcium gluconate Calcium undecylenate Capsicum Captan Capsicum, fluid extract of Chloroxylenol Carbon Colloidal oatmeal Cascara sagrada extract Cresol, saponated Catechu, tincture Ethohexadiol Catnip Eucalyptol Chamomile flowers Juniper tar Charcoal, wood Lauryl isoquinolinium bromide Chloroform Menthol Cinnamon oil Mercury oleate Cinnamon tincture Methylbenzethonium chloride Citrus pectin Methyl salicylate Diastase Phenol Diastase malt Phenolate sodium Dog grass Pine tar Elecampane Povidone-iodine Ether Resorcinol Fennel acid Sodium borate Galega Sodium salicylate Ginger Thymol Glycine Undecylenic acid Hydrastis canadensis (golden seal) Hectorite (8) Digestive aid drug products—(i) Ap- Horsetail proved as of May 7, 1991. Huckleberry Hydrastis fluid extract Bismuth sodium tartrate Hydrochloric acid Calcium carbonate Iodine Cellulase Iron ox bile Dehydrocholic acid Johnswort Dihydroxyaluminum sodium carbonate Juniper Duodenal substance Kaolin, colloidal Garlic, dehydrated Knotgrass Glutamic acid hydrochloride Lactic acid Hemicellulase Lactose Homatropine methylbromide Lavender compound, tincture of Magnesium hydroxide Linden Magnesium trisilicate Lipase Ox bile extract Lysine hydrochloride Pancreatin Mannitol Pancrelipase Mycozyme Papain Peppermint oil Myrrh, fluid extract of Pepsin Nettle Sodium bicarbonate Nickel-pectin Sodium citrate Nux vomica extract Sorbitol Orthophosphoric acid Papaya, natural (ii) Approved as of November 10, 1993. Pectin

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Peppermint Methapyrilene hydrochloride Peppermint spirit Methyl nicotinate Phenacetin Methyl salicylate Potassium bicarbonate Pectin Potassium carbonate Salicylamide Protease Strong ammonia solution Prolase Tannic acid Rhubarb fluid extract Thymol Senna Tripelennamine hydrochloride Sodium chloride Trolamine salicylate Sodium salicylate Turpentine oil Stem bromelain Zinc sulfate Strawberry Strychnine (vi) Insect bite and sting drug products. Tannic acid Alcohol Trillium Alcohol, ethoxylated alkyl Woodruff Benzalkonium chloride (iii) Charcoal, activated Calamine (9) [Reserved] Ergot fluidextract (10) External analgesic drug products— Ferric chloride Panthenol (i) Analgesic and anesthetic drug prod- Peppermint oil ucts. Pyrilamine maleate Aspirin Sodium borate Chloral hydrate Trolamine salicylate Chlorobutanol Turpentine oil Cyclomethycaine sulfate Zinc oxide Eugenol Zirconium oxide Hexylresorcinol (vii) Poison ivy, poison oak, and poison Methapyrilene hydrochloride Salicylamide sumac drug products. Thymol Alcohol (ii) Counterirritant drug products. Aspirin Benzethonium chloride Chloral hydrate Benzocaine (0.5 to 1.25 percent) Eucalyptus oil Bithionol Calamine (iii) Male genital desensitizer drug Cetalkonium chloride products. Chloral hydrate Benzyl alcohol Chlorobutanol Camphorated metacresol Chlorpheniramine maleate Ephedrine hydrochloride Creosote, beechwood Cyclomethycaine sulfate (iv) Diaper rash drug products. Any in- Dexpanthenol gredient(s) labeled with claims or di- Diperodon hydrochloride rections for use in the treatment and/ Eucalyptus oil or prevention of diaper rash. Eugenol (v) Fever blister and cold sore treatment Glycerin Glycol salicylate drug products. Hectorite Allyl isothiocyanate Hexylresorcinol Aspirin Hydrogen peroxide Bismuth sodium tartrate Impatiens biflora tincture Camphor (exceeding 3 percent) Iron oxide Capsaicin Isopropyl alcohol Capsicum Lanolin Capsicum oleoresin Lead acetate Chloral hydrate Merbromin Chlorobutanol Mercuric chloride Cyclomethycaine sulfate Methapyrilene hydrochloride Eucalyptus oil Panthenol Eugenol Parethoxycaine hydrochloride Glycol salicylate Phenyltoloxamine dihydrogen citrate Hexylresorcinol Povidone-vinylacetate copolymers Histamine dihydrochloride Pyrilamine maleate Menthol (exceeding 1 percent) Salicylamide

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Salicylic acid (C) Stimulant laxatives—Approved as of Simethicone November 5, 2002. Sulfur Tannic acid Aloe ingredients (aloe, aloe extract, aloe Thymol flower extract) Trolamine salicylate Cascara sagrada ingredients (casanthranol, Turpentine oil cascara fluidextract aromatic, cascara Zirconium oxide sagrada bark, cascara sagrada extract, cascara sagrada fluidextract). Zyloxin (11) [Reserved] (13) [Reserved] (14) Oral health care drug products (12) Laxative drug products—(i)(A) (nonantimicrobial). Bulk laxatives. Antipyrine Agar Camphor Carrageenan (degraded) Cresol Carrageenan (native) Dibucaine Guar gun Dibucaine hydrochloride (i)(B) Bulk laxatives—Approved as of Eucalyptol Lidocaine March 29, 2007. Lidocaine hydrochloride Granular dosage forms containing psyllium Methly salicylate (hemicellulose), psyllium hydrophilic Myrrh tincture mucilloid, psyllium seed, psyllium seed Pyrilamine maleate (blond), psyllium seed husks, plantago Sorbitol husks, or plantago seed including, but not Sugars limited to, any granules that are: Tetracaine (1) Swallowed dry prior to drinking liquid, Tetracaine hydrochloride (2) Dispersed, suspended, or partially dis- Thymol solved in liquid prior to swallowing, (15) Topical otic drug products—(i) For (3) Chewed, partially chewed, or unchewed, the prevention of swimmer’s ear and for and then washed down (or swallowed) with the drying of water-clogged ears, ap- liquid, or (4) Sprinkled over food. proved as of May 7, 1991. (ii) Saline laxative. Acetic acid (ii) For the prevention of swimmer’s ear, Tartaric acid approved as of August 15, 1995. (iii) Stool softener. Glycerin and anhydrous glycerin Poloxamer 188 Isopropyl alcohol (iv)(A) Stimulant laxatives—Approved (16) Poison treatment drug products. as of May 7, 1991. Ipecac fluidextract Aloin Ipecac tincture Bile salts/acids Zinc sulfate Calcium pantothenate (17) Skin bleaching drug products. Calomel Colocynth Mercury, ammoniated Elaterin resin (18) Skin protectant drug products— Frangula (i)(A) Ingredients—Approved as of May 7, Gamboge Ipomea 1991. Jalap Allantoin (wound healing claims only) Ox bile Sulfur Podophyllum resin Tannic acid Prune concentrate dehydrate Zinc acetate (wound healing claims only) Prune powder Rhubarb, Chinese (B) Ingredients—Approved as of June 4, Sodium Oleate 2004; June 6, 2005, for products with annual sales less than $25,000. (iv)(B) Stimulant laxatives—Approved as of January 29, 1999. Beeswax Bismuth subnitrate Danthron Boric acid Phenolphthalein Cetyl alcohol

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Glyceryl stearate (iv) Fever blister and cold sore treat- Isopropyl palmitate ment drug products. Live yeast cell derivative Shark liver oil Bismuth subnitrate Stearyl alcohol Boric acid Pyridoxine hydrochloride (ii) Astringent drug products. Sulfur Acetone Tannic acid Alcohol Topical starch Alum, ammonium Trolamine Alum, potassium Zinc sulfate Aluminum chlorhydroxy complex (v) Insect bite and sting drug products— Aromatics (A) Ingredients—Approved as of November Benzalkonium chloride Benzethonium chloride 10, 1993. Benzocaine Alcohol Benzoic acid Alcohol, ethoxylated alkyl Boric acid Ammonia solution, strong Calcium acetate (except calcium acetate Ammonium hydroxide monohydrate when combined with alu- Benzalkonium chloride minum sulfate tetradecahydrate to provide Camphor an aluminum acetate solution as described Ergot fluid extract in § 347.20(b) of this chapter) Ferric chloride Camphor gum Menthol Clove oil Peppermint oil Colloidal oatmeal Phenol Cresol Pyrilamine maleate Cupric sulfate Sodium borate Eucalyptus oil Trolamine Eugenol Turpentine oil Ferric subsulfate (Monsel’s Solution) Zirconium oxide Honey Isopropyl alcohol (B) Ingredients—Approved as of June 4, Menthol 2004; June 6, 2005, for products with an- Methyl salicylate nual sales less than $25,000. Oxyquinoline sulfate P-t-butyl-m-cresol Beeswax Peppermint oil Bismuth subnitrate Phenol Boric acid Polyoxeythylene laurate Cetyl alcohol Potassium ferrocyanide Glyceryl stearate Sage oil Isopropyl palmitate Silver nitrate Live yeast cell derivative Sodium borate Shark liver oil Sodium diacetate Stearyl alcohol Talc (vi) Poison ivy, poison oak, and poison Tannic acid glycerite sumac drug products—(A) Ingredients— Thymol Topical starch Approved as of November 10, 1993. Zinc chloride Alcohol Zinc oxide Anion and cation exchange resins buffered Zinc phenolsulfonate Benzethonium chloride Zinc stearate Benzocaine Zinc sulfate Benzyl alcohol (iii) Diaper rash drug products. Bismuth subnitrate Bithionol Aluminum hydroxide Boric acid Cocoa butter Camphor Cysteine hydrochloride Cetalkonium chloride Glycerin Chloral hydrate Protein hydrolysate Chlorpheniramine maleate Racemethionine Creosote Sulfur Diperodon hydrochloride Tannic acid Diphenhydramine hydrochloride Zinc acetate Eucalyptus oil Zinc carbonate Ferric chloride

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Glycerin Copper Hectorite Copper gluconate Hydrogen peroxide Corn oil Impatiens biflora tincture Corn syrup Iron oxide Corn silk, potassium extract Isopropyl alcohol Cupric sulfate Lanolin Cyanocobalamin (vitamin B12) Lead acetate Cystine Lidocaine Dextrose Menthol Docusate sodium Merbromin Ergocalciferol Mercuric chloride Ferric ammonium citrate Panthenol Ferric pyrophosphate Parethoxycaine hydrochloride Ferrous fumarate Phenol Ferrous gluconate Phenyltoloxamine dihydrogen citrate Ferrous sulfate (iron) Povidone-vinylacetate copolymers Flax seed Salicylic acid Folic acid Simethicone Fructose Tannic acid Guar gum Topical starch Histidine Trolamine Hydrastis canadensis Turpentine oil Inositol Zirconium oxide Iodine Zyloxin Isoleucine Juniper, potassium extract (B) Ingredients—Approved as of June 4, Karaya gum 2004; June 6, 2005, for products with an- Kelp nual sales less than $25,000. Lactose Lecithin Beeswax Leucine Bismuth subnitrate Liver concentrate Boric acid Lysine Cetyl alcohol Lysine hydrochloride Glyceryl stearate Magnesium Isopropyl palmitate Magnesium oxide Live yeast cell derivative Malt Shark liver oil Maltodextrin Stearyl alcohol Manganese citrate (19) [Reserved] Mannitol (20) Weight control drug products. Methionine Methylcellulose Alcohol Mono- and di-glycerides Alfalfa Niacinamide Alginic acid Organic vegetables Anise oil Pancreatin Arginine Pantothenic acid Ascorbic acid Papain Bearberry Papaya enzymes Biotin Pepsin Bone marrow, red Phenacetin Buchu Phenylalanine Buchu, potassium extract Phosphorus Caffeine Phytolacca Caffeine citrate Pineapple enzymes Calcium Plantago seed Calcium carbonate Potassium citrate Calcium caseinate Pyridoxine hydrochloride (vitamin B6) Calcium lactate Riboflavin Calcium pantothenate Rice polishings Carboxymethylcellulose sodium Saccharin Carrageenan Sea minerals Cholecalcierol Sesame seed Choline Sodium Chondrus Sodium bicarbonate Citric acid Sodium caseinate Cnicus benedictus Sodium chloride (salt)

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Soybean protein Dichlorophen Soy meal Menthol Sucrose Methylparaben Thiamine hydrochloride (vitamin B1) Oxyquinoline Thiamine mononitrate (vitamin B1 mono- Oxyquinoline sulfate nitrate) Phenol Threonine Phenolate sodium Tricalcium phosphate Phenyl salicylate Tryptophan Propionic acid Tyrosine Propylparaben Uva ursi, potassium extract Resorcinol Valine Salicylic acid Vegetable Sodium borate Vitamin A Sodium caprylate Vitamin A acetate Sodium propionate Vitamin A palmitate Sulfur Vitamin E Tannic acid Wheat germ Thymol Xanthan gum Tolindate Yeast Triacetin Zinc caprylate (21) Ophthalmic drug products. (i) Oph- Zinc propionate thalmic anesthetic drug products. (iii) Any ingredient(s) labeled with Antipyrine claims or directions for use on the Piperocaine hydrochloride scalp or on the nails. (ii) Ophthalmic anti-infective drug (iv) Ingredients. products. Camphorated metacresol Boric acid Chloroxylenol Mild silver protein m-cresol Yellow mercuric oxide Nystatin (iii) Ophthalmic astringent drug prod- (23) Internal analgesic drug products— ucts. (i) Approved as of November 10, 1993. Infusion of rose petals Aminobenzoic acid Antipyrine (iv) Ophthalmic demulcent drug prod- Aspirin, aluminum ucts. Calcium salicylate Codeine Polyethylene glycol 6000 Codeine phosphate (v) Ophthalmic vasoconstrictor drug Codeine sulfate products. Iodoantipyrine Lysine aspirin Phenylephrine hydrochloride (less than 0.08 Methapyrilene fumarate percent) Phenacetin (22) Topical antifungal drug products. Pheniramine maleate Pyrilamine maleate (i) Diaper rash drug products. Any ingre- Quinine dient(s) labeled with claims or direc- Salsalate tions for use in the treatment and/or Sodium aminobenzoate prevention of diaper rash. (ii) Approved as of February 22, 1999. (ii) Ingredients. Any atropine ingredient Alcloxa Any ephedrine ingredient Alum, potassium Aluminum sulfate (24) Orally administered menstrual drug Amyltricresols, secondary products—(i) Approved as of November 10, Basic fuchsin 1993. Benzethonium chloride Benzoic acid Alcohol Benzoxiquine Alfalfa leaves Boric acid Aloes Camphor Asclepias tuberosa Candicidin Asparagus Chlorothymol Barosma Coal tar Bearberry (extract of uva ursi)

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Bearberry fluidextract (extract of bearberry) Benzyl alcohol Blessed thistle (cnicus benedictus) Benzyl benzoate Buchu powdered extract (extract of buchu) Chlorophenothane (dichlorodiphenyl tri- Calcium lactate chloroethane) Calcium pantothenate Coconut oil soap, aqueous Capsicum oleoresin Copper oleate Cascara fluidextract, aromatic (extract of Docusate sodium cascara) Formic acid Chlorprophenpyridamine maleate Isobornyl thiocyanoacetate Cimicifuga racemosa Picrotoxin Codeine Propylene glycol Collinsonia (extract stone root) Sabadilla alkaloids Corn silk Sulfur, sublimed Couch grass Thiocyanoacetate Dog grass extract Ethyl nitrite (ii) Approved as of June 14, 1994. The Ferric chloride combination of pyrethrum extract (for- Ferrous sulfate merly named pyrethrins) and piperonyl Gentiana lutea (gentian) butoxide in an aerosol dosage formula- Glycyrrhiza (licorice) tion. Homatropine methylbromide (26) Anorectal drug products—(i) Anti- Hydrangea, powdered extract (extract of hy- cholinergic drug products. drangea) Hydrastis canadensis (golden seal) Atropine Hyoscyamine sulfate Belladonna extract Juniper oil (oil of juniper) Magnesium sulfate (ii) Antiseptic drug products. Methapyrilene hydrochloride Boric acid Methenamine Boroglycerin Methylene blue Hydrastis Natural estrogenic hormone Phenol Niacinamide Resorcinol Nutmeg oil (oil of nutmeg) Sodium salicylic acid phenolate Oil of erigeron Parsley (iii) Astringent drug products. Peppermint spirit Tannic acid Pepsin, essence Phenacetin (iv) Counterirritant drug products. Phenindamine tartrate Phenyl salicylate Camphor (greater than 3 to 11 percent) Piscidia erythrina Hydrastis Pipsissewa Menthol (1.25 to 16 percent) Potassium acetate Turpentine oil (rectified) (6 to 50 percent) Potassium nitrate (v) Keratolytic drug products. Riboflavin Saw palmetto Precipitated sulfur Senecio aureus Sublimed sulfur Sodium benzoate (vi) Local anesthetic drug products. Sodium nitrate Sucrose Diperodon Sulferated oils of turpentine Phenacaine hydrochloride Taraxacum officinale Theobromine sodium salicylate (vii) Other drug products. Theophylline Collinsonia extract Thiamine hydrochloride Escherichia coli vaccines Triticum Lappa extract Turpentine, venice (venice turpertine) Leptandra extract Urea Live yeast cell derivative (ii) Approved as of February 22, 1999. Mullein Any atropine ingredient (viii) Protectant drug products. Any ephedrine ingredient Bismuth oxide (25) Pediculicide drug products—(i) Ap- Bismuth subcarbonate proved as of November 10, 1993. Bismuth subgallate Bismuth subnitrate Benzocaine Lanolin alcohols

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(ix) Vasoconstrictor drug products. Tribromsalan Triclocarban Epinephrine undecylenate Triclosan (x) Wound healinq drug products. Triple Dye Undecoylium chloride iodine complex Cholecalciferol Cod liver oil (iv) Consumer antiseptic body wash Live yeast cell derivative drug products. Approved as of Sep- Peruvian balsam tember 6, 2017. Shark liver oil Cloflucarban Vitamin A Fluorosalan (xi) Combination drug products. Any Hexachlorophene combination drug product containing Hexylresorcinol hydrocortisone and pramoxine hydro- Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) chloride. Iodine tincture (27) Topical antimicrobial drug prod- Methylbenzethonium chloride ucts—(i) First aid antiseptic drug prod- Nonylphenoxypoly (ethyleneoxy) ucts. ethanoliodine Phenol (greater than 1.5 percent) Ammoniated mercury Phenol (less than 1.5 percent) Calomel (mercurous chloride) Poloxamer iodine complex Merbromin (mercurochrome) Povidone-iodine (5 to 10 percent) Mercufenol chloride (ortho- Secondary amyltricresols chloromercuriphenol, ortho- Sodium oxychlorosene hydroxyphenylmercuric chloride) Tribromsalan Mercuric chloride (bichloride of mercury, Triclocarban mercury chloride) Triclosan Mercuric oxide, yellow Triple Dye Mercuric salicylate Undecoylium chloride iodine complex Mercuric sulfide, red Mercury (v) [Reserved] Mercury oleate (vi) Health care personnel hand wash Mercury sulfide drug products. Approved as of December Nitromersol 20, 2018. Para-chloromercuriphenol Phenylmercuric nitrate Cloflucarban Thimerosal Fluorosalan Vitromersol Hexachlorophene Zyloxin Hexylresorcinol Iodine complex (ammonium ether sulfate (ii) Diaper rash drug products. and polyoxyethylene sorbitan monolaurate) Para-chloromercuriphenol Iodine complex (phosphate ester of Any other ingredient containing mercury alkylaryloxy polyethylene glycol) (iii) Consumer antiseptic hand wash Methylbenzethonium chloride drug products. Approved as of Sep- Nonylphenoxypoly (ethyleneoxy) tember 6, 2017. ethanoliodine Phenol Cloflucarban Poloxamer-iodine complex Fluorosalan Secondary amyltricresols Hexachlorophene Sodium oxychlorosene Hexylresorcinol Tribromsalan Iodine complex (ammonium ether sulfate Triclocarban and polyoxyethylene sorbitan Triclosan monolaurate) Undecoylium chloride iodine complex Iodine complex (phosphate ester of (vii) [Reserved] alkylaryloxy polyethylene glycol) (viii) Surgical hand scrub drug prod- Methylbenzethonium chloride ucts. Approved as of December 20, 2018. Nonylphenoxypoly (ethyleneoxy) ethanoliodine Cloflucarban Phenol (greater than 1.5 percent) Fluorosalan Phenol (less than 1.5 percent) Hexachlorophene Poloxamer iodine complex Hexylresorcinol Povidone-iodine (5 to 10 percent) Iodine complex (ammonium ether sulfate Secondary amyltricresols and polyoxyethylene sorbitan Sodium oxychlorosene monolaurate)

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Iodine complex (phosphate ester of (ii) Any ingredients labeled with any alkylaryloxy polyethylene glycol) of the following or similar claims. In- Methylbenzethonium chloride stant protection or protection imme- Nonylphenoxypoly (ethyleneoxy) diately upon application. ethanoliodine Phenol Claims for ‘‘all-day’’ protection or Poloxamer-iodine complex extended wear claims citing a specific Secondary amyltricresols number of hours of protection that is Sodium oxychlorosene inconsistent with the directions for ap- Tribromsalan plication in 21 CFR 201.327. Triclocarban Triclosan (30) [Reserved] Undecoylium chloride iodine complex (b) Any OTC drug product that is labeled, represented, or promoted for the (ix) [Reserved] uses specified and containing any ac- (x) Patient antiseptic skin preparation tive ingredient(s) as specified in para- drug products. Approved as of December graph (a) of this section is regarded as 20, 2018. a new drug within the meaning of sec- Cloflucarban tion 210(p) of the Federal Food, Drug, Fluorosalan and Cosmetic Act (the Act), for which Hexachlorophene an approved new drug application Hexylresorcinol under section 505 of the Act and part Iodine complex (phosphate ester of 314 of this chapter is required for mar- alkylaryloxy polyethylene glycol) Iodine tincture (USP) keting. In the absence of an approved Iodine topical solution (USP) new drug application, such product is Mercufenol chloride also misbranded under section 502 of Methylbenzethonium chloride the Act. Nonylphenoxypoly (ethyleneoxy) (c) Clinical investigations designed ethanoliodine to obtain evidence that any drug prod- Phenol uct labeled, represented, or promoted Poloxamer-iodine complex for the OTC uses and containing any Secondary amyltricresols active ingredient(s) as specified in Sodium oxychlorosene Tribromsalan paragraph (a) of this section is safe and Triclocarban effective for the purpose intended must Triclosan comply with the requirements and pro- Triple dye cedures governing the use of investiga- Undecoylium chloride iodine complex tional new drugs set forth in part 312 of Combination of calomel, oxyquinoline ben- this chapter. zoate, triethanolamine, and phenol deriva- (d) Any OTC drug product that is not tive in compliance with this section is sub- Combination of mercufenol chloride and secondary amyltricresols in 50 percent alcohol ject to regulatory action if initially in- (28) Vaginal contraceptive drug prod- troduced or initially delivered for in- ucts—(i) Approved as of October 22, 1998. troduction into interstate commerce after the dates specified in paragraphs Dodecaethylene glycol monolaurate (poly- (d)(1) through (d)(42) of this section. ethylene glycol 600 monolaurate) (1) May 7, 1991, for products subject Laureth 10S to paragraphs (a)(1) through (a)(2)(i), Methoxypolyoxyethyleneglycol 550 laurate (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), Phenylmercuric acetate Phenylmercuric nitrate (a)(6)(ii)(A), (a)(7) (except as covered by Any other ingredient containing mercury paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (ii) Approved as of November 5, 2002. (a)(12)(i)(A), (a)(12)(ii) through Octoxynol 9 (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (29) Sunscreen drug products. (i) Ingre- (a)(16) through (a)(18)(i)(A), (a)(18)(ii) dients. (except as covered by paragraph (d)(22) of this section), (a)(18)(iii), (a)(18)(iv), Diethanolamine methoxycinnamate (a)(18)(v)(A), and (a)(18)(vi)(A) of this Digalloyl trioleate Ethyl 4-[bis(hydroxypropyl)] aminobenzoate section. Glyceryl aminobenzoate (2) February 10, 1992, for products Lawsone with dihydroxyacetone subject to paragraph (a)(20) of this sec- Red petrolatum tion.

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(3) December 4, 1992, for products sub- (15) September 23, 1994, for products ject to paragraph (a)(7) of this section subject to paragraph (a)(22)(iv) of this that contain menthol as an anti- section. pruritic in combination with the anti- (16) June 14, 1994, for products subject dandruff ingredient coal tar identified to paragraph (a)(25)(ii) of this section. in § 358.710(a)(1) of this chapter. This (17) April 19, 2004, for products subsection does not apply to products al- ject to paragraph (a)(3)(ii) of this sec- lowed by § 358.720(b) of this chapter tion. April 18, 2005, for products with after April 5, 2007. annual sales less than $25,000. (4) February 28, 1990, for products (18) August 15, 1995, for products sub- subject to paragraph (a)(6)(iii) of this ject to paragraph (a)(15)(ii) of this sec- section, except those that contain ipe- tion. cac. (19) October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this (5) September 14, 1993, for products section. subject to paragraph (a)(6)(iii) of this (20) January 29, 1996, for products section that contain ipecac. subject to paragraph (a)(6)(iv)(B) of (6) December 9, 1993, for products sub- this section. ject to paragraph (a)(6)(i)(B) of this (21) April 21, 1994, for products subsection. ject to paragraph (a)(8)(iii) of this sec- (7) March 6, 1989, for products subject tion. to paragraph (a)(21) of this section, ex- (22) April 21, 1993, for products sub- cept those that contain ophthalmic ject to paragraph (a)(18)(ii) of this sec- anti-infective ingredients listed in tion that contain ferric subsulfate. paragraph (a)(21)(ii). (23) August 23, 1995, for products sub- (8) June 18, 1993, for products subject ject to paragraph (a)(6)(ii)(B) of this to paragraph (a)(21) of this section that section. contain ophthalmic anti-infective in- (24) October 7, 1996, for products sub- gredients. ject to paragraph (a)(2)(ii) of this sec- (9) June 18, 1993, for products subject tion. to paragraph (a)(10)(iv) of this section. (25) June 19, 1996, for products subject (10) June 18, 1993, for products subject to paragraph (a)(6)(iv)(C) of this sec- to paragraph (a)(22)(i) of this section. tion. (11) November 10, 1993, for products (26) February 22, 1999, for products subject to paragraphs (a)(8)(ii), subject to paragraphs (a)(23)(ii) and (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (a)(24)(ii) of this section. (except products that contain ferric (27) [Reserved] subsulfate as covered by paragraph (28) October 22, 1998, for products sub- (d)(22) of this section and except prod- ject to paragraphs (a)(27) and (a)(28)(i) ucts that contain calcium acetate of this section. monohydrate as covered by paragraph (29) January 29, 1999, for products subject to paragraph (a)(12)(iv)(B) of (d)(39) of this section) through this section. (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (30) November 5, 2002, for products (a)(23)(i), (a)(24)(i), and (a)(25) of this subject to paragraph (a)(12)(iv)(C) of section. this section. (12) March 2, 1994, for products sub- (31) December 31, 2002, for products ject to paragraph (a)(22)(iii) of this sec- subject to paragraph (a)(29)(i) of this tion. section. (13) August 5, 1991, for products sub- (32) June 4, 2004, for products subject ject to paragraph (a)(26) of this section, to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), except for those that contain live yeast and (a)(18)(vi)(B) of this section. June cell derivative and a combination of 6, 2005, for products with annual sales hydrocortisone and pramoxine hydro- less than $25,000. chloride. (33) October 29, 2001, for products sub- (14) September 2, 1994, for products ject to paragraph (a)(6)(iv)(D) of this subject to paragraph (a)(26)(vii) and section. (a)(26)(x) of this section that contain (34) December 9, 2004, for products live yeast cell derivative. subject to paragraph (a)(4)(ii) of this

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section. June 9, 2005, for products with used to treat or prevent this condition, annual sales less than $25,000. quinine sulfate has caused adverse (35) [Reserved] events such as transient visual and au- (36) November 5, 2002, for products ditory disturbances, dizziness, fever, subject to paragraph (a)(28)(ii) of this nausea, vomiting, and diarrhea. Qui- section. nine sulfate may cause unpredictable (37) September 25, 2003, for products serious and life-threatening hyper- subject to paragraph (a)(26)(xi) of this sensitivity reactions requiring medical section. intervention and hospitalization; fa- (38) October 1, 2007, for products sub- talities have been reported. The risk ject to paragraph (a)(12)(i)(B) of this section. associated with use of quinine sulfate, (39) September 6, 2010, for products in the absence of evidence of its effec- subject to paragraph (a)(18)(ii) of this tiveness, outweighs any potential ben- section that contain calcium acetate efit in treating and/or preventing this monohydrate, except as provided in benign, self-limiting condition. Based § 347.20(b) of this chapter. upon the adverse benefit-to-risk ratio, (40) December 17, 2012, for products any drug product containing quinine or subject to paragraph (a)(29)(ii) of this quinine sulfate cannot be considered section. December 17, 2013, for products generally recognized as safe for the with annual sales less than $25,000. treatment and/or prevention of noc- (41) September 6, 2017, for products turnal leg muscle cramps. subject to paragraph (a)(27)(iii) or (iv) (b) Any OTC drug product that is la- of this section. beled, represented, or promoted for the (42) December 20, 2018, for products treatment and/or prevention of noc- subject to paragraphs (a)(27)(vi) turnal leg muscle cramps is regarded as through (x) of this section. a new drug within the meaning of sec- [55 FR 46919, Nov. 7, 1990] tion 201(p) of the Federal Food, Drug, EDITORIAL NOTE: For FEDERAL REGISTER ci- and Cosmetic Act (the act), for which tations affecting § 310.545, see the List of CFR an approved application or abbreviated Sections Affected, which appears in the application under section 505 of the act Finding Aids section of the printed volume and part 314 of this chapter is required and at www.govinfo.gov. for marketing. In the absence of an ap- EFFECTIVE DATE NOTE: At 61 FR 9571, Mar. proved new drug application or abbre- 8, 1996, in § 310.545 in paragraph (a)(6)(ii)(B), viated new drug application, such prod- the entry for ‘‘l-desoxyephedrine (topical)’’ was stayed until further notice. uct is also misbranded under section 502 of the act. § 310.546 Drug products containing ac- (c) Clinical investigations designed tive ingredients offered over-the- to obtain evidence that any drug prod- counter (OTC) for the treatment uct labeled, represented, or promoted and/or prevention of nocturnal leg muscle cramps. for OTC use for the treatment and/or prevention of nocturnal leg muscle (a) Quinine sulfate alone or in com- cramps is safe and effective for the pur- bination with vitamin E has been pose intended must comply with the represent in over-the-counter (OTC) drug quirements and procedures governing products for the treatment and/or prevention of nocturnal leg muscle the use of investigational new drugs cramps, i.e., a condition of localized set forth in part 312 of this chapter. pain in the lower extremities usually (d) After February 22, 1995, any such occurring in middle life and beyond OTC drug product initially introduced with no regular pattern concerning or initially delivered for introduction time or severity. There is a lack of ade- into interstate commerce that is not in quate data to establish general rec- compliance with this section is subject ognition of the safety and effectiveness to regulatory action. of quinine sulfate, vitamin E, or any other ingredients for OTC use in the [59 FR 43252, Aug. 22, 1994] treatment and/or prevention of nocturnal leg muscle cramps. In the doses

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§ 310.547 Drug products containing § 310.548 Drug products containing quinine offered over-the-counter colloidal silver ingredients or silver (OTC) for the treatment and/or pre- salts offered over-the-counter (OTC) vention of malaria. for the treatment and/or prevention of disease. (a) Quinine and quinine salts have been used OTC for the treatment and/or (a) Colloidal silver ingredients and silver salts have been marketed in prevention of malaria, a serious and over-the-counter (OTC) drug products potentially life-threatening disease. for the treatment and prevention of nu- Quinine is no longer the drug of choice merous disease conditions. There are for the treatment and/or prevention of serious and complicating aspects to most types of malaria. In addition, many of the diseases these silver ingre- there are serious and complicating as- dients purport to treat or prevent. Fur- pects of the disease itself and some po- ther, there is a lack of adequate data tentially serious and life-threatening to establish general recognition of the risks associated with the use of quinine safety and effectiveness of colloidal sil- at doses employed for the treatment of ver ingredients or silver salts for OTC malaria. There is a lack of adequate use in the treatment or prevention of data to establish general recognition of any disease. These ingredients and the safety of quinine drug products for salts include, but are not limited to, OTC use in the treatment and/or pre- silver proteins, mild silver protein, vention of malaria. Therefore, quinine strong silver protein, silver, silver ion, or quinine salts cannot be safely and silver chloride, silver cyanide, silver effectively used for the treatment and/ iodide, silver oxide, and silver phosphate. or prevention of malaria except under (b) Any OTC drug product containing the care and supervision of a doctor. colloidal silver ingredients or silver (b) Any OTC drug product containing salts that is labeled, represented, or quinine or quinine salts that is labeled, promoted for the treatment and/or pre- represented, or promoted for the treat- vention of any disease is regarded as a ment and/or prevention of malaria is new drug within the meaning of section regarded as a new drug within the 201(p) of the Federal Food, Drug, and meaning of section 201(p) of the act, for Cosmetic Act (the act) for which an ap- which an approved application or ab- proved application or abbreviated ap- breviated application under section 505 plication under section 505 of the act of the act and part 314 of this chapter and part 314 of this chapter is required is required for marketing. In the ab- for marketing. In the absence of an ap- sence of an approved new drug applica- proved new drug application or abbre- tion or abbreviated new drug applica- viated new drug application, such prod- tion, such product is also misbranded uct is also misbranded under section under section 502 of the act. 502 of the act. (c) Clinical investigations designed (c) Clinical investigations designed to obtain evidence that any drug prod- to obtain evidence that any drug product labeled, represented, or promoted uct containing colloidal silver or silver for OTC use for the treatment and/or salts labeled, represented, or promoted prevention of malaria is safe and effec- for any OTC drug use is safe and effective for the purpose intended must tive for the purpose intended must comply with the requirements and pro- comply with the requirements and procedures governing the use of investiga- cedures governing the use of investigational new drugs as set forth in part 312 tional new drugs set forth in part 312 of of this chapter. this chapter. (d) After September 16, 1999, any such (d) After April 20, 1998, any such OTC OTC drug product containing colloidal drug product initially introduced or silver or silver salts initially intro- initially delivered for introduction into duced or initially delivered for intro- interstate commerce that is not in duction into interstate commerce that compliance with this section is subject is not in compliance with this section to regulatory action. is subject to regulatory action. [63 FR 13528, Mar. 20, 1998] [64 FR 44658, Aug. 17, 1999]

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PART 312—INVESTIGATIONAL NEW 312.68 Inspection of investigator’s records and reports. DRUG APPLICATION 312.69 Handling of controlled substances. 312.70 Disqualification of a clinical investi- Subpart A—General Provisions gator. Sec. 312.1 Scope. Subpart E—Drugs Intended to Treat Life- 312.2 Applicability. threatening and Severely-debilitating 312.3 Definitions and interpretations. Illnesses 312.6 Labeling of an investigational new drug. 312.80 Purpose. 312.7 Promotion of investigational drugs. 312.81 Scope. 312.8 Charging for investigational drugs 312.82 Early consultation. under an IND. 312.83 Treatment protocols. 312.10 Waivers. 312.84 Risk-benefit analysis in review of marketing applications for drugs to treat Subpart B—Investigational New Drug life-threatening and severely-debilitating Application (IND) illnesses. 312.85 Phase 4 studies. 312.20 Requirement for an IND. 312.86 Focused FDA regulatory research. 312.21 Phases of an investigation. 312.87 Active monitoring of conduct and 312.22 General principles of the IND submis- evaluation of clinical trials. sion. 312.23 IND content and format. 312.88 Safeguards for patient safety. 312.30 Protocol amendments. 312.31 Information amendments. Subpart F—Miscellaneous 312.32 IND safety reporting. 312.110 Import and export requirements. 312.33 Annual reports. 312.38 Withdrawal of an IND. 312.120 Foreign clinical studies not conducted under an IND. Subpart C—Administrative Actions 312.130 Availability for public disclosure of data and information in an IND. 312.40 General requirements for use of an in- 312.140 Address for correspondence. vestigational new drug in a clinical in- 312.145 Guidance documents. vestigation. 312.41 Comment and advice on an IND. Subpart G—Drugs for Investigational Use in 312.42 Clinical holds and requests for modi- Laboratory Research Animals or in fication. 312.44 Termination. Vitro Tests 312.45 Inactive status. 312.160 Drugs for investigational use in lab- 312.47 Meetings. oratory research animals or in vitro 312.48 Dispute resolution. tests. Subpart D—Responsibilities of Sponsors Subpart H [Reserved] and Investigators 312.50 General responsibilities of sponsors. Subpart I—Expanded Access to 312.52 Transfer of obligations to a contract Investigational Drugs for Treatment Use research organization. 312.53 Selecting investigators and monitors. 312.300 General. 312.54 Emergency research under § 50.24 of 312.305 Requirements for all expanded ac- this chapter. cess uses. 312.55 Informing investigators. 312.310 Individual patients, including for 312.56 Review of ongoing investigations. emergency use. 312.57 Recordkeeping and record retention. 312.315 Intermediate-size patient popu- 312.58 Inspection of sponsor’s records and lations. reports. 312.320 Treatment IND or treatment pro- 312.59 Disposition of unused supply of inves- tocol. tigational drug. 312.60 General responsibilities of investiga- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, tors. 355, 360bbb, 371; 42 U.S.C. 262. 312.61 Control of the investigational drug. SOURCE: 52 FR 8831, Mar. 19, 1987, unless 312.62 Investigator recordkeeping and otherwise noted. record retention. 312.64 Investigator reports. EDITORIAL NOTE: Nomenclature changes to 312.66 Assurance of IRB review. part 312 appear at 69 FR 13717, Mar. 24, 2004.

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Subpart A—General Provisions and with the requirements for informed consent set forth in part 50; and § 312.1 Scope. (v) The investigation is conducted in (a) This part contains procedures and compliance with the requirements of requirements governing the use of in- § 312.7. vestigational new drugs, including pro- (2)(i) A clinical investigation involv- cedures and requirements for the sub- ing an in vitro diagnostic biological mission to, and review by, the Food product listed in paragraph (b)(2)(ii) of and Drug Administration of investiga- this section is exempt from the re- tional new drug applications (IND’s). quirements of this part if (a) it is in- An investigational new drug for which tended to be used in a diagnostic proce- an IND is in effect in accordance with dure that confirms the diagnosis made this part is exempt from the premar- by another, medically established, di- keting approval requirements that are agnostic product or procedure and (b) it otherwise applicable and may be is shipped in compliance with § 312.160. shipped lawfully for the purpose of con- (ii) In accordance with paragraph ducting clinical investigations of that (b)(2)(i) of this section, the following drug. products are exempt from the require- (b) References in this part to regula- ments of this part: (a) blood grouping tions in the Code of Federal Regula- serum; (b) reagent red blood cells; and tions are to chapter I of title 21, unless (c) anti-human globulin. otherwise noted. (3) A drug intended solely for tests in vitro or in laboratory research animals § 312.2 Applicability. is exempt from the requirements of (a) Applicability. Except as provided this part if shipped in accordance with in this section, this part applies to all § 312.160. clinical investigations of products that (4) FDA will not accept an applica- are subject to section 505 of the Federal tion for an investigation that is ex- Food, Drug, and Cosmetic Act or to the empt under the provisions of paragraph licensing provisions of the Public (b)(1) of this section. Health Service Act (58 Stat. 632, as (5) A clinical investigation involving amended (42 U.S.C. 201 et seq.)). use of a placebo is exempt from the re- (b) Exemptions. (1) The clinical inves- quirements of this part if the investigation of a drug product that is law- tigation does not otherwise require fully marketed in the United States is submission of an IND. exempt from the requirements of this (6) A clinical investigation involving part if all the following apply: an exception from informed consent (i) The investigation is not intended under § 50.24 of this chapter is not ex- to be reported to FDA as a well-con- empt from the requirements of this trolled study in support of a new indi- part. cation for use nor intended to be used (c) Bioavailability studies. The applica- to support any other significant change bility of this part to in vivo bio- in the labeling for the drug; availability studies in humans is sub- (ii) If the drug that is undergoing in- ject to the provisions of § 320.31. vestigation is lawfully marketed as a (d) Unlabeled indication. This part prescription drug product, the inves- does not apply to the use in the prac- tigation is not intended to support a tice of medicine for an unlabeled indi- significant change in the advertising cation of a new drug product approved for the product; under part 314 or of a licensed biologi- (iii) The investigation does not in- cal product. volve a route of administration or dos- (e) Guidance. FDA may, on its own age level or use in a patient population initiative, issue guidance on the appli- or other factor that significantly in- cability of this part to particular increases the risks (or decreases the ac- vestigational uses of drugs. On request, ceptability of the risks) associated FDA will advise on the applicability of with the use of the drug product; this part to a planned clinical inves- (iv) The investigation is conducted in tigation. compliance with the requirements for [52 FR 8831, Mar. 19, 1987, as amended at 61 institutional review set forth in part 56 FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999]

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§ 312.3 Definitions and interpretations. tion the drug is administered or dis- (a) The definitions and interpreta- pensed to a subject). In the event an in- tions of terms contained in section 201 vestigation is conducted by a team of of the Act apply to those terms when individuals, the investigator is the re- used in this part: sponsible leader of the team. ‘‘Sub- (b) The following definitions of terms investigator’’ includes any other indi- also apply to this part: vidual member of that team. Act means the Federal Food, Drug, Marketing application means an appli- and Cosmetic Act (secs. 201–902, 52 cation for a new drug submitted under Stat. 1040 et seq., as amended (21 U.S.C. section 505(b) of the act or a biologics 301–392)). license application for a biological Clinical investigation means any ex- product submitted under the Public periment in which a drug is adminis- Health Service Act. tered or dispensed to, or used involv- Sponsor means a person who takes re- ing, one or more human subjects. For sponsibility for and initiates a clinical the purposes of this part, an experi- investigation. The sponsor may be an ment is any use of a drug except for the individual or pharmaceutical company, use of a marketed drug in the course of governmental agency, academic insti- medical practice. tution, private organization, or other Contract research organization means a organization. The sponsor does not ac- person that assumes, as an independent tually conduct the investigation unless contractor with the sponsor, one or the sponsor is a sponsor-investigator. A more of the obligations of a sponsor, person other than an individual that e.g., design of a protocol, selection or uses one or more of its own employees monitoring of investigations, evalua- to conduct an investigation that it has tion of reports, and preparation of ma- initiated is a sponsor, not a sponsor-in- terials to be submitted to the Food and vestigator, and the employees are in- Drug Administration. vestigators. FDA means the Food and Drug Ad- Sponsor-Investigator means an indi- ministration. vidual who both initiates and conducts IND means an investigational new an investigation, and under whose im- drug application. For purposes of this mediate direction the investigational part, ‘‘IND’’ is synonymous with ‘‘No- drug is administered or dispensed. The tice of Claimed Investigational Exemp- term does not include any person other tion for a New Drug.’’ than an individual. The requirements Independent ethics committee (IEC) applicable to a sponsor-investigator means a review panel that is respon- under this part include both those ap- sible for ensuring the protection of the plicable to an investigator and a spon- rights, safety, and well-being of human sor. subjects involved in a clinical inves- Subject means a human who partici- tigation and is adequately constituted pates in an investigation, either as a to provide assurance of that protec- recipient of the investigational new tion. An institutional review board drug or as a control. A subject may be (IRB), as defined in § 56.102(g) of this a healthy human or a patient with a chapter and subject to the require- disease. ments of part 56 of this chapter, is one [52 FR 8831, Mar. 19, 1987, as amended at 64 type of IEC. FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; Investigational new drug means a new 73 FR 22815, Apr. 28, 2008] drug or biological drug that is used in a clinical investigation. The term also § 312.6 Labeling of an investigational includes a biological product that is new drug. used in vitro for diagnostic purposes. (a) The immediate package of an in- The terms ‘‘investigational drug’’ and vestigational new drug intended for ‘‘investigational new drug’’ are deemed human use shall bear a label with the to be synonymous for purposes of this statement ‘‘Caution: New Drug—Lim- part. ited by Federal (or United States) law Investigator means an individual who to investigational use.’’ actually conducts a clinical investiga- (b) The label or labeling of an inves- tion (i.e., under whose immediate direc- tigational new drug shall not bear any

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statement that is false or misleading in § 312.8 Charging for investigational any particular and shall not represent drugs under an IND. that the investigational new drug is (a) General criteria for charging. (1) A safe or effective for the purposes for sponsor must meet the applicable re- which it is being investigated. quirements in paragraph (b) of this sec- (c) The appropriate FDA Center Di- tion for charging in a clinical trial or rector, according to the procedures set paragraph (c) of this section for charg- forth in §§ 201.26 or 610.68 of this chap- ing for expanded access to an investiga- ter, may grant an exception or alter- tional drug for treatment use under native to the provision in paragraph (a) subpart I of this part, except that spon- of this section, to the extent that this sors need not fulfill the requirements provision is not explicitly required by in this section to charge for an ap- statute, for specified lots, batches, or proved drug obtained from another en- other units of a human drug product tity not affiliated with the sponsor for that is or will be included in the Stra- use as part of the clinical trial evalua- tegic National Stockpile. tion (e.g., in a clinical trial of a new use of the approved drug, for use of the [52 FR 8831, Mar. 19, 1987, as amended at 72 approved drug as an active control). FR 73599, Dec. 28, 2007] (2) A sponsor must justify the amount to be charged in accordance § 312.7 Promotion of investigational with paragraph (d) of this section. drugs. (3) A sponsor must obtain prior writ- (a) Promotion of an investigational new ten authorization from FDA to charge drug. A sponsor or investigator, or any for an investigational drug. person acting on behalf of a sponsor or (4) FDA will withdraw authorization investigator, shall not represent in a to charge if it determines that charg- promotional context that an investiga- ing is interfering with the development tional new drug is safe or effective for of a drug for marketing approval or the purposes for which it is under in- that the criteria for the authorization vestigation or otherwise promote the are no longer being met. drug. This provision is not intended to (b) Charging in a clinical trial—(1) restrict the full exchange of scientific Charging for a sponsor’s drug. A sponsor information concerning the drug, in- who wishes to charge for its investiga- cluding dissemination of scientific tional drug, including investigational findings in scientific or lay media. use of its approved drug, must: Rather, its intent is to restrict pro- (i) Provide evidence that the drug has motional claims of safety or effective- a potential clinical benefit that, if ness of the drug for a use for which it demonstrated in the clinical investiga- is under investigation and to preclude tions, would provide a significant ad- commercialization of the drug before it vantage over available products in the is approved for commercial distribu- diagnosis, treatment, mitigation, or tion. prevention of a disease or condition; (b) Commercial distribution of an inves- (ii) Demonstrate that the data to be obtained from the clinical trial would tigational new drug. A sponsor or inves- be essential to establishing that the tigator shall not commercially dis- drug is effective or safe for the purpose tribute or test market an investiga- of obtaining initial approval of a drug, tional new drug. or would support a significant change (c) Prolonging an investigation. A in the labeling of an approved drug sponsor shall not unduly prolong an in- (e.g., new indication, inclusion of com- vestigation after finding that the re- parative safety information); and sults of the investigation appear to es- (iii) Demonstrate that the clinical tablish sufficient data to support a trial could not be conducted without marketing application. charging because the cost of the drug is [52 FR 8831, Mar. 19, 1987, as amended at 52 extraordinary to the sponsor. The cost FR 19476, May 22, 1987; 67 FR 9585, Mar. 4, may be extraordinary due to manufac- 2002; 74 FR 40899, Aug. 13, 2009] turing complexity, scarcity of a natural resource, the large quantity of

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drug needed (e.g., due to the size or du- and equipment used to manufacture ration of the trial), or some combina- the quantity of drug needed for the use tion of these or other extraordinary for which charging is authorized) or circumstances (e.g., resources available costs to acquire the drug from another to a sponsor). manufacturing source, and direct costs (2) Duration of charging in a clinical to ship and handle (e.g., store) the trial. Unless FDA specifies a shorter pe- drug. riod, charging may continue for the (ii) Indirect costs include costs in- length of the clinical trial. curred primarily to produce the drug (c) Charging for expanded access to infor commercial sale (e.g., costs for fa- vestigational drug for treatment use. (1) A cilities and equipment used to manu- sponsor who wishes to charge for ex- facture the supply of investigational panded access to an investigational drug, but that are primarily intended drug for treatment use under subpart I to produce large quantities of drug for of this part must provide reasonable eventual commercial sale) and research assurance that charging will not inter- and development, administrative, fere with developing the drug for mar- labor, or other costs that would be in- keting approval. curred even if the clinical trial or (2) For expanded access under § 312.320 treatment use for which charging is au- (treatment IND or treatment protocol), thorized did not occur. such assurance must include: (2) For expanded access to an inves- (i) Evidence of sufficient enrollment tigational drug for treatment use in any ongoing clinical trial(s) needed under §§ 312.315 (intermediate-size pa- for marketing approval to reasonably tient populations) and 312.320 (treat- assure FDA that the trial(s) will be ment IND or treatment protocol), in successfully completed as planned; addition to the direct costs described (ii) Evidence of adequate progress in in paragraph (d)(1)(i) of this section, a the development of the drug for mar- sponsor may recover the costs of moni- keting approval; and toring the expanded access IND or pro- (iii) Information submitted under the tocol, complying with IND reporting general investigational plan requirements, and other administrative (§ 312.23(a)(3)(iv)) specifying the drug costs directly associated with the ex- development milestones the sponsor panded access IND. plans to meet in the next year. (3) To support its calculation for cost (3) The authorization to charge is recovery, a sponsor must provide sup- limited to the number of patients au- porting documentation to show that thorized to receive the drug under the the calculation is consistent with the requirements of paragraphs (d)(1) and, treatment use, if there is a limitation. if applicable, (d)(2) of this section. The (4) Unless FDA specifies a shorter pe- documentation must be accompanied riod, charging for expanded access to by a statement that an independent an investigational drug for treatment certified public accountant has reuse under subpart I of this part may viewed and approved the calculations. continue for 1 year from the time of FDA authorization. A sponsor may re- [74 FR 40899, Aug. 13, 2009] quest that FDA reauthorize charging for additional periods. § 312.10 Waivers. (d) Costs recoverable when charging for (a) A sponsor may request FDA to an investigational drug. (1) A sponsor waive applicable requirement under may recover only the direct costs of this part. A waiver request may be sub- making its investigational drug avail- mitted either in an IND or in an infor- able. mation amendment to an IND. In an (i) Direct costs are costs incurred by emergency, a request may be made by a sponsor that can be specifically and telephone or other rapid communica- exclusively attributed to providing the tion means. A waiver request is re- drug for the investigational use for quired to contain at least one of the which FDA has authorized cost recov- following: ery. Direct costs include costs per unit (1) An explanation why the sponsor’s to manufacture the drug (e.g., raw ma- compliance with the requirement is un- terials, labor, and nonreusable supplies necessary or cannot be achieved;

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(2) A description of an alternative phases are conducted sequentially, submission or course of action that they may overlap. These three phases satisfies the purpose of the require- of an investigation are a follows: ment; or (a) Phase 1. (1) Phase 1 includes the (3) Other information justifying a initial introduction of an investiga- waiver. tional new drug into humans. Phase 1 (b) FDA may grant a waiver if it studies are typically closely monitored finds that the sponsor’s noncompliance and may be conducted in patients or would not pose a significant and unrea- normal volunteer subjects. These stud- sonable risk to human subjects of the ies are designed to determine the me- investigation and that one of the fol- tabolism and pharmacologic actions of lowing is met: the drug in humans, the side effects as- (1) The sponsor’s compliance with the requirement is unnecessary for the sociated with increasing doses, and, if agency to evaluate the application, or possible, to gain early evidence on ef- compliance cannot be achieved; fectiveness. During Phase 1, sufficient (2) The sponsor’s proposed alter- information about the drug’s phar- native satisfies the requirement; or macokinetics and pharmacological ef- (3) The applicant’s submission other- fects should be obtained to permit the wise justifies a waiver. design of well-controlled, scientifically valid, Phase 2 studies. The total num- [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9585, Mar. 4, ber of subjects and patients included in 2002] Phase 1 studies varies with the drug, but is generally in the range of 20 to 80. Subpart B—Investigational New (2) Phase 1 studies also include stud- Drug Application (IND) ies of drug metabolism, structure-activity relationships, and mechanism of § 312.20 Requirement for an IND. action in humans, as well as studies in (a) A sponsor shall submit an IND to which investigational drugs are used as FDA if the sponsor intends to conduct research tools to explore biological a clinical investigation with an inves- phenomena or disease processes. tigational new drug that is subject to (b) Phase 2. Phase 2 includes the con- § 312.2(a). trolled clinical studies conducted to (b) A sponsor shall not begin a clin- evaluate the effectiveness of the drug ical investigation subject to § 312.2(a) for a particular indication or indica- until the investigation is subject to an tions in patients with the disease or IND which is in effect in accordance condition under study and to deter- with § 312.40. mine the common short-term side ef- (c) A sponsor shall submit a separate fects and risks associated with the IND for any clinical investigation in- drug. Phase 2 studies are typically well volving an exception from informed controlled, closely monitored, and con- consent under § 50.24 of this chapter. ducted in a relatively small number of Such a clinical investigation is not patients, usually involving no more permitted to proceed without the prior than several hundred subjects. written authorization from FDA. FDA (c) Phase 3. Phase 3 studies are ex- shall provide a written determination panded controlled and uncontrolled 30 days after FDA receives the IND or trials. They are performed after pre- earlier. liminary evidence suggesting effective- [52 FR 8831, Mar. 19, 1987, as amended at 61 ness of the drug has been obtained, and FR 51529, Oct. 2, 1996; 62 FR 32479, June 16, are intended to gather the additional 1997] information about effectiveness and § 312.21 Phases of an investigation. safety that is needed to evaluate the overall benefit-risk relationship of the An IND may be submitted for one or drug and to provide an adequate basis more phases of an investigation. The for physician labeling. Phase 3 studies clinical investigation of a previously untested drug is generally divided into usually include from several hundred three phases. Although in general the to several thousand subjects.

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§ 312.22 General principles of the IND tigator who uses, as a research tool, an submission. investigational new drug that is al- (a) FDA’s primary objectives in re- ready subject to a manufacturer’s IND viewing an IND are, in all phases of the or marketing application should follow investigation, to assure the safety and the same general format, but ordi- rights of subjects, and, in Phase 2 and narily may, if authorized by the manu- 3, to help assure that the quality of the facturer, refer to the manufacturer’s scientific evaluation of drugs is ade- IND or marketing application in pro- quate to permit an evaluation of the viding the technical information sup- drug’s effectiveness and safety. There- porting the proposed clinical investiga- fore, although FDA’s review of Phase 1 tion. A sponsor-investigator who uses submissions will focus on assessing the an investigational drug not subject to safety of Phase 1 investigations, FDA’s a manufacturer’s IND or marketing ap- review of Phases 2 and 3 submissions plication is ordinarily required to sub- will also include an assessment of the mit all technical information sup- scientific quality of the clinical inves- porting the IND, unless such informa- tigations and the likelihood that the tion may be referenced from the sci- investigations will yield data capable entific literature. of meeting statutory standards for marketing approval. § 312.23 IND content and format. (b) The amount of information on a (a) A sponsor who intends to conduct particular drug that must be submitted a clinical investigation subject to this in an IND to assure the accomplish- part shall submit an ‘‘Investigational ment of the objectives described in New Drug Application’’ (IND) includ- paragraph (a) of this section depends ing, in the following order: upon such factors as the novelty of the (1) Cover sheet (Form FDA–1571). A drug, the extent to which it has been cover sheet for the application con- studied previously, the known or sustaining the following: pected risks, and the developmental (i) The name, address, and telephone phase of the drug. number of the sponsor, the date of the (c) The central focus of the initial application, and the name of the inves- IND submission should be on the gen- tigational new drug. eral investigational plan and the proto- (ii) Identification of the phase or cols for specific human studies. Subse- phases of the clinical investigation to quent amendments to the IND that be conducted. contain new or revised protocols should (iii) A commitment not to begin clin- build logically on previous submissions ical investigations until an IND cov- and should be supported by additional ering the investigations is in effect. information, including the results of (iv) A commitment that an Institu- animal toxicology studies or other tional Review Board (IRB) that com- human studies as appropriate. Annual plies with the requirements set forth in reports to the IND should serve as the part 56 will be responsible for the ini- focus for reporting the status of studies tial and continuing review and ap- being conducted under the IND and proval of each of the studies in the pro- should update the general investiga- posed clinical investigation and that tional plan for the coming year. the investigator will report to the IRB (d) The IND format set forth in proposed changes in the research activ- § 312.23 should be followed routinely by ity in accordance with the require- sponsors in the interest of fostering an ments of part 56. efficient review of applications. Spon- (v) A commitment to conduct the in- sors are expected to exercise consider- vestigation in accordance with all able discretion, however, regarding the other applicable regulatory require- content of information submitted in ments. each section, depending upon the kind (vi) The name and title of the person of drug being studied and the nature of responsible for monitoring the conduct the available information. Section and progress of the clinical investiga- 312.23 outlines the information needed tions. for a commercially sponsored IND for a (vii) The name(s) and title(s) of the new molecular entity. A sponsor-inves- person(s) responsible under § 312.32 for

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review and evaluation of information evaluating the drug; (d) the kinds of relevant to the safety of the drug. clinical trials to be conducted in the (viii) If a sponsor has transferred any first year following the submission (if obligations for the conduct of any clin- plans are not developed for the entire ical study to a contract research orga- year, the sponsor should so indicate); nization, a statement containing the (e) the estimated number of patients to name and address of the contract re- be given the drug in those studies; and search organization, identification of (f) any risks of particular severity or the clinical study, and a listing of the seriousness anticipated on the basis of obligations transferred. If all obliga- the toxicological data in animals or tions governing the conduct of the prior studies in humans with the drug study have been transferred, a general or related drugs. statement of this transfer—in lieu of a (4) [Reserved] listing of the specific obligations trans- (5) Investigator’s brochure. If required ferred—may be submitted. under § 312.55, a copy of the investiga- (ix) The signature of the sponsor or tor’s brochure, containing the fol- the sponsor’s authorized representa- lowing information: tive. If the person signing the applica- (i) A brief description of the drug tion does not reside or have a place of substance and the formulation, includ- business within the United States, the ing the structural formula, if known. IND is required to contain the name (ii) A summary of the pharma- and address of, and be countersigned cological and toxicological effects of by, an attorney, agent, or other au- the drug in animals and, to the extent thorized official who resides or main- known, in humans. tains a place of business within the (iii) A summary of the pharmaco- United States. kinetics and biological disposition of (2) A table of contents. the drug in animals and, if known, in (3) Introductory statement and general humans. investigational plan. (i) A brief introduc- (iv) A summary of information relat- tory statement giving the name of the ing to safety and effectiveness in hu- drug and all active ingredients, the mans obtained from prior clinical stud- drug’s pharmacological class, the ies. (Reprints of published articles on structural formula of the drug (if such studies may be appended when known), the formulation of the dosage useful.) form(s) to be used, the route of admin- (v) A description of possible risks and istration, and the broad objectives and side effects to be anticipated on the planned duration of the proposed clin- basis of prior experience with the drug ical investigation(s). under investigation or with related (ii) A brief summary of previous drugs, and of precautions or special human experience with the drug, with monitoring to be done as part of the in- reference to other IND’s if pertinent, vestigational use of the drug. and to investigational or marketing ex- (6) Protocols. (i) A protocol for each perience in other countries that may planned study. (Protocols for studies be relevant to the safety of the pro- not submitted initially in the IND posed clinical investigation(s). should be submitted in accordance with (iii) If the drug has been withdrawn § 312.30(a).) In general, protocols for from investigation or marketing in any Phase 1 studies may be less detailed country for any reason related to safe- and more flexible than protocols for ty or effectiveness, identification of Phase 2 and 3 studies. Phase 1 protocols the country(ies) where the drug was should be directed primarily at pro- withdrawn and the reasons for the viding an outline of the investigation— withdrawal. an estimate of the number of patients (iv) A brief description of the overall to be involved, a description of safety plan for investigating the drug product exclusions, and a description of the for the following year. The plan should dosing plan including duration, dose, or include the following: (a) The rationale method to be used in determining for the drug or the research study; (b) dose—and should specify in detail only the indication(s) to be studied; (c) the those elements of the study that are general approach to be followed in critical to safety, such as necessary

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monitoring of vital signs and blood ures to be taken to monitor the effects chemistries. Modifications of the ex- of the drug in human subjects and to perimental design of Phase 1 studies minimize risk. that do not affect critical safety as- (7) Chemistry, manufacturing, and con- sessments are required to be reported trol information. (i) As appropriate for to FDA only in the annual report. the particular investigations covered (ii) In Phases 2 and 3, detailed proto- by the IND, a section describing the cols describing all aspects of the study composition, manufacture, and control should be submitted. A protocol for a of the drug substance and the drug Phase 2 or 3 investigation should be de- product. Although in each phase of the signed in such a way that, if the spon- investigation sufficient information is sor anticipates that some deviation required to be submitted to assure the from the study design may become nec- proper identification, quality, purity, essary as the investigation progresses, and strength of the investigational alternatives or contingencies to pro- drug, the amount of information need- vide for such deviation are built into ed to make that assurance will vary the protocols at the outset. For exam- with the phase of the investigation, the ple, a protocol for a controlled short- proposed duration of the investigation, term study might include a plan for an the dosage form, and the amount of in- early crossover of nonresponders to an formation otherwise available. FDA alternative therapy. recognizes that modifications to the (iii) A protocol is required to contain method of preparation of the new drug the following, with the specific ele- substance and dosage form and changes ments and detail of the protocol rein the dosage form itself are likely as flecting the above distinctions depend- the investigation progresses. There- ing on the phase of study: fore, the emphasis in an initial Phase 1 (a) A statement of the objectives and submission should generally be placed purpose of the study. on the identification and control of the (b) The name and address and a state- raw materials and the new drug sub- ment of the qualifications (curriculum stance. Final specifications for the vitae or other statement of qualifica- drug substance and drug product are tions) of each investigator, and the not expected until the end of the inves- name of each subinvestigator (e.g., re- tigational process. search fellow, resident) working under (ii) It should be emphasized that the the supervision of the investigator; the amount of information to be submitted name and address of the research fa- depends upon the scope of the proposed cilities to be used; and the name and clinical investigation. For example, al- address of each reviewing Institutional though stability data are required in Review Board. all phases of the IND to demonstrate (c) The criteria for patient selection that the new drug substance and drug and for exclusion of patients and an es- product are within acceptable chemical timate of the number of patients to be and physical limits for the planned du- studied. ration of the proposed clinical inves- (d) A description of the design of the tigation, if very short-term tests are study, including the kind of control proposed, the supporting stability data group to be used, if any, and a descrip- can be correspondingly limited. tion of methods to be used to minimize (iii) As drug development proceeds bias on the part of subjects, investiga- and as the scale or production is tors, and analysts. changed from the pilot-scale produc- (e) The method for determining the tion appropriate for the limited initial dose(s) to be administered, the planned clinical investigations to the larger- maximum dosage, and the duration of scale production needed for expanded individual patient exposure to the clinical trials, the sponsor should sub- drug. mit information amendments to sup- (f) A description of the observations plement the initial information sub- and measurements to be made to fulfill mitted on the chemistry, manufac- the objectives of the study. turing, and control processes with in- (g) A description of clinical proce- formation appropriate to the expanded dures, laboratory tests, or other meas- scope of the investigation.

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(iv) Reflecting the distinctions de- sion under § 25.30 or 25.31 or an environ- scribed in this paragraph (a)(7), and mental assessment under § 25.40. based on the phase(s) to be studied, the (8) Pharmacology and toxicology infor- submission is required to contain the mation. Adequate information about following: pharmacological and toxicological (a) Drug substance. A description of studies of the drug involving labora- the drug substance, including its phys- tory animals or in vitro, on the basis of ical, chemical, or biological character- which the sponsor has concluded that istics; the name and address of its man- it is reasonably safe to conduct the ufacturer; the general method of prepa- proposed clinical investigations. The ration of the drug substance; the ac- kind, duration, and scope of animal and ceptable limits and analytical methods other tests required varies with the du- used to assure the identity, strength, ration and nature of the proposed clin- quality, and purity of the drug sub- ical investigations. Guidance docu- stance; and information sufficient to ments are available from FDA that de- support stability of the drug substance scribe ways in which these require- during the toxicological studies and ments may be met. Such information is the planned clinical studies. Reference required to include the identification to the current edition of the United and qualifications of the individuals States Pharmacopeia—National For- who evaluated the results of such stud- mulary may satisfy relevant require- ies and concluded that it is reasonably ments in this paragraph. safe to begin the proposed investiga- (b) Drug product. A list of all compo- tions and a statement of where the in- nents, which may include reasonable vestigations were conducted and where alternatives for inactive compounds, the records are available for inspec- used in the manufacture of the inves- tion. As drug development proceeds, tigational drug product, including both the sponsor is required to submit infor- those components intended to appear mational amendments, as appropriate, in the drug product and those which with additional information pertinent may not appear but which are used in to safety. the manufacturing process, and, where (i) Pharmacology and drug disposition. applicable, the quantitative composi- A section describing the pharma- tion of the investigational drug prod- cological effects and mechanism(s) of uct, including any reasonable vari- action of the drug in animals, and in- ations that may be expected during the formation on the absorption, distribu- investigational stage; the name and ad- tion, metabolism, and excretion of the dress of the drug product manufac- drug, if known. turer; a brief general description of the (ii) Toxicology. (a) An integrated sum- manufacturing and packaging proce- mary of the toxicological effects of the dure as appropriate for the product; the drug in animals and in vitro. Depend- acceptable limits and analytical meth- ing on the nature of the drug and the ods used to assure the identity, phase of the investigation, the descrip- strength, quality, and purity of the tion is to include the results of acute, drug product; and information suffi- subacute, and chronic toxicity tests; cient to assure the product’s stability tests of the drug’s effects on reproduc- during the planned clinical studies. tion and the developing fetus; any spe- Reference to the current edition of the cial toxicity test related to the drug’s United States Pharmacopeia—National particular mode of administration or Formulary may satisfy certain require- conditions of use (e.g., inhalation, der- ments in this paragraph. mal, or ocular toxicology); and any in (c) A brief general description of the vitro studies intended to evaluate drug composition, manufacture, and control toxicity. of any placebo used in a controlled (b) For each toxicology study that is clinical trial. intended primarily to support the safe- (d) Labeling. A copy of all labels and ty of the proposed clinical investiga- labeling to be provided to each investi- tion, a full tabulation of data suitable gator. for detailed review. (e) Environmental analysis require- (iii) For each nonclinical laboratory ments. A claim for categorical exclu- study subject to the good laboratory

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practice regulations under part 58, a mation on special topics may be need- statement that the study was con- ed. Such information shall be sub- ducted in compliance with the good mitted in this section as follows: laboratory practice regulations in part (i) Drug dependence and abuse poten- 58, or, if the study was not conducted tial. If the drug is a psychotropic sub- in compliance with those regulations, a stance or otherwise has abuse poten- brief statement of the reason for the tial, a section describing relevant clin- noncompliance. ical studies and experience and studies (9) Previous human experience with the in test animals. investigational drug. A summary of pre- (ii) Radioactive drugs. If the drug is a vious human experience known to the radioactive drug, sufficient data from applicant, if any, with the investiga- animal or human studies to allow a tional drug. The information is re- reasonable calculation of radiation-ab- quired to include the following: sorbed dose to the whole body and crit- (i) If the investigational drug has been investigated or marketed pre- ical organs upon administration to a viously, either in the United States or human subject. Phase 1 studies of ra- other countries, detailed information dioactive drugs must include studies about such experience that is relevant which will obtain sufficient data for to the safety of the proposed investiga- dosimetry calculations. tion or to the investigation’s rationale. (iii) Pediatric studies. Plans for assess- If the drug has been the subject of con- ing pediatric safety and effectiveness. trolled trials, detailed information on (iv) Other information. A brief state- such trials that is relevant to an as- ment of any other information that sessment of the drug’s effectiveness for would aid evaluation of the proposed the proposed investigational use(s) clinical investigations with respect to should also be provided. Any published their safety or their design and poten- material that is relevant to the safety tial as controlled clinical trials to sup- of the proposed investigation or to an port marketing of the drug. assessment of the drug’s effectiveness (11) Relevant information. If requested for its proposed investigational use by FDA, any other relevant informa- should be provided in full. Published tion needed for review of the applica- material that is less directly relevant tion. may be supplied by a bibliography. (b) Information previously submitted. (ii) If the drug is a combination of The sponsor ordinarily is not required drugs previously investigated or mar- to resubmit information previously keted, the information required under submitted, but may incorporate the in- paragraph (a)(9)(i) of this section formation by reference. A reference to should be provided for each active drug information submitted previously must component. However, if any component identify the file by name, reference in such combination is subject to an number, volume, and page number approved marketing application or is where the information can be found. A otherwise lawfully marketed in the reference to information submitted to United States, the sponsor is not required to submit published material the agency by a person other than the concerning that active drug component sponsor is required to contain a writ- unless such material relates directly to ten statement that authorizes the ref- the proposed investigational use (in- erence and that is signed by the person cluding publications relevant to com- who submitted the information. ponent-component interaction). (c) Material in a foreign language. The (iii) If the drug has been marketed sponsor shall submit an accurate and outside the United States, a list of the complete English translation of each countries in which the drug has been part of the IND that is not in English. marketed and a list of the countries in The sponsor shall also submit a copy of which the drug has been withdrawn each original literature publication for from marketing for reasons potentially which an English translation is sub- related to safety or effectiveness. mitted. (10) Additional information. In certain (d) Number of copies. The sponsor applications, as described below, infor- shall submit an original and two copies

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of all submissions to the IND file, in- (b) Changes in a protocol. (1) A sponsor cluding the original submission and all shall submit a protocol amendment de- amendments and reports. scribing any change in a Phase 1 pro- (e) Numbering of IND submissions. tocol that significantly affects the Each submission relating to an IND is safety of subjects or any change in a required to be numbered serially using Phase 2 or 3 protocol that significantly a single, three-digit serial number. The affects the safety of subjects, the scope initial IND is required to be numbered of the investigation, or the scientific 000; each subsequent submission (e.g., quality of the study. Examples of amendment, report, or correspondence) changes requiring an amendment under is required to be numbered chrono- this paragraph include: logically in sequence. (i) Any increase in drug dosage or du- (f) Identification of exception from in- ration of exposure of individual sub- formed consent. If the investigation in- jects to the drug beyond that in the volves an exception from informed concurrent protocol, or any significant in- sent under § 50.24 of this chapter, the crease in the number of subjects under sponsor shall prominently identify on study. the cover sheet that the investigation (ii) Any significant change in the de- is subject to the requirements in § 50.24 sign of a protocol (such as the addition of this chapter. or dropping of a control group). (iii) The addition of a new test or [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, procedure that is intended to improve 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599, monitoring for, or reduce the risk of, a July 29, 1997; 63 FR 66669, Dec. 2, 1998; 65 FR side effect or adverse event; or the 56479, Sept. 19, 2000; 67 FR 9585, Mar. 4, 2002] dropping of a test intended to monitor safety. § 312.30 Protocol amendments. (2)(i) A protocol change under para- Once an IND is in effect, a sponsor graph (b)(1) of this section may be shall amend it as needed to ensure that made provided two conditions are met: the clinical investigations are con- (a) The sponsor has submitted the ducted according to protocols included change to FDA for its review; and in the application. This section sets (b) The change has been approved by forth the provisions under which new the IRB with responsibility for review protocols may be submitted and and approval of the study. The sponsor changes in previously submitted proto- may comply with these two conditions cols may be made. Whenever a sponsor in either order. intends to conduct a clinical investiga- (ii) Notwithstanding paragraph tion with an exception from informed (b)(2)(i) of this section, a protocol consent for emergency research as set change intended to eliminate an appar- forth in § 50.24 of this chapter, the spon- ent immediate hazard to subjects may sor shall submit a separate IND for be implemented immediately provided such investigation. FDA is subsequently notified by pro- (a) New protocol. Whenever a sponsor tocol amendment and the reviewing intends to conduct a study that is not IRB is notified in accordance with covered by a protocol already con- § 56.104(c). tained in the IND, the sponsor shall (c) New investigator. A sponsor shall submit to FDA a protocol amendment submit a protocol amendment when a containing the protocol for the study. new investigator is added to carry out Such study may begin provided two a previously submitted protocol, except conditions are met: (1) The sponsor has that a protocol amendment is not re- submitted the protocol to FDA for its quired when a licensed practitioner is review; and (2) the protocol has been added in the case of a treatment pro- approved by the Institutional Review tocol under § 312.315 or § 312.320. Once Board (IRB) with responsibility for re- the investigator is added to the study, view and approval of the study in ac- the investigational drug may be cordance with the requirements of part shipped to the investigator and the in- 56. The sponsor may comply with these vestigator may begin participating in two conditions in either order. the study. The sponsor shall notify

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FDA of the new investigator within 30 sible, to include these all in a single days of the investigator being added. submission. (d) Content and format. A protocol [52 FR 8831, Mar. 19, 1987, as amended at 52 amendment is required to be promi- FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, nently identified as such (i.e., ‘‘Pro- 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar. tocol Amendment: New Protocol’’, 4, 2002; 74 FR 40942, Aug. 13, 2009] ‘‘Protocol Amendment: Change in Pro- § 312.31 Information amendments. tocol’’, or ‘‘Protocol Amendment: New Investigator’’), and to contain the fol- (a) Requirement for information amend- lowing: ment. A sponsor shall report in an in- (1)(i) In the case of a new protocol, a formation amendment essential information on the IND that is not within copy of the new protocol and a brief de- the scope of a protocol amendment, scription of the most clinically signifi- IND safety reports, or annual report. cant differences between it and pre- Examples of information requiring an vious protocols. information amendment include: (ii) In the case of a change in pro- (1) New toxicology, chemistry, or tocol, a brief description of the change other technical information; or and reference (date and number) to the (2) A report regarding the discontinu- submission that contained the pro- ance of a clinical investigation. tocol. (b) Content and format of an informa- (iii) In the case of a new investigator, tion amendment. An information amend- the investigator’s name, the qualifica- ment is required to bear prominent tions to conduct the investigation, ref- identification of its contents (e.g., ‘‘In- erence to the previously submitted pro- formation Amendment: Chemistry, tocol, and all additional information Manufacturing, and Control’’, ‘‘Infor- about the investigator’s study as is re- mation Amendment: Pharmacology- Toxicology’’, ‘‘Information Amend- quired under § 312.23(a)(6)(iii)(b). ment: Clinical’’), and to contain the (2) Reference, if necessary, to specific following: technical information in the IND or in (1) A statement of the nature and a concurrently submitted information purpose of the amendment. amendment to the IND that the spon- (2) An organized submission of the sor relies on to support any clinically data in a format appropriate for sci- significant change in the new or entific review. amended protocol. If the reference is (3) If the sponsor desires FDA to com- made to supporting information al- ment on an information amendment, a ready in the IND, the sponsor shall request for such comment. identify by name, reference number, (c) When submitted. Information volume, and page number the location amendments to the IND should be sub- of the information. mitted as necessary but, to the extent (3) If the sponsor desires FDA to com- feasible, not more than every 30 days. ment on the submission, a request for [52 FR 8831, Mar. 19, 1987, as amended at 52 such comment and the specific ques- FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, tions FDA’s response should address. 1988; 67 FR 9585, Mar. 4, 2002] (e) When submitted. A sponsor shall § 312.32 IND safety reporting. submit a protocol amendment for a new protocol or a change in protocol (a) Definitions. The following defini- before its implementation. Protocol tions of terms apply to this section: amendments to add a new investigator Adverse event means any untoward or to provide additional information medical occurrence associated with the use of a drug in humans, whether or about investigators may be grouped not considered drug related. and submitted at 30-day intervals. Life-threatening adverse event or life- When several submissions of new proto- threatening suspected adverse reaction. cols or protocol changes are antici- An adverse event or suspected adverse pated during a short period, the spon- reaction is considered ‘‘life-threat- sor is encouraged, to the extent fea- ening’’ if, in the view of either the investigator or sponsor, its occurrence

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places the patient or subject at imme- in the current application, as amended. diate risk of death. It does not include For example, under this definition, he- an adverse event or suspected adverse patic necrosis would be unexpected (by reaction that, had it occurred in a virtue of greater severity) if the inves- more severe form, might have caused tigator brochure referred only to ele- death. vated hepatic enzymes or hepatitis. Serious adverse event or serious sus- Similarly, cerebral thromboembolism pected adverse reaction. An adverse and cerebral vasculitis would be unex- event or suspected adverse reaction is pected (by virtue of greater specificity) considered ‘‘serious’’ if, in the view of if the investigator brochure listed only either the investigator or sponsor, it cerebral vascular accidents. ‘‘Unex- results in any of the following out- pected,’’ as used in this definition, also comes: Death, a life-threatening ad- refers to adverse events or suspected verse event, inpatient hospitalization adverse reactions that are mentioned or prolongation of existing hospitaliza- in the investigator brochure as occur- tion, a persistent or significant inca- ring with a class of drugs or as antici- pacity or substantial disruption of the pated from the pharmacological prop- ability to conduct normal life func- erties of the drug, but are not specifi- tions, or a congenital anomaly/birth cally mentioned as occurring with the defect. Important medical events that particular drug under investigation. may not result in death, be life-threat- (b) Review of safety information. The ening, or require hospitalization may sponsor must promptly review all in- be considered serious when, based upon formation relevant to the safety of the appropriate medical judgment, they drug obtained or otherwise received by may jeopardize the patient or subject the sponsor from foreign or domestic and may require medical or surgical sources, including information derived intervention to prevent one of the out- from any clinical or epidemiological comes listed in this definition. Exam- investigations, animal or in vitro stud- ples of such medical events include al- ies, reports in the scientific literature, lergic bronchospasm requiring inten- and unpublished scientific papers, as sive treatment in an emergency room well as reports from foreign regulatory or at home, blood dyscrasias or convul- authorities and reports of foreign com- sions that do not result in inpatient mercial marketing experience for drugs hospitalization, or the development of that are not marketed in the United drug dependency or drug abuse. States. Suspected adverse reaction means any (c)(1) IND safety reports. The sponsor adverse event for which there is a rea- must notify FDA and all participating sonable possibility that the drug investigators (i.e., all investigators to caused the adverse event. For the pur- whom the sponsor is providing drug poses of IND safety reporting, ‘‘reason- under its INDs or under any investiga- able possibility’’ means there is evi- tor’s IND) in an IND safety report of dence to suggest a causal relationship potential serious risks, from clinical between the drug and the adverse trials or any other source, as soon as event. Suspected adverse reaction impossible, but in no case later than 15 plies a lesser degree of certainty about calendar days after the sponsor deter- causality than adverse reaction, which mines that the information qualifies means any adverse event caused by a for reporting under paragraph (c)(1)(i), drug. (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of this Unexpected adverse event or unexpected section. In each IND safety report, the suspected adverse reaction. An adverse sponsor must identify all IND safety event or suspected adverse reaction is reports previously submitted to FDA considered ‘‘unexpected’’ if it is not concerning a similar suspected adverse listed in the investigator brochure or is reaction, and must analyze the signifi- not listed at the specificity or severity cance of the suspected adverse reaction that has been observed; or, if an inves- in light of previous, similar reports or tigator brochure is not required or any other relevant information. available, is not consistent with the (i) Serious and unexpected suspected risk information described in the gen- adverse reaction. The sponsor must re- eral investigational plan or elsewhere port any suspected adverse reaction

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that is both serious and unexpected. pects of the overall conduct of the clin- The sponsor must report an adverse ical investigation. event as a suspected adverse reaction (iv) Increased rate of occurrence of seri- only if there is evidence to suggest a ous suspected adverse reactions. The causal relationship between the drug sponsor must report any clinically im- and the adverse event, such as: portant increase in the rate of a seri- (A) A single occurrence of an event ous suspected adverse reaction over that is uncommon and known to be that listed in the protocol or investi- strongly associated with drug exposure gator brochure. (e.g., angioedema, hepatic injury, Ste- (v) Submission of IND safety reports. vens-Johnson Syndrome); The sponsor must submit each IND (B) One or more occurrences of an safety report in a narrative format or event that is not commonly associated on FDA Form 3500A or in an electronic with drug exposure, but is otherwise format that FDA can process, review, uncommon in the population exposed and archive. FDA will periodically to the drug (e.g., tendon rupture); issue guidance on how to provide the (C) An aggregate analysis of specific electronic submission (e.g., method of events observed in a clinical trial (such transmission, media, file formats, prep- as known consequences of the under- aration and organization of files). The lying disease or condition under inves- sponsor may submit foreign suspected tigation or other events that com- adverse reactions on a Council for monly occur in the study population International Organizations of Medical independent of drug therapy) that indi- Sciences (CIOMS) I Form instead of a cates those events occur more fre- FDA Form 3500A. Reports of overall quently in the drug treatment group findings or pooled analyses from pub- than in a concurrent or historical con- lished and unpublished in vitro, ani- trol group. mal, epidemiological, or clinical stud- (ii) Findings from other studies. The ies must be submitted in a narrative sponsor must report any findings from format. Each notification to FDA must epidemiological studies, pooled anal- bear prominent identification of its ysis of multiple studies, or clinical contents, i.e., ‘‘IND Safety Report,’’ studies (other than those reported and must be transmitted to the review under paragraph (c)(1)(i) of this sec- division in the Center for Drug Evalua- tion), whether or not conducted under tion and Research or in the Center for an IND, and whether or not conducted Biologics Evaluation and Research by the sponsor, that suggest a signifi- that has responsibility for review of cant risk in humans exposed to the the IND. Upon request from FDA, the drug. Ordinarily, such a finding would sponsor must submit to FDA any addi- result in a safety-related change in the tional data or information that the protocol, informed consent, investi- agency deems necessary, as soon as gator brochure (excluding routine up- possible, but in no case later than 15 dates of these documents), or other as- calendar days after receiving the re- pects of the overall conduct of the clin- quest. ical investigation. (2) Unexpected fatal or life-threatening (iii) Findings from animal or in vitro suspected adverse reaction reports. The testing. The sponsor must report any sponsor must also notify FDA of any findings from animal or in vitro test- unexpected fatal or life-threatening ing, whether or not conducted by the suspected adverse reaction as soon as sponsor, that suggest a significant risk possible but in no case later than 7 cal- in humans exposed to the drug, such as endar days after the sponsor’s initial reports of mutagenicity, receipt of the information. teratogenicity, or carcinogenicity, or (3) Reporting format or frequency. FDA reports of significant organ toxicity at may require a sponsor to submit IND or near the expected human exposure. safety reports in a format or at a fre- Ordinarily, any such findings would re- quency different than that required sult in a safety-related change in the under this paragraph. The sponsor may protocol, informed consent, investi- also propose and adopt a different re- gator brochure (excluding routine up- porting format or frequency if the dates of these documents), or other as- change is agreed to in advance by the

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director of the FDA review division tributed to an adverse event. A sponsor that has responsibility for review of need not admit, and may deny, that the IND. the report or information submitted by (4) Investigations of marketed drugs. A the sponsor constitutes an admission sponsor of a clinical study of a drug that the drug caused or contributed to marketed or approved in the United an adverse event. States that is conducted under an IND [75 FR 59961, Sept. 29, 2010] is required to submit IND safety reports for suspected adverse reactions § 312.33 Annual reports. that are observed in the clinical study, A sponsor shall within 60 days of the at domestic or foreign study sites. The anniversary date that the IND went sponsor must also submit safety infor- into effect, submit a brief report of the mation from the clinical study as pre- progress of the investigation that in- scribed by the postmarketing safety re- cludes: porting requirements (e.g., §§ 310.305, (a) Individual study information. A 314.80, and 600.80 of this chapter). brief summary of the status of each (5) Reporting study endpoints. Study study in progress and each study com- endpoints (e.g., mortality or major pleted during the previous year. The morbidity) must be reported to FDA by summary is required to include the fol- the sponsor as described in the protocol lowing information for each study: and ordinarily would not be reported (1) The title of the study (with any under paragraph (c) of this section. appropriate study identifiers such as However, if a serious and unexpected protocol number), its purpose, a brief adverse event occurs for which there is statement identifying the patient pop- evidence suggesting a causal relation- ulation, and a statement as to whether ship between the drug and the event the study is completed. (e.g., death from anaphylaxis), the (2) The total number of subjects ini- event must be reported under tially planned for inclusion in the § 312.32(c)(1)(i) as a serious and unex- study; the number entered into the pected suspected adverse reaction even study to date, tabulated by age group, if it is a component of the study end- gender, and race; the number whose point (e.g., all-cause mortality). participation in the study was com- (d) Followup. (1) The sponsor must pleted as planned; and the number who promptly investigate all safety infor- dropped out of the study for any rea- mation it receives. son. (2) Relevant followup information to (3) If the study has been completed, an IND safety report must be sub- or if interim results are known, a brief mitted as soon as the information is description of any available study re- available and must be identified as sults. such, i.e., ‘‘Followup IND Safety Re- (b) Summary information. Information port.’’ obtained during the previous year’s (3) If the results of a sponsor’s inves- clinical and nonclinical investigations, tigation show that an adverse event including: not initially determined to be report- (1) A narrative or tabular summary able under paragraph (c) of this section showing the most frequent and most is so reportable, the sponsor must re- serious adverse experiences by body port such suspected adverse reaction in system. an IND safety report as soon as pos- (2) A summary of all IND safety re- sible, but in no case later than 15 cal- ports submitted during the past year. endar days after the determination is (3) A list of subjects who died during made. participation in the investigation, with (e) Disclaimer. A safety report or the cause of death for each subject. other information submitted by a spon- (4) A list of subjects who dropped out sor under this part (and any release by during the course of the investigation FDA of that report or information) in association with any adverse experi- does not necessarily reflect a conclu- ence, whether or not thought to be sion by the sponsor or FDA that the re- drug related. port or information constitutes an ad- (5) A brief description of what, if any- mission that the drug caused or con- thing, was obtained that is pertinent to

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an understanding of the drug’s actions, Institutional Review Boards, together including, for example, information with the reasons for such withdrawal. about dose response, information from [52 FR 8831, Mar. 19, 1987, as amended at 52 controlled trials, and information FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, about bioavailability. 2002] (6) A list of the preclinical studies (including animal studies) completed Subpart C—Administrative Actions or in progress during the past year and a summary of the major preclinical § 312.40 General requirements for use findings. of an investigational new drug in a (7) A summary of any significant clinical investigation. manufacturing or microbiological (a) An investigational new drug may changes made during the past year. be used in a clinical investigation if (c) A description of the general inves- the following conditions are met: tigational plan for the coming year to (1) The sponsor of the investigation replace that submitted 1 year earlier. submits an IND for the drug to FDA; The general investigational plan shall the IND is in effect under paragraph (b) contain the information required under of this section; and the sponsor com- § 312.23(a)(3)(iv). plies with all applicable requirements (d) If the investigator brochure has in this part and parts 50 and 56 with re- been revised, a description of the revi- spect to the conduct of the clinical in- sion and a copy of the new brochure. vestigations; and (e) A description of any significant (2) Each participating investigator Phase 1 protocol modifications made conducts his or her investigation in during the previous year and not pre- compliance with the requirements of viously reported to the IND in a pro- this part and parts 50 and 56. tocol amendment. (b) An IND goes into effect: (f) A brief summary of significant (1) Thirty days after FDA receives foreign marketing developments with the IND, unless FDA notifies the spon- the drug during the past year, such as sor that the investigations described in approval of marketing in any country the IND are subject to a clinical hold or withdrawal or suspension from mar- under § 312.42; or keting in any country. (2) On earlier notification by FDA (g) If desired by the sponsor, a log of that the clinical investigations in the any outstanding business with respect IND may begin. FDA will notify the to the IND for which the sponsor re- sponsor in writing of the date it requests or expects a reply, comment, or ceives the IND. meeting. (c) A sponsor may ship an investiga- [52 FR 8831, Mar. 19, 1987, as amended at 52 tional new drug to investigators named FR 23031, June 17, 1987; 63 FR 6862, Feb. 11, in the IND: 1998; 67 FR 9585, Mar. 4, 2002] (1) Thirty days after FDA receives the IND; or § 312.38 Withdrawal of an IND. (2) On earlier FDA authorization to (a) At any time a sponsor may with- ship the drug. draw an effective IND without preju- (d) An investigator may not admin- dice. ister an investigational new drug to (b) If an IND is withdrawn, FDA shall human subjects until the IND goes into be so notified, all clinical investiga- effect under paragraph (b) of this sections conducted under the IND shall be tion. ended, all current investigators notified, and all stocks of the drug re- § 312.41 Comment and advice on an turned to the sponsor or otherwise dis- IND. posed of at the request of the sponsor (a) FDA may at any time during the in accordance with § 312.59. course of the investigation commu- (c) If an IND is withdrawn because of nicate with the sponsor orally or in a safety reason, the sponsor shall writing about deficiencies in the IND promptly so inform FDA, all partici- or about FDA’s need for more data or pating investigators, and all reviewing information.

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(b) On the sponsor’s request, FDA (iv) The IND does not contain suffi- will provide advice on specific matters cient information required under relating to an IND. Examples of such § 312.23 to assess the risks to subjects of advice may include advice on the ade- the proposed studies. quacy of technical data to support an (v) The IND is for the study of an in- investigational plan, on the design of a vestigational drug intended to treat a clinical trial, and on whether proposed life-threatening disease or condition investigations are likely to produce the that affects both genders, and men or data and information that is needed to women with reproductive potential meet requirements for a marketing ap- who have the disease or condition plication. being studied are excluded from eligi- (c) Unless the communication is ac- bility because of a risk or potential companied by a clinical hold order risk from use of the investigational under § 312.42, FDA communications drug of reproductive toxicity (i.e., af- with a sponsor under this section are fecting reproductive organs) or devel- solely advisory and do not require any opmental toxicity (i.e., affecting poten- modification in the planned or ongoing tial offspring). The phrase ‘‘women clinical investigations or response to with reproductive potential’’ does not the agency. include pregnant women. For purposes [52 FR 8831, Mar. 19, 1987, as amended at 52 of this paragraph, ‘‘life-threatening ill- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, nesses or diseases’’ are defined as ‘‘dis- 2002] eases or conditions where the likelihood of death is high unless the course § 312.42 Clinical holds and requests for of the disease is interrupted.’’ The clin- modification. ical hold would not apply under this (a) General. A clinical hold is an order paragraph to clinical studies con- issued by FDA to the sponsor to delay ducted: a proposed clinical investigation or to (A) Under special circumstances, suspend an ongoing investigation. The such as studies pertinent only to one clinical hold order may apply to one or gender (e.g., studies evaluating the ex- more of the investigations covered by cretion of a drug in semen or the ef- an IND. When a proposed study is fects on menstrual function); placed on clinical hold, subjects may (B) Only in men or women, as long as not be given the investigational drug. a study that does not exclude members When an ongoing study is placed on of the other gender with reproductive clinical hold, no new subjects may be potential is being conducted concur- recruited to the study and placed on rently, has been conducted, or will the investigational drug; patients al- take place within a reasonable time ready in the study should be taken off agreed upon by the agency; or therapy involving the investigational (C) Only in subjects who do not suffer drug unless specifically permitted by from the disease or condition for which FDA in the interest of patient safety. the drug is being studied. (b) Grounds for imposition of clinical (2) Clinical hold of a Phase 2 or 3 study hold—(1) Clinical hold of a Phase 1 study under an IND. FDA may place a pro- under an IND. FDA may place a proposed or ongoing Phase 2 or 3 inves- posed or ongoing Phase 1 investigation tigation on clinical hold if it finds on clinical hold if it finds that: that: (i) Human subjects are or would be (i) Any of the conditions in para- exposed to an unreasonable and signifi- graphs (b)(1)(i) through (b)(1)(v) of this cant risk of illness or injury; section apply; or (ii) The clinical investigators named (ii) The plan or protocol for the in- in the IND are not qualified by reason vestigation is clearly deficient in de- of their scientific training and experi- sign to meet its stated objectives. ence to conduct the investigation de- (3) Clinical hold of an expanded access scribed in the IND; IND or expanded access protocol. FDA (iii) The investigator brochure is may place an expanded access IND or misleading, erroneous, or materially expanded access protocol on clinical incomplete; or hold under the following conditions:

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(i) Final use. FDA may place a pro- controlled investigation is not actively posed expanded access IND or treat- pursuing marketing approval of the in- ment use protocol on clinical hold if it vestigational drug with due diligence; is determined that: or (A) The pertinent criteria in subpart (viii) The Commissioner determines I of this part for permitting the ex- that it would not be in the public inter- panded access use to begin are not sat- est for the study to be conducted or isfied; or continued. FDA ordinarily intends that (B) The expanded access IND or ex- clinical holds under paragraphs panded access protocol does not comply (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this with the requirements for expanded ac- section would only apply to additional cess submissions in subpart I of this enrollment in nonconcurrently con- part. trolled trials rather than eliminating (ii) Ongoing use. FDA may place an continued access to individuals already ongoing expanded access IND or ex- receiving the investigational drug. panded access protocol on clinical hold (5) Clinical hold of any investigation in- if it is determined that the pertinent volving an exception from informed con- criteria in subpart I of this part for sent under § 50.24 of this chapter. FDA permitting the expanded access are no may place a proposed or ongoing inves- longer satisfied. tigation involving an exception from (4) Clinical hold of any study that is informed consent under § 50.24 of this not designed to be adequate and well-con- chapter on clinical hold if it is deter- trolled. FDA may place a proposed or mined that: ongoing investigation that is not de- (i) Any of the conditions in para- signed to be adequate and well-con- graphs (b)(1) or (b)(2) of this section trolled on clinical hold if it finds that: apply; or (i) Any of the conditions in para- (ii) The pertinent criteria in § 50.24 of graph (b)(1) or (b)(2) of this section this chapter for such an investigation apply; or to begin or continue are not submitted (ii) There is reasonable evidence the or not satisfied. investigation that is not designed to be (6) Clinical hold of any investigation adequate and well-controlled is imped- involving an exception from informed ing enrollment in, or otherwise inter- consent under § 50.23(d) of this chapter. fering with the conduct or completion FDA may place a proposed or ongoing of, a study that is designed to be an investigation involving an exception adequate and well-controlled investiga- from informed consent under § 50.23(d) tion of the same or another investiga- of this chapter on clinical hold if it is tional drug; or determined that: (iii) Insufficient quantities of the in- (i) Any of the conditions in para- vestigational drug exist to adequately graphs (b)(1) or (b)(2) of this section conduct both the investigation that is apply; or not designed to be adequate and well- (ii) A determination by the President controlled and the investigations that to waive the prior consent requirement are designed to be adequate and well- for the administration of an investiga- controlled; or tional new drug has not been made. (iv) The drug has been studied in one (c) Discussion of deficiency. Whenever or more adequate and well-controlled FDA concludes that a deficiency exists investigations that strongly suggest in a clinical investigation that may be lack of effectiveness; or grounds for the imposition of clinical (v) Another drug under investigation hold FDA will, unless patients are ex- or approved for the same indication posed to immediate and serious risk, and available to the same patient popu- attempt to discuss and satisfactorily lation has demonstrated a better po- resolve the matter with the sponsor be- tential benefit/risk balance; or fore issuing the clinical hold order. (vi) The drug has received marketing (d) Imposition of clinical hold. The approval for the same indication in the clinical hold order may be made by same patient population; or telephone or other means of rapid com- (vii) The sponsor of the study that is munication or in writing. The clinical designed to be an adequate and well- hold order will identify the studies

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under the IND to which the hold ap- be placed on inactive status by FDA plies, and will briefly explain the basis under § 312.45. for the action. The clinical hold order [52 FR 8831, Mar. 19, 1987, as amended at 52 will be made by or on behalf of the Di- FR 19477, May 22, 1987; 57 FR 13249, Apr. 15, vision Director with responsibility for 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, review of the IND. As soon as possible, Dec. 14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR and no more than 30 days after imposi- 34971, June 1, 2000; 74 FR 40942, Aug. 13, 2009] tion of the clinical hold, the Division § 312.44 Termination. Director will provide the sponsor a written explanation of the basis for the (a) General. This section describes the hold. procedures under which FDA may terminate an IND. If an IND is termi- (e) Resumption of clinical investiga- nated, the sponsor shall end all clinical tions. An investigation may only re- investigations conducted under the sume after FDA (usually the Division IND and recall or otherwise provide for Director, or the Director’s designee, the disposition of all unused supplies of with responsibility for review of the the drug. A termination action may be IND) has notified the sponsor that the based on deficiencies in the IND or in investigation may proceed. Resump- the conduct of an investigation under tion of the affected investigation(s) an IND. Except as provided in para- will be authorized when the sponsor graph (d) of this section, a termination corrects the deficiency(ies) previously shall be preceded by a proposal to ter- cited or otherwise satisfies the agency minate by FDA and an opportunity for that the investigation(s) can proceed. the sponsor to respond. FDA will, in FDA may notify a sponsor of its deter- general, only initiate an action under mination regarding the clinical hold by this section after first attempting to telephone or other means of rapid com- resolve differences informally or, when munication. If a sponsor of an IND that appropriate, through the clinical hold has been placed on clinical hold re- procedures described in § 312.42. quests in writing that the clinical hold (b) Grounds for termination—(1) Phase be removed and submits a complete re- 1. FDA may propose to terminate an sponse to the issue(s) identified in the IND during Phase 1 if it finds that: clinical hold order, FDA shall respond (i) Human subjects would be exposed in writing to the sponsor within 30-cal- to an unreasonable and significant risk of illness or injury. endar days of receipt of the request and (ii) The IND does not contain suffi- the complete response. FDA’s response cient information required under will either remove or maintain the § 312.23 to assess the safety to subjects clinical hold, and will state the reasons of the clinical investigations. for such determination. Notwith- (iii) The methods, facilities, and con- standing the 30-calendar day response trols used for the manufacturing, proc- time, a sponsor may not proceed with a essing, and packing of the investiga- clinical trial on which a clinical hold tional drug are inadequate to establish has been imposed until the sponsor has and maintain appropriate standards of been notified by FDA that the hold has identity, strength, quality, and purity been lifted. as needed for subject safety. (f) Appeal. If the sponsor disagrees (iv) The clinical investigations are with the reasons cited for the clinical being conducted in a manner substan- hold, the sponsor may request recon- tially different than that described in sideration of the decision in accord- the protocols submitted in the IND. ance with § 312.48. (v) The drug is being promoted or dis- (g) Conversion of IND on clinical hold tributed for commercial purposes not to inactive status. If all investigations justified by the requirements of the in- covered by an IND remain on clinical vestigation or permitted by § 312.7. hold for 1 year or more, the IND may (vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part.

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(vii) The sponsor fails promptly to in- the nonacceptance and provide the vestigate and inform the Food and sponsor with an opportunity for a regu- Drug Administration and all investiga- latory hearing before FDA under part tors of serious and unexpected adverse 16 on the question of whether the IND experiences in accordance with § 312.32 should be terminated. The sponsor’s re- or fails to make any other report request for a regulatory hearing must be quired under this part. made within 10 days of the sponsor’s (viii) The sponsor fails to submit an receipt of FDA’s notification of non- accurate annual report of the inves- acceptance. tigations in accordance with § 312.33. (d) Immediate termination of IND. Not- (ix) The sponsor fails to comply with withstanding paragraphs (a) through any other applicable requirement of (c) of this section, if at any time FDA this part, part 50, or part 56. concludes that continuation of the in- (x) The IND has remained on inactive vestigation presents an immediate and status for 5 years or more. substantial danger to the health of in- (xi) The sponsor fails to delay a proposed investigation under the IND or dividuals, the agency shall imme- to suspend an ongoing investigation diately, by written notice to the spon- that has been placed on clinical hold sor from the Director of the Center for under § 312.42(b)(4). Drug Evaluation and Research or the (2) Phase 2 or 3. FDA may propose to Director of the Center for Biologics terminate an IND during Phase 2 or Evaluation and Research, terminate Phase 3 if FDA finds that: the IND. An IND so terminated is sub- (i) Any of the conditions in para- ject to reinstatement by the Director graphs (b)(1)(i) through (b)(1)(xi) of this on the basis of additional submissions section apply; or that eliminate such danger. If an IND (ii) The investigational plan or pro- is terminated under this paragraph, the tocol(s) is not reasonable as a bona fide agency will afford the sponsor an op- scientific plan to determine whether or portunity for a regulatory hearing not the drug is safe and effective for under part 16 on the question of wheth- use; or er the IND should be reinstated. (iii) There is convincing evidence [52 FR 8831, Mar. 19, 1987, as amended at 52 that the drug is not effective for the FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, purpose for which it is being inves- 1990; 57 FR 13249, Apr. 15, 1992; 67 FR 9586, tigated. Mar. 4, 2002] (3) FDA may propose to terminate a treatment IND if it finds that: § 312.45 Inactive status. (i) Any of the conditions in para- (a) If no subjects are entered into graphs (b)(1)(i) through (x) of this sec- clinical studies for a period of 2 years tion apply; or or more under an IND, or if all inves- (ii) Any of the conditions in tigations under an IND remain on clin- § 312.42(b)(3) apply. (c) Opportunity for sponsor response. ical hold for 1 year or more, the IND (1) If FDA proposes to terminate an may be placed by FDA on inactive sta- IND, FDA will notify the sponsor in tus. This action may be taken by FDA writing, and invite correction or expla- either on request of the sponsor or on nation within a period of 30 days. FDA’s own initiative. If FDA seeks to (2) On such notification, the sponsor act on its own initiative under this sec- may provide a written explanation or tion, it shall first notify the sponsor in correction or may request a conference writing of the proposed inactive status. with FDA to provide the requested ex- Upon receipt of such notification, the planation or correction. If the sponsor sponsor shall have 30 days to respond does not respond to the notification as to why the IND should continue to within the allocated time, the IND remain active. shall be terminated. (b) If an IND is placed on inactive (3) If the sponsor responds but FDA status, all investigators shall be so no- does not accept the explanation or cor- tified and all stocks of the drug shall rection submitted, FDA shall inform be returned or otherwise disposed of in the sponsor in writing of the reason for accordance with § 312.59.

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(c) A sponsor is not required to sub- during the drug investigation process, mit annual reports to an IND on inac- meetings between FDA and a sponsor tive status. An inactive IND is, how- can be especially helpful in minimizing ever, still in effect for purposes of the wasteful expenditures of time and public disclosure of data and informa- money and thus in speeding the drug tion under § 312.130. development and evaluation process. In (d) A sponsor who intends to resume particular, FDA has found that meet- clinical investigation under an IND ings at the end of Phase 2 of an inves- placed on inactive status shall submit tigation (end-of-Phase 2 meetings) are a protocol amendment under § 312.30 of considerable assistance in planning containing the proposed general inves- later studies and that meetings held tigational plan for the coming year and near completion of Phase 3 and before appropriate protocols. If the protocol submission of a marketing application amendment relies on information pre- (‘‘pre-NDA’’ meetings) are helpful in viously submitted, the plan shall ref- developing methods of presentation erence such information. Additional in- and submission of data in the mar- formation supporting the proposed in- keting application that facilitate re- vestigation, if any, shall be submitted view and allow timely FDA response. in an information amendment. Not- (1) —(i) withstanding the provisions of § 312.30, End-of-Phase 2 meetings Pur- clinical investigations under an IND on pose. The purpose of an end-of-phase 2 inactive status may only resume (1) 30 meeting is to determine the safety of days after FDA receives the protocol proceeding to Phase 3, to evaluate the amendment, unless FDA notifies the Phase 3 plan and protocols and the ade- sponsor that the investigations de- quacy of current studies and plans to scribed in the amendment are subject assess pediatric safety and effective- to a clinical hold under § 312.42, or (2) ness, and to identify any additional in- on earlier notification by FDA that the formation necessary to support a mar- clinical investigations described in the keting application for the uses under protocol amendment may begin. investigation. (e) An IND that remains on inactive (ii) Eligibility for meeting. While the status for 5 years or more may be ter- end-of-Phase 2 meeting is designed pri- minated under § 312.44. marily for IND’s involving new molecular entities or major new uses of mar- [52 FR 8831, Mar. 19, 1987, as amended at 52 keted drugs, a sponsor of any IND may FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, 2002] request and obtain an end-of-Phase 2 meeting. § 312.47 Meetings. (iii) Timing. To be most useful to the (a) General. Meetings between a spon- sponsor, end-of-Phase 2 meetings sor and the agency are frequently use- should be held before major commit- ful in resolving questions and issues ments of effort and resources to spe- raised during the course of a clinical cific Phase 3 tests are made. The sched- investigation. FDA encourages such uling of an end-of-Phase 2 meeting is meetings to the extent that they aid in not, however, intended to delay the the evaluation of the drug and in the transition of an investigation from solution of scientific problems con- Phase 2 to Phase 3. cerning the drug, to the extent that (iv) Advance information. At least 1 FDA’s resources permit. The general month in advance of an end-of-Phase 2 principle underlying the conduct of meeting, the sponsor should submit such meetings is that there should be background information on the spon- free, full, and open communication sor’s plan for Phase 3, including sum- about any scientific or medical ques- maries of the Phase 1 and 2 investigation that may arise during the clinical tions, the specific protocols for Phase 3 investigation. These meetings shall be clinical studies, plans for any addi- conducted and documented in accord- tional nonclinical studies, plans for pe- ance with part 10. diatric studies, including a time line (b) ‘‘End-of-Phase 2’’ meetings and for protocol finalization, enrollment, meetings held before submission of a mar- completion, and data analysis, or infor- keting application. At specific times mation to support any planned request

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for waiver or deferral of pediatric stud- status of ongoing or needed studies ies, and, if available, tentative labeling adequate to assess pediatric safety and for the drug. The recommended con- effectiveness, to acquaint FDA review- tents of such a submission are de- ers with the general information to be scribed more fully in FDA Staff Man- submitted in the marketing applica- ual Guide 4850.7 that is publicly avail- tion (including technical information), able under FDA’s public information to discuss appropriate methods for sta- regulations in part 20. tistical analysis of the data, and to dis- (v) Conduct of meeting. Arrangements cuss the best approach to the presen- for an end-of-Phase 2 meeting are to be tation and formatting of data in the made with the division in FDA’s Center marketing application. Arrangements for Drug Evaluation and Research or for such a meeting are to be initiated the Center for Biologics Evaluation by the sponsor with the division re- and Research which is responsible for sponsible for review of the IND. To per- review of the IND. The meeting will be mit FDA to provide the sponsor with scheduled by FDA at a time convenient the most useful advice on preparing a to both FDA and the sponsor. Both the marketing application, the sponsor sponsor and FDA may bring consult- should submit to FDA’s reviewing divi- ants to the meeting. The meeting sion at least 1 month in advance of the should be directed primarily at estab- meeting the following information: lishing agreement between FDA and (i) A brief summary of the clinical the sponsor of the overall plan for studies to be submitted in the applica- Phase 3 and the objectives and design tion. of particular studies. The adequacy of (ii) A proposed format for organizing the technical information to support the submission, including methods for Phase 3 studies and/or a marketing ap- presenting the data. plication may also be discussed. FDA (iii) Information on the status of will also provide its best judgment, at needed or ongoing pediatric studies. that time, of the pediatric studies that (iv) Any other information for discus- will be required for the drug product sion at the meeting. and whether their submission will be [52 FR 8831, Mar. 19, 1987, as amended at 52 deferred until after approval. Agree- FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, ments reached at the meeting on these 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar. matters will be recorded in minutes of 4, 2002] the conference that will be taken by FDA in accordance with § 10.65 and pro- § 312.48 Dispute resolution. vided to the sponsor. The minutes (a) General. The Food and Drug Ad- along with any other written material ministration is committed to resolving provided to the sponsor will serve as a differences between sponsors and FDA permanent record of any agreements reviewing divisions with respect to re- reached. Barring a significant sci- quirements for IND’s as quickly and entific development that requires oth- amicably as possible through the coop- erwise, studies conducted in accord- erative exchange of information and ance with the agreement shall be pre- views. sumed to be sufficient in objective and (b) Administrative and procedural design for the purpose of obtaining issues. When administrative or proce- marketing approval for the drug. dural disputes arise, the sponsor should (2) ‘‘Pre-NDA’’ and ‘‘pre-BLA’’ meet- first attempt to resolve the matter ings. FDA has found that delays associ- with the division in FDA’s Center for ated with the initial review of a mar- Drug Evaluation and Research or Cen- keting application may be reduced by ter for Biologics Evaluation and Re- exchanges of information about a pro- search which is responsible for review posed marketing application. The pri- of the IND, beginning with the con- mary purpose of this kind of exchange sumer safety officer assigned to the ap- is to uncover any major unresolved plication. If the dispute is not resolved, problems, to identify those studies that the sponsor may raise the matter with the sponsor is relying on as adequate the person designated as ombudsman, and well-controlled to establish the whose function shall be to investigate drug’s effectiveness, to identify the what has happened and to facilitate a

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timely and equitable resolution. Appro- Subpart D—Responsibilities of priate issues to raise with the ombuds- Sponsors and Investigators man include resolving difficulties in scheduling meetings and obtaining § 312.50 General responsibilities of timely replies to inquiries. Further de- sponsors. tails on this procedure are contained in Sponsors are responsible for selecting FDA Staff Manual Guide 4820.7 that is qualified investigators, providing them publicly available under FDA’s public with the information they need to con- information regulations in part 20. duct an investigation properly, ensur- (c) Scientific and medical disputes. (1) ing proper monitoring of the investiga- When scientific or medical disputes tion(s), ensuring that the investiga- arise during the drug investigation tion(s) is conducted in accordance with process, sponsors should discuss the the general investigational plan and matter directly with the responsible protocols contained in the IND, main- reviewing officials. If necessary, spon- taining an effective IND with respect sors may request a meeting with the to the investigations, and ensuring appropriate reviewing officials and that FDA and all participating inves- management representatives in order tigators are promptly informed of sig- to seek a resolution. Requests for such nificant new adverse effects or risks meetings shall be directed to the direc- with respect to the drug. Additional tor of the division in FDA’s Center for specific responsibilities of sponsors are Drug Evaluation and Research or Cen- described elsewhere in this part. ter for Biologics Evaluation and Re- § 312.52 Transfer of obligations to a search which is responsible for review contract research organization. of the IND. FDA will make every attempt to grant requests for meetings (a) A sponsor may transfer responsibility for any or all of the obligations that involve important issues and that set forth in this part to a contract re- can be scheduled at mutually conven- search organization. Any such transfer ient times. shall be described in writing. If not all (2) The ‘‘end-of-Phase 2’’ and ‘‘pre- obligations are transferred, the writing NDA’’ meetings described in § 312.47(b) is required to describe each of the obli- will also provide a timely forum for gations being assumed by the contract discussing and resolving scientific and research organization. If all obligations medical issues on which the sponsor are transferred, a general statement disagrees with the agency. that all obligations have been trans- (3) In requesting a meeting designed ferred is acceptable. Any obligation not to resolve a scientific or medical discovered by the written description pute, applicants may suggest that FDA shall be deemed not to have been trans- seek the advice of outside experts, in ferred. which case FDA may, in its discretion, (b) A contract research organization invite to the meeting one or more of its that assumes any obligation of a spon- advisory committee members or other sor shall comply with the specific regu- consultants, as designated by the agen- lations in this chapter applicable to cy. Applicants may rely on, and may this obligation and shall be subject to bring to any meeting, their own con- the same regulatory action as a spon- sultants. For major scientific and med- sor for failure to comply with any obli- ical policy issues not resolved by infor- gation assumed under these regula- mal meetings, FDA may refer the mat- tions. Thus, all references to ‘‘sponsor’’ ter to one of its standing advisory com- in this part apply to a contract research organization to the extent that mittees for its consideration and rec- it assumes one or more obligations of ommendations. the sponsor. [52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990] § 312.53 Selecting investigators and monitors. (a) Selecting investigators. A sponsor shall select only investigators qualified

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by training and experience as appro- chure, including the potential risks priate experts to investigate the drug. and side effects of the drug; and (b) Control of drug. A sponsor shall (g) Will ensure that all associates, ship investigational new drugs only to colleagues, and employees assisting in investigators participating in the in- the conduct of the study(ies) are investigation. formed about their obligations in (c) Obtaining information from the in- meeting the above commitments. vestigator. Before permitting an investi- (vii) A commitment by the investigator to begin participation in an in- gator that, for an investigation subject vestigation, the sponsor shall obtain to an institutional review requirement the following: under part 56, an IRB that complies (1) A signed investigator statement with the requirements of that part will (Form FDA–1572) containing: be responsible for the initial and con- (i) The name and address of the in- tinuing review and approval of the clin- vestigator; ical investigation and that the investi- (ii) The name and code number, if gator will promptly report to the IRB any, of the protocol(s) in the IND iden- all changes in the research activity and tifying the study(ies) to be conducted all unanticipated problems involving by the investigator; risks to human subjects or others, and (iii) The name and address of any will not make any changes in the re- medical school, hospital, or other research without IRB approval, except search facility where the clinical inves- where necessary to eliminate apparent tigation(s) will be conducted; immediate hazards to the human subjects. (iv) The name and address of any (viii) A list of the names of the sub- clinical laboratory facilities to be used investigators (e.g., research fellows, in the study; residents) who will be assisting the in- (v) The name and address of the IRB vestigator in the conduct of the inves- that is responsible for review and ap- tigation(s). proval of the study(ies); (2) Curriculum vitae. A curriculum (vi) A commitment by the investi- vitae or other statement of qualifica- gator that he or she: tions of the investigator showing the (a) Will conduct the study(ies) in ac- education, training, and experience cordance with the relevant, current that qualifies the investigator as an ex- protocol(s) and will only make changes pert in the clinical investigation of the in a protocol after notifying the spon- drug for the use under investigation. sor, except when necessary to protect (3) Clinical protocol. (i) For Phase 1 in- the safety, the rights, or welfare of vestigations, a general outline of the subjects; planned investigation including the es- (b) Will comply with all requirements timated duration of the study and the regarding the obligations of clinical in- maximum number of subjects that will vestigators and all other pertinent re- be involved. quirements in this part; (ii) For Phase 2 or 3 investigations, (c) Will personally conduct or super- an outline of the study protocol includ- vise the described investigation(s); ing an approximation of the number of (d) Will inform any potential subjects subjects to be treated with the drug that the drugs are being used for inves- and the number to be employed as con- tigational purposes and will ensure trols, if any; the clinical uses to be in- that the requirements relating to ob- vestigated; characteristics of subjects taining informed consent (21 CFR part by age, sex, and condition; the kind of 50) and institutional review board re- clinical observations and laboratory view and approval (21 CFR part 56) are tests to be conducted; the estimated met; duration of the study; and copies or a (e) Will report to the sponsor adverse description of case report forms to be experiences that occur in the course of used. the investigation(s) in accordance with (4) Financial disclosure information. § 312.64; Sufficient accurate financial informa- (f) Has read and understands the in- tion to allow the sponsor to submit formation in the investigator’s bro- complete and accurate certification or

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disclosure statements required under (b) The sponsor shall, as the overall part 54 of this chapter. The sponsor investigation proceeds, keep each par- shall obtain a commitment from the ticipating investigator informed of new clinical investigator to promptly up- observations discovered by or reported date this information if any relevant to the sponsor on the drug, particu- changes occur during the course of the larly with respect to adverse effects investigation and for 1 year following and safe use. Such information may be the completion of the study. distributed to investigators by means (d) Selecting monitors. A sponsor shall of periodically revised investigator select a monitor qualified by training brochures, reprints or published stud- and experience to monitor the progress ies, reports or letters to clinical inves- of the investigation. tigators, or other appropriate means. [52 FR 8831, Mar. 19, 1987, as amended at 52 Important safety information is re- FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, quired to be relayed to investigators in 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. accordance with § 312.32. 4, 2002] [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, § 312.54 Emergency research under 2002] § 50.24 of this chapter. (a) The sponsor shall monitor the § 312.56 Review of ongoing investiga- progress of all investigations involving tions. an exception from informed consent (a) The sponsor shall monitor the under § 50.24 of this chapter. When the progress of all clinical investigations sponsor receives from the IRB informa- being conducted under its IND. tion concerning the public disclosures (b) A sponsor who discovers that an required by § 50.24(a)(7)(ii) and (a)(7)(iii) investigator is not complying with the of this chapter, the sponsor promptly signed agreement (Form FDA–1572), the shall submit to the IND file and to general investigational plan, or the re- Docket Number 95S–0158 in the Divi- quirements of this part or other appli- sion of Dockets Management (HFA– cable parts shall promptly either se- 305), Food and Drug Administration, cure compliance or discontinue ship- 5630 Fishers Lane, rm. 1061, Rockville, ments of the investigational new drug MD 20852, copies of the information to the investigator and end the inves- that was disclosed, identified by the tigator’s participation in the investiga- IND number. tion. If the investigator’s participation (b) The sponsor also shall monitor in the investigation is ended, the spon- such investigations to identify when an sor shall require that the investigator IRB determines that it cannot approve dispose of or return the investigational the research because it does not meet drug in accordance with the require- the criteria in the exception in ments of § 312.59 and shall notify FDA. § 50.24(a) of this chapter or because of (c) The sponsor shall review and other relevant ethical concerns. The evaluate the evidence relating to the sponsor promptly shall provide this in- safety and effectiveness of the drug as formation in writing to FDA, inves- it is obtained from the investigator. tigators who are asked to participate The sponsors shall make such reports in this or a substantially equivalent to FDA regarding information relevant clinical investigation, and other IRB’s to the safety of the drug as are re- that are asked to review this or a sub- quired under § 312.32. The sponsor shall stantially equivalent investigation. make annual reports on the progress of [61 FR 51530, Oct. 2, 1996, as amended at 68 FR the investigation in accordance with 24879, May 9, 2003] § 312.33. (d) A sponsor who determines that its § 312.55 Informing investigators. investigational drug presents an unrea- (a) Before the investigation begins, a sonable and significant risk to subjects sponsor (other than a sponsor-investi- shall discontinue those investigations gator) shall give each participating that present the risk, notify FDA, all clinical investigator an investigator institutional review boards, and all in- brochure containing the information vestigators who have at any time par- described in § 312.23(a)(5). ticipated in the investigation of the

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discontinuance, assure the disposition § 312.58 Inspection of sponsor’s of all stocks of the drug outstanding as records and reports. required by § 312.59, and furnish FDA (a) FDA inspection. A sponsor shall with a full report of the sponsor’s ac- upon request from any properly au- tions. The sponsor shall discontinue thorized officer or employee of the the investigation as soon as possible, Food and Drug Administration, at rea- and in no event later than 5 working days after making the determination sonable times, permit such officer or that the investigation should be dis- employee to have access to and copy continued. Upon request, FDA will con- and verify any records and reports refer with a sponsor on the need to dis- lating to a clinical investigation con- continue an investigation. ducted under this part. Upon written request by FDA, the sponsor shall sub- [52 FR 8831, Mar. 19, 1987, as amended at 52 mit the records or reports (or copies of FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, them) to FDA. The sponsor shall dis- 2002] continue shipments of the drug to any § 312.57 Recordkeeping and record re- investigator who has failed to maintain tention. or make available records or reports of (a) A sponsor shall maintain ade- the investigation as required by this quate records showing the receipt, part. shipment, or other disposition of the (b) Controlled substances. If an inves- investigational drug. These records are tigational new drug is a substance list- required to include, as appropriate, the ed in any schedule of the Controlled name of the investigator to whom the Substances Act (21 U.S.C. 801; 21 CFR drug is shipped, and the date, quantity, part 1308), records concerning ship- and batch or code mark of each such ment, delivery, receipt, and disposition shipment. of the drug, which are required to be (b) A sponsor shall maintain com- kept under this part or other applica- plete and accurate records showing any ble parts of this chapter shall, upon the financial interest in § 54.4(a)(3)(i), request of a properly authorized em- (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this ployee of the Drug Enforcement Ad- chapter paid to clinical investigators ministration of the U.S. Department of by the sponsor of the covered study. A Justice, be made available by the in- sponsor shall also maintain complete vestigator or sponsor to whom the re- and accurate records concerning all quest is made, for inspection and copy- other financial interests of investiga- ing. In addition, the sponsor shall as- tors subject to part 54 of this chapter. sure that adequate precautions are (c) A sponsor shall retain the records taken, including storage of the inves- and reports required by this part for 2 tigational drug in a securely locked, years after a marketing application is substantially constructed cabinet, or approved for the drug; or, if an applica- other securely locked, substantially tion is not approved for the drug, until constructed enclosure, access to which 2 years after shipment and delivery of is limited, to prevent theft or diversion the drug for investigational use is dis- of the substance into illegal channels continued and FDA has been so noti- of distribution. fied. (d) A sponsor shall retain reserve § 312.59 Disposition of unused supply samples of any test article and ref- of investigational drug. erence standard identified in, and used The sponsor shall assure the return in any of the bioequivalence or bio- of all unused supplies of the investiga- availability studies described in, tional drug from each individual inves- § 320.38 or § 320.63 of this chapter, and tigator whose participation in the in- release the reserve samples to FDA vestigation is discontinued or termi- upon request, in accordance with, and nated. The sponsor may authorize al- for the period specified in § 320.38. ternative disposition of unused supplies [52 FR 8831, Mar. 19, 1987, as amended at 52 of the investigational drug provided FR 23031, June 17, 1987; 58 FR 25926, Apr. 28, this alternative disposition does not 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. expose humans to risks from the drug. 4, 2002] The sponsor shall maintain written

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records of any disposition of the drug tional drug or employed as a control in in accordance with § 312.57. the investigation. Case histories in- [52 FR 8831, Mar. 19, 1987, as amended at 52 clude the case report forms and sup- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, porting data including, for example, 2002] signed and dated consent forms and medical records including, for example, § 312.60 General responsibilities of in- progress notes of the physician, the investigators. dividual’s hospital chart(s), and the An investigator is responsible for en- nurses’ notes. The case history for each suring that an investigation is con- individual shall document that in- ducted according to the signed investi- formed consent was obtained prior to gator statement, the investigational participation in the study. plan, and applicable regulations; for (c) Record retention. An investigator protecting the rights, safety, and wel- shall retain records required to be fare of subjects under the investiga- maintained under this part for a period tor’s care; and for the control of drugs of 2 years following the date a mar- under investigation. An investigator keting application is approved for the shall, in accordance with the provi- drug for the indication for which it is sions of part 50 of this chapter, obtain being investigated; or, if no application the informed consent of each human is to be filed or if the application is not subject to whom the drug is adminis- approved for such indication, until 2 tered, except as provided in §§ 50.23 or years after the investigation is discon- 50.24 of this chapter. Additional spe- tinued and FDA is notified. cific responsibilities of clinical investigators are set forth in this part and [52 FR 8831, Mar. 19, 1987, as amended at 52 in parts 50 and 56 of this chapter. FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, 1996; 67 FR 9586, Mar. 4, 2002] [52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51530, Oct. 2, 1996] § 312.64 Investigator reports. § 312.61 Control of the investigational (a) Progress reports. The investigator drug. shall furnish all reports to the sponsor An investigator shall administer the of the drug who is responsible for col- drug only to subjects under the inves- lecting and evaluating the results ob- tigator’s personal supervision or under tained. The sponsor is required under the supervision of a subinvestigator re- § 312.33 to submit annual reports to sponsible to the investigator. The in- FDA on the progress of the clinical investigator shall not supply the inves- vestigations. tigational drug to any person not au- (b) Safety reports. An investigator thorized under this part to receive it. must immediately report to the sponsor any serious adverse event, whether § 312.62 Investigator recordkeeping or not considered drug related, includ- and record retention. ing those listed in the protocol or in- (a) Disposition of drug. An investi- vestigator brochure and must include gator is required to maintain adequate an assessment of whether there is a records of the disposition of the drug, reasonable possibility that the drug including dates, quantity, and use by caused the event. Study endpoints that subjects. If the investigation is termi- are serious adverse events (e.g., all- nated, suspended, discontinued, or cause mortality) must be reported in completed, the investigator shall re- accordance with the protocol unless turn the unused supplies of the drug to there is evidence suggesting a causal the sponsor, or otherwise provide for relationship between the drug and the disposition of the unused supplies of event (e.g., death from anaphylaxis). In the drug under § 312.59. that case, the investigator must imme- (b) Case histories. An investigator is diately report the event to the sponsor. required to prepare and maintain ade- The investigator must record non- quate and accurate case histories that serious adverse events and report them record all observations and other data to the sponsor according to the time- pertinent to the investigation on each table for reporting specified in the pro- individual administered the investiga- tocol.

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(c) Final report. An investigator shall § 312.69 Handling of controlled sub- provide the sponsor with an adequate stances. report shortly after completion of the If the investigational drug is subject investigator’s participation in the in- to the Controlled Substances Act, the vestigation. investigator shall take adequate pre- (d) Financial disclosure reports. The cautions, including storage of the in- clinical investigator shall provide the vestigational drug in a securely locked, sponsor with sufficient accurate finan- substantially constructed cabinet, or cial information to allow an applicant other securely locked, substantially to submit complete and accurate cer- constructed enclosure, access to which tification or disclosure statements as is limited, to prevent theft or diversion required under part 54 of this chapter. of the substance into illegal channels The clinical investigator shall prompt- of distribution. ly update this information if any relevant changes occur during the course § 312.70 Disqualification of a clinical of the investigation and for 1 year fol- investigator. lowing the completion of the study. (a) If FDA has information indicating that an investigator (including a spon- [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63 FR 5252, Feb. 2, sor-investigator) has repeatedly or de- 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963, liberately failed to comply with the re- Sept. 29, 2010] quirements of this part, part 50 or part 56 of this chapter, or has repeatedly or § 312.66 Assurance of IRB review. deliberately submitted to FDA or to the sponsor false information in any An investigator shall assure that an required report, the Center for Drug IRB that complies with the require- Evaluation and Research or the Center ments set forth in part 56 will be re- for Biologics Evaluation and Research sponsible for the initial and continuing will furnish the investigator written review and approval of the proposed notice of the matter complained of and clinical study. The investigator shall offer the investigator an opportunity also assure that he or she will prompt- to explain the matter in writing, or, at ly report to the IRB all changes in the the option of the investigator, in an in- research activity and all unanticipated formal conference. If an explanation is problems involving risk to human sub- offered and accepted by the applicable jects or others, and that he or she will Center, the Center will discontinue the not make any changes in the research disqualification proceeding. If an ex- without IRB approval, except where planation is offered but not accepted necessary to eliminate apparent imme- by the applicable Center, the investi- diate hazards to human subjects. gator will be given an opportunity for [52 FR 8831, Mar. 19, 1987, as amended at 52 a regulatory hearing under part 16 of FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, this chapter on the question of whether 2002] the investigator is eligible to receive test articles under this part and eligi- § 312.68 Inspection of investigator’s ble to conduct any clinical investiga- records and reports. tion that supports an application for a An investigator shall upon request research or marketing permit for prod- from any properly authorized officer or ucts regulated by FDA. employee of FDA, at reasonable times, (b) After evaluating all available in- permit such officer or employee to formation, including any explanation have access to, and copy and verify any presented by the investigator, if the records or reports made by the investi- Commissioner determines that the in- gator pursuant to § 312.62. The investi- vestigator has repeatedly or delib- gator is not required to divulge subject erately failed to comply with the re- names unless the records of particular quirements of this part, part 50 or part individuals require a more detailed 56 of this chapter, or has repeatedly or study of the cases, or unless there is deliberately submitted to FDA or to reason to believe that the records do the sponsor false information in any not represent actual case studies, or do required report, the Commissioner will not represent actual results obtained. notify the investigator, the sponsor of

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any investigation in which the investi- of any obligation under any other ap- gator has been named as a participant, plicable regulation to submit to FDA and the reviewing institutional review the results of the investigation. boards (IRBs) that the investigator is (e) If the Commissioner determines, not eligible to receive test articles after the unreliable data submitted by under this part. The notification to the the investigator are eliminated from investigator, sponsor, and IRBs will consideration, that the continued ap- provide a statement of the basis for proval of the product for which the such determination. The notification data were submitted cannot be justi- also will explain that an investigator fied, the Commissioner will proceed to determined to be ineligible to receive withdraw approval of the product in ac- test articles under this part will be in- cordance with the applicable provisions eligible to conduct any clinical inves- of the relevant statutes. tigation that supports an application (f) An investigator who has been de- for a research or marketing permit for termined to be ineligible under para- products regulated by FDA, including graph (b) of this section may be rein- drugs, biologics, devices, new animal stated as eligible when the Commis- drugs, foods, including dietary supple- sioner determines that the investigator ments, that bear a nutrient content has presented adequate assurances that claim or a health claim, infant for- the investigator will employ all test mulas, food and color additives, and to- articles, and will conduct any clinical bacco products. investigation that supports an applica- (c) Each application or submission to tion for a research or marketing per- FDA under the provisions of this chap- mit for products regulated by FDA, ter containing data reported by an in- solely in compliance with the applica- vestigator who has been determined to ble provisions of this chapter. be ineligible to receive FDA-regulated [77 FR 25359, Apr. 30, 2012] test articles is subject to examination to determine whether the investigator Subpart E—Drugs Intended to has submitted unreliable data that are essential to the continuation of an in- Treat Life-threatening and Se- vestigation or essential to the approval verely-debilitating Illnesses of a marketing application, or essential to the continued marketing of an AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371; FDA-regulated product. 42 U.S.C. 262. (d) If the Commissioner determines, SOURCE: 53 FR 41523, Oct. 21, 1988, unless after the unreliable data submitted by otherwise noted. the investigator are eliminated from consideration, that the data remaining § 312.80 Purpose. are inadequate to support a conclusion The purpose of this section is to es- that it is reasonably safe to continue tablish procedures designed to expedite the investigation, the Commissioner the development, evaluation, and mar- will notify the sponsor, who shall have keting of new therapies intended to an opportunity for a regulatory hear- treat persons with life-threatening and ing under part 16 of this chapter. If a severely-debilitating illnesses, espe- danger to the public health exists, how- cially where no satisfactory alter- ever, the Commissioner shall termi- native therapy exists. As stated nate the IND immediately and notify § 314.105(c) of this chapter, while the the sponsor and the reviewing IRBs of statutory standards of safety and effec- the termination. In such case, the tiveness apply to all drugs, the many sponsor shall have an opportunity for a kinds of drugs that are subject to regulatory hearing before FDA under them, and the wide range of uses for part 16 on the question of whether the those drugs, demand flexibility in ap- IND should be reinstated. The deter- plying the standards. The Food and mination that an investigation may Drug Administration (FDA) has deter- not be considered in support of a re- mined that it is appropriate to exercise search or marketing application or a the broadest flexibility in applying the notification or petition submission statutory standards, while preserving does not, however, relieve the sponsor appropriate guarantees for safety and

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effectiveness. These procedures reflect meeting with FDA-reviewing officials. the recognition that physicians and pa- The primary purpose of this meeting is tients are generally willing to accept to review and reach agreement on the greater risks or side effects from prod- design of animal studies needed to ini- ucts that treat life-threatening and se- tiate human testing. The meeting may verely-debilitating illnesses, than they also provide an opportunity for dis- would accept from products that treat cussing the scope and design of phase 1 less serious illnesses. These procedures testing, plans for studying the drug also reflect the recognition that the product in pediatric populations, and benefits of the drug need to be evalu- the best approach for presentation and ated in light of the severity of the disease being treated. The procedure out- formatting of data in the IND. lined in this section should be inter- (b) End-of-phase 1 meetings. When data preted consistent with that purpose. from phase 1 clinical testing are available, the sponsor may again request a § 312.81 Scope. meeting with FDA-reviewing officials. This section applies to new drug and The primary purpose of this meeting is biological products that are being stud- to review and reach agreement on the ied for their safety and effectiveness in design of phase 2 controlled clinical treating life-threatening or severely- trials, with the goal that such testing debilitating diseases. will be adequate to provide sufficient (a) For purposes of this section, the data on the drug’s safety and effective- term ‘‘life-threatening’’ means: ness to support a decision on its ap- (1) Diseases or conditions where the provability for marketing, and to dis- likelihood of death is high unless the cuss the need for, as well as the design course of the disease is interrupted; and timing of, studies of the drug in pe- and diatric patients. For drugs for life- (2) Diseases or conditions with poten- threatening diseases, FDA will provide tially fatal outcomes, where the end its best judgment, at that time, wheth- point of clinical trial analysis is sur- er pediatric studies will be required vival. and whether their submission will be (b) For purposes of this section, the deferred until after approval. The pro- term ‘‘severely debilitating’’ means cedures outlined in § 312.47(b)(1) with diseases or conditions that cause major irreversible morbidity. respect to end-of-phase 2 conferences, (c) Sponsors are encouraged to con- including documentation of agree- sult with FDA on the applicability of ments reached, would also be used for these procedures to specific products. end-of-phase 1 meetings. [53 FR 41523, Oct. 21, 1988, as amended at 64 [53 FR 41523, Oct. 21, 1988, as amended at 63 FR 401, Jan. 5, 1999] FR 66669, Dec. 2, 1998]

§ 312.82 Early consultation. § 312.83 Treatment protocols. For products intended to treat life- If the preliminary analysis of phase 2 threatening or severely-debilitating ill- test results appears promising, FDA nesses, sponsors may request to meet may ask the sponsor to submit a treat- with FDA-reviewing officials early in ment protocol to be reviewed under the the drug development process to review procedures and criteria listed in and reach agreement on the design of §§ 312.305 and 312.320. Such a treatment necessary preclinical and clinical stud- protocol, if requested and granted, ies. Where appropriate, FDA will invite would normally remain in effect while to such meetings one or more outside the complete data necessary for a mar- expert scientific consultants or advi- keting application are being assembled sory committee members. To the ex- by the sponsor and reviewed by FDA tent FDA resources permit, agency re- (unless grounds exist for clinical hold viewing officials will honor requests of ongoing protocols, as provided in for such meetings § 312.42(b)(3)(ii)). (a) Pre-investigational new drug (IND) meetings. Prior to the submission of the [53 FR 41523, Oct. 21, 1988, as amended at 76 initial IND, the sponsor may request a FR 13880, Mar. 15, 2011]

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§ 312.84 Risk-benefit analysis in review sponsor to conduct certain post- of marketing applications for drugs marketing (phase 4) studies to delin- to treat life-threatening and se- eate additional information about the verely-debilitating illnesses. drug’s risks, benefits, and optimal use. (a) FDA’s application of the statu- These studies could include, but would tory standards for marketing approval not be limited to, studying different shall recognize the need for a medical doses or schedules of administration risk-benefit judgment in making the than were used in phase 2 studies, use final decision on approvability. As part of the drug in other patient popu- of this evaluation, consistent with the lations or other stages of the disease, statement of purpose in § 312.80, FDA or use of the drug over a longer period will consider whether the benefits of of time. the drug outweigh the known and potential risks of the drug and the need § 312.86 Focused FDA regulatory re- to answer remaining questions about search. risks and benefits of the drug, taking At the discretion of the agency, FDA into consideration the severity of the may undertake focused regulatory re- disease and the absence of satisfactory search on critical rate-limiting aspects alternative therapy. of the preclinical, chemical/manufac- (b) In making decisions on whether turing, and clinical phases of drug de- to grant marketing approval for prod- velopment and evaluation. When initi- ucts that have been the subject of an ated, FDA will undertake such re- end-of-phase 1 meeting under § 312.82, FDA will usually seek the advice of search efforts as a means for meeting a outside expert scientific consultants or public health need in facilitating the advisory committees. Upon the filing development of therapies to treat life- of such a marketing application under threatening or severely debilitating ill- § 314.101 or part 601 of this chapter, FDA nesses. will notify the members of the relevant standing advisory committee of the ap- § 312.87 Active monitoring of conduct and evaluation of clinical trials. plication’s filing and its availability for review. For drugs covered under this section, (c) If FDA concludes that the data the Commissioner and other agency of- presented are not sufficient for mar- ficials will monitor the progress of the keting approval, FDA will issue a com- conduct and evaluation of clinical plete response letter under § 314.110 of trials and be involved in facilitating this chapter or the biological product their appropriate progress. licensing procedures. Such letter, in describing the deficiencies in the appli- § 312.88 Safeguards for patient safety. cation, will address why the results of All of the safeguards incorporated the research design agreed to under within parts 50, 56, 312, 314, and 600 of § 312.82, or in subsequent meetings, this chapter designed to ensure the have not provided sufficient evidence safety of clinical testing and the safety for marketing approval. Such letter of products following marketing ap- will also describe any recommenda- proval apply to drugs covered by this tions made by the advisory committee section. This includes the requirements regarding the application. for informed consent (part 50 of this (d) Marketing applications submitted chapter) and institutional review under the procedures contained in this boards (part 56 of this chapter). These section will be subject to the require- safeguards further include the review ments and procedures contained in part of animal studies prior to initial 314 or part 600 of this chapter, as well human testing (§ 312.23), and the moni- as those in this subpart. toring of adverse drug experiences [53 FR 41523, Oct. 21, 1988, as amended at 73 through the requirements of IND safe- FR 39607, July 10, 2008] ty reports (§ 312.32), safety update reports during agency review of a mar- § 312.85 Phase 4 studies. keting application (§ 314.50 of this chap- Concurrent with marketing approval, ter), and postmarketing adverse reac- FDA may seek agreement from the tion reporting (§ 314.80 of this chapter).

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Subpart F—Miscellaneous Programs (HFG–1), Food and Drug Ad- ministration, 5600 Fishers Lane, Rock- § 312.110 Import and export require- ville, MD 20857, at the time the drug is ments. first exported and maintains records (a) Imports. An investigational new documenting compliance with this drug offered for import into the United paragraph. The certification shall de- States complies with the requirements scribe the drug that is to be exported of this part if it is subject to an IND (i.e., trade name (if any), generic name, that is in effect for it under § 312.40 and: and dosage form), identify the country (1) The consignee in the United States or countries to which the drug is to be is the sponsor of the IND; (2) the con- exported, and affirm that: signee is a qualified investigator (i) The drug is intended for export; named in the IND; or (3) the consignee (ii) The drug is intended for inves- is the domestic agent of a foreign spon- tigational use in a foreign country; sor, is responsible for the control and (iii) The drug meets the foreign pur- distribution of the investigational chaser’s or consignee’s specifications; drug, and the IND identifies the con- (iv) The drug is not in conflict with signee and describes what, if any, ac- the importing country’s laws; tions the consignee will take with re- (v) The outer shipping package is la- spect to the investigational drug. beled to show that the package is in- (b) Exports. An investigational new tended for export from the United drug may be exported from the United States; States for use in a clinical investiga- (vi) The drug is not sold or offered for tion under any of the following condi- sale in the United States; tions: (vii) The clinical investigation will (1) An IND is in effect for the drug be conducted in accordance with under § 312.40, the drug complies with § 312.120; the laws of the country to which it is (viii) The drug is manufactured, proc- being exported, and each person who essed, packaged, and held in substan- receives the drug is an investigator in tial conformity with current good man- a study submitted to and allowed to ufacturing practices; proceed under the IND; or (ix) The drug is not adulterated with- (2) The drug has valid marketing au- in the meaning of section 501(a)(1), thorization in Australia, Canada, (a)(2)(A), (a)(3), (c), or (d) of the act; Israel, Japan, New Zealand, Switzer- (x) The drug does not present an im- land, South Africa, or in any country minent hazard to public health, either in the European Union or the European in the United States, if the drug were Economic Area, and complies with the to be reimported, or in the foreign laws of the country to which it is being country; and exported, section 802(b)(1)(A), (f), and (xi) The drug is labeled in accordance (g) of the act, and § 1.101 of this chap- with the foreign country’s laws. ter; or (5) In the event of a national emer- (3) The drug is being exported to Aus- gency in a foreign country, where the tralia, Canada, Israel, Japan, New Zea- national emergency necessitates expor- land, Switzerland, South Africa, or to tation of an investigational new drug, any country in the European Union or the requirements in paragraph (b)(4) of the European Economic Area, and com- this section apply as follows: plies with the laws of the country to (i) Situations where the investigational which it is being exported, the applica- new drug is to be stockpiled in anticipa- ble provisions of section 802(c), (f), and tion of a national emergency. There may (g) of the act, and § 1.101 of this chap- be instances where exportation of an ter. Drugs exported under this para- investigational new drug is needed so graph that are not the subject of an that the drug may be stockpiled and IND are exempt from the label require- made available for use by the import- ment in § 312.6(a); or ing country if and when a national (4) Except as provided in paragraph emergency arises. In such cases: (b)(5) of this section, the person export- (A) A person may export an inves- ing the drug sends a written certifi- tigational new drug under paragraph cation to the Office of International (b)(4) of this section without making

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an affirmation with respect to any one (A) A person may export an inves- or more of paragraphs (b)(4)(i), tigational new drug under paragraph (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), (b)(4) of this section without making (b)(4)(viii), and/or (b)(4)(ix) of this sec- an affirmation with respect to any one tion, provided that he or she: or more of paragraphs (b)(4)(i), (1) Provides a written statement ex- (b)(4)(iv), (b)(4)(v), (b)(4)(vi), (b)(4)(vii), plaining why compliance with each (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), such paragraph is not feasible or is provided that he or she: contrary to the best interests of the in- (1) Provides a written statement ex- dividuals who may receive the inves- plaining why compliance with each tigational new drug; such paragraph is not feasible or is (2) Provides a written statement contrary to the best interests of the in- from an authorized official of the im- dividuals who are expected to receive porting country’s government. The the investigational new drug and statement must attest that the official agrees with the exporter’s statement (2) Provides sufficient information made under paragraph (b)(5)(i)(A)(1) of from an authorized official of the im- this section; explain that the drug is to porting country’s government to en- be stockpiled solely for use of the im- able the Secretary, or his or her des- porting country in a national emer- ignee, to decide whether a national gency; and describe the potential na- emergency has developed or is devel- tional emergency that warrants expor- oping in the importing country, wheth- tation of the investigational new drug er the investigational new drug will be under this provision; and used solely for that national emer- (3) Provides a written statement gency, and whether prompt exportation showing that the Secretary of Health of the investigational new drug is nec- and Human Services (the Secretary), or essary. Persons who wish to obtain a his or her designee, agrees with the determination from the Secretary findings of the authorized official of should direct their requests to Sec- the importing country’s government. retary’s Operations Center, Office of Persons who wish to obtain a written Emergency Operations and Security statement from the Secretary should Programs, Office of Public Health direct their requests to Secretary’s Op- Emergency Preparedness, Office of the erations Center, Office of Emergency Secretary, Department of Health and Operations and Security Programs, Of- Human Services, 200 Independence Ave. fice of Public Health Emergency Pre- SW., Washington, DC 20201. Requests paredness, Office of the Secretary, De- may be also be sent by FAX: 202–619– partment of Health and Human Serv- 7870 or by e-mail: [email protected]. ices, 200 Independence Ave. SW., Wash- (B) Exportation may proceed without ington, DC 20201. Requests may be also prior FDA authorization. be sent by FAX: 202–619–7870 or by e- (c) Limitations. Exportation under mail: [email protected]. paragraph (b) of this section may not (B) Exportation may not proceed occur if: until FDA has authorized exportation (1) For drugs exported under para- of the investigational new drug. FDA graph (b)(1) of this section, the IND may deny authorization if the state- pertaining to the clinical investigation ments provided under paragraphs is no longer in effect; (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) of this section are inadequate or if expor- (2) For drugs exported under para- tation is contrary to public health. graph (b)(2) of this section, the require- (ii) Situations where the investigational ments in section 802(b)(1), (f), or (g) of new drug is to be used for a sudden and the act are no longer met; immediate national emergency. There (3) For drugs exported under para- may be instances where exportation of graph (b)(3) of this section, the require- an investigational new drug is needed ments in section 802(c), (f), or (g) of the so that the drug may be used in a sud- act are no longer met; den and immediate national emergency (4) For drugs exported under para- that has developed or is developing. In graph (b)(4) of this section, the condi- such cases: tions underlying the certification or

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the statements submitted under para- § 50.24(a) of this chapter, or that the graph (b)(5) of this section are no measures described in the study pro- longer met; or tocol or elsewhere will protect the (5) For any investigational new drugs rights, safety, and well-being of sub- under this section, the drug no longer jects; and complies with the laws of the import- (ii) FDA is able to validate the data ing country. from the study through an onsite in- (d) Insulin and antibiotics. New insulin spection if the agency deems it nec- and antibiotic drug products may be essary. exported for investigational use in ac- (2) Although FDA will not accept as cordance with section 801(e)(1) of the support for an IND or application for act without complying with this sec- marketing approval a study that does tion. not meet the conditions of paragraph [52 FR 8831, Mar. 19, 1987, as amended at 52 (a)(1) of this section, FDA will examine FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999; data from such a study. 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23, (3) Marketing approval of a new drug 2005] based solely on foreign clinical data is governed by § 314.106 of this chapter. § 312.120 Foreign clinical studies not (b) Supporting information. A sponsor conducted under an IND. or applicant who submits data from a (a) Acceptance of studies. (1) FDA will foreign clinical study not conducted accept as support for an IND or appli- under an IND as support for an IND or cation for marketing approval (an ap- application for marketing approval plication under section 505 of the act or must submit to FDA, in addition to in- section 351 of the Public Health Service formation required elsewhere in parts Act (the PHS Act) (42 U.S.C. 262)) a 312, 314, or 601 of this chapter, a de- well-designed and well-conducted for- scription of the actions the sponsor or eign clinical study not conducted under applicant took to ensure that the re- an IND, if the following conditions are search conformed to GCP as described met: in paragraph (a)(1)(i) of this section. (i) The study was conducted in ac- The description is not required to du- cordance with good clinical practice plicate information already submitted (GCP). For the purposes of this section, in the IND or application for mar- GCP is defined as a standard for the de- keting approval. Instead, the descrip- sign, conduct, performance, moni- tion must provide either the following toring, auditing, recording, analysis, information or a cross-reference to an- and reporting of clinical trials in a way other section of the submission where that provides assurance that the data the information is located: and reported results are credible and (1) The investigator’s qualifications; accurate and that the rights, safety, (2) A description of the research fa- and well-being of trial subjects are pro- cilities; tected. GCP includes review and ap- (3) A detailed summary of the pro- proval (or provision of a favorable tocol and results of the study and, opinion) by an independent ethics com- should FDA request, case records main- mittee (IEC) before initiating a study, tained by the investigator or addi- continuing review of an ongoing study tional background data such as hos- by an IEC, and obtaining and docu- pital or other institutional records; menting the freely given informed con- (4) A description of the drug sub- sent of the subject (or a subject’s le- stance and drug product used in the gally authorized representative, if the study, including a description of the subject is unable to provide informed components, formulation, specifica- consent) before initiating a study. GCP tions, and, if available, bioavailability does not require informed consent in of the specific drug product used in the life-threatening situations when the clinical study; IEC reviewing the study finds, before (5) If the study is intended to support initiation of the study, that informed the effectiveness of a drug product, in- consent is not feasible and either that formation showing that the study is the conditions present are consistent adequate and well controlled under with those described in § 50.23 or § 314.126 of this chapter;

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(6) The name and address of the IEC (2) FDA may grant a waiver if it finds that reviewed the study and a state- that doing so would be in the interest ment that the IEC meets the definition of the public health. in § 312.3 of this chapter. The sponsor or (d) Records. A sponsor or applicant applicant must maintain records sup- must retain the records required by porting such statement, including this section for a foreign clinical study records of the names and qualifications not conducted under an IND as follows: of IEC members, and make these (1) If the study is submitted in sup- records available for agency review port of an application for marketing upon request; approval, for 2 years after an agency (7) A summary of the IEC’s decision decision on that application; to approve or modify and approve the (2) If the study is submitted in sup- study, or to provide a favorable opin- port of an IND but not an application ion; for marketing approval, for 2 years (8) A description of how informed after the submission of the IND. consent was obtained; (9) A description of what incentives, [73 FR 22815, Apr. 28, 2008] if any, were provided to subjects to § 312.130 Availability for public disclo- participate in the study; sure of data and information in an (10) A description of how the spon- IND. sor(s) monitored the study and ensured (a) The existence of an investiga- that the study was carried out consist- ently with the study protocol; and tional new drug application will not be disclosed by FDA unless it has pre- (11) A description of how investiga- viously been publicly disclosed or ac- tors were trained to comply with GCP (as described in paragraph (a)(1)(i) of knowledged. this section) and to conduct the study (b) The availability for public disclo- in accordance with the study protocol, sure of all data and information in an and a statement on whether written investigational new drug application commitments by investigators to com- for a new drug will be handled in ac- ply with GCP and the protocol were ob- cordance with the provisions estab- tained. Any signed written commit- lished in § 314.430 for the confidentiality ments by investigators must be main- of data and information in applications tained by the sponsor or applicant and submitted in part 314. The availability made available for agency review upon for public disclosure of all data and in- request. formation in an investigational new (c) Waivers. (1) A sponsor or applicant drug application for a biological prod- may ask FDA to waive any applicable uct will be governed by the provisions requirements under paragraphs (a)(1) of §§ 601.50 and 601.51. and (b) of this section. A waiver re- (c) Notwithstanding the provisions of quest may be submitted in an IND or in § 314.430, FDA shall disclose upon re- an information amendment to an IND, quest to an individual to whom an in- or in an application or in an amend- vestigational new drug has been given ment or supplement to an application a copy of any IND safety report relat- submitted under part 314 or 601 of this ing to the use in the individual. chapter. A waiver request is required (d) The availability of information to contain at least one of the following: required to be publicly disclosed for in- (i) An explanation why the sponsor’s vestigations involving an exception or applicant’s compliance with the re- from informed consent under § 50.24 of quirement is unnecessary or cannot be this chapter will be handled as follows: achieved; Persons wishing to request the publicly (ii) A description of an alternative disclosable information in the IND that submission or course of action that was required to be filed in Docket satisfies the purpose of the require- Number 95S–0158 in the Division of ment; or Dockets Management (HFA–305), Food (iii) Other information justifying a and Drug Administration, 5630 Fishers waiver. Lane, rm. 1061, Rockville, MD 20852,

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shall submit a request under the Free- Administration, 5600 Fishers Lane, dom of Information Act. Rockville, MD 20857. [52 FR 8831, Mar. 19, 1987. Redesignated at 53 [70 FR 14981, Mar. 24, 2005, as amended at 74 FR 41523, Oct. 21, 1988, as amended at 61 FR FR 13113, Mar. 26, 2009; 74 FR 55771, Oct. 29, 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68 2009; 75 FR 37295, June 29, 2010; 80 FR 18091, FR 24879, May 9, 2003] Apr. 3, 2015; 81 FR 17066, Mar. 28, 2016; 84 FR 6673, Feb. 28, 2019] § 312.140 Address for correspondence. § 312.145 Guidance documents. (a) A sponsor must send an initial IND submission to the Center for Drug (a) FDA has made available guidance Evaluation and Research (CDER) or to documents under § 10.115 of this chapter the Center for Biologics Evaluation to help you to comply with certain re- and Research (CBER), depending on the quirements of this part. Center responsible for regulating the (b) The Center for Drug Evaluation product as follows: and Research (CDER) and the Center for Biologics Evaluation and Research (1) For drug products regulated by (CBER) maintain lists of guidance doc- CDER. Send the IND submission to the uments that apply to the centers’ regu- Central Document Room, Center for lations. The lists are maintained on Drug Evaluation and Research, Food the Internet and are published annu- and Drug Administration, 5901–B ally in the FEDERAL REGISTER. A re- Ammendale Rd., Beltsville, MD 20705– quest for a copy of the CDER list 1266. should be directed to the Office of (2) For biological products regulated by Training and Communications, Divi- CDER. Send the IND submission to the sion of Drug Information, Center for Central Document Room, Center for Drug Evaluation and Research, Food Drug Evaluation and Research, Food and Drug Administration, 10903 New and Drug Administration, 5901–B Hampshire Ave., Silver Spring, MD Ammendale Rd., Beltsville, MD 20705– 20993–0002. A request for a copy of the 1266. CBER list should be directed to the (3) For biological products regulated by Food and Drug Administration, Center CBER. Send the IND submission to the for Biologics Evaluation and Research, Food and Drug Administration, Center Office of Communication, Outreach and for Biologics Evaluation and Research, Development, 10903 New Hampshire Document Control Center, 10903 New Ave., Bldg. 71, Rm. 3103, Silver Spring, Hampshire Ave., Bldg. 71, Rm. G112, MD 20993–0002. Silver Spring, MD 20993–0002. [65 FR 56479, Sept. 19, 2000, as amended at 74 (b) On receiving the IND, the respon- FR 13113, Mar. 26, 2009; 80 FR 18091, Apr. 3, sible Center will inform the sponsor 2015] which one of the divisions in CDER or CBER is responsible for the IND. Subpart G—Drugs for Investiga- Amendments, reports, and other cor- tional Use in Laboratory Re- respondence relating to matters cov- search Animals or In Vitro ered by the IND should be sent to the Tests appropriate center at the address indicated in this section and marked to the § 312.160 Drugs for investigational use attention of the responsible division. in laboratory research animals or The outside wrapper of each submis- in vitro tests. sion shall state what is contained in (a) Authorization to ship. (1)(i) A per- the submission, for example, ‘‘IND Ap- son may ship a drug intended solely for plication’’, ‘‘Protocol Amendment’’, tests in vitro or in animals used only etc. for laboratory research purposes if it is (c) All correspondence relating to ex- labeled as follows: port of an investigational drug under CAUTION: Contains a new drug for inves- § 312.110(b)(2) shall be submitted to the tigational use only in laboratory research International Affairs Staff (HFY–50), animals, or for tests in vitro. Not for use in Office of Health Affairs, Food and Drug humans.

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(ii) A person may ship a biological the return of all unused supplies of the product for investigational in vitro di- drug from individual investigators agnostic use that is listed in whenever the investigation discon- § 312.2(b)(2)(ii) if it is labeled as follows: tinues or the investigation is termi- CAUTION: Contains a biological product nated. The person who ships the drug for investigational in vitro diagnostic tests may authorize in writing alternative only. disposition of unused supplies of the drug provided this alternative disposi- (2) A person shipping a drug under tion does not expose humans to risks paragraph (a) of this section shall use from the drug, either directly or indi- due diligence to assure that the con- rectly (e.g., through food-producing signee is regularly engaged in con- animals). The shipper shall maintain ducting such tests and that the ship- records of any alternative disposition. ment of the new drug will actually be used for tests in vitro or in animals [52 FR 8831, Mar. 19, 1987, as amended at 52 used only for laboratory research. FR 23031, June 17, 1987. Redesignated at 53 (3) A person who ships a drug under FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4, paragraph (a) of this section shall 2002] maintain adequate records showing the name and post office address of the ex- Subpart H [Reserved] pert to whom the drug is shipped and the date, quantity, and batch or code Subpart I—Expanded Access to mark of each shipment and delivery. Investigational Drugs for Treat- Records of shipments under paragraph ment Use (a)(1)(i) of this section are to be maintained for a period of 2 years after the shipment. Records and reports of data SOURCE: 74 FR 40942, Aug. 13, 2009, unless and shipments under paragraph otherwise noted. (a)(1)(ii) of this section are to be main- § 312.300 General. tained in accordance with § 312.57(b). The person who ships the drug shall (a) Scope. This subpart contains the upon request from any properly au- requirements for the use of investiga- thorized officer or employee of the tional new drugs and approved drugs Food and Drug Administration, at rea- where availability is limited by a risk sonable times, permit such officer or evaluation and mitigation strategy employee to have access to and copy (REMS) when the primary purpose is to and verify records required to be main- diagnose, monitor, or treat a patient’s tained under this section. disease or condition. The aim of this (b) Termination of authorization to subpart is to facilitate the availability ship. FDA may terminate authoriza- of such drugs to patients with serious tion to ship a drug under this section if diseases or conditions when there is no it finds that: comparable or satisfactory alternative (1) The sponsor of the investigation therapy to diagnose, monitor, or treat has failed to comply with any of the the patient’s disease or condition. conditions for shipment established (b) Definitions. The following defini- under this section; or tions of terms apply to this subpart: (2) The continuance of the investiga- Immediately life-threatening disease or tion is unsafe or otherwise contrary to condition means a stage of disease in the public interest or the drug is used which there is reasonable likelihood for purposes other than bona fide sci- that death will occur within a matter entific investigation. FDA will notify of months or in which premature death the person shipping the drug of its find- is likely without early treatment. ing and invite immediate correction. If Serious disease or condition means a correction is not immediately made, disease or condition associated with the person shall have an opportunity morbidity that has substantial impact for a regulatory hearing before FDA on day-to-day functioning. Short-lived pursuant to part 16. and self-limiting morbidity will usu- (c) Disposition of unused drug. The ally not be sufficient, but the mor- person who ships the drug under para- bidity need not be irreversible, pro- graph (a) of this section shall assure vided it is persistent or recurrent.

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Whether a disease or condition is seri- narily be tried before resorting to the ous is a matter of clinical judgment, investigational drug or an explanation based on its impact on such factors as of why the use of the investigational survival, day-to-day functioning, or the drug is preferable to the use of avail- likelihood that the disease, if left unable therapeutic options; treated, will progress from a less severe (iii) The criteria for patient selection condition to a more serious one. or, for an individual patient, a description of the patient’s disease or condi- § 312.305 Requirements for all ex- tion, including recent medical history panded access uses. and previous treatments of the disease The criteria, submission require- or condition; ments, safeguards, and beginning treat- (iv) The method of administration of ment information set out in this sec- the drug, dose, and duration of ther- tion apply to all expanded access uses apy; described in this subpart. Additional (v) A description of the facility where criteria, submission requirements, and the drug will be manufactured; safeguards that apply to specific types (vi) Chemistry, manufacturing, and of expanded access are described in controls information adequate to en- §§ 312.310 through 312.320. sure the proper identification, quality, (a) Criteria. FDA must determine purity, and strength of the investiga- that: tional drug; (1) The patient or patients to be (vii) Pharmacology and toxicology treated have a serious or immediately information adequate to conclude that life-threatening disease or condition, the drug is reasonably safe at the dose and there is no comparable or satisfac- and duration proposed for expanded ac- tory alternative therapy to diagnose, cess use (ordinarily, information that monitor, or treat the disease or condi- would be adequate to permit clinical tion; testing of the drug in a population of (2) The potential patient benefit jus- the size expected to be treated); and tifies the potential risks of the treat- (viii) A description of clinical proce- ment use and those potential risks are dures, laboratory tests, or other moni- not unreasonable in the context of the toring necessary to evaluate the effects disease or condition to be treated; and of the drug and minimize its risks. (3) Providing the investigational drug (3) The expanded access submission for the requested use will not interfere and its mailing cover must be plainly with the initiation, conduct, or com- marked ‘‘EXPANDED ACCESS SUB- pletion of clinical investigations that MISSION.’’ If the expanded access sub- could support marketing approval of mission is for a treatment IND or the expanded access use or otherwise treatment protocol, the applicable box compromise the potential development on Form FDA 1571 must be checked. of the expanded access use. (c) Safeguards. The responsibilities of (b) Submission. (1) An expanded access sponsors and investigators set forth in submission is required for each type of subpart D of this part are applicable to expanded access described in this sub- expanded access use under this subpart part. The submission may be a new as described in this paragraph. IND or a protocol amendment to an ex- (1) A licensed physician under whose isting IND. Information required for a immediate direction an investigational submission may be supplied by refer- drug is administered or dispensed for ring to pertinent information con- an expanded access use under this sub- tained in an existing IND if the sponsor part is considered an investigator, for of the existing IND grants a right of purposes of this part, and must comply reference to the IND. with the responsibilities for investiga- (2) The expanded access submission tors set forth in subpart D of this part must include: to the extent they are applicable to the (i) A cover sheet (Form FDA 1571) expanded access use. meeting the requirements of § 312.23(a); (2) An individual or entity that sub- (ii) The rationale for the intended use mits an expanded access IND or proof the drug, including a list of available tocol under this subpart is considered a therapeutic options that would ordi- sponsor, for purposes of this part, and

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must comply with the responsibilities earlier notification by FDA that the for sponsors set forth in subpart D of expanded access use may begin. this part to the extent they are appli- (2) Protocols. With the following ex- cable to the expanded access use. ceptions, expanded access use under a (3) A licensed physician under whose protocol submitted under an existing immediate direction an investigational IND may begin as described in drug is administered or dispensed, and § 312.30(a). who submits an IND for expanded ac- (i) Expanded access use under the cess use under this subpart is consid- emergency procedures described in ered a sponsor-investigator, for purposes § 312.310(d) may begin when the use is of this part, and must comply with the authorized by the FDA reviewing offi- responsibilities for sponsors and inves- cial. tigators set forth in subpart D of this (ii) Expanded access use under part to the extent they are applicable § 312.320 may begin 30 days after FDA to the expanded access use. receives the protocol or upon earlier (4) Investigators. In all cases of ex- notification by FDA that use may panded access, investigators are re- begin. sponsible for reporting adverse drug (3) Clinical holds. FDA may place any events to the sponsor, ensuring that expanded access IND or protocol on the informed consent requirements of clinical hold as described in § 312.42. part 50 of this chapter are met, ensuring that IRB review of the expanded ac- § 312.310 Individual patients, includ- cess use is obtained in a manner con- ing for emergency use. sistent with the requirements of part Under this section, FDA may permit 56 of this chapter, and maintaining ac- an investigational drug to be used for curate case histories and drug disposi- the treatment of an individual patient tion records and retaining records in a by a licensed physician. manner consistent with the require- (a) Criteria. The criteria in § 312.305(a) ments of § 312.62. Depending on the type must be met; and the following deter- of expanded access, other investigator minations must be made: responsibilities under subpart D may (1) The physician must determine also apply. that the probable risk to the person (5) Sponsors. In all cases of expanded from the investigational drug is not access, sponsors are responsible for greater than the probable risk from the submitting IND safety reports and an- disease or condition; and nual reports (when the IND or protocol (2) FDA must determine that the pa- continues for 1 year or longer) to FDA tient cannot obtain the drug under an- as required by §§ 312.32 and 312.33, en- other IND or protocol. suring that licensed physicians are (b) Submission. The expanded access qualified to administer the investiga- submission must include information tional drug for the expanded access adequate to demonstrate that the cri- use, providing licensed physicians with teria in § 312.305(a) and paragraph (a) of the information needed to minimize this section have been met. The ex- the risk and maximize the potential panded access submission must meet benefits of the investigational drug the requirements of § 312.305(b). (the investigator’s brochure must be (1) If the drug is the subject of an ex- provided if one exists for the drug), isting IND, the expanded access sub- maintaining an effective IND for the mission may be made by the sponsor or expanded access use, and maintaining by a licensed physician. adequate drug disposition records and (2) A sponsor may satisfy the submis- retaining records in a manner con- sion requirements by amending its ex- sistent with the requirements of isting IND to include a protocol for in- § 312.57. Depending on the type of ex- dividual patient expanded access. panded access, other sponsor respon- (3) A licensed physician may satisfy sibilities under subpart D may also the submission requirements by ob- apply. taining from the sponsor permission (d) Beginning treatment—(1) INDs. An for FDA to refer to any information in expanded access IND goes into effect 30 the IND that would be needed to sup- days after FDA receives the IND or on port the expanded access request (right

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of reference) and by providing any submit an expanded access submission other required information not con- within 15 working days of FDA’s au- tained in the IND (usually only the in- thorization of the use. formation specific to the individual pa- [74 FR 40942, Aug. 13, 2009, as amended at 75 tient). FR 32659, June 9, 2010; 80 FR 18091, Apr. 3, (c) Safeguards. (1) Treatment is gen- 2015] erally limited to a single course of therapy for a specified duration unless § 312.315 Intermediate-size patient FDA expressly authorizes multiple populations. courses or chronic therapy. Under this section, FDA may permit (2) At the conclusion of treatment, an investigational drug to be used for the licensed physician or sponsor must the treatment of a patient population provide FDA with a written summary smaller than that typical of a treat- of the results of the expanded access ment IND or treatment protocol. FDA use, including adverse effects. may ask a sponsor to consolidate ex- (3) FDA may require sponsors to panded access under this section when monitor an individual patient ex- the agency has received a significant panded access use if the use is for an number of requests for individual pa- extended duration. tient expanded access to an investiga- (4) When a significant number of tional drug for the same use. similar individual patient expanded ac- (a) Need for expanded access. Expanded cess requests have been submitted, access under this section may be need- FDA may ask the sponsor to submit an ed in the following situations: IND or protocol for the use under (1) Drug not being developed. The drug § 312.315 or § 312.320. is not being developed, for example, be- (d) Emergency procedures. If there is cause the disease or condition is so an emergency that requires the patient rare that the sponsor is unable to re- to be treated before a written submis- cruit patients for a clinical trial. sion can be made, FDA may authorize (2) Drug being developed. The drug is the expanded access use to begin with- being studied in a clinical trial, but pa- out a written submission. The FDA re- tients requesting the drug for expanded viewing official may authorize the access use are unable to participate in emergency use by telephone. the trial. For example, patients may (1) Emergency expanded access use not be able to participate in the trial may be requested by telephone, fac- because they have a different disease or simile, or other means of electronic stage of disease than the one being communications. For investigational studied or otherwise do not meet the biological drug products regulated by enrollment criteria, because enroll- the Center for Biologics Evaluation ment in the trial is closed, or because and Research, the request should be di- the trial site is not geographically ac- rected to the Office of Communication, cessible. Outreach and Development, Center for (3) Approved or related drug. (i) The Biologics Evaluation and Research, 240- drug is an approved drug product that 402-8010 or 1–800–835–4709, e-mail: is no longer marketed for safety rea- [email protected]. For all other inves- sons or is unavailable through mar- tigational drugs, the request for au- keting due to failure to meet the con- thorization should be directed to the ditions of the approved application, or Division of Drug Information, Center (ii) The drug contains the same ac- for Drug Evaluation and Research, 301– tive moiety as an approved drug prod- 796–3400, e-mail: [email protected]. uct that is unavailable through mar- After normal working hours (8 a.m. to keting due to failure to meet the con- 4:30 p.m.), the request should be di- ditions of the approved application or a rected to the FDA Emergency Call Cen- drug shortage. ter, 866–300–4374, e-mail: emer- (b) Criteria. The criteria in § 312.305(a) [email protected]. must be met; and FDA must determine (2) The licensed physician or sponsor that: must explain how the expanded access (1) There is enough evidence that the use will meet the requirements of drug is safe at the dose and duration §§ 312.305 and 312.310 and must agree to proposed for expanded access use to

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justify a clinical trial of the drug in tocol to ensure that licensed physi- the approximate number of patients ex- cians comply with the protocol and the pected to receive the drug under ex- regulations applicable to investigators. panded access; and (2) There is at least preliminary clin- § 312.320 Treatment IND or treatment ical evidence of effectiveness of the protocol. drug, or of a plausible pharmacologic Under this section, FDA may permit effect of the drug to make expanded ac- an investigational drug to be used for cess use a reasonable therapeutic op- widespread treatment use. tion in the anticipated patient popu- (a) Criteria. The criteria in § 312.305(a) lation. must be met, and FDA must determine (c) Submission. The expanded access that: submission must include information (1) Trial status. (i) The drug is being adequate to satisfy FDA that the cri- investigated in a controlled clinical teria in § 312.305(a) and paragraph (b) of trial under an IND designed to support this section have been met. The ex- a marketing application for the expanded access submission must meet panded access use, or the requirements of § 312.305(b). In addition: (ii) All clinical trials of the drug (1) The expanded access submission have been completed; and must state whether the drug is being (2) Marketing status. The sponsor is developed or is not being developed and actively pursuing marketing approval describe the patient population to be of the drug for the expanded access use treated. with due diligence; and (2) If the drug is not being actively (3) Evidence. (i) When the expanded developed, the sponsor must explain access use is for a serious disease or why the drug cannot currently be de- condition, there is sufficient clinical veloped for the expanded access use and evidence of safety and effectiveness to under what circumstances the drug support the expanded access use. Such could be developed. evidence would ordinarily consist of (3) If the drug is being studied in a data from phase 3 trials, but could con- clinical trial, the sponsor must explain sist of compelling data from completed why the patients to be treated cannot phase 2 trials; or be enrolled in the clinical trial and (ii) When the expanded access use is under what circumstances the sponsor for an immediately life-threatening would conduct a clinical trial in these disease or condition, the available sci- patients. entific evidence, taken as a whole, pro- (d) Safeguards. (1) Upon review of the vides a reasonable basis to conclude IND annual report, FDA will determine that the investigational drug may be whether it is appropriate for the ex- effective for the expanded access use panded access to continue under this and would not expose patients to an section. unreasonable and significant risk of ill- (i) If the drug is not being actively ness or injury. This evidence would or- developed or if the expanded access use dinarily consist of clinical data from is not being developed (but another use phase 3 or phase 2 trials, but could be is being developed), FDA will consider based on more preliminary clinical evi- whether it is possible to conduct a clin- dence. ical study of the expanded access use. (b) Submission. The expanded access (ii) If the drug is being actively de- submission must include information veloped, FDA will consider whether adequate to satisfy FDA that the cri- providing the investigational drug for teria in § 312.305(a) and paragraph (a) of expanded access use is interfering with this section have been met. The ex- the clinical development of the drug. panded access submission must meet (iii) As the number of patients en- the requirements of § 312.305(b). rolled increases, FDA may ask the (c) Safeguard. The sponsor is respon- sponsor to submit an IND or protocol sible for monitoring the treatment pro- for the use under § 312.320. tocol to ensure that licensed physi- (2) The sponsor is responsible for cians comply with the protocol and the monitoring the expanded access pro- regulations applicable to investigators.

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PART 314—APPLICATIONS FOR FDA 314.105 Approval of an NDA and an ANDA. APPROVAL TO MARKET A NEW 314.106 Foreign data. 314.107 Date of approval of a 505(b)(2) appli- DRUG cation or ANDA. 314.108 New drug product exclusivity. Subpart A—General Provisions 314.110 Complete response letter to the ap- Sec. plicant. 314.1 Scope of this part. 314.120 [Reserved] 314.2 Purpose. 314.122 Submitting an abbreviated applica- 314.3 Definitions. tion for, or a 505(j)(2)(C) petition that relies on, a listed drug that is no longer Subpart B—Applications marketed. 314.125 Refusal to approve an NDA. 314.50 Content and format of an NDA. 314.126 Adequate and well-controlled stud- 314.52 Notice of certification of invalidity, ies. unenforceability, or noninfringement of 314.127 Refusal to approve an ANDA. a patent. 314.53 Submission of patent information. 314.150 Withdrawal of approval of an appli- 314.54 Procedure for submission of a cation or abbreviated application. 505(b)(2) application requiring investiga- 314.151 Withdrawal of approval of an abbre- tions for approval of a new indication viated new drug application under sec- for, or other change from, a listed drug. tion 505(j)(5) of the act. 314.55 Pediatric use information. 314.152 Notice of withdrawal of approval of 314.60 Amendments to an unapproved appli- an application or abbreviated application cation, supplement, or resubmission. for a new drug. 314.65 Withdrawal by the applicant of an un- 314.153 Suspension of approval of an abbre- approved application. viated new drug application. 314.70 Supplements and other changes to an 314.160 Approval of an application or abbre- approved NDA. viated application for which approval 314.71 Procedures for submission of a sup- was previously refused, suspended, or plement to an approved application. withdrawn. 314.72 Change in ownership of an applica- 314.161 Determination of reasons for vol- tion. untary withdrawal of a listed drug. 314.80 Postmarketing reporting of adverse 314.162 Removal of a drug product from the drug experiences. list. 314.81 Other postmarketing reports. 314.170 Adulteration and misbranding of an 314.90 Waivers. approved drug. Subpart C—Abbreviated Applications Subpart E—Hearing Procedures for New 314.92 Drug products for which abbreviated Drugs applications may be submitted. 314.93 Petition to request a change from a 314.200 Notice of opportunity for hearing; listed drug. notice of participation and request for 314.94 Content and format of an ANDA. hearing; grant or denial of hearing. 314.95 Notice of certification of invalidity, 314.201 Procedure for hearings. unenforceability, or noninfringement of 314.235 Judicial review. a patent. 314.96 Amendments to an unapproved Subpart F [Reserved] ANDA. 314.97 Supplements and other changes to an Subpart G—Miscellaneous Provisions approved ANDA. 314.98 Postmarketing reports. 314.410 Imports and exports of new drugs. 314.99 Other responsibilities of an applicant 314.420 Drug master files. of an ANDA. 314.430 Availability for public disclosure of data and information in an application Subpart D—FDA Action on Applications or abbreviated application. and Abbreviated Applications 314.440 Addresses for applications and ab- 314.100 Timeframes for reviewing applica- breviated applications. tions and abbreviated applications. 314.445 Guidance documents. 314.101 Filing an NDA and receiving an ANDA. Subpart H—Accelerated Approval of New 314.102 Communications between FDA and Drugs for Serious or Life-Threatening Ill- applicants. nesses 314.103 Dispute resolution. 314.104 Drugs with potential for abuse. 314.500 Scope.

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314.510 Approval based on a surrogate end- the approval of drugs shown to be safe point or on an effect on a clinical end- and effective; and (b) ensure the dis- point other than survival or irreversible approval of drugs not shown to be safe morbidity. 314.520 Approval with restrictions to assure and effective. These regulations are safe use. also intended to establish an effective 314.530 Withdrawal procedures. system for FDA’s surveillance of mar- 314.540 Postmarketing safety reporting. keted drugs. These regulations shall be 314.550 Promotional materials. construed in light of these objectives. 314.560 Termination of requirements.

Subpart I—Approval of New Drugs When § 314.3 Definitions. Human Efficacy Studies Are Not Ethical (a) The definitions and interpreta- or Feasible tions contained in section 201 of the Federal Food, Drug, and Cosmetic Act 314.600 Scope. 314.610 Approval based on evidence of effec- apply to those terms when used in this tiveness from studies in animals. part and part 320 of this chapter. 314.620 Withdrawal procedures. (b) The following definitions of terms 314.630 Postmarketing safety reporting. apply to this part and part 320 of this 314.640 Promotional materials. chapter: 314.650 Termination of requirements. 180-day exclusivity period is the 180- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, day period beginning on the date of the 355, 355a, 355f, 356, 356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k–1. first commercial marketing of the drug (including the commercial marketing SOURCE: 50 FR 7493, Feb. 22, 1985, unless of the reference listed drug) by any otherwise noted. first applicant. The 180-day period ends EDITORIAL NOTE: Nomenclature changes to on the day before the date on which an part 314 appear at 69 FR 13717, Mar. 24, 2004; ANDA submitted by an applicant other 81 FR 69639, Oct. 6, 2016. than a first applicant could be approved. Subpart A—General Provisions 505(b)(2) application is an NDA sub- § 314.1 Scope of this part. mitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (a) This part sets forth procedures for a drug for which at least some of and requirements for the submission the investigations described in section to, and the review by, the Food and 505(b)(1)(A) of the Federal Food, Drug, Drug Administration of applications and Cosmetic Act and relied upon by and abbreviated applications to market a new drug under section 505 of the the applicant for approval of the NDA Federal Food, Drug, and Cosmetic Act, were not conducted by or for the appli- as well as amendments, supplements, cant and for which the applicant has and postmarketing reports to them. not obtained a right of reference or use (b) This part does not apply to drug from the person by or for whom the in- products subject to licensing by FDA vestigations were conducted. under the Public Health Service Act (58 Abbreviated application, abbreviated Stat. 632 as amended (42 U.S.C. 201 et new drug application, or ANDA is the ap- seq.)) and subchapter F of chapter I of plication described under § 314.94, in- title 21 of the Code of Federal Regula- cluding all amendments and supple- tions. ments to the application. (c) References in this part to regula- Acknowledgment letter is a written, tions in the Code of Federal Regula- postmarked communication from FDA tions are to chapter I of title 21, unless to an applicant stating that the Agen- otherwise noted. cy has determined that an ANDA is [50 FR 7493, Feb. 22, 1985, as amended at 57 sufficiently complete to permit a sub- FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999] stantive review. An acknowledgment letter indicates that the ANDA is re- § 314.2 Purpose. garded as received. The purpose of this part is to estab- Act is the Federal Food, Drug, and lish an efficient and thorough drug re- Cosmetic Act (section 201 et seq. (21 view process in order to: (a) Facilitate U.S.C. 301 et seq.)).

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Active ingredient is any component the listed drug in blister packs, unit that is intended to furnish pharma- doses, or similar packaging for use in cological activity or other direct effect institutions), product code, labeler in the diagnosis, cure, mitigation, code, trade name, or trademark that treatment, or prevention of disease, or differs from that of the listed drug. to affect the structure or any function Bioavailability is the rate and extent of the body of man or other animals. to which the active ingredient or ac- The term includes those components tive moiety is absorbed from a drug that may undergo chemical change in product and becomes available at the the manufacture of the drug product site of drug action. For drug products and be present in the drug product in a that are not intended to be absorbed modified form intended to furnish the into the bloodstream, bioavailability specified activity or effect. may be assessed by scientifically valid Active moiety is the molecule or ion, measurements intended to reflect the excluding those appended portions of rate and extent to which the active in- the molecule that cause the drug to be gredient or active moiety becomes an ester, salt (including a salt with hy- available at the site of drug action. drogen or coordination bonds), or other Bioequivalence is the absence of a sig- noncovalent derivative (such as a com- nificant difference in the rate and ex- plex, chelate, or clathrate) of the mol- tent to which the active ingredient or ecule, responsible for the physiological active moiety in pharmaceutical or pharmacological action of the drug equivalents or pharmaceutical alter- substance. natives becomes available at the site of ANDA holder is the applicant that drug action when administered at the owns an approved ANDA. same molar dose under similar condi- Applicant is any person who submits tions in an appropriately designed an NDA (including a 505(b)(2) applica- study. Where there is an intentional tion) or ANDA or an amendment or difference in rate (e.g., in certain ex- supplement to an NDA or ANDA under tended-release dosage forms), certain this part to obtain FDA approval of a pharmaceutical equivalents or alter- new drug and any person who owns an natives may be considered bioequiva- approved NDA (including a 505(b)(2) ap- lent if there is no significant difference plication) or ANDA. in the extent to which the active ingre- Application, new drug application, or dient or moiety from each product be- NDA is the application described under comes available at the site of drug ac- § 314.50, including all amendments and tion. This applies only if the difference supplements to the application. An in the rate at which the active ingre- NDA refers to ‘‘stand-alone’’ applica- dient or moiety becomes available at tions submitted under section 505(b)(1) the site of drug action is intentional of the Federal Food, Drug, and Cos- and is reflected in the proposed label- metic Act and to 505(b)(2) applications. ing, is not essential to the attainment Approval letter is a written commu- of effective body drug concentrations nication to an applicant from FDA ap- on chronic use, and is considered medi- proving an NDA or an ANDA. cally insignificant for the drug. For Assess the effects of the change is to drug products that are not intended to evaluate the effects of a manufacturing be absorbed into the bloodstream, bio- change on the identity, strength, qual- equivalence may be assessed by sci- ity, purity, and potency of a drug prod- entifically valid measurements in- uct as these factors may relate to the tended to reflect the rate and extent to safety or effectiveness of the drug prod- which the active ingredient or active uct. moiety becomes available at the site of Authorized generic drug is a listed drug action. drug, as defined in this section, that Bioequivalence requirement is a re- has been approved under section 505(c) quirement imposed by FDA for in vitro of the Federal Food, Drug, and Cos- and/or in vivo testing of specified drug metic Act and is marketed, sold, or dis- products that must be satisfied as a tributed directly or indirectly to the condition of marketing. retail class of trade with labeling, Class 1 resubmission is the resubmis- packaging (other than repackaging as sion of an NDA or efficacy supplement,

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following receipt of a complete re- Dosage form is the physical mani- sponse letter, that contains one or festation containing the active and in- more of the following: Final printed la- active ingredients that delivers a dose beling, draft labeling, certain safety of the drug product. This includes such updates, stability updates to support factors as: provisional or final dating periods, (1) The physical appearance of the commitments to perform post- drug product; marketing studies (including proposals (2) The physical form of the drug for such studies), assay validation product prior to dispensing to the pa- data, final release testing on the last tient; lots used to support approval, minor (3) The way the product is adminis- reanalyses of previously submitted tered; and data, and other comparatively minor (4) The design features that affect information. frequency of dosing. Class 2 resubmission is the resubmis- Drug product is a finished dosage sion of an NDA or efficacy supplement, form, e.g., tablet, capsule, or solution, following receipt of a complete re- that contains a drug substance, gen- sponse letter, that includes any item erally, but not necessarily, in associa- not specified in the definition of ‘‘Class tion with one or more other ingredi- 1 resubmission,’’ including any item ents. that would require presentation to an Drug substance is an active ingredient advisory committee. that is intended to furnish pharma- Commercial marketing is the introduc- cological activity or other direct effect tion or delivery for introduction into in the diagnosis, cure, mitigation, interstate commerce of a drug product treatment, or prevention of disease or described in an ANDA, outside the con- to affect the structure or any function trol of the ANDA applicant, except of the human body, but does not in- that the term does not include transfer clude intermediates used in the syn- of the drug product for investigational thesis of such ingredient. use under part 312 of this chapter or Efficacy supplement is a supplement transfer of the drug product to parties to an approved NDA proposing to make identified in the ANDA for reasons one or more related changes from other than sale. Commercial mar- among the following changes to prod- keting includes the introduction or de- uct labeling: livery for introduction into interstate (1) Add or modify an indication or commerce of the reference listed drug claim; by the ANDA applicant. (2) Revise the dose or dose regimen; Complete response letter is a written (3) Provide for a new route of admin- communication to an applicant from istration; FDA usually describing all of the defi- (4) Make a comparative efficacy ciencies that the Agency has identified claim naming another drug product; in an NDA or ANDA that must be satis- (5) Significantly alter the intended factorily addressed before it can be ap- patient population; proved. (6) Change the marketing status from Component is any ingredient intended prescription to over-the-counter use; for use in the manufacture of a drug (7) Provide for, or provide evidence of product, including those that may not effectiveness necessary for, the tradi- appear in such drug product. tional approval of a product originally Date of approval is the date on the ap- approved under subpart H of this part; proval letter from FDA stating that or the NDA or ANDA is approved, except (8) Incorporate other information that the date of approval for an NDA based on at least one adequate and described in section 505(x)(1) of the well-controlled clinical study. Federal Food, Drug, and Cosmetic Act FDA or Agency is the Food and Drug is determined as described in section Administration. 505(x)(2) of the Federal Food, Drug, and First applicant is an ANDA applicant Cosmetic Act. ‘‘Date of approval’’ re- that, on the first day on which a sub- fers only to a final approval and not to stantially complete application con- a tentative approval. taining a paragraph IV certification is

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submitted for approval of a drug, sub- 505(b)(2) application is regarded as filed mits a substantially complete applica- or the ANDA is regarded as received. tion that contains, and for which the Paragraph IV certification is a patent applicant lawfully maintains, a para- certification of invalidity, unenforce- graph IV certification for the drug. ability, or noninfringement described Inactive ingredient is any component in § 314.50(i)(1)(i)(A)(4) or other than an active ingredient. § 314.94(a)(12)(i)(A)(4). Listed drug is a new drug product that Patent owner is the owner of the pat- has been approved under section 505(c) ent for which information is submitted of the Federal Food, Drug, and Cos- for an NDA. metic Act for safety and effectiveness Pharmaceutical alternatives are drug or under section 505(j) of the Federal products that contain the identical Food, Drug, and Cosmetic Act, which therapeutic moiety, or its precursor, has not been withdrawn or suspended but not necessarily in the same under section 505(e)(1) through (5) or amount or dosage form or as the same section 505(j)(6) of the Federal Food, salt or ester. Each such drug product Drug, and Cosmetic Act, and which has individually meets either the identical not been withdrawn from sale for what or its own respective compendial or FDA has determined are reasons of other applicable standard of identity, safety or effectiveness. Listed drug sta- strength, quality, and purity, including tus is evidenced by the drug product’s potency and, where applicable, content identification in the current edition of uniformity, disintegration times, and/ FDA’s ‘‘Approved Drug Products With or dissolution rates. Therapeutic Equivalence Evaluations’’ Pharmaceutical equivalents are drug (the list) as an approved drug. A drug products in identical dosage forms and product is deemed to be a listed drug route(s) of administration that contain on the date of approval for the NDA or identical amounts of the identical active drug ingredient, i.e., the same salt ANDA for that drug product. or ester of the same therapeutic moi- NDA holder is the applicant that owns ety, or, in the case of modified-release an approved NDA. dosage forms that require a reservoir Newly acquired information is data, or overage or such forms as prefilled analyses, or other information not pre- syringes where residual volume may viously submitted to the Agency, vary, that deliver identical amounts of which may include (but is not limited the active drug ingredient over the to) data derived from new clinical stud- identical dosing period; do not nec- ies, reports of adverse events, or new essarily contain the same inactive in- analyses of previously submitted data gredients; and meet the identical (e.g., meta-analyses) if the studies, compendial or other applicable stand- events, or analyses reveal risks of a dif- ard of identity, strength, quality, and ferent type or greater severity or fre- purity, including potency and, where quency than previously included in applicable, content uniformity, disinte- submissions to FDA. gration times, and/or dissolution rates. Original application or original NDA is Postmark is an independently a pending NDA for which FDA has verifiable evidentiary record of the never issued a complete response letter date on which a document is trans- or approval letter, or an NDA that was mitted, in an unmodifiable format, to submitted again after FDA had refused another party. For postmarks made by to file it or after it was withdrawn the U.S. Postal Service or a designated without being approved. delivery service, the date of trans- Paragraph IV acknowledgment letter is mission is the date on which the docu- a written, postmarked communication ment is received by the domestic mail from FDA to an applicant stating that service of the U.S. Postal Service or by the Agency has determined that a a designated delivery service. For post- 505(b)(2) application or ANDA con- marks documenting an electronic taining a paragraph IV certification is event, the date of transmission is the sufficiently complete to permit a sub- date (in a particular time zone) that stantive review. A paragraph IV ac- FDA sends the electronic transmission knowledgment letter indicates that the on its host system as evidenced by a

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verifiable record. If the sender and the (1)(i) The total quantity of drug sub- intended recipient are located in dif- stance in mass or units of activity in a ferent time zones, it is the sender’s dosage unit or container closure (e.g., time zone that provides the controlling weight/unit dose, weight/volume or date of electronic transmission. weight/weight in a container closure, Reference listed drug is the listed drug or units/volume or units/weight in a identified by FDA as the drug product container closure); and/or, as applica- upon which an applicant relies in seek- ble. ing approval of its ANDA. (ii) The concentration of the drug Reference standard is the drug product substance in mass or units of activity selected by FDA that an applicant per unit volume or mass (e.g., weight/ seeking approval of an ANDA must use weight, weight/volume, or units/vol- in conducting an in vivo bioequiva- ume); or lence study required for approval. (2) Such other criteria the Agency es- Resubmission, in the context of a com- tablishes for determining the amount plete response letter, is submission by of drug substance contained in, deliv- the applicant of all materials needed to ered, or deliverable from a drug prod- fully address all deficiencies identified uct if the weights and measures de- in the complete response letter. An scribed in paragraph (i) of this defini- NDA or ANDA for which FDA issued a tion do not apply (e.g., certain drug-device combination products for which complete response letter, but which the amount of drug substance is emit- was withdrawn before approval and ted per use or unit time). later submitted again, is not a resub- Substantially complete application is an mission. ANDA that on its face is sufficiently Right of reference or use is the author- complete to permit a substantive re- ity to rely upon, and otherwise use, an view. Sufficiently complete means that investigation for the purpose of obtain- the ANDA contains all the information ing approval of an NDA, including the required under section 505(j)(2)(A) of ability to make available the under- the Federal Food, Drug, and Cosmetic lying raw data from the investigation Act and does not contain a deficiency for FDA audit, if necessary. described in § 314.101(d) and (e). Same drug product formulation is the Tentative approval is notification that formulation of the drug product sub- an NDA or ANDA otherwise meets the mitted for approval and any formula- requirements for approval under the tions that have minor differences in Federal Food, Drug, and Cosmetic Act, composition or method of manufacture but cannot be approved because there from the formulation submitted for ap- is a 7-year period of orphan exclusivity proval, but are similar enough to be for a listed drug under section 527 of relevant to the Agency’s determination the Federal Food, Drug, and Cosmetic of bioequivalence. Act and § 316.31 of this chapter, or that Specification is the quality standard a 505(b)(2) application or ANDA other- (i.e., tests, analytical procedures, and wise meets the requirements for ap- acceptance criteria) provided in an approval under the Federal Food, Drug, proved NDA or ANDA to confirm the and Cosmetic Act, but cannot be ap- quality of drug substances, drug prod- proved until the conditions in ucts, intermediates, raw materials, re- § 314.107(b)(1)(iii), (b)(3), or (c) are met; agents, components, in-process mate- because there is a period of exclusivity rials, container closure systems, and for the listed drug under § 314.108; be- other materials used in the production cause there is a period of pediatric ex- of a drug substance or drug product. clusivity for the listed drug under sec- For the purpose of this definition, action 505A of the Federal Food, Drug, ceptance criteria means numerical lim- and Cosmetic Act; because there is a its, ranges, or other criteria for the period of exclusivity for the listed drug tests described. under section 505E of the Federal Food, Strength is the amount of drug sub- Drug, and Cosmetic Act; or because a stance contained in, delivered, or deliv- court order pursuant to 35 U.S.C. erable from a drug product, which in- 271(e)(4)(A) orders that the NDA or cludes: ANDA may be approved no earlier than

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the date specified. A drug product that (a) Application form. The applicant is granted tentative approval is not an must submit a completed and signed approved drug and will not be approved application form that contains the fol- until FDA issues an approval letter lowing: after any necessary additional review (1) The name and address of the ap- of the NDA or ANDA. plicant; the date of the NDA; the NDA The list is the list of approved drug number if previously issued (for exam- products published in FDA’s current ple, if the NDA is a resubmission or an ‘‘Approved Drug Products With Thera- amendment or supplement); the name peutic Equivalence Evaluations,’’ of the drug product, including its es- available electronically on FDA’s Web tablished, proprietary, code, and chem- site at http://www.fda.gov/cder. Therapeutic equivalents are approved ical names; the dosage form and drug products that are pharmaceutical strength; the route of administration; equivalents for which bioequivalence the identification numbers of all INDs has been demonstrated, and that can be (as defined in § 312.3(b) of this chapter) expected to have the same clinical ef- that are referenced in the NDA; the fect and safety profile when adminis- identification numbers of all drug mas- tered to patients under the conditions ter files and other applications under specified in the labeling. this part that are referenced in the NDA; and the drug product’s proposed [81 FR 69636, Oct. 6, 2016] indications for use. (2) A statement whether the submis- Subpart B—Applications sion is an original submission, a § 314.50 Content and format of an 505(b)(2) application, a resubmission, or NDA. a supplement to an application under NDAs and supplements to approved § 314.70. NDAs are required to be submitted in (3) A statement whether the appli- the form and contain the information, cant proposes to market the drug prod- as appropriate for the particular sub- uct as a prescription or an over-the- mission, required under this section. counter product. Three copies of the NDA are required: (4) A check-list identifying what en- An archival copy, a review copy, and a closures required under this section the field copy. An NDA for a new chemical applicant is submitting. entity will generally contain an appli- (5) The applicant, or the applicant’s cation form, an index, a summary, five attorney, agent, or other authorized of- or six technical sections, case report ficial must sign the NDA. If the person tabulations of patient data, case report signing the NDA does not reside or forms, drug samples, and labeling, in- have a place of business within the cluding, if applicable, any Medication United States, the NDA is required to Guide required under part 208 of this contain the name and address of, and chapter. Other NDAs will generally be countersigned by, an attorney, contain only some of those items, and agent, or other authorized official who information will be limited to that resides or maintains a place of business needed to support the particular sub- within the United States. mission. These include an NDA of the type described in section 505(b)(2) of (b) Index. The archival copy of the the Federal Food, Drug, and Cosmetic NDA is required to contain a com- Act, an amendment, and a supplement. prehensive index by volume number The NDA is required to contain reports and page number to the summary of all investigations of the drug prod- under paragraph (c) of this section, the uct sponsored by the applicant, and all technical sections under paragraph (d) other information about the drug perti- of this section, and the supporting in- nent to an evaluation of the NDA that formation under paragraph (f) of this is received or otherwise obtained by section. the applicant from any source. FDA (c) Summary. (1) An NDA is required will maintain guidance documents on to contain a summary of the NDA in the format and content of NDAs to as- enough detail that the reader may gain sist applicants in their preparation. a good general understanding of the

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data and information in the NDA, in- from marketing for any reason related cluding an understanding of the quan- to safety or effectiveness, and a list of titative aspects of the data. The sum- countries in which applications for mary is not required for supplements marketing are pending. The descrip- under § 314.70. Resubmissions of an NDA tion is required to describe both mar- should contain an updated summary, keting by the applicant and, if known, as appropriate. The summary should the marketing history of other persons. discuss all aspects of the NDA, and (iv) A summary of the chemistry, synthesize the information into a well- manufacturing, and controls section of structured and unified document. The the NDA. summary should be written at approxi- (v) A summary of the nonclinical mately the level of detail required for pharmacology and toxicology section publication in, and meet the editorial of the NDA. standards generally applied by, ref- (vi) A summary of the human phar- ereed scientific and medical journals. macokinetics and bioavailability sec- In addition to the agency personnel re- tion of the NDA. viewing the summary in the context of (vii) A summary of the microbiology their review of the NDA, FDA may fur- section of the NDA (for anti-infective nish the summary to FDA advisory drugs only). committee members and agency offi- (viii) A summary of the clinical data cials whose duties require an under- section of the NDA, including the re- standing of the NDA. To the extent sults of statistical analyses of the clin- possible, data in the summary should ical trials. be presented in tabular and graphic (ix) A concluding discussion that pre- forms. FDA has prepared a guideline sents the benefit and risk consider- under § 10.90(b) that provides informa- ations related to the drug, including a tion about how to prepare a summary. discussion of any proposed additional The summary required under this para- studies or surveillance the applicant graph may be used by FDA or the ap- intends to conduct postmarketing. plicant to prepare the Summary Basis (d) Technical sections. The NDA is re- of Approval document for public disclo- quired to contain the technical sec- sure (under § 314.430(e)(2)(ii)) when the tions described below. Each technical NDA is approved. section is required to contain data and (2) The summary is required to con- information in sufficient detail to pertain the following information: mit the agency to make a knowledge- (i) The proposed text of the labeling, able judgment about whether to ap- including, if applicable, any Medica- prove the NDA or whether grounds tion Guide required under part 208 of exist under section 505(d) of the Fed- this chapter, for the drug, with annota- eral Food, Drug, and Cosmetic Act to tions to the information in the sum- refuse to approve the NDA. The re- mary and technical sections of the quired technical sections are as fol- NDA that support the inclusion of each lows: statement in the labeling, and, if the (1) Chemistry, manufacturing, and con- NDA is for a prescription drug, state- trols section. A section describing the ments describing the reasons for omit- composition, manufacture, and speci- ting a section or subsection of the la- fication of the drug substance and the beling format in § 201.57 of this chapter. drug product, including the following: (ii) A statement identifying the phar- (i) Drug substance. A full description macologic class of the drug and a dis- of the drug substance including its cussion of the scientific rationale for physical and chemical characteristics the drug, its intended use, and the po- and stability; the name and address of tential clinical benefits of the drug its manufacturer; the method of syn- product. thesis (or isolation) and purification of (iii) A brief description of the mar- the drug substance; the process con- keting history, if any, of the drug out- trols used during manufacture and side the United States, including a list packaging; and the specifications nec- of the countries in which the drug has essary to ensure the identity, strength, been marketed, a list of any countries quality, and purity of the drug sub- in which the drug has been withdrawn stance and the bioavailability of the

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drug products made from the sub- packaging, or testing of the drug prod- stance, including, for example, tests, uct and identification of the operation analytical procedures, and acceptance performed by each contract facility; criteria relating to stability, sterility, and the results of any test performed particle size, and crystalline form. The on the components used in the manu- NDA may provide additionally for the facture of the drug product as required use of alternatives to meet any of these by § 211.84(d) of this chapter and on the requirements, including alternative drug product as required by § 211.165 of sources, process controls, and analyt- this chapter. ical procedures. Reference to the cur- (c) The proposed or actual master rent edition of the U.S. Pharmacopeia production record, including a descrip- and the National Formulary may sat- tion of the equipment, to be used for isfy relevant requirements in this para- the manufacture of a commercial lot of graph. the drug product or a comparably de- (ii)((a)) Drug product. A list of all tailed description of the production components used in the manufacture of process for a representative batch of the drug product (regardless of whether the drug product. they appear in the drug product) and a (iii) Environmental impact. The NDA is statement of the composition of the required to contain either a claim for drug product; the specifications for categorical exclusion under § 25.30 or each component; the name and address 25.31 of this chapter or an environ- of each manufacturer of the drug prod- mental assessment under § 25.40 of this uct; a description of the manufacturing chapter. and packaging procedures and in-proc- (iv) The applicant may, at its option, ess controls for the drug product; the submit a complete chemistry, manu- specifications necessary to ensure the facturing, and controls section 90 to 120 identity, strength, quality, purity, po- days before the anticipated submission tency, and bioavailability of the drug of the remainder of the NDA. FDA will product, including, for example, tests, review such early submissions as re- analytical procedures, and acceptance criteria relating to sterility, dissolu- sources permit. tion rate, container closure systems; (v) The applicant must include a and stability data with proposed expi- statement certifying that the field ration dating. The NDA may provide copy of the NDA has been provided to additionally for the use of alternatives the applicant’s home FDA district of- to meet any of these requirements, in- fice. cluding alternative components, manu- (2) Nonclinical pharmacology and toxi- facturing and packaging procedures, cology section. A section describing, in-process controls, and analytical pro- with the aid of graphs and tables, ani- cedures. Reference to the current edi- mal and in vitro studies with drug, in- tion of the U.S. Pharmacopeia and the cluding the following: National Formulary may satisfy rel- (i) Studies of the pharmacological ac- evant requirements in this paragraph. tions of the drug in relation to its pro- (b) Unless provided by paragraph posed therapeutic indication and stud- (d)(1)(ii)(a) of this section, for each ies that otherwise define the pharma- batch of the drug product used to con- cologic properties of the drug or are duct a bioavailability or bioequiva- pertinent to possible adverse effects. lence study described in § 320.38 or (ii) Studies of the toxicological ef- § 320.63 of this chapter or used to con- fects of the drug as they relate to the duct a primary stability study: The drug’s intended clinical uses, includ- batch production record; the specifica- ing, as appropriate, studies assessing tion for each component and for the the drug’s acute, subacute, and chronic drug product; the names and addresses toxicity; carcinogenicity; and studies of the sources of the active and of toxicities related to the drug’s par- noncompendial inactive components ticular mode of administration or con- and of the container and closure sys- ditions of use. tem for the drug product; the name and (iii) Studies, as appropriate, of the ef- address of each contract facility in- fects of the drug on reproduction and volved in the manufacture, processing, on the developing fetus.

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(iv) Any studies of the absorption, (ii) A description of the anti- distribution, metabolism, and excre- microbial spectra of the drug, includ- tion of the drug in animals. ing results of in vitro preclinical stud- (v) For each nonclinical laboratory ies to demonstrate concentrations of study subject to the good laboratory the drug required for effective use. practice regulations under part 58 a (iii) A description of any known statement that it was conducted in mechanisms of resistance to the drug, compliance with the good laboratory including results of any known epi- practice regulations in part 58, or, if demiologic studies to demonstrate the study was not conducted in compli- prevalence of resistance factors. ance with those regulations, a brief (iv) A description of clinical microbi- statement of the reason for the non- ology laboratory procedures (for exam- compliance. ple, in vitro sensitivity discs) needed (3) Human pharmacokinetics and bio- for effective use of the drug. availability section. A section describing the human pharmacokinetic data and (5) Clinical data section. A section de- human bioavailability data, or infor- scribing the clinical investigations of mation supporting a waiver of the sub- the drug, including the following: mission of in vivo bioavailability data (i) A description and analysis of each under subpart B of part 320, including clinical pharmacology study of the the following: drug, including a brief comparison of (i) A description of each of the bio- the results of the human studies with availability and pharmacokinetic stud- the animal pharmacology and toxi- ies of the drug in humans performed by cology data. or on behalf of the applicant that in- (ii) A description and analysis of each cludes a description of the analytical controlled clinical study pertinent to a procedures and statistical methods proposed use of the drug, including the used in each study and a statement protocol and a description of the statis- with respect to each study that it ei- tical analyses used to evaluate the ther was conducted in compliance with study. If the study report is an interim the institutional review board regula- analysis, this is to be noted and a pro- tions in part 56, or was not subject to jected completion date provided. Con- the regulations under § 56.104 or § 56.105, trolled clinical studies that have not and that it was conducted in compli- been analyzed in detail for any reason ance with the informed consent regula- (e.g., because they have been discon- tions in part 50. tinued or are incomplete) are to be in- (ii) If the NDA describes in the chem- cluded in this section, including a copy istry, manufacturing, and controls sec- of the protocol and a brief description tion tests, analytical procedures, and of the results and status of the study. acceptance criteria needed to assure (iii) A description of each uncon- the bioavailability of the drug product or drug substance, or both, a statement trolled clinical study, a summary of in this section of the rationale for es- the results, and a brief statement ex- tablishing the tests, analytical proce- plaining why the study is classified as dures, and acceptance criteria, includ- uncontrolled. ing data and information supporting (iv) A description and analysis of any the rationale. other data or information relevant to (iii) A summarizing discussion and an evaluation of the safety and effec- analysis of the pharmacokinetics and tiveness of the drug product obtained metabolism of the active ingredients or otherwise received by the applicant and the bioavailability or bioequiva- from any source, foreign or domestic, lence, or both, of the drug product. including information derived from (4) Microbiology section. If the drug is clinical investigations, including con- an anti-infective drug, a section de- trolled and uncontrolled studies of uses scribing the microbiology data, includ- of the drug other than those proposed ing the following: in the NDA, commercial marketing ex- (i) A description of the biochemical perience, reports in the scientific lit- basis of the drug’s action on microbial erature, and unpublished scientific pa- physiology. pers.

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(v) An integrated summary of the dition, the reports must include the data demonstrating substantial evi- case report forms for each patient who dence of effectiveness for the claimed died during a clinical study or who did indications. Evidence is also required not complete the study because of an to support the dosage and administra- adverse event (unless this requirement tion section of the labeling, including is waived). The applicant must submit support for the dosage and dose inter- these reports (1) 4 months after the ini- val recommended. The effectiveness tial submission; (2) in a resubmission data must be presented by gender, age, following receipt of a complete re- and racial subgroups and must identify sponse letter; and (3) at other times as any modifications of dose or dose inter- requested by FDA. Before submitting val needed for specific subgroups. Ef- the first such report, applicants are en- fectiveness data from other subgroups couraged to consult with FDA regard- of the population of patients treated, ing further details on its form and con- when appropriate, such as patients tent. with renal failure or patients with dif- (vii) If the drug has a potential for ferent levels of severity of the disease, abuse, a description and analysis of also must be presented. studies or information related to abuse (vi) A summary and updates of safety of the drug, including a proposal for information, as follows: scheduling under the Controlled Sub- (a) The applicant must submit an instances Act. A description of any stud- tegrated summary of all available in- ies related to overdosage is also re- formation about the safety of the drug quired, including information on dialy- product, including pertinent animal sis, antidotes, or other treatments, if data, demonstrated or potential ad- known. verse effects of the drug, clinically sig- (viii) An integrated summary of the nificant drug/drug interactions, and benefits and risks of the drug, includ- other safety considerations, such as ing a discussion of why the benefits ex- data from epidemiological studies of ceed the risks under the conditions related drugs. The safety data must be stated in the labeling. presented by gender, age, and racial (ix) A statement with respect to each subgroups. When appropriate, safety clinical study involving human sub- data from other subgroups of the popu- jects that it either was conducted in lation of patients treated also must be compliance with the institutional represented, such as for patients with view board regulations in part 56, or renal failure or patients with different was not subject to the regulations levels of severity of the disease. A de- under § 56.104 or § 56.105, and that it was scription of any statistical analyses conducted in compliance with the in- performed in analyzing safety data formed consent regulations in part 50. should also be included, unless already (x) If a sponsor has transferred any included under paragraph (d)(5)(ii) of obligations for the conduct of any clin- this section. ical study to a contract research orga- (b) The applicant must, under section nization, a statement containing the 505(i) of the Federal Food, Drug, and name and address of the contract re- Cosmetic Act, update periodically its search organization, identification of pending NDA with new safety informa- the clinical study, and a listing of the tion learned about the drug that may obligations transferred. If all obliga- reasonably affect the statement of con- tions governing the conduct of the traindications, warnings, precautions, study have been transferred, a general and adverse reactions in the draft la- statement of this transfer—in lieu of a beling and, if applicable, any Medica- listing of the specific obligations trans- tion Guide required under part 208 of ferred—may be submitted. this chapter. These ‘‘safety update re- (xi) If original subject records were ports’’ must include the same kinds of audited or reviewed by the sponsor in information (from clinical studies, ani- the course of monitoring any clinical mal studies, and other sources) and study to verify the accuracy of the case must be submitted in the same format reports submitted to the sponsor, a list as the integrated summary in para- identifying each clinical study so au- graph (d)(5)(vi)(a) of this section. In ad- dited or reviewed.

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(6) Statistical section. A section de- nized in an official compendium need scribing the statistical evaluation of not be submitted). clinical data, including the following: (ii) Samples of the finished market (i) A copy of the information sub- package, if requested by FDA. mitted under paragraph (d)(5)(ii) of this (2) The applicant must submit the section concerning the description and following in the archival copy of the analysis of each controlled clinical NDA: study, and the documentation and sup- (i) Three copies of the analytical pro- porting statistical analyses used in cedures and related descriptive infor- evaluating the controlled clinical stud- mation contained in the chemistry, ies. manufacturing, and controls section (ii) A copy of the information sub- under paragraph (d)(1) of this section mitted under paragraph (d)(5)(vi)(a) of for the drug substance and the drug this section concerning a summary of product that are necessary for FDA’s information about the safety of the laboratories to perform all necessary drug product, and the documentation tests on the samples and to validate and supporting statistical analyses the applicant’s analytical procedures. used in evaluating the safety informa- The related descriptive information in- tion. cludes a description of each sample; (7) Pediatric use section. A section de- the proposed regulatory specifications scribing the investigation of the drug for the drug; a detailed description of for use in pediatric populations, includ- the methods of analysis; supporting ing an integrated summary of the in- data for accuracy, specificity, precision formation (the clinical pharmacology and ruggedness; and complete results studies, controlled clinical studies, or of the applicant’s tests on each sample. uncontrolled clinical studies, or other (ii) Copies of the label and all label- data or information) that is relevant to ing for the drug product (including, if the safety and effectiveness and bene- applicable, any Medication Guide re- fits and risks of the drug in pediatric quired under part 208 of this chapter) populations for the claimed indica- for the drug product (4 copies of draft tions, a reference to the full descrip- labeling or 12 copies of final printed lations of such studies provided under beling). paragraphs (d)(3) and (d)(5) of this sec- (f) Case report forms and tabulations. tion, and information required to be The archival copy of the NDA is re- submitted under § 314.55. quired to contain the following case re- (e) Samples and labeling. (1) Upon report tabulations and case report forms: quest from FDA, the applicant must (1) Case report tabulations. The NDA is submit the samples described below to required to contain tabulations of the the places identified in the Agency’s data from each adequate and well-con- request. FDA generally will ask appli- trolled study under § 314.126 (Phase 2 cants to submit samples directly to and Phase 3 studies as described in two or more Agency laboratories that §§ 312.21 (b) and (c) of this chapter), tab- will perform all necessary tests on the ulations of the data from the earliest samples and validate the applicant’s clinical pharmacology studies (Phase 1 analytical procedures. studies as described in § 312.21(a) of this (i) Four representative samples of the chapter), and tabulations of the safety following, each sample in sufficient data from other clinical studies. Rou- quantity to permit FDA to perform tine submission of other patient data three times each test described in the from uncontrolled studies is not re- NDA to determine whether the drug quired. The tabulations are required to substance and the drug product meet include the data on each patient in the specifications given in the NDA: each study, except that the applicant (a) The drug product proposed for may delete those tabulations which the marketing; agency agrees, in advance, are not per- (b) The drug substance used in the tinent to a review of the drug’s safety drug product from which the samples or effectiveness. Upon request, FDA of the drug product were taken; and will discuss with the applicant in a (c) Reference standards and blanks ‘‘pre-NDA’’ conference those tabula- (except that reference standards recog- tions that may be appropriate for such

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deletion. Barring unforeseen cir- file by name, reference number, vol- cumstances, tabulations agreed to be ume, and page number in the agency’s deleted at such a conference will not be records where the information can be requested during the conduct of FDA’s found. A reference to information sub- review of the NDA. If such unforeseen mitted to the agency by a person other circumstances do occur, any request than the applicant is required to con- for deleted tabulations will be made by tain a written statement that author- the director of the FDA division re- izes the reference and that is signed by sponsible for reviewing the NDA, in ac- the person who submitted the informa- cordance with paragraph (f)(3) of this tion. section. (2) The applicant must submit an ac- (2) Case report forms. The NDA is re- curate and complete English trans- quired to contain copies of individual lation of each part of the NDA that is case report forms for each patient who not in English. The applicant must died during a clinical study or who did submit a copy of each original lit- not complete the study because of an erature publication for which an adverse event, whether believed to be English translation is submitted. drug related or not, including patients (3) If an applicant who submits an receiving reference drugs or placebo. NDA under section 505(b) of the Federal This requirement may be waived by Food, Drug, and Cosmetic Act obtains FDA for specific studies if the case re- a ‘‘right of reference or use,’’ as defined port forms are unnecessary for a proper under § 314.3(b), to an investigation de- review of the study. scribed in clause (A) of section 505(b)(1) (3) Additional data. The applicant of the Federal Food, Drug, and Cos- must submit to FDA additional case metic Act, the applicant must include report forms and tabulations needed to in its NDA a written statement signed conduct a proper review of the NDA, as by the owner of the data from each requested by the director of the FDA such investigation that the applicant division responsible for reviewing the may rely on in support of the approval NDA. The applicant’s failure to submit of its NDA, and provide FDA access to, information requested by FDA within the underlying raw data that provide 30 days after receipt of the request may the basis for the report of the inves- result in the agency viewing any even- tigation submitted in its NDA. tual submission as a major amendment under § 314.60 and extending the review (h) Patent information. The NDA is re- period as necessary. If desired by the quired to contain the patent informa- applicant, the FDA division director tion described under § 314.53. will verify in writing any request for (i) Patent certification—(1) Contents. A additional data that was made orally. 505(b)(2) application is required to con- (4) Presentation and format. Appli- tain the following: cants are invited to meet with FDA be- (i) Patents claiming drug substance, fore submitting an NDA to discuss the drug product, or method of use. (A) An presentation and format of supporting appropriate patent certification or information. If the applicant and FDA statement with respect to each patent agree, the applicant may submit tab- issued by the U.S. Patent and Trade- ulations of patient data and case report mark Office that, in the opinion of the forms in an alternate form. applicant and to the best of its knowl- (g) Other. The following general re- edge, claims the drug substance or drug quirements apply to the submission of product on which investigations that information within the summary under are relied upon by the applicant for ap- paragraph (c) of this section and within proval of its 505(b)(2) application were the technical sections under paragraph conducted or that claims an approved (d) of this section. use for such drug and for which infor- (1) The applicant ordinarily is not re- mation is required to be filed under quired to resubmit information pre- section 505(b) and (c) of the Federal viously submitted, but may incor- Food, Drug, and Cosmetic Act and porate the information by reference. A § 314.53. For each such patent, the ap- reference to information submitted plicant must provide the patent num- previously is required to identify the ber and certify, in its opinion and to

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the best of its knowledge, one of the lent to the drug product for which the following circumstances: original 505(b)(2) application is sub- (1) That the patent information has mitted, an appropriate patent certifi- not been submitted to FDA. The application or statement under this section cant must entitle such a certification with respect to each patent that claims ‘‘Paragraph I Certification’’; the drug substance or drug product or (2) That the patent has expired. The that claims an approved use for one applicant must entitle such a certifi- such drug product. cation ‘‘Paragraph II Certification’’; (ii) No relevant patents. If, in the opin- (3) The date on which the patent will ion of the applicant and to the best of expire. The applicant must entitle such its knowledge, there are no patents de- a certification ‘‘Paragraph III Certifi- scribed in paragraph (i)(1)(i) of this sec- cation’’; or tion, a certification in the following (4)(i) That the patent is invalid, un- form: enforceable, or will not be infringed by In the opinion and to the best knowledge of the manufacture, use, or sale of the (name of applicant), there are no patents that drug product for which the 505(b)(2) ap- claim the drug or drugs on which investiga- plication is submitted. The applicant tions that are relied upon in this 505(b)(2) ap- must entitle such a certification plication were conducted or that claim a use ‘‘Paragraph IV Certification’’. This cer- of such drug or drugs. tification must be submitted in the fol- (iii) Method-of-use patent. (A) If infor- lowing form: mation that is submitted under section I, (name of applicant), certify that Patent 505(b) or (c) of the Federal Food, Drug, No. llll (is invalid, unenforceable, or will and Cosmetic Act and § 314.53 is for a not be infringed by the manufacture, use, or method-of-use patent, and the labeling sale of) (name of proposed drug product) for for the drug product for which the ap- which this 505(b)(2) application is submitted. plicant is seeking approval does not in- (ii) The certification must be accom- clude an indication or other condition panied by a statement that the appli- of use that is covered by the method- cant will comply with the require- of-use patent, a statement explaining ments under § 314.52(a) with respect to that the method-of-use patent does not providing a notice to each owner of the claim a proposed indication or other patent or its representative and to the condition of use. NDA holder (or, if the NDA holder does (B) If the labeling of the drug product not reside or maintain a place of busi- for which the applicant is seeking ap- ness within the United States, its at- proval includes an indication or other torney, agent, or other authorized offi- condition of use that, according to the cial) for the drug product that is patent information submitted under claimed by the patent or a use of which section 505(b) or (c) of the Federal is claimed by the patent and with the Food, Drug, and Cosmetic Act and requirements under § 314.52(b) with re- § 314.53 or in the opinion of the appli- spect to sending the notice and under cant, is claimed by a method-of-use § 314.52(c) with respect to the content of patent, the applicant must submit an the notice. applicable certification under para- (B) If the drug on which investiga- graph (i)(1)(i) of this section. tions that are relied upon by the appli- (2) [Reserved] cant were conducted is itself a licensed (3) Licensing agreements. If a 505(b)(2) generic drug of a patented drug first application is submitted for a drug or approved under section 505(b) of the method of using a drug claimed by a Federal Food, Drug, and Cosmetic Act, patent and the applicant has a licens- an appropriate patent certification or ing agreement with the patent owner, statement under this section with re- the applicant must submit a paragraph spect to each patent that claims the IV certification as to that patent and a first-approved patented drug or that statement that the applicant has been claims an approved use for such a drug. granted a patent license. If the patent (C) If, before the date of submission owner consents to approval of the of an original 505(b)(2) application, 505(b)(2) application (if otherwise eligi- there is a drug product approved in an ble for approval) as of a specific date, NDA that is pharmaceutically equiva- the 505(b)(2) application must contain a

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written statement from the patent paragraph (i)(1)(iii) of this section as to owner that it has a licensing agree- that patent. ment with the applicant and that it (5) Disputed patent information. If an consents to approval of the 505(b)(2) ap- applicant disputes the accuracy or rel- plication as of a specific date. evance of patent information sub- (4) Untimely filing of patent informa- mitted to FDA, the applicant may seek tion. (i) If a patent described in para- a confirmation of the correctness of graph (i)(1)(i)(A) of this section is the patent information in accordance issued and the holder of the approved with the procedures under § 314.53(f). NDA for the patented drug does not file Unless the patent information is with- with FDA the required information on drawn, the applicant must submit an the patent within 30 days of issuance of appropriate certification or statement the patent, an applicant who submitted for each listed patent. a 505(b)(2) application that, before the (6) Amended certifications. A patent submission of the patent information, certification or statement submitted contained an appropriate patent cer- under paragraphs (i)(1)(i) through (iii) tification or statement is not required of this section may be amended at any to submit a patent certification or time before the approval of the 505(b)(2) statement to address the patent or pat- application. An applicant must submit ent information that is late-listed with an amended certification as an amend- respect to the pending 505(b)(2) applica- ment to a pending 505(b)(2) application. tion. Except as provided in § 314.53(f)(1), If an applicant with a pending 505(b)(2) an NDA holder’s amendment to the de- application voluntarily makes a patent scription of the approved method(s) of certification for an untimely filed pat- use claimed by the patent will be con- ent, the applicant may withdraw the sidered untimely filing of patent infor- patent certification for the untimely mation unless: filed patent. Once an amendment is (A) The amendment to the descrip- submitted to change the certification, tion of the approved method(s) of use the 505(b)(2) application will no longer claimed by the patent is submitted be considered to contain the prior cer- within 30 days of patent issuance; tification. (B) The amendment to the descrip- (i) After finding of infringement. An ap- tion of the approved method(s) of use plicant who has submitted a paragraph claimed by the patent is submitted IV certification and is sued for patent within 30 days of approval of a cor- infringement must submit an amend- responding change to product labeling; ment to change its certification if a or court enters a final decision from (C) The amendment to the descrip- which no appeal has been or can be tion of the approved method(s) of use taken, or signs and enters a settlement claimed by the patent is submitted order or consent decree in the action within 30 days of a decision by the U.S. that includes a finding that the patent Patent and Trademark Office or by a is infringed, unless the final decision, Federal district court, the Court of Ap- settlement order, or consent decree peals for the Federal Circuit, or the also finds the patent to be invalid. In U.S. Supreme Court that is specific to its amendment, the applicant must cer- the patent and alters the construction tify under paragraph (i)(1)(i)(A)(3) of of a method-of-use claim(s) of the pat- this section that the patent will expire ent, and the amendment contains a on a specific date or, with respect to a copy of the decision. patent claiming a method of use, the (ii) An applicant whose 505(b)(2) ap- applicant may instead provide a state- plication is submitted after the NDA ment under paragraph (i)(1)(iii) of this holder’s untimely filing of patent in- section if the applicant amends its formation or whose 505(b)(2) applica- 505(b)(2) application such that the ap- tion was previously filed but did not plicant is no longer seeking approval contain an appropriate patent certifi- for a method of use claimed by the pat- cation or statement at the time of the ent. Once an amendment for the patent submission must submit a cer- change has been submitted, the tification under paragraph (i)(1)(i) of 505(b)(2) application will no longer be this section and/or a statement under considered to contain a paragraph IV

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certification to the patent. If a final (2) An applicant must submit an ap- decision finds the patent to be invalid propriate patent certification or state- and infringed, an amended certification ment under paragraph (i)(1) of this sec- is not required. tion if, after submission of the 505(b)(2) (ii) After request to remove a patent or application, a new patent is issued by patent information from the list. If the the U.S. Patent and Trademark Office list reflects that an NDA holder has re- that, in the opinion of the applicant quested that a patent or patent infor- and to the best of its knowledge, mation be removed from the list and no claims a listed drug relied upon or that ANDA applicant is eligible for 180-day claims an approved use for such listed exclusivity based on a paragraph IV drug for which information is required certification to that patent, the patent to be filed under section 505(b) and (c) or patent information will be removed of the Federal Food, Drug, and Cos- and any applicant with a pending metic Act and § 314.53. 505(b)(2) application (including a ten- (B) An applicant is not required to tatively approved 505(b)(2) application) who has made a certification with resubmit a supplement to change a sub- spect to such patent must submit an mitted certification when information amendment to withdraw its certifi- on an otherwise applicable patent is cation. In the amendment, the appli- submitted after the approval of the cant must state the reason for with- 505(b)(2) application. drawing the certification or statement (j) Claimed exclusivity. A new drug (that the patent has been removed product, upon approval, may be enti- from the list). If the list reflects that tled to a period of marketing exclu- an NDA holder has requested that a sivity under the provisions of § 314.108. patent or patent information be re- If an applicant believes its drug prod- moved from the list and one or more uct is entitled to a period of exclu- first applicants are eligible for 180-day sivity, it must submit with the NDA exclusivity based on a paragraph IV prior to approval the following infor- certification to that patent, the patent mation: will remain listed until any 180-day ex- (1) A statement that the applicant is clusivity based on that patent has ex- claiming exclusivity. pired or has been extinguished. A (2) A reference to the appropriate 505(b)(2) applicant is not required to paragraph under § 314.108 that supports provide or maintain a certification to a its claim. patent or patent information that re- (3) If the applicant claims exclusivity mains listed only for purposes of a first under § 314.108(b)(2), information to applicant’s 180-day exclusivity for its show that, to the best of its knowledge ANDA. Once an amendment to with- or belief, a drug has not previously draw the certification has been sub- been approved under section 505(b) of mitted, the 505(b)(2) application will no the Federal Food, Drug, and Cosmetic longer be considered to contain a para- Act containing any active moiety in graph IV certification to the patent. If the drug for which the applicant is removal of a patent from the list results in there being no patents listed seeking approval. for the listed drug(s) identified in the (4) If the applicant claims exclusivity 505(b)(2) application, the applicant under § 314.108(b)(4) or (b)(5), the fol- must submit an amended certification lowing information to show that the reflecting that there are no listed pat- NDA contains ‘‘new clinical investiga- ents. tions’’ that are ‘‘essential to approval (iii) Other amendments. (A) Except as of the NDA or supplement’’ and were provided in paragraphs (i)(4) and ‘‘conducted or sponsored by the appli- (i)(6)(iii)(B) of this section: cant:’’ (1) An applicant must amend a sub- (i) ‘‘New clinical investigations.’’ A cer- mitted certification or statement if, at tification that to the best of the appli- any time before the approval of the cant’s knowledge each of the clinical 505(b)(2) application, the applicant investigations included in the NDA learns that the submitted certification meets the definition of ‘‘new clinical or statement is no longer accurate; and investigation’’ set forth in § 314.108(a).

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(ii) ‘‘Essential to approval.’’ A list of statement or both as required by part all published studies or publicly avail- 54 of this chapter. able reports of clinical investigations (l) Format of an original NDA—(1) Ar- known to the applicant through a lit- chival copy. The applicant must submit erature search that are relevant to the a complete archival copy of the NDA conditions for which the applicant is that contains the information required seeking approval, a certification that under paragraphs (a) through (f) of this the applicant has thoroughly searched section. FDA will maintain the archi- the scientific literature and, to the val copy during the review of the NDA best of the applicant’s knowledge, the to permit individual reviewers to refer list is complete and accurate and, in to information that is not contained in the applicant’s opinion, such published their particular technical sections of studies or publicly available reports do the NDA, to give other agency per- not provide a sufficient basis for the sonnel access to the NDA for official approval of the conditions for which business, and to maintain in one place the applicant is seeking approval with- a complete copy of the NDA. Except as out reference to the new clinical inves- required by paragraph (l)(1)(i) of this tigation(s) in the NDA, and an expla- section, applicants may submit the ar- nation as to why the studies or reports chival copy on paper or in electronic are insufficient. format provided that electronic sub- (iii) ‘‘Conducted or sponsored by.’’ If missions are made in accordance with the applicant was the sponsor named in part 11 of this chapter. the Form FDA 1571 for an IND under (i) Labeling. The content of labeling which the new clinical investigation(s) required under § 201.100(d)(3) of this that is essential to the approval of its chapter (commonly referred to as the NDA was conducted, identification of package insert or professional label- the IND by number. If the applicant ing), including all text, tables, and fig- was not the sponsor of the IND under ures, must be submitted to the agency which the clinical investigation(s) was in electronic format as described in conducted, a certification that the ap- paragraph (l)(5) of this section. This re- plicant or its predecessor in interest quirement is in addition to the require- provided substantial support for the ments of paragraph (e)(2)(ii) of this sec- clinical investigation(s) that is essen- tion that copies of the formatted label tial to the approval of its NDA, and in- and all labeling be submitted. Submis- formation supporting the certification. sions under this paragraph must be To demonstrate ‘‘substantial support,’’ made in accordance with part 11 of this an applicant must either provide a cer- chapter, except for the requirements of tified statement from a certified public § 11.10(a), (c) through (h), and (k), and accountant that the applicant provided the corresponding requirements of 50 percent or more of the cost of con- § 11.30. ducting the study or provide an expla- (ii) [Reserved] nation of why FDA should consider the (2) Review copy. The applicant must applicant to have conducted or spon- submit a review copy of the NDA. Each sored the study if the applicant’s finan- of the technical sections, described in cial contribution to the study is less paragraphs (d)(1) through (6) of this than 50 percent or the applicant did not section, in the review copy is required sponsor the investigational new drug. to be separately bound with a copy of A predecessor in interest is an entity, the application form required under e.g., a corporation, that the applicant paragraph (a) of this section and a copy has taken over, merged with, or pur- of the summary required under para- chased, or from which the applicant graph (c) of this section. has purchased all rights to the drug. (3) Field copy. The applicant must Purchase of nonexclusive rights to a submit a field copy of the NDA that clinical investigation after it is com- contains the technical section de- pleted is not sufficient to satisfy this scribed in paragraph (d)(1) of this sec- definition. tion, a copy of the application form re- (k) Financial certification or disclosure quired under paragraph (a) of this sec- statement. The NDA must contain a fi- tion, a copy of the summary required nancial certification or disclosure under paragraph (c) of this section, and

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a certification that the field copy is a cial may be obtained by sending a writ- true copy of the technical section de- ten or electronic communication to the scribed in paragraph (d)(1) of this sec- Central Document Room, Attn: Orange tion contained in the archival and re- Book Staff, Center for Drug Evaluation view copies of the NDA. and Research, Food and Drug Adminis- (4) Binding folders. The applicant may tration, 5901–B Ammendale Rd., Belts- obtain from FDA sufficient folders to ville, MD 20705–1266, or to the Orange bind the archival, the review, and the Book Staff at the email address listed field copies of the NDA. on the Agency’s Web site at http:// (5) Electronic format submissions. Elec- www.fda.gov. tronic format submissions must be in a (3) This paragraph (a) does not apply form that FDA can process, review, and to a method-of-use patent that does archive. FDA will periodically issue not claim a use for which the applicant guidance on how to provide the elec- is seeking approval. tronic submission (e.g., method of (4) An applicant may send notice by transmission, media, file formats, prep- an alternative method only if FDA has aration and organization of files). agreed in advance that the method will [50 FR 7493, Feb. 22, 1985] produce an acceptable form of documentation. EDITORIAL NOTE: For FEDERAL REGISTER ci- (b) Sending the notice. (1) Except as tations affecting § 314.50, see the List of CFR provided under paragraph (d) of this Sections Affected, which appears in the Finding Aids section of the printed volume section, the applicant must send the and at www.govinfo.gov. notice required by paragraph (a) of this section on or after the date of filing de- § 314.52 Notice of certification of inva- scribed in § 314.101(a)(2) or (3), as appli- lidity, unenforceability, or non- cable, but not later than 20 days after infringement of a patent. the date of the postmark on the para- (a) Notice of certification. For each graph IV acknowledgment letter. The patent that claims the listed drug or 20-day clock described in this para- drugs relied upon or that claims a use graph (b) begins on the day after the for such listed drug or drugs and for date of the postmark on the paragraph which the 505(b)(2) applicant submits a IV acknowledgment letter. When the paragraph IV certification, the appli- 20th day falls on Saturday, Sunday, or cant must send notice of such certifi- a Federal holiday, the 20th day will be cation by registered or certified mail, the next day that is not a Saturday, return receipt requested, or by a des- Sunday, or Federal holiday. ignated delivery service, as defined in (2) Any notice required by paragraph paragraph (g) of this section, to each of (a) of this section is invalid if it is sent the following persons: before the date of filing described in (1) Each owner of the patent that is § 314.101(a)(2) or, if FDA notifies the ap- the subject of the certification or the plicant that FDA has refused to file the representative designated by the owner 505(b)(2) application, before the date to receive the notice. The name and ad- described in § 314.101(a)(3) on which the dress of the patent owner or its rep- 505(b)(2) application is filed. The appli- resentative may be obtained from the cant will not have complied with this U.S. Patent and Trademark Office; and paragraph (b) until it sends valid no- (2) The holder of the approved NDA tice. under section 505(b) of the Federal (3) The applicant must submit to Food, Drug, and Cosmetic Act for each FDA an amendment to its 505(b)(2) ap- drug product which is claimed by the plication that includes a statement patent or a use of which is claimed by certifying that the notice has been pro- the patent and for which the applicant vided to each person identified under is seeking approval, or, if the NDA paragraph (a) of this section and that holder does not reside or maintain a the notice met the content require- place of business within the United ment under paragraph (c) of this sec- States, the NDA holder’s attorney, tion. A copy of the notice itself need agent, or other authorized official. The not be submitted to the Agency. name and address of the NDA holder or (c) Content of a notice. In the notice, its attorney, agent, or authorized offi- the applicant must cite section

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505(b)(3)(D) of the Federal Food, Drug, its 505(b)(2) application that includes a and Cosmetic Act and the notice must paragraph IV certification, the appli- include, but is not limited to, the fol- cant must send the notice required by lowing information: paragraph (a) of this section at the (1) A statement that a 505(b)(2) appli- same time that the amendment or sup- cation that contains any required bio- plement to the 505(b)(2) application is availability or bioequivalence studies submitted to FDA, regardless of wheth- has been submitted by the applicant er the applicant has already given no- and filed by FDA. tice with respect to another such cer- (2) The NDA number. tification contained in the 505(b)(2) ap- (3) The established name, if any, as plication or in an amendment or sup- defined in section 502(e)(3) of the Fed- plement to the 505(b)(2) application. eral Food, Drug, and Cosmetic Act, of (2) If, before the date of filing de- the proposed drug product. scribed in § 314.101(a)(2) or (3), as appli- (4) The active ingredient, strength, cable, an applicant submits a para- and dosage form of the proposed drug graph IV certification in an amend- product. ment, the applicant must send the no- (5) The patent number and expiration tice required by paragraph (a) of this date of each patent on the list alleged section in accordance with the proce- to be invalid, unenforceable, or not in- dures in paragraph (b) of this section. fringed. (3) An applicant that submits an (6) A detailed statement of the fac- amendment or supplement to seek ap- tual and legal basis of the applicant’s proval of a different strength must pro- opinion that the patent is not valid, vide notice of any paragraph IV certifi- unenforceable, or will not be infringed. The applicant must include in the de- cation in accordance with paragraph tailed statement: (d)(1) or (2) of this section, as applica- (i) For each claim of a patent alleged ble. not to be infringed, a full and detailed (e) Documentation of timely sending explanation of why the claim is not in- and receipt of notice. The applicant fringed. must amend its 505(b)(2) application to (ii) For each claim of a patent al- provide documentation of the date of leged to be invalid or unenforceable, a receipt of the notice required under full and detailed explanation of the paragraph (a) of this section by each grounds supporting the allegation. person provided the notice. The amend- (7) If the applicant alleges that the ment must be submitted to FDA within patent will not be infringed and the ap- 30 days after the last date on which no- plicant seeks to preserve the option to tice was received by a person described later file a civil action for declaratory in paragraph (a) of this section. The ap- judgment in accordance with section plicant’s amendment also must include 505(c)(3)(D) of the Federal Food, Drug, documentation that its notice was sent and Cosmetic Act, then the notice on a date that complies with the time- must be accompanied by an offer of frame required by paragraph (b) or (d) confidential access to the 505(b)(2) ap- of this section, as applicable. FDA will plication for the sole and limited pur- accept, as adequate documentation of pose of evaluating possible infringe- the date the notice was sent, a copy of ment of the patent that is the subject the registered mail receipt, certified of the paragraph IV certification. mail receipt, or receipt from a des- (8) If the applicant does not reside or ignated delivery service, as defined in have a place of business in the United paragraph (g) of this section. FDA will States, the name and address of an accept as adequate documentation of agent in the United States authorized the date of receipt a return receipt, a to accept service of process for the ap- signature proof of delivery by a des- plicant. ignated delivery service, or a letter ac- (d) Amendment or supplement to a knowledging receipt by the person pro- 505(b)(2) application. (1) If, after the vided the notice. An applicant may date of filing described in § 314.101(a)(2) rely on another form of documentation or (3), as applicable, an applicant sub- only if FDA has agreed to such docu- mits an amendment or supplement to mentation in advance. A copy of the

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notice itself need not be submitted to form, set forth in paragraph (c) of this the Agency. section for each patent that claims the (f) Forty-five day period after receipt of drug or a method of using the drug that notice. If the requirements of this sec- is the subject of the NDA or amend- tion are met, the Agency will presume ment or supplement to it and with re- the notice to be complete and suffi- spect to which a claim of patent in- cient and will count the day following fringement could reasonably be as- the date of receipt of the notice by the serted if a person not licensed by the patent owner or its representative and owner of the patent engaged in the by the approved NDA holder or its at- manufacture, use, or sale of the drug torney, agent, or other authorized offi- product. For purposes of this part, such cial as the first day of the 45-day period patents consist of drug substance (ac- provided for in section 505(c)(3)(C) of tive ingredient) patents, drug product the Federal Food, Drug, and Cosmetic (formulation and composition) patents, Act. FDA may, if the applicant amends and method-of-use patents. For patents its 505(b)(2) application with a written that claim the drug substance, the ap- statement that a later date should be plicant must submit information only used, count from such later date. on those patents that claim the drug (g) Designated delivery services. (1) For substance that is the subject of the purposes of this section, the term pending or approved NDA or that claim ‘‘designated delivery service’’ is any a drug substance that is the same as delivery service provided by a trade or the active ingredient that is the sub- business that the Agency determines: ject of the approved or pending NDA. (i) Is available to the general public For patents that claim only a poly- throughout the United States; morph that is the same as the active (ii) Records electronically to its ingredient described in the approved or database, kept in the regular course of pending NDA, the applicant must cer- its business, or marks on the cover in tify in the required FDA declaration which any item referred to in this sec- form that the applicant has test data, tion is to be delivered, the date on as set forth in paragraph (b)(2) of this which such item was given to such section, demonstrating that a drug trade or business for delivery; and product containing the polymorph will (iii) Provides overnight or 2-day de- perform the same as the drug product livery service throughout the United described in the NDA. For patents that States. claim a drug product, the applicant (2) FDA may periodically issue guid- must submit information only on those ance regarding designated delivery patents that claim the drug product, as services. is defined in § 314.3, that is described in [81 FR 69641, Oct. 6, 2016, as amended at 84 FR the pending or approved NDA. For pat- 6673, Feb. 28, 2019] ents that claim a method of use, the applicant must submit information § 314.53 Submission of patent informa- only on those patents that claim indi- tion. cations or other conditions of use for (a) Who must submit patent informa- which approval is sought or has been tion. This section applies to any appli- granted in the NDA. The applicant cant who submits to FDA an NDA or must separately identify each pending an amendment to it under section or approved method of use and related 505(b) of the Federal Food, Drug, and patent claim(s). For approved NDAs, Cosmetic Act and § 314.50 or a supple- the NDA holder’s description of the ment to an approved NDA under patented method of use required by § 314.70, except as provided in paragraph paragraph (c)(2)(ii)(P)(3) of this section (d)(2) of this section. must describe only the approved meth- (b) Patents for which information must od(s) of use claimed by the patent for be submitted and patents for which infor- which a claim of patent infringement mation must not be submitted—(1) General could reasonably be asserted if a person requirements. An applicant described in not licensed by the owner of the patent paragraph (a) of this section must sub- engaged in the manufacture, use, or mit to its NDA the required informa- sale of the drug product. If the meth- tion, on the required FDA declaration od(s) of use claimed by the patent does

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not cover an indication or other ap- drug product; such specifications and proved condition of use in its entirety, analytical methods as are necessary to the applicant must describe only the assure the identity, strength, quality, specific approved method of use purity, and bioavailability of the drug claimed by the patent for which a product, including release and stability claim of patent infringement could rea- data complying with the approved sonably be asserted if a person not li- product specifications to demonstrate censed by the owner of the patent en- pharmaceutical equivalence and com- gaged in the manufacture, use, or sale parable product stability; and of the drug product. For approved (v) Comparative in vitro dissolution NDAs, the NDA holder submitting in- testing on 12 dosage units each of the formation on the method-of-use patent executed test batch and the NDA prod- must identify with specificity the sec- uct. tion(s) and subsection(s) of the ap- (c) Reporting requirements—(1) General proved labeling that describes the requirements. An applicant described in method(s) of use claimed by the patent paragraph (a) of this section must sub- submitted. Process patents, patents mit the required patent information claiming packaging, patents claiming described in paragraph (c)(2) of this metabolites, and patents claiming section for each patent that meets the intermediates are not covered by this requirements described in paragraph section, and information on these pat- (b) of this section. We will not accept ents must not be submitted to FDA. the patent information unless it is sub- (2) Test data for submission of patent mitted on the appropriate form, Form information for patents that claim only a FDA 3542 or 3542a, and contains the in- polymorph. The test data, referenced in formation required in paragraph (c)(2) paragraph (b)(1) of this section, must of this section. These forms may be ob- include the following: tained on the Internet at http:// (i) A full description of the poly- www.fda.gov by searching for ‘‘forms’’. morphic form of the drug substance, in- (2) Drug substance (active ingredient), cluding its physical and chemical char- drug product (formulation or composi- acteristics and stability; the method of tion), and method-of-use patents—(i) synthesis (or isolation) and purifi- Original declaration. For each patent cation of the drug substance; the proc- that claims a drug substance (active ess controls used during manufacture ingredient), drug product (formulation and packaging; and such specifications and composition), or method of use, the and analytical methods as are nec- applicant must submit Form FDA essary to assure the identity, strength, 3542a. The following information and quality, and purity of the polymorphic verification is required, subject to the form of the drug substance; exceptions listed in paragraph (ii) The executed batch record for a (c)(2)(i)(S) of this section: drug product containing the poly- (A) NDA number; morphic form of the drug substance (B) The NDA applicant’s name, full and documentation that the batch was address, phone number and, if avail- manufactured under current good man- able, fax number and email address; ufacturing practice requirements; (C) Trade name (or proposed trade (iii) Demonstration of bioequivalence name) of new drug; between the executed batch of the drug (D) Active ingredient(s) of new drug; product that contains the polymorphic (E) Strength(s) of new drug; form of the drug substance and the (F) Dosage form(s) and route(s) of ad- drug product as described in the NDA; ministration of new drug, and whether (iv) A list of all components used in the applicant proposes to market the the manufacture of the drug product new drug for prescription use or over- containing the polymorphic form and a the-counter use; statement of the composition of the (G) U.S. patent number, issue date, drug product; a statement of the speci- and expiration date of patent sub- fications and analytical methods for mitted; each component; a description of the (H) The patent owner’s name, full ad- manufacturing and packaging proce- dress, phone number and, if available, dures and in-process controls for the fax number and email address;

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(I) The name, full address, phone (O) Information on each method-of- number and, if available, fax number use patent, including the following: and email address of an agent or rep- (1) Whether the patent claims one or resentative who resides or maintains a more methods of using the drug prod- place of business within the United uct for which approval is being sought States authorized to receive notice of and a description of each pending patent certification under section method of use and related patent claim 505(b)(3) and (j)(2)(B) of the Federal of the patent being submitted; Food, Drug, and Cosmetic Act and (2) Identification of the specific sec- §§ 314.52 and 314.95 (if patent owner or tion(s) and subsection(s) of the pro- NDA applicant or holder does not re- posed labeling for the drug product side or have a place of business within that describes the method of use the United States); claimed by the patent submitted; and (J) Information on whether the pat- (3) An applicant that submits infor- ent has been submitted previously for mation for a patent that claims one or the NDA or supplement; more methods of using the drug prod- (K) If the patent has been submitted uct must also submit information de- previously for listing, identify all scribed in either paragraph (c)(2)(i)(M) change(s) from the previously sub- or (N) of this section, regarding wheth- mitted patent information and specify er that patent also claims either the whether the change is related to the drug substance (active ingredient) or patent or related to an FDA action or the drug product (composition/formula- procedure; tion). (L) Information on whether the pat- (P) Whether there are no relevant ent is a product-by-process patent in patents that claim the drug substance which the product claimed is novel; (active ingredient), drug product (for- (M) Information on the drug sub- mulation or composition), or method(s) stance (active ingredient) patent, in- of use, for which the applicant is seek- cluding the following: ing approval and with respect to which (1) Whether the patent claims a drug a claim of patent infringement could substance that is an active ingredient reasonably be asserted if a person not in the drug product described in the licensed by the owner of the patent en- NDA or supplement; gaged in the manufacture, use, or sale (2) Whether the patent claims only a of the drug product; polymorph that is the same active in- (Q) A signed verification that states: gredient that is described in the pend- The undersigned declares that this is an ing NDA or supplement; accurate and complete submission of patent (3) Whether the applicant has test information for the NDA, amendment, or data, described in paragraph (b)(2) of supplement pending under section 505 of the Federal Food, Drug, and Cosmetic Act. This this section, demonstrating that a drug time-sensitive patent information is sub- product containing only the polymorph mitted pursuant to 21 CFR 314.53. I attest will perform the same as the drug prod- that I am familiar with 21 CFR 314.53 and uct described in the NDA or supple- this submission complies with the requirement, and a description of the poly- ments of the regulation. I verify under pen- morphic form(s) claimed by the patent alty of perjury that the foregoing is true and for which such test data exist; correct. (4) Whether the patent claims only a (R) Information on whether the ap- metabolite of the active ingredient; plicant, patent owner or attorney, and agent, representative, or other author- (5) Whether the patent claims only ized official signed the form; the name an intermediate; of the person; and the full address, (N) Information on the drug product phone number and, if available, the fax (composition/formulation) patent, in- number and email address; and cluding the following: (S) Exceptions to required submis- (1) Whether the patent claims the sion of patent information: drug product for which approval is (1) If an applicant submits the infor- being sought, as defined in § 314.3; and mation described in paragraph (2) Whether the patent claims only (c)(2)(i)(M) of this section for a patent an intermediate; that claims the drug substance (active

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ingredient) and meets the requirements listed in paragraph (c)(2)(ii)(T) of this for listing on that basis, then the appli- section: cant is not required to provide the in- (A) NDA number; formation described in paragraph (B) The NDA holder’s name, full ad- (c)(2)(i)(N) of this section on whether dress, phone number and, if available, that patent also claims the drug prod- fax number and email address; uct (composition/formulation); (C) Trade name of new drug; (2) If an applicant submits the infor- (D) Active ingredient(s) of new drug; mation described in paragraph (E) Strength(s) of new drug; (c)(2)(i)(N) of this section for a patent (F) Dosage form(s) and route(s) of ad- that claims the drug product (composi- ministration of new drug, and whether tion/formulation) and meets the re- the new drug is approved for prescrip- quirements for listing on that basis, tion use or over-the-counter use; then the applicant is not required to (G) Approval date of NDA or supple- provide the information described in ment; paragraph (c)(2)(i)(M) of this section on (H) U.S. patent number, issue date, whether that patent also claims the and expiration date of patent sub- drug substance (active ingredient); mitted; (3) If the applicant submits a supplement for a change other than one of (I) The patent owner’s name, full ad- the changes listed under paragraph dress, phone number and, if available, (d)(2)(i) of this section, then the patent fax number and email address; information submission requirements (J) The name, full address, phone of paragraph (d)(2)(ii) of this section number and, if available, fax number apply. and email address of an agent or rep- (ii) Submission of patent information resentative who resides or maintains a upon and after approval. Within 30 days place of business within the United after the date of approval of its NDA or States authorized to receive notice of supplement, the applicant must submit patent certification under section Form FDA 3542 for each patent that 505(b)(3) and (j)(2)(B) of the Federal claims the drug substance (active in- Food, Drug, and Cosmetic Act and gredient), drug product (formulation §§ 314.52 and 314.95 (if patent owner or and composition), or approved method NDA applicant or holder does not re- of use. FDA will not list or publish pat- side or have a place of business within ent information if it is not provided on the United States); this form or if the patent declaration (K) Information on whether the pat- does not contain the required informa- ent has been submitted previously for tion or indicates the patent is not eli- the NDA or supplement; gible for listing. Patent information (L) If the patent has been submitted must also be submitted for patents previously for listing, identify all issued after the date of approval of the change(s) from the previously sub- NDA as required in paragraph (c)(2)(ii) mitted patent information and specify of this section. As described in para- whether the change is related to the graph (d)(3) of this section, to be time- patent or related to an FDA action or ly filed, patent information for patents procedure; issued after the date of approval of the (M) Information on whether the pat- NDA must be submitted to FDA within ent is a product-by-process patent in 30 days of the date of issuance of the which the product claimed is novel; patent. If the applicant submits the re- (N) Information on the drug sub- quired patent information within the stance (active ingredient) patent, in- 30 days, but we notify an applicant that cluding the following: a declaration form is incomplete or (1) Whether the patent claims a drug shows that the patent is not eligible substance that is an active ingredient for listing, the applicant must submit in the drug product described in the ap- an acceptable declaration form within proved NDA; 15 days of FDA notification to be con- (2) Whether the patent claims only a sidered timely filed. The following in- polymorph that is the same as the ac- formation and verification statement tive ingredient that is described in the is required, subject to the exceptions approved NDA;

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(3) Whether the applicant has test or (O) of this section, regarding wheth- data, described in paragraph (b)(2) of er that patent also claims either the this section, demonstrating that a drug drug substance (active ingredient) or product containing only the polymorph the drug product (composition/formula- will perform the same as the drug prod- tion). uct described in the approved NDA and (Q) Whether there are no relevant a description of the polymorphic patents that claim the approved drug form(s) claimed by the patent for substance (active ingredient), the ap- which such test data exist; proved drug product (formulation or (4) Whether the patent claims only a composition), or approved method(s) of metabolite of the active ingredient; use and with respect to which a claim and of patent infringement could reason- (5) Whether the patent claims only ably be asserted if a person not li- an intermediate; censed by the owner of the patent en- (O) Information on the drug product gaged in the manufacture, use, or sale (composition/formulation) patent, in- of the drug product; cluding the following: (R) A signed verification that states: (1) Whether the patent claims the approved drug product as defined in The undersigned declares that this is an § 314.3; and accurate and complete submission of patent information for the NDA, amendment, or (2) Whether the patent claims only supplement approved under section 505 of the an intermediate; Federal Food, Drug, and Cosmetic Act. This (P) Information on each method-of- time-sensitive patent information or reuse patent, including the following: sponse to a request under 21 CFR 314.53(f)(1) (1) Whether the patent claims one or is submitted pursuant to 21 CFR 314.53. I at- more approved methods of using the test that I am familiar with 21 CFR 314.53 approved drug product and a descrip- and this submission complies with the re- tion of each approved method of use quirements of the regulation. I verify under penalty of perjury that the foregoing is true and related patent claim of the patent and correct. being submitted; (2) Identification of the specific sec- (S) Information on whether the appli- tion(s) and subsection(s) of the ap- cant, patent owner or attorney, agent, proved labeling for the drug product representative, or other authorized of- that describes the method of use ficial signed the form; the name of the claimed by the patent submitted; person; and the full address, phone (3) The description of the patented number and, if available, the fax num- method of use as required for publica- ber and email address; and tion, which must contain adequate in- (T) Exceptions to required submis- formation to assist 505(b)(2) and ANDA sion of patent information: applicants in determining whether a (1) If an applicant submits the infor- listed method-of-use patent claims a mation described in paragraph use for which the 505(b)(2) or ANDA ap- (c)(2)(ii)(N) of this section for a patent plicant is not seeking approval (for ex- that claims the drug substance (active ample, if the method(s) of use claimed ingredient) and meets the requirements by the patent does not cover an indica- for listing on that basis, then the appli- tion or other approved condition of use cant is not required to provide the in- in its entirety, then the applicant must formation described in paragraph describe only the specific approved (c)(2)(ii)(O) of this section on whether method of use claimed by the patent that patent also claims the drug prod- for which a claim of patent infringe- uct (composition/formulation). ment could reasonably be asserted if a (2) If an applicant submits the infor- person not licensed by the owner of the mation described in paragraph patent engaged in the manufacture, (c)(2)(ii)(O) of this section for a patent use, or sale of the drug product); and that claims the drug product (composi- (4) An applicant that submits infor- tion/formulation) and meets the re- mation for a patent that claims one or quirements for listing on that basis, more methods of using the drug prod- then the applicant is not required to uct must also submit information de- provide the information described in scribed in either paragraph (c)(2)(ii)(N) paragraph (c)(2)(ii)(N) of this section

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on whether that patent also claims the (C) To change the drug product from drug substance (active ingredient). prescription use to over-the-counter (3) If the applicant submits a supple- use. ment for a change other than one of (ii) If the applicant submits a supple- the changes listed under paragraph ment for a change other than one of (d)(2)(i) of this section, then the patent the changes listed under paragraph information submission requirements (d)(2)(i) of this section (for example, to of paragraph (d)(2)(ii) of this section change the formulation, to add a new apply. indication or other condition of use, or (3) No relevant patents. If the appli- to make any other patented change re- cant believes that there are no relevant garding the drug substance, drug prod- patents that claim the drug substance uct, or any method of use), the fol- (active ingredient), drug product (for- lowing patent information submission mulation or composition), or the meth- requirements apply: od(s) of use for which the applicant has (A) If existing patents for which in- received approval, and with respect to formation required by paragraph (c) of which a claim of patent infringement this section has already been sub- could reasonably be asserted if a person mitted to FDA for the product ap- not licensed by the owner of the patent proved in the original NDA claim the engaged in the manufacture, use, or changed product, the applicant is not sale of the drug product, the applicant required to resubmit this patent infor- will verify this information in the ap- mation pursuant to paragraph (c) of propriate form, Form FDA 3542 or this section unless the published de- 3542a. scription of the patented method of use (4) Authorized signature. The declara- would change upon approval of the sup- tions required by this section must be plement, and FDA will continue to list signed by the applicant or patent this patent information for the prod- owner, or the applicant’s or patent uct; owner’s attorney, agent (representa- (B) If one or more existing patents tive), or other authorized official. for which information has already been (d) When and where to submit patent submitted to FDA no longer claim the information—(1) Original NDA. An appli- changed product, the applicant must cant must submit with its original submit a request under paragraph NDA submitted under this part, the in- (f)(2)(iv) of this section to remove that formation described in paragraph (c) of patent information from the list at the this section on each drug substance time of approval of the supplement; (active ingredient), drug product (for- (C) If one or more existing drug sub- mulation and composition), and meth- stance (active ingredient), drug prod- od-of-use patent issued before the NDA uct (formulation and composition), or is filed with FDA and for which patent method-of-use patents claim the information is required to be submitted changed product for which approval is under this section. If a patent is issued sought in the supplement and such pat- after the NDA is filed with FDA but be- ent information has not been sub- fore the NDA is approved, the applicant mitted to FDA, the applicant must must, within 30 days of the date of submit the patent information required issuance of the patent, submit the re- under paragraph (c) of this section. quired patent information in an (3) Newly issued patents. If a patent is amendment to the NDA under § 314.60. issued for a drug substance, drug prod- (2) Supplements. (i) An applicant must uct, or method of use after an NDA is submit patent information required approved, the applicant must submit to under paragraph (c) of this section for FDA, as described in paragraph (d)(4) of a patent that claims the drug sub- this section, the required patent infor- stance, drug product, or method of use mation within 30 days of the date of for which approval is sought in any of issuance of the patent. If the required the following supplements: patent information is not submitted (A) To add or change the dosage form within 30 days of the issuance of the or route of administration; patent, FDA will list the patent, but (B) To add or change the strength; or patent certifications or statements

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will be governed by the provisions re- and for each method-of-use patent, the garding untimely filed patent informa- description of the method of use tion at §§ 314.50(i)(4) and (6) and claimed by the patent as required by 314.94(a)(12)(vi) and (viii). § 314.53(c)(2)(ii)(P)(3). FDA will publish (4) Submission of Forms FDA 3542a and such patent information upon approval 3542—(i) Patent information submitted of the NDA, or, if the patent informa- with the filing of an NDA, amendment, or tion is submitted by the applicant after supplement. The applicant must submit approval of an NDA as provided under patent information required by para- paragraph (d)(2) of this section, as soon graphs (c)(1) and (c)(2)(i) of this section as possible after the submission to the and § 314.50(h) or § 314.70(f) on Form Agency of the patent information. A FDA 3542a to the Central Document request for copies of the submitted pat- Room, Center for Drug Evaluation and ent information must be sent in writ- Research, Food and Drug Administra- ing to the Freedom of Information tion, 5901–B Ammendale Rd., Beltsville, Staff at the address listed on the Agen- MD 20705–1266, or to FDA in an elec- cy’s Web site at http://www.fda.gov. The tronic format submission that complies submitted patent information, and re- with § 314.50(l)(5). Form FDA 3542a quests to remove a patent or patent in- should not be submitted to the Orange formation from the list, may be subject Book Staff in the Office of Generic to public disclosure. Drugs. (f) Correction of patent information er- (ii) Patent information submitted upon rors—(1) Requests by persons other than and after approval of an NDA or supple- the NDA holder. If any person disputes ment. The applicant must submit pat- the accuracy or relevance of patent in- ent information required by paragraphs formation submitted to the Agency (c)(1) and (c)(2)(ii) of this section on under this section and published by Form FDA 3542 to the Central Docu- FDA in the list, or believes that an ment Room, Center for Drug Evalua- NDA holder has failed to submit re- tion and Research, Food and Drug Ad- quired patent information, that person ministration, 5901–B Ammendale Rd., must first notify the Agency in a writ- Beltsville, MD 20705–1266, or to FDA in ten or electronic communication titled an electronic format submission that ‘‘314.53(f) Patent Listing Dispute.’’ The complies with § 314.50(l)(5). Form FDA patent listing dispute communication 3542 should not be submitted to the Or- must include a statement of dispute ange Book Staff in the Office of Ge- that describes the specific grounds for neric Drugs. disagreement regarding the accuracy (5) Submission date. Patent informa- or relevance of patent information for tion will be considered to be submitted FDA to send to the applicable NDA to FDA for purposes of paragraph (d)(3) holder. For a dispute regarding the ac- of this section as of the earlier of the curacy or relevance of patent informa- date the information submitted on tion regarding an approved method of Form FDA 3542 is date-stamped by the using the drug product, this statement Central Document Room, or officially of dispute must be only a narrative de- received by FDA in an electronic for- scription (no more than 250 words) of mat submission that complies with the person’s interpretation of the scope § 314.50(l)(5). of the patent. This statement of dis- (6) Identification. Each submission of pute must only contain information for patent information, except information which the person consents to disclosure submitted with an original NDA, must because FDA will send the text of the bear prominent identification as to its statement to the applicable NDA hold- contents, i.e., ‘‘Patent Information,’’ er without review or redaction. The or, if submitted after approval of an patent listing dispute communication NDA, ‘‘Time Sensitive Patent Informa- should be directed to the Central Docu- tion.’’ ment Room, Attn: Orange Book Staff, (e) Public disclosure of patent informa- Center for Drug Evaluation and Re- tion. FDA will publish in the list the search, Food and Drug Administration, patent number and expiration date of 5901–B Ammendale Rd., Beltsville, MD each patent that is required to be, and 20705–1266, or to the Orange Book Staff is, submitted to FDA by an applicant, at the email address listed on the

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Agency’s Web site at http:// of the statement to the person who www.fda.gov. submitted the patent listing dispute (i) Communication with the NDA hold- without review or redaction. er—(A) Drug substance or drug product (1) If the NDA holder confirms the claim. For requests submitted under correctness of the patent information, this paragraph (f)(1) that are directed provides the narrative description re- to the accuracy or relevance of sub- quired by paragraph (f)(1)(i)(B) of this mitted patent information regarding a section, and includes the signed drug substance or drug product claim, verification required by paragraph the Agency will send the statement of (c)(2)(ii)(R) of this section within 30 dispute to the applicable NDA holder. days of the date on which the Agency The NDA holder must confirm the cor- sends the statement of dispute, the rectness of the patent information and Agency will not change the patent in- include the signed verification required formation in the Orange Book. by paragraph (c)(2)(ii)(R) of this section or withdraw or amend the patent (2) If the NDA holder responds to the information in accordance with para- patent listing dispute with amended graph (f)(2) of this section within 30 patent information in accordance with days of the date on which the Agency paragraph (f)(2) of this section, pro- sends the statement of dispute. Unless vides the narrative description re- the NDA holder withdraws or amends quired by paragraph (f)(1)(i)(B) of this its patent information in response to section, and includes the signed the patent listing dispute, the Agency verification required by paragraph will not change the patent information (c)(2)(ii)(R) of this section within 30 in the Orange Book. days of the date on which the Agency (B) Method-of-use claim. For requests sends the statement of dispute, FDA submitted under this paragraph (f)(1) will update the Orange Book to reflect that are directed to the accuracy or the amended patent information. relevance of submitted patent informa- (ii) Patent certification or statement tion regarding an approved method of during and after patent listing dispute. A using the drug product, FDA will send 505(b)(2) application or ANDA must the statement of dispute to the NDA contain an appropriate certification or holder. The NDA holder must confirm statement for each listed patent, in- the correctness of its description of the cluding the disputed patent, during and approved method of use claimed by the after the patent listing dispute. patent that has been included as the (iii) Information on patent listing dis- ‘‘Use Code’’ in the Orange Book, or putes. FDA will promptly post informa- withdraw or amend the patent information on its Web site regarding whether tion in accordance with paragraph (f)(2) a patent listing dispute has been sub- of this section, provide a narrative de- mitted for a published description of a scription (no more than 250 words) of patented method of use for a drug prod- the NDA holder’s interpretation of the scope of the patent that explains why uct and whether the NDA holder has the existing or amended ‘‘Use Code’’ timely responded to the patent listing describes only the specific approved dispute. method of use claimed by the patent (2) Requests by the NDA holder—(i) for which a claim of patent infringe- Patents or patent claims that no longer ment could reasonably be asserted if a meet the statutory requirements for list- person not licensed by the owner of the ing. If the NDA holder determines that patent engaged in the manufacture, a patent or patent claim no longer use, or sale of the drug product, and in- meets the requirements for listing in clude the signed verification required section 505(b)(1) or (c)(2) of the Federal by paragraph (c)(2)(ii)(R) of this sec- Food, Drug, and Cosmetic Act (includ- tion within 30 days of the date on ing if there has been a judicial finding which the Agency sends the statement of invalidity for a listed patent, from of dispute. The narrative description which no appeal has been or can be must only contain information for taken), the NDA holder is required to which the NDA holder consents to dis- promptly notify FDA to amend the closure because FDA will send the text patent information or withdraw the

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patent or patent information and re- mitted on Form FDA 3542 and may be quest that the patent or patent infor- submitted by letter. Withdrawal of a mation be removed from the list. If the patent and a request to remove a pat- NDA holder is required by court order ent from the list must contain the fol- to amend patent information or with- lowing information: draw a patent from the list, it must (A) The NDA number to which the resubmit an amendment to its NDA that quest applies; includes a copy of the order, within 14 (B) Each product(s) approved in the days of the date the order was entered, NDA to which the request applies; and to the Central Document Room, Center (C) The patent number. for Drug Evaluation and Research, [81 FR 69643, Oct. 6, 2016, as amended at 84 FR Food and Drug Administration, 5901–B 6673, Feb. 28, 2019] Ammendale Rd., Beltsville, MD 20705– 1266. The amendment to the NDA must § 314.54 Procedure for submission of a bear the identification described in 505(b)(2) application requiring in- paragraph (d)(6) of this section. FDA vestigations for approval of a new will remove a patent or patent infor- indication for, or other change mation from the list if there is no first from, a listed drug. applicant eligible for 180-day exclu- (a) The Federal Food, Drug, and Cos- sivity based on a paragraph IV certifi- metic Act does not permit approval of cation to that patent or after the 180- an ANDA for a new indication, nor does day exclusivity period of a first appli- it permit approval of other changes in cant based on that patent has expired a listed drug if investigations, other or has been extinguished. than bioavailability or bioequivalence (ii) Patent term restoration. If the term studies, are essential to the approval of of a listed patent is extended pursuant the change. Any person seeking ap- to 35 U.S.C. 156(e), the NDA holder proval of a drug product that rep- must submit on Form FDA 3542 a cor- resents a modification of a listed drug rection to the expiration date of the (e.g., a new indication or new dosage patent. This correction must be sub- form) and for which investigations, mitted within 30 days of receipt of a other than bioavailability or bio- certificate of extension as described in equivalence studies, are essential to 35 U.S.C. 156(e)(1) or documentation of the approval of the changes may, ex- an extension of the term of the patent cept as provided in paragraph (b) of as described in 35 U.S.C. 156(e)(2). this section, submit a 505(b)(2) applica- (iii) Submission of corrections or tion. This 505(b)(2) application need changes to patent information. Correc- contain only that information needed tions or changes to previously sub- to support the modification(s) of the mitted patent information, other than listed drug. withdrawal of a patent and requests to (1) The applicant must submit a com- remove a patent from the list, must be plete archival copy of the application submitted on Form FDA 3542 or 3542a, that contains the following: as appropriate, in an amendment or (i) The information required under supplement to the NDA. The amend- § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and ment or supplement to the NDA must (g), except that § 314.50(d)(1)(ii)(c) must bear the identification described in contain the proposed or actual master paragraph (d)(6) of this section. We will production record, including a descrip- not accept the corrections or changes tion of the equipment, to be used for unless they are submitted on the ap- the manufacture of a commercial lot of propriate forms. the drug product. (iv) Submission of patent withdrawals (ii) The information required under and requests to remove a patent from the § 314.50 (d)(2), (d)(4) (if an anti-infective list. Withdrawal of a patent and re- drug), (d)(5), (d)(6), and (f) as needed to quests to remove a patent from the list support the safety and effectiveness of must be submitted to the same ad- the drug product. dresses described in paragraph (d)(4)(ii) (iii) Identification of each listed drug of this section, except that the with- for which FDA has made a finding of drawal or request to remove a patent safety and effectiveness and on which from the list is not required to be sub- finding the applicant relies in seeking

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approval of its proposed drug product nical sections described in § 314.50(d)(2), by established name, if any, propri- (d)(4) through (6), and (f) when needed etary name, dosage form, strength, to support the modification. Each of route of administration, name of listed the technical sections in the review drug’s application holder, and listed copy is required to be separately bound drug’s approved NDA number. The list- with a copy of the information required ed drug(s) identified as relied upon under § 314.50(a), (b), and (c) and a copy must include a drug product approved of the proposed labeling. in an NDA that: (3) The information required by (A) Is pharmaceutically equivalent to § 314.50 (d)(2), (d)(4) (if an anti-infective the drug product for which the original drug), (d)(5), (d)(6), and (f) for the listed 505(b)(2) application is submitted; and drug on which the applicant relies (B) Was approved before the original must be satisfied by reference to the 505(b)(2) application was submitted. listed drug under paragraph (a)(1)(iii) (iv) If the applicant is seeking ap- of this section. proval only for a new indication and (4) The applicant must submit a field not for the indications approved for the copy of the 505(b)(2) application that listed drug on which the applicant re- contains the technical section de- lies, a certification so stating. scribed in § 314.50(d)(1), a copy of the in- (v) Any patent information required formation required under § 314.50(a) and under section 505(b)(1) of the Federal (c), and certification that the field Food, Drug, and Cosmetic Act with re- copy is a true copy of the technical sec- spect to any patent which claims the tion described in § 314.50(d)(1) contained drug for which approval is sought or a in the archival and review copies of the method of using such drug and to 505(b)(2) application. which a claim of patent infringement (b) A 505(b)(2) application may not be could reasonably be asserted if a person submitted under this section for a drug not licensed by the owner of the patent product whose only difference from a engaged in the manufacture, use, or listed drug is that: sale of the drug product. (1) The extent to which its active in- (vi) Any patent certification or state- gredient(s) is absorbed or otherwise ment required under section 505(b)(2) of made available to the site of action is the Federal Food, Drug, and Cosmetic less than that of the listed drug; or Act with respect to any relevant pat- (2) The rate at which its active ingre- ents that claim the listed drug(s) on dient(s) is absorbed or otherwise made which investigations relied on by the available to the site of action is unin- applicant for approval of the applica- tentionally less than that of the listed tion were conducted, or that claim a drug. use for the listed drug(s). A 505(b)(2) ap- [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. plicant seeking approval of a drug that 28, 1992, as amended at 58 FR 47351, Sept. 8, is pharmaceutically equivalent to a 1993; 59 FR 50364, Oct. 3, 1994; 81 FR 69647, listed drug approved in an NDA implic- Oct. 6, 2016] itly relies upon one such pharmaceutically equivalent listed drug. § 314.55 Pediatric use information. (vii) If the applicant believes the (a) Required assessment. Except as pro- change for which it is seeking approval vided in paragraphs (b), (c), and (d) of is entitled to a period of exclusivity, this section, each application for a new the information required under active ingredient, new indication, new § 314.50(j). dosage form, new dosing regimen, or (2) The applicant must submit a re- new route of administration shall con- view copy that contains the technical tain data that are adequate to assess sections described in § 314.50(d)(1), ex- the safety and effectiveness of the drug cept that the section described in product for the claimed indications in § 314.50(d)(1)(ii)(c) must contain the pro- all relevant pediatric subpopulations, posed or actual master production and to support dosing and administra- record, including a description of the tion for each pediatric subpopulation equipment, to be used for the manufac- for which the drug is safe and effective. ture of a commercial lot of the drug Where the course of the disease and the product, and § 314.50(d)(3), and the tech- effects of the drug are sufficiently

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similar in adults and pediatric pa- paragraph (a) of this section if the ap- tients, FDA may conclude that pedi- plicant certifies that: atric effectiveness can be extrapolated (i) The drug product does not rep- from adequate and well-controlled resent a meaningful therapeutic ben- studies in adults usually supplemented efit over existing treatments for pedi- with other information obtained in pe- atric patients and is not likely to be diatric patients, such as pharmaco- used in a substantial number of pedi- kinetic studies. Studies may not be atric patients; needed in each pediatric age group, if (ii) Necessary studies are impossible data from one age group can be extrap- or highly impractical because, e.g., the olated to another. Assessments of safe- number of such patients is so small or ty and effectiveness required under this geographically dispersed; or section for a drug product that rep- (iii) There is evidence strongly sug- resents a meaningful therapeutic ben- gesting that the drug product would be efit over existing treatments for pedi- ineffective or unsafe in all pediatric atric patients must be carried out age groups. using appropriate formulations for (3) Partial waiver. An applicant may each age group(s) for which the assess- request a waiver of the requirements of ment is required. paragraph (a) of this section with re- (b) Deferred submission. (1) FDA may, spect to a specified pediatric age group, on its own initiative or at the request if the applicant certifies that: of an applicant, defer submission of (i) The drug product does not rep- some or all assessments of safety and resent a meaningful therapeutic ben- effectiveness described in paragraph (a) efit over existing treatments for pedi- of this section until after approval of atric patients in that age group, and is the drug product for use in adults. De- not likely to be used in a substantial ferral may be granted if, among other number of patients in that age group; reasons, the drug is ready for approval (ii) Necessary studies are impossible in adults before studies in pediatric pa- or highly impractical because, e.g., the tients are complete, or pediatric stud- number of patients in that age group is ies should be delayed until additional so small or geographically dispersed; safety or effectiveness data have been (iii) There is evidence strongly sug- collected. If an applicant requests de- gesting that the drug product would be ferred submission, the request must ineffective or unsafe in that age group; provide a certification from the appli- or cant of the grounds for delaying pedi- (iv) The applicant can demonstrate atric studies, a description of the that reasonable attempts to produce a planned or ongoing studies, and evi- pediatric formulation necessary for dence that the studies are being or will that age group have failed. be conducted with due diligence and at (4) FDA action on waiver. FDA shall the earliest possible time. grant a full or partial waiver, as appro- (2) If FDA determines that there is priate, if the agency finds that there is an adequate justification for tempo- a reasonable basis on which to con- rarily delaying the submission of as- clude that one or more of the grounds sessments of pediatric safety and effec- for waiver specified in paragraphs (c)(2) tiveness, the drug product may be ap- or (c)(3) of this section have been met. proved for use in adults subject to the If a waiver is granted on the ground requirement that the applicant submit that it is not possible to develop a pedi- the required assessments within a spec- atric formulation, the waiver will ified time. cover only those pediatric age groups (c) Waivers—(1) General. FDA may requiring that formulation. If a waiver grant a full or partial waiver of the re- is granted because there is evidence quirements of paragraph (a) of this sec- that the product would be ineffective tion on its own initiative or at the re- or unsafe in pediatric populations, this quest of an applicant. A request for a information will be included in the waiver must provide an adequate jus- product’s labeling. tification. (5) Definition of ‘‘meaningful thera- (2) Full waiver. An applicant may re- peutic benefit’’. For purposes of this sec- quest a waiver of the requirements of tion and § 201.23 of this chapter, a drug

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will be considered to offer a meaningful viewing the resubmission is the ‘‘re- therapeutic benefit over existing thera- view cycle’’ rather than the ‘‘initial re- pies if FDA estimates that: view cycle.’’) FDA may instead defer (i) If approved, the drug would rep- review of the amendment until the sub- resent a significant improvement in sequent review cycle. If the agency ex- the treatment, diagnosis, or prevention tends the initial review cycle for an of a disease, compared to marketed original NDA, efficacy supplement, or products adequately labeled for that resubmission under this paragraph, the use in the relevant pediatric popu- division responsible for reviewing the lation. Examples of how improvement NDA, supplement, or resubmission will might be demonstrated include, for ex- notify the applicant of the extension. ample, evidence of increased effective- The initial review cycle for an original ness in treatment, prevention, or diag- NDA, efficacy supplement, or resubmis- nosis of disease, elimination or sub- sion of an NDA or efficacy supplement stantial reduction of a treatment-lim- may be extended only once due to sub- iting drug reaction, documented en- mission of a major amendment. FDA hancement of compliance, or evidence may, at its discretion, review any sub- of safety and effectiveness in a new sequent major amendment during the subpopulation; or initial review cycle (as extended) or (ii) The drug is in a class of drugs or defer review until the subsequent re- for an indication for which there is a view cycle. need for additional therapeutic op- (2) Submission of a major amend- tions. ment to an original NDA, efficacy sup- (d) Exemption for orphan drugs. This plement, or resubmission of an NDA or section does not apply to any drug for efficacy supplement more than 3 an indication or indications for which months before the end of the initial re- orphan designation has been granted view cycle will not extend the cycle. under part 316, subpart C, of this chap- FDA may, at its discretion, review ter. such an amendment during the initial [63 FR 66670, Dec. 2, 1998] review cycle or defer review until the subsequent review cycle. § 314.60 Amendments to an unap- (3) Submission of an amendment to proved NDA, supplement, or resub- an original NDA, efficacy supplement, mission. or resubmission of an NDA or efficacy (a) Submission of NDA. FDA generally supplement that is not a major amend- assumes that when an original NDA, ment will not extend the initial review supplement to an approved NDA, or re- cycle. FDA may, at its discretion, resubmission of an NDA or supplement is view such an amendment during the submitted to the Agency for review, initial review cycle or defer review the applicant believes that the Agency until the subsequent review cycle. can approve the NDA, supplement, or (4) Submission of a major amend- resubmission as submitted. However, ment to a manufacturing supplement the applicant may submit an amend- within 2 months of the end of the ini- ment to an NDA, supplement, or resub- tial review cycle constitutes an agree- mission that has been filed under ment by the applicant under section § 314.101 but is not yet approved. 505(c) of the Federal Food, Drug, and (b) Submission of major amendment. (1) Cosmetic Act to extend the initial re- Submission of a major amendment to view cycle by 2 months. FDA may in- an original NDA, efficacy supplement, stead defer review of the amendment or resubmission of an NDA or efficacy until the subsequent review cycle. If supplement within 3 months of the end the agency extends the initial review of the initial review cycle constitutes cycle for a manufacturing supplement an agreement by the applicant under under this paragraph, the division re- section 505(c) of the Federal Food, sponsible for reviewing the supplement Drug, and Cosmetic Act to extend the will notify the applicant of the exten- initial review cycle by 3 months. (For sion. The initial review cycle for a references to a resubmission of an NDA manufacturing supplement may be ex- or efficacy supplement in paragraph (b) tended only once due to submission of of this section, the timeframe for re- a major amendment. FDA may, at its

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discretion, review any subsequent mission of the NDA, which may not be major amendment during the initial accepted except as provided in accord- review cycle (as extended) or defer re- ance with section 505(c)(3)(E)(ii) of the view until the subsequent review cycle. Federal Food, Drug, and Cosmetic Act. (5) Submission of an amendment to a (d) Field copy. The applicant must supplement other than an efficacy or submit a field copy of each amendment manufacturing supplement will not ex- to a section of the NDA described in tend the initial review cycle. FDA § 314.50(d)(1). The applicant must in- may, at its discretion, review such an clude in its submission of each such amendment during the initial review amendment to FDA a statement certi- cycle or defer review until the subse- fying that a field copy of the amend- quent review cycle. ment has been sent to the applicant’s (6) A major amendment may not include data to support an indication or home FDA district office. claim that was not included in the (e) Different drug. An applicant may original NDA, supplement, or resub- not amend a 505(b)(2) application to mission, but it may include data to seek approval of a drug that is a dif- support a minor modification of an in- ferent drug from the drug in the origi- dication or claim that was included in nal submission of the 505(b)(2) applica- the original NDA, supplement, or re- tion. For purposes of this paragraph submission. (e), a drug is a different drug if it has (7) When FDA defers review of an been modified to have a different ac- amendment until the subsequent re- tive ingredient, different route of ad- view cycle, the agency will notify the ministration, different dosage form, or applicant of the deferral in the com- difference in excipients that requires plete response letter sent to the appli- either a separate clinical study to es- cant under § 314.110 of this part. tablish safety or effectiveness or, for (c) Limitation on certain amend- topical products, that requires a sepa- ments.(1) An unapproved NDA may not rate in vivo demonstration of bio- be amended if all of the following con- equivalence. However, notwithstanding ditions apply: the limitation described in this para- (i) The unapproved NDA is for a drug graph (e), an applicant may amend the for which a previous NDA has been ap- 505(b)(2) application to seek approval of proved and granted a period of exclu- a different strength. sivity in accordance with section 505(c)(3)(E)(ii) of the Federal Food, (f) Patent certification requirements. (1) Drug, and Cosmetic Act that has not An amendment to a 505(b)(2) applica- expired; tion is required to contain an appro- (ii) The applicant seeks to amend the priate patent certification or state- unapproved NDA to include a published ment described in § 314.50(i) or a recer- report of an investigation that was tification for a previously submitted conducted or sponsored by the appli- paragraph IV certification if approval cant entitled to exclusivity for the is sought for any of the following types drug; of amendments: (iii) The applicant has not obtained a (i) To add a new indication or other right of reference or use to the inves- condition of use; tigation described in paragraph (ii) To add a new strength; (c)(1)(ii) of this section; and (iii) To make other than minor (iv) The report of the investigation changes in product formulation; or described in paragraph (c)(1)(ii) of this (iv) To change the physical form or section would be essential to the ap- crystalline structure of the active in- proval of the unapproved NDA. gredient. (2) The submission of an amendment described in paragraph (c)(1) of this (2) If the amendment to the 505(b)(2) section will cause the unapproved NDA application does not contain a patent to be deemed to be withdrawn by the certification or statement, the appli- applicant under § 314.65 on the date of cant must verify that the proposed receipt by FDA of the amendment. The change described in the amendment is amendment will be considered a resub-

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not one of the types of amendments de- uting a drug product made with a man- scribed in paragraph (f)(1) of this sec- ufacturing change. tion. (3) Notwithstanding the requirements [50 FR 7493, Feb. 22, 1985, as amended at 57 of paragraphs (b) and (c) of this sec- FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, tion, an applicant must make a change 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr. provided for in those paragraphs in ac- 8, 2004; 73 FR 39608, July 10, 2008; 81 FR 69648, cordance with a regulation or guidance Oct. 6, 2016] that provides for a less burdensome notification of the change (for example, § 314.65 Withdrawal by the applicant by submission of a supplement that of an unapproved application. does not require approval prior to dis- An applicant may at any time with- tribution of the product or in an an- draw an application that is not yet ap- nual report). proved by notifying the Food and Drug (4) The applicant must promptly re- Administration in writing. If, by the vise all promotional labeling and ad- time it receives such notice, the agen- vertising to make it consistent with cy has identified any deficiencies in any labeling change implemented in the application, we will list such defi- accordance with paragraphs (b) and (c) ciencies in the letter we send the appli- of this section. cant acknowledging the withdrawal. A (5) Except for a supplement providing decision to withdraw the application is for a change in the labeling, the appli- without prejudice to refiling. The agen- cant must include in each supplement cy will retain the application and will and amendment to a supplement pro- provide a copy to the applicant on re- viding for a change under paragraph (b) quest under the fee schedule in § 20.45 of or (c) of this section a statement certi- FDA’s public information regulations. fying that a field copy has been pro- [50 FR 7493, Feb. 22, 1985, as amended at 68 vided in accordance with § 314.440(a)(4). FR 25287, May 12, 2003; 73 FR 39609, July 10, (6) A supplement or annual report 2008] must include a list of all changes contained in the supplement or annual re- § 314.70 Supplements and other port. For supplements, this list must changes to an approved NDA. be provided in the submission. (a) Changes to an approved NDA. (1)(i) (b) Changes requiring supplement sub- Except as provided in paragraph mission and approval prior to distribution (a)(1)(ii) of this section, the applicant of the product made using the change must notify FDA about each change in (major changes). (1) A supplement must each condition established in an ap- be submitted for any change in the proved NDA beyond the variations al- drug substance, drug product, produc- ready provided for in the NDA. The no- tion process, quality controls, equip- tice is required to describe the change ment, or facilities that has a substan- fully. Depending on the type of change, tial potential to have an adverse effect the applicant must notify FDA about on the identity, strength, quality, pu- the change in a supplement under para- rity, or potency of the drug product as graph (b) or (c) of this section or by in- these factors may relate to the safety clusion of the information in the an- or effectiveness of the drug product. nual report to the NDA under para- (2) These changes include, but are not graph (d) of this section. limited to: (ii) The submission and grant of a (i) Except those described in para- written request for an exception or al- graphs (c) and (d) of this section, ternative under § 201.26 of this chapter changes in the qualitative or quan- satisfies the applicable requirements in titative formulation of the drug prod- paragraphs (a) through (c) of this sec- uct, including inactive ingredients, or tion. However, any grant of a request in the specifications provided in the for an exception or alternative under approved NDA; § 201.26 of this chapter must be reported (ii) Changes requiring completion of as part of the annual report to the NDA studies in accordance with part 320 of under paragraph (d) of this section. this chapter to demonstrate the (2) The NDA holder must assess the equivalence of the drug product to the effects of the change before distrib- drug product as manufactured without

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the change or to the reference listed lidity assessment because of signifi- drug; cant questions regarding the integrity (iii) Changes that may affect drug of the data supporting that NDA. substance or drug product sterility as- (3) The applicant must obtain ap- surance, such as changes in drug sub- proval of a supplement from FDA prior stance, drug product, or component to distribution of a drug product made sterilization method(s) or an addition, using a change under paragraph (b) of deletion, or substitution of steps in an this section. Except for submissions aseptic processing operation; under paragraph (e) of this section, the (iv) Changes in the synthesis or man- following information must be con- ufacture of the drug substance that tained in the supplement: may affect the impurity profile and/or (i) A detailed description of the pro- the physical, chemical, or biological posed change; properties of the drug substance; (ii) The drug product(s) involved; (v) The following labeling changes: (iii) The manufacturing site(s) or (A) Changes in labeling, except those area(s) affected; described in paragraphs (c)(6)(iii), (iv) A description of the methods (d)(2)(ix), or (d)(2)(x) of this section; used and studies performed to assess (B) If applicable, any change to a the effects of the change; Medication Guide required under part (v) The data derived from such stud- 208 of this chapter, except for changes ies; in the information specified in (vi) For a natural product, a recom- § 208.20(b)(8)(iii) and (b)(8)(iv) of this binant DNA-derived protein/ chapter; and polypeptide, or a complex or conjugate (C) Any change to the information of a drug substance with a monoclonal required by § 201.57(a) of this chapter, antibody, relevant validation protocols with the following exceptions that may and a list of relevant standard oper- be reported in an annual report under ating procedures must be provided in paragraph (d)(2)(x) of this section: addition to the requirements in para- (1) Removal of a listed section(s) graphs (b)(3)(iv) and (b)(3)(v) of this specified in § 201.57(a)(5) of this chapter; section; and and (vii) For sterilization process and (2) Changes to the most recent revi- test methodologies related to steriliza- sion date of the labeling as specified in tion process validation, relevant vali- § 201.57(a)(15) of this chapter. dation protocols and a list of relevant (vi) Changes in a drug product con- standard operating procedures must be tainer closure system that controls the provided in addition to the require- drug product delivered to a patient or ments in paragraphs (b)(3)(iv) and changes in the type (e.g., glass to high (b)(3)(v) of this section. density polyethylene (HDPE), HDPE to (4) An applicant may ask FDA to ex- polyvinyl chloride, vial to syringe) or pedite its review of a supplement for composition (e.g., one HDPE resin to public health reasons or if a delay in another HDPE resin) of a packaging making the change described in it component that may affect the impu- would impose an extraordinary hard- rity profile of the drug product. ship on the applicant. Such a supple- (vii) Changes solely affecting a nat- ment should be plainly marked: ‘‘Prior ural product, a recombinant DNA-de- Approval Supplement-Expedited Re- rived protein/polypeptide, or a complex view Requested.’’ or conjugate of a drug substance with a (c) Changes requiring supplement sub- monoclonal antibody for the following: mission at least 30 days prior to distribu- (A) Changes in the virus or adven- tion of the drug product made using the titious agent removal or inactivation change (moderate changes). (1) A supple- method(s); ment must be submitted for any (B) Changes in the source material or change in the drug substance, drug cell line; and product, production process, quality (C) Establishment of a new master controls, equipment, or facilities that cell bank or seed. has a moderate potential to have an (viii) Changes to a drug product adverse effect on the identity, under an NDA that is subject to a va- strength, quality, purity, or potency of

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the drug product as these factors may uct in accordance with paragraph (b) of relate to the safety or effectiveness of this section; or the drug product. If the supplement (ii) Any of the information required provides for a labeling change under under paragraph (c)(4) of this section is paragraph (c)(6)(iii) of this section, 12 missing; the applicant must not dis- copies of the final printed labeling tribute the drug product made using must be included. the change until the supplement has (2) These changes include, but are not been amended to provide the missing limited to: information. (i) A change in the container closure (6) The agency may designate a cat- system that does not affect the quality egory of changes for the purpose of proof the drug product, except those de- viding that, in the case of a change in scribed in paragraphs (b) and (d) of this such category, the holder of an ap- section; and proved NDA may commence distribu- (ii) Changes solely affecting a nat- tion of the drug product involved upon ural protein, a recombinant DNA-de- receipt by the agency of a supplement rived protein/polypeptide or a complex for the change. These changes include, or conjugate of a drug substance with a but are not limited to: monoclonal antibody, including: (i) Addition to a specification or (A) An increase or decrease in pro- changes in the methods or controls to duction scale during finishing steps provide increased assurance that the that involves different equipment; and drug substance or drug product will (B) Replacement of equipment with have the characteristics of identity, that of a different design that does not strength, quality, purity, or potency affect the process methodology or proc- that it purports or is represented to ess operating parameters. possess; (iii) Relaxation of an acceptance cri- (ii) A change in the size and/or shape terion or deletion of a test to comply of a container for a nonsterile drug with an official compendium that is product, except for solid dosage forms, consistent with FDA statutory and reg- without a change in the labeled ulatory requirements. amount of drug product or from one (3) A supplement submitted under container closure system to another; paragraph (c)(1) of this section is re- (iii) Changes in the labeling to reflect quired to give a full explanation of the newly acquired information, except for basis for the change and identify the changes to the information required in date on which the change is to be § 201.57(a) of this chapter (which must made. The supplement must be labeled be made under paragraph (b)(2)(v)(C) of ‘‘Supplement—Changes Being Effected this section), to accomplish any of the in 30 Days’’ or, if applicable under following: paragraph (c)(6) of this section, ‘‘Sup- (A) To add or strengthen a contra- plement—Changes Being Effected.’’ indication, warning, precaution, or ad- (4) Pending approval of the supple- verse reaction for which the evidence ment by FDA, except as provided in of a causal association satisfies the paragraph (c)(6) of this section, dis- standard for inclusion in the labeling tribution of the drug product made under § 201.57(c) of this chapter; using the change may begin not less (B) To add or strengthen a statement than 30 days after receipt of the supple- about drug abuse, dependence, psycho- ment by FDA. The information listed logical effect, or overdosage; in paragraphs (b)(3)(i) through (C) To add or strengthen an instruc- (b)(3)(vii) of this section must be con- tion about dosage and administration tained in the supplement. that is intended to increase the safe (5) The applicant must not distribute use of the drug product; the drug product made using the (D) To delete false, misleading, or un- change if within 30 days following supported indications for use or claims FDA’s receipt of the supplement, FDA for effectiveness; or informs the applicant that either: (E) Any labeling change normally re- (i) The change requires approval quiring a supplement submission and prior to distribution of the drug prod- approval prior to distribution of the

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drug product that FDA specifically re- dure described in the approved NDA, or quests be submitted under this provi- deletion of an alternative analytical sion. procedure; (7) If the agency disapproves the sup- (viii) The addition by embossing, de- plemental NDA, it may order the man- bossing, or engraving of a code imprint ufacturer to cease distribution of the to a solid oral dosage form drug prod- drug product(s) made with the manu- uct other than a modified release dos- facturing change. age form, or a minor change in an ex- (d) Changes to be described in an an- isting code imprint; nual report (minor changes). (1) Changes (ix) A change in the labeling con- in the drug substance, drug product, cerning the description of the drug production process, quality controls, product or in the information about equipment, or facilities that have a how the drug product is supplied, that minimal potential to have an adverse does not involve a change in the dosage effect on the identity, strength, qual- strength or dosage form; and ity, purity, or potency of the drug (x) An editorial or similar minor product as these factors may relate to change in labeling, including a change the safety or effectiveness of the drug to the information allowed by para- product must be documented by the ap- graphs (b)(2)(v)(C)(1) and (2) of this sec- plicant in the next annual report in action. cordance with § 314.81(b)(2). (3) For changes under this category, (2) These changes include, but are not the applicant is required to submit in limited to: the annual report: (i) Any change made to comply with a change to an official compendium, (i) A statement by the holder of the except a change described in paragraph approved NDA that the effects of the (c)(2)(iii) of this section, that is con- change have been assessed; sistent with FDA statutory and regu- (ii) A full description of the manufac- latory requirements. turing and controls changes, including (ii) The deletion or reduction of an the manufacturing site(s) or area(s) in- ingredient intended to affect only the volved; color of the drug product; (iii) The date each change was imple- (iii) Replacement of equipment with mented; that of the same design and operating (iv) Data from studies and tests per- principles except those equipment formed to assess the effects of the changes described in paragraph (c) of change; and, this section; (v) For a natural product, recom- (iv) A change in the size and/or shape binant DNA-derived protein/ of a container containing the same polypeptide, complex or conjugate of a number of dosage units for a nonsterile drug substance with a monoclonal anti- solid dosage form drug product, with- body, sterilization process or test out a change from one container clo- methodology related to sterilization sure system to another; process validation, a cross-reference to (v) A change within the container relevant validation protocols and/or closure system for a nonsterile drug standard operating procedures. product, based upon a showing of (e) Protocols. An applicant may sub- equivalency to the approved system mit one or more protocols describing under a protocol approved in the NDA the specific tests and studies and ac- or published in an official compendium; ceptance criteria to be achieved to (vi) An extension of an expiration demonstrate the lack of adverse effect dating period based upon full shelf life for specified types of manufacturing data on production batches obtained changes on the identity, strength, from a protocol approved in the NDA; quality, purity, and potency of the (vii) The addition or revision of an al- drug product as these factors may re- ternative analytical procedure that late to the safety or effectiveness of provides the same or increased assur- the drug product. Any such protocols, ance of the identity, strength, quality, if not included in the approved NDA, or purity, or potency of the material changes to an approved protocol, must being tested as the analytical proce- be submitted as a supplement requiring

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approval from FDA prior to distribution form and appropriate technical tion of a drug product produced with sections, samples, and labeling; except the manufacturing change. The supple- that a supplement for a change other ment, if approved, may subsequently than a change in labeling is required justify a reduced reporting category for also to contain a field copy. the particular change because the use (c) All procedures and actions that of the protocol for that type of change apply to applications under this part, reduces the potential risk of an adverse including actions by applicants and the effect. Food and Drug Administration, also (f) Patent information. The applicant apply to supplements except as speci- must comply with the patent informa- fied otherwise in this part. tion requirements under section 505(c)(2) of the Federal Food, Drug, and [50 FR 7493, Feb. 22, 1985, as amended at 50 Cosmetic Act and § 314.53. FR 21238, May 23, 1985; 58 FR 47352, Sept. 8, (g) Claimed exclusivity. If an applicant 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609, claims exclusivity under § 314.108 upon July 10, 2008] approval of a supplement for change to its previously approved drug product, § 314.72 Change in ownership of an ap- the applicant must include with its plication. supplement the information required (a) An applicant may transfer owner- under § 314.50(j). ship of its application. At the time of (h) Different drug. An applicant may transfer the new and former owners are not supplement a 505(b)(2) application required to submit information to the to seek approval of a drug that is a dif- Food and Drug Administration as fol- ferent drug from the drug in the ap- lows: proved 505(b)(2) application. For pur- (1) The former owner shall submit a poses of this paragraph (h), a drug is a letter or other document that states different drug if it has been modified to that all rights to the application have have a different active ingredient, dif- been transferred to the new owner. ferent route of administration, different dosage form, or difference in (2) The new owner shall submit an excipients that requires either a sepa- application form signed by the new rate clinical study to establish safety owner and a letter or other document or effectiveness or, for topical prod- containing the following: ucts, that requires a separate in vivo (i) The new owner’s commitment to demonstration of bioequivalence. How- agreements, promises, and conditions ever, notwithstanding the limitation made by the former owner and con- described in this paragraph (h), an ap- tained in the application; plicant may supplement the 505(b)(2) (ii) The date that the change in own- application to seek approval of a dif- ership is effective; and ferent strength. (iii) Either a statement that the new [69 FR 18764, Apr. 8, 2004, as amended at 71 owner has a complete copy of the ap- FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28, proved application, including supple- 2007; 73 FR 49609, Aug. 22, 2008; 81 FR 69648, ments and records that are required to Oct. 6, 2016] be kept under § 314.81, or a request for a copy of the application from FDA’s § 314.71 Procedures for submission of a supplement to an approved appli- files. FDA will provide a copy of the cation. application to the new owner under the fee schedule in § 20.45 of FDA’s public (a) Only the applicant may submit a information regulations. supplement to an application. (b) All procedures and actions that (b) The new owner shall advise FDA apply to an application under § 314.50 about any change in the conditions in also apply to supplements, except that the approved application under § 314.70, the information required in the supple- except the new owner may advise FDA ment is limited to that needed to sup- in the next annual report about a port the change. A supplement is re- change in the drug product’s label or quired to contain an archival copy and labeling to change the product’s brand a review copy that include an applica-

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or the name of its manufacturer, pack- judgment, they may jeopardize the pa- er, or distributor. tient or subject and may require med- [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, ical or surgical intervention to prevent 1985, as amended at 50 FR 21238, May 23, 1985; one of the outcomes listed in this defi- 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12, nition. Examples of such medical 2003] events include allergic bronchospasm requiring intensive treatment in an § 314.80 Postmarketing reporting of emergency room or at home, blood adverse drug experiences. dyscrasias or convulsions that do not (a) Definitions. The following defini- result in inpatient hospitalization, or tions of terms apply to this section: the development of drug dependency or Adverse drug experience. Any adverse drug abuse. event associated with the use of a drug Unexpected adverse drug experience. in humans, whether or not considered Any adverse drug experience that is drug related, including the following: not listed in the current labeling for An adverse event occurring in the the drug product. This includes events course of the use of a drug product in that may be symptomatically and professional practice; an adverse event pathophysiologically related to an occurring from drug overdose whether event listed in the labeling, but differ accidental or intentional; an adverse from the event because of greater se- event occurring from drug abuse; an verity or specificity. For example, adverse event occurring from drug under this definition, hepatic necrosis withdrawal; and any failure of expected would be unexpected (by virtue of pharmacological action. greater severity) if the labeling only Individual case safety report (ICSR). A referred to elevated hepatic enzymes or description of an adverse drug experi- hepatitis. Similarly, cerebral thrombo- ence related to an individual patient or embolism and cerebral vasculitis would subject. be unexpected (by virtue of greater ICSR attachments. Documents related to the adverse drug experience de- specificity) if the labeling only listed scribed in an ICSR, such as medical cerebral vascular accidents. ‘‘Unex- records, hospital discharge summaries, pected,’’ as used in this definition, re- or other documentation. fers to an adverse drug experience that Disability. A substantial disruption of has not been previously observed (i.e., a person’s ability to conduct normal included in the labeling) rather than life functions. from the perspective of such experience Life-threatening adverse drug experi- not being anticipated from the pharma- ence. Any adverse drug experience that cological properties of the pharma- places the patient, in the view of the ceutical product. initial reporter, at immediate risk of (b) Review of adverse drug experiences. death from the adverse drug experience Each applicant having an approved ap- as it occurred, i.e., it does not include plication under § 314.50 or, in the case an adverse drug experience that, had it of a 505(b)(2) application, an effective occurred in a more severe form, might approved application, must promptly have caused death. review all adverse drug experience in- Serious adverse drug experience. Any formation obtained or otherwise re- adverse drug experience occurring at ceived by the applicant from any any dose that results in any of the fol- source, foreign or domestic, including lowing outcomes: Death, a life-threat- information derived from commercial ening adverse drug experience, inpa- marketing experience, postmarketing tient hospitalization or prolongation of clinical investigations, postmarketing existing hospitalization, a persistent or epidemiological/surveillance studies, significant disability/incapacity, or a reports in the scientific literature, and congenital anomaly/birth defect. Im- unpublished scientific papers. Appli- portant medical events that may not cants are not required to resubmit to result in death, be life-threatening, or FDA adverse drug experience reports require hospitalization may be consid- forwarded to the applicant by FDA; ered a serious adverse drug experience however, applicants must submit all when, based upon appropriate medical followup information on such reports

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to FDA. Any person subject to the re- comply with the requirements of this porting requirements under paragraph section. Under this circumstance, the (c) of this section must also develop nonapplicant must maintain a record written procedures for the surveillance, of this action which must include: receipt, evaluation, and reporting of (A) A copy of each adverse drug expe- postmarketing adverse drug experi- rience report; ences to FDA. (B) The date the report was received (c) Reporting requirements. The appli- by the nonapplicant; cant must submit to FDA adverse drug (C) The date the report was sub- experience information as described in mitted to the applicant; and this section. Except as provided in (D) The name and address of the ap- paragraph (g)(2) of this section, these plicant. reports must be submitted to the Agen- (2) Periodic adverse drug experience re- cy in electronic format as described in ports. (i) The applicant must report paragraph (g)(1) of this section. each adverse drug experience not re- (1)(i) Postmarketing 15-day ‘‘Alert reported under paragraph (c)(1)(i) of this ports’’. The applicant must report each adverse drug experience that is both se- section at quarterly intervals, for 3 rious and unexpected, whether foreign years from the date of approval of the or domestic, as soon as possible but no application, and then at annual inter- later than 15 calendar days from initial vals. The applicant must submit each receipt of the information by the appli- quarterly report within 30 days of the cant. close of the quarter (the first quarter beginning on the date of approval of (ii) Postmarketing 15-day ‘‘Alert re- the application) and each annual report ports’’—followup. The applicant must promptly investigate all adverse drug within 60 days of the anniversary date experiences that are the subject of of approval of the application. Upon these postmarketing 15-day Alert re- written notice, FDA may extend or reports and must submit followup reports establish the requirement that an ap- within 15 calendar days of receipt of plicant submit quarterly reports, or re- new information or as requested by quire that the applicant submit reports FDA. If additional information is not under this section at different times obtainable, records should be main- than those stated. For example, the tained of the unsuccessful steps taken agency may reestablish a quarterly re- to seek additional information. porting requirement following the approval of a major supplement. Fol- (iii) Submission of reports. The requirements of paragraphs (c)(1)(i) and lowup information to adverse drug ex- (c)(1)(ii) of this section, concerning the periences submitted in a periodic resubmission of postmarketing 15-day port may be submitted in the next peri- Alert reports, also apply to any person odic report. other than the applicant whose name (ii) Each periodic report is required appears on the label of an approved to contain: drug product as a manufacturer, pack- (A) Descriptive information. (1) A nar- er, or distributor (nonapplicant). To rative summary and analysis of the in- avoid unnecessary duplication in the formation in the report; submission to FDA of reports required (2) An analysis of the 15-day Alert re- by paragraphs (c)(1)(i) and (c)(1)(ii) of ports submitted during the reporting this section, obligations of a non- interval (all 15-day Alert reports being applicant may be met by submission of appropriately referenced by the appli- all reports of serious adverse drug ex- cant’s patient identification code, ad- periences to the applicant. If a non- verse reaction term(s), and date of sub- applicant elects to submit adverse drug mission to FDA); experience reports to the applicant (3) A history of actions taken since rather than to FDA, the nonapplicant the last report because of adverse drug must submit, by any appropriate experiences (for example, labeling means, each report to the applicant changes or studies initiated); and within 5 calendar days of initial receipt (4) An index consisting of a line list- of the information by the non- ing of the applicant’s patient identi- applicant, and the applicant must then fication code, and adverse reaction

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term(s) for all ICSRs submitted under (iv) Description of adverse drug expe- paragraph (c)(2)(ii)(B) of this section. rience (including a concise medical (B) ICSRs for serious, expected, and narrative); nonserious adverse drug experiences. An (v) Adverse drug experience term(s); ICSR for each adverse drug experience (vi) Description of relevant tests, in- not reported under paragraph (c)(1)(i) cluding dates and laboratory data; and of this section (all serious, expected (vii) Other relevant patient history, and nonserious adverse drug experi- including preexisting medical condi- ences). All such ICSRs must be sub- tions. mitted to FDA (either individually or (3) Suspect medical product(s). in one or more batches) within the (i) Name; timeframe specified in paragraph (ii) Dose, frequency, and route of ad- (c)(2)(i) of this section. ICSRs must ministration used; only be submitted to FDA once. (iii) Therapy dates; (iii) Periodic reporting, except for in- (iv) Diagnosis for use (indication); formation regarding 15-day Alert re- (v) Whether the product is a prescrip- ports, does not apply to adverse drug tion or nonprescription product; experience information obtained from (vi) Whether the product is a com- postmarketing studies (whether or not bination product as defined in § 3.2(e) of conducted under an investigational this chapter; new drug application), from reports in (vii) Whether adverse drug experience the scientific literature, and from for- abated after drug use stopped or dose eign marketing experience. reduced; (d) Scientific literature. A 15-day Alert (viii) Whether adverse drug experi- report based on information in the sci- ence reappeared after reintroduction of entific literature must be accompanied drug; by a copy of the published article. The (ix) Lot number; 15-day reporting requirements in para- (x) Expiration date; graph (c)(1)(i) of this section (i.e., seri- (xi) National Drug Code (NDC) num- ous, unexpected adverse drug experi- ber; and ences) apply only to reports found in (xii) Concomitant medical products scientific and medical journals either and therapy dates. as case reports or as the result of a for- (4) Initial reporter information. mal clinical trial. (i) Name, address, and telephone (e) Postmarketing studies. An applicant number; is not required to submit a 15-day Alert (ii) Whether the initial reporter is a report under paragraph (c) of this sec- health care professional; and tion for an adverse drug experience ob- (iii) Occupation, if a health care pro- tained from a postmarketing study fessional. (whether or not conducted under an in- (5) Applicant information. vestigational new drug application) un- (i) Applicant name and contact office less the applicant concludes that there address; is a reasonable possibility that the (ii) Telephone number; drug caused the adverse experience. (iii) Report source, such as sponta- (f) Information reported on ICSRs. neous, literature, or study; ICSRs include the following informa- (iv) Date the report was received by tion: applicant; (v) Application number and type; (1) Patient information. (vi) Whether the ICSR is a 15-day (i) Patient identification code; ‘‘Alert report’’; (ii) Patient age at the time of adverse (vii) Whether the ICSR is an initial drug experience, or date of birth; report or followup report; and (iii) Patient gender; and (viii) Unique case identification num- (iv) Patient weight. ber, which must be the same in the ini- (2) Adverse drug experience. tial report and any subsequent fol- (i) Outcome attributed to adverse lowup report(s). drug experience; (g) Electronic format for submissions. (ii) Date of adverse drug experience; (1) Safety report submissions, includ- (iii) Date of ICSR submission; ing ICSRs, ICSR attachments, and the

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descriptive information in periodic re- approval of the application and, thus, ports, must be in an electronic format prohibit continued marketing of the that FDA can process, review, and ar- drug product that is the subject of the chive. FDA will issue guidance on how application. to provide the electronic submission (l) Disclaimer. A report or information (e.g., method of transmission, media, submitted by an applicant under this file formats, preparation and organiza- section (and any release by FDA of tion of files). that report or information) does not (2) An applicant or nonapplicant may necessarily reflect a conclusion by the request, in writing, a temporary waiver applicant or FDA that the report or in- of the requirements in paragraph (g)(1) formation constitutes an admission of this section. These waivers will be that the drug caused or contributed to granted on a limited basis for good an adverse effect. An applicant need cause shown. FDA will issue guidance not admit, and may deny, that the re- on requesting a waiver of the require- port or information submitted under ments in paragraph (g)(1) of this sec- this section constitutes an admission tion. that the drug caused or contributed to (h) Multiple reports. An applicant an adverse effect. For purposes of this should not include in reports under provision, the term ‘‘applicant’’ also this section any adverse drug experi- includes any person reporting under ences that occurred in clinical trials if paragraph (c)(1)(iii) of this section. they were previously submitted as part of the approved application. If a report [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, applies to a drug for which an appli- 1985, as amended at 50 FR 21238, May 23, 1985; cant holds more than one approved ap- 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13, plication, the applicant should submit 1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, the report to the application that was Apr. 28, 1992; 62 FR 34168, June 25, 1997; 62 FR 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26, 1998; first approved. If a report refers to 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, more than one drug marketed by an ap- 2004; 74 FR 13113, Mar. 26, 2009; 79 FR 33088, plicant, the applicant should submit June 10, 2014] the report to the application for the drug listed first in the report. § 314.81 Other postmarketing reports. (i) Patient privacy. An applicant (a) Applicability. Each applicant shall should not include in reports under make the reports for each of its ap- this section the names and addresses of proved applications and abbreviated individual patients; instead, the appli- applications required under this sec- cant should assign a unique code for tion and section 505(k) of the act. identification of the patient. The applicant should include the name of the re- (b) Reporting requirements. The appli- porter from whom the information was cant shall submit to the Food and Drug received as part of the initial reporter Administration at the specified times information, even when the reporter is two copies of the following reports: the patient. The names of patients, (1) NDA—Field alert report. The appli- health care professionals, hospitals, cant shall submit information of the and geographical identifiers in adverse following kinds about distributed drug drug experience reports are not releas- products and articles to the FDA dis- able to the public under FDA’s public trict office that is responsible for the information regulations in part 20 of facility involved within 3 working days this chapter. of receipt by the applicant. The infor- (j) Recordkeeping. The applicant must mation may be provided by telephone maintain for a period of 10 years or other rapid communication means, records of all adverse drug experiences with prompt written followup. The re- known to the applicant, including raw port and its mailing cover should be data and any correspondence relating plainly marked: ‘‘NDA—Field Alert Re- to adverse drug experiences. port.’’ (k) Withdrawal of approval. If an ap- (i) Information concerning any inci- plicant fails to establish and maintain dent that causes the drug product or records and make reports required its labeling to be mistaken for, or ap- under this section, FDA may withdraw plied to, another article.

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(ii) Information concerning any bac- mestic use and the quantities distrib- teriological contamination, or any sig- uted for foreign use. Disclosure of fi- nificant chemical, physical, or other nancial or pricing data is not required. change or deterioration in the distrib- (b) Authorized generic drugs. If appli- uted drug product, or any failure of one cable, the date each authorized generic or more distributed batches of the drug drug (as defined in § 314.3) entered the product to meet the specification es- market, the date each authorized ge- tablished for it in the application. neric drug ceased being distributed, (2) Annual report. The applicant shall and the corresponding trade or brand submit each year within 60 days of the name. Each dosage form and/or anniversary date of U.S. approval of strength is a different authorized ge- the application, two copies of the re- neric drug and should be listed sepa- port to the FDA division responsible rately. The first annual report sub- for reviewing the application. Each an- mitted on or after January 25, 2010 nual report is required to be accom- must include the information listed in panied by a completed transmittal this paragraph for any authorized ge- Form FDA 2252 (Transmittal of Peri- neric drug that was marketed during odic Reports for Drugs for Human Use), the time period covered by an annual and must include all the information report submitted after January 1, 1999. required under this section that the ap- If information is included in the annual plicant received or otherwise obtained report with respect to any authorized during the annual reporting interval generic drug, a copy of that portion of that ends on the U.S. anniversary date. the annual report must be sent to the The report is required to contain in the Food and Drug Administration, Center order listed: for Drug Evaluation and Research, Of- (i) Summary. A brief summary of sig- fice of New Drug Quality Assessment, nificant new information from the pre- Bldg. 21, rm. 2562, 10903 New Hampshire vious year that might affect the safety, Ave., Silver Spring, MD 20993–0002, and effectiveness, or labeling of the drug marked ‘‘Authorized Generic Submis- product. The report is also required to sion’’ or, by e-mail, to the Authorized contain a brief description of actions Generics electronic mailbox at the applicant has taken or intends to [email protected] with take as a result of this new informa- ‘‘Authorized Generic Submission’’ indi- tion, for example, submit a labeling cated in the subject line. However, at supplement, add a warning to the label- such time that FDA has required that ing, or initiate a new study. The sum- annual reports be submitted in an elec- mary shall briefly state whether label- tronic format, the information re- ing supplements for pediatric use have quired by this paragraph must be sub- been submitted and whether new stud- mitted as part of the annual report, in ies in the pediatric population to sup- the electronic format specified for sub- port appropriate labeling for the pedi- mission of annual reports at that time, atric population have been initiated. and not as a separate submission under Where possible, an estimate of patient the preceding sentence in this para- exposure to the drug product, with spe- graph. cial reference to the pediatric popu- (iii) Labeling. (a) Currently used pro- lation (neonates, infants, children, and fessional labeling, patient brochures or adolescents) shall be provided, includ- package inserts (if any), and a rep- ing dosage form. resentative sample of the package la- (ii)(a) Distribution data. Information bels. about the quantity of the drug product (b) The content of labeling required distributed under the approved applica- under § 201.100(d)(3) of this chapter (i.e., tion, including that distributed to dis- the package insert or professional la- tributors. The information is required beling), including all text, tables, and to include the National Drug Code figures, must be submitted in elec- (NDC) number, the total number of tronic format. Electronic format sub- dosage units of each strength or po- missions must be in a form that FDA tency distributed (e.g., 100,000/5 milli- can process, review, and archive. FDA gram tablets, 50,000/10 milliliter vials), will periodically issue guidance on how and the quantities distributed for do- to provide the electronic submission

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(e.g., method of transmission, media, that do not contain tabulations or file formats, preparation and organiza- summaries of original data should not tion of files). Submissions under this be reported. paragraph must be made in accordance (b) Summaries of completed unpub- with part 11 of this chapter, except for lished clinical trials, or prepublication the requirements of § 11.10(a), (c) manuscripts if available, conducted by, through (h), and (k), and the cor- or otherwise obtained by, the appli- responding requirements of § 11.30. cant. Supporting information should (c) A summary of any changes in la- not be reported. (A study is considered beling that have been made since the completed 1 year after it is concluded.) last report listed by date in the order (c) Analysis of available safety and in which they were implemented, or if efficacy data in the pediatric popu- no changes, a statement of that fact. lation and changes proposed in the la- (iv) Chemistry, manufacturing, and beling based on this information. An controls changes. (a) Reports of experi- assessment of data needed to ensure ences, investigations, studies, or tests appropriate labeling for the pediatric involving chemical or physical prop- population shall be included. erties, or any other properties of the (vii) Status reports of postmarketing drug (such as the drug’s behavior or study commitments. A status report of properties in relation to microorga- each postmarketing study of the drug nisms, including both the effects of the product concerning clinical safety, drug on microorganisms and the effects clinical efficacy, clinical pharma- of microorganisms on the drug). These cology, and nonclinical toxicology that reports are only required for new infor- is required by FDA (e.g., accelerated mation that may affect FDA’s previous approval clinical benefit studies, pedi- conclusions about the safety or effec- atric studies) or that the applicant has tiveness of the drug product. committed, in writing, to conduct ei- (b) A full description of the manufac- ther at the time of approval of an ap- turing and controls changes not requir- plication for the drug product or a sup- ing a supplemental application under plement to an application, or after ap- § 314.70 (b) and (c), listed by date in the proval of the application or a supple- order in which they were implemented. ment. For pediatric studies, the status (v) Nonclinical laboratory studies. Cop- report shall include a statement indi- ies of unpublished reports and sum- cating whether postmarketing clinical maries of published reports of new toxi- studies in pediatric populations were cological findings in animal studies required by FDA under § 201.23 of this and in vitro studies (e.g., mutage- chapter. The status of these post- nicity) conducted by, or otherwise ob- marketing studies shall be reported an- tained by, the applicant concerning the nually until FDA notifies the appli- ingredients in the drug product. The cant, in writing, that the agency con- applicant shall submit a copy of a pub- curs with the applicant’s determina- lished report if requested by FDA. tion that the study commitment has (vi) Clinical data. (a) Published clin- been fulfilled or that the study is ei- ical trials of the drug (or abstracts of ther no longer feasible or would no them), including clinical trials on safe- longer provide useful information. ty and effectiveness; clinical trials on (a) Content of status report. The fol- new uses; biopharmaceutic, pharmaco- lowing information must be provided kinetic, and clinical pharmacology for each postmarketing study reported studies; and reports of clinical experi- under this paragraph: ence pertinent to safety (for example, (1) Applicant’s name. epidemiologic studies or analyses of ex- (2) Product name. Include the ap- perience in a monitored series of pa- proved drug product’s established name tients) conducted by or otherwise ob- and proprietary name, if any. tained by the applicant. Review arti- (3) NDA, ANDA, and supplement num- cles, papers describing the use of the ber. drug product in medical practice, pa- (4) Date of U.S. approval of NDA or pers and abstracts in which the drug is ANDA. used as a research tool, promotional (5) Date of postmarketing study commit- articles, press clippings, and papers ment.

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(6) Description of postmarketing study graph (b)(2)(vii)(a)(8) of this section. If commitment. The description must in- the study has been completed, include clude sufficient information to unique- the date the study was completed and ly describe the study. This information the date the final study report was sub- may include the purpose of the study, mitted to FDA, as applicable. Provide a the type of study, the patient popu- revised schedule, as well as the rea- lation addressed by the study and the son(s) for the revision, if the schedule indication(s) and dosage(s) that are to under paragraph (b)(2)(vii)(a)(7) of this be studied. section has changed since the last re- (7) Schedule for completion and report- port. ing of the postmarketing study commit- (b) Public disclosure of information. Ex- ment. The schedule should include the cept for the information described in actual or projected dates for submis- this paragraph, FDA may publicly dis- sion of the study protocol to FDA, close any information described in completion of patient accrual or initi- paragraph (b)(2)(vii) of this section, ation of an animal study, completion of the study, submission of the final concerning a postmarketing study, if study report to FDA, and any addi- the agency determines that the infor- tional milestones or submissions for mation is necessary to identify the ap- which projected dates were specified as plicant or to establish the status of the part of the commitment. In addition, it study, including the reasons, if any, for should include a revised schedule, as failure to conduct, complete, and re- appropriate. If the schedule has been port the study. Under this section, previously revised, provide both the FDA will not publicly disclose trade se- original schedule and the most recent, crets, as defined in § 20.61 of this chap- previously submitted revision. ter, or information, described in § 20.63 (8) Current status of the postmarketing of this chapter, the disclosure of which study commitment. The status of each would constitute an unwarranted inva- postmarketing study should be cat- sion of personal privacy. egorized using one of the following (viii) Status of other postmarketing terms that describes the study’s status studies. A status report of any post- on the anniversary date of U.S. ap- marketing study not included under proval of the application or other paragraph (b)(2)(vii) of this section agreed upon date: that is being performed by, or on behalf (i) Pending. The study has not been of, the applicant. A status report is to initiated, but does not meet the cri- be included for any chemistry, manu- terion for delayed. facturing, and controls studies that the (ii) Ongoing. The study is proceeding applicant has agreed to perform and for according to or ahead of the original all product stability studies. schedule described under paragraph (ix) Log of outstanding regulatory busi- (b)(2)(vii)(a)(7) of this section. ness. To facilitate communications be- (iii) Delayed. The study is behind the tween FDA and the applicant, the re- original schedule described under para- port may, at the applicant’s discretion, graph (b)(2)(vii)(a)(7) of this section. (iv) Terminated. The study was ended also contain a list of any open regu- before completion but a final study re- latory business with FDA concerning port has not been submitted to FDA. the drug product subject to the appli- (v) Submitted. The study has been cation (e.g., a list of the applicant’s un- completed or terminated and a final answered correspondence with the study report has been submitted to agency, a list of the agency’s unan- FDA. swered correspondence with the appli- (9) Explanation of the study’s status. cant). Provide a brief description of the sta- (3) Other reporting—(i) Advertisements tus of the study, including the patient and promotional labeling. The applicant accrual rate (expressed by providing shall submit specimens of mailing the number of patients or subjects en- pieces and any other labeling or adver- rolled to date, and the total planned tising devised for promotion of the enrollment), and an explanation of the drug product at the time of initial dis- study’s status identified under para- semination of the labeling and at the

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time of initial publication of the adver- (c) Notifications required by para- tisement for a prescription drug prod- graph (b)(3)(iii)(a) of this section must uct. Mailing pieces and labeling that include the following information: are designed to contain samples of a (1) The name of the drug subject to drug product are required to be com- the notification, including the NDC for plete, except the sample of the drug such drug; product may be omitted. Each submis- (2) The name of the applicant; sion is required to be accompanied by a (3) Whether the notification relates completed transmittal Form FDA–2253 to a permanent discontinuance of the (Transmittal of Advertisements and drug or an interruption in manufac- Promotional Labeling for Drugs for turing of the drug; Human Use) and is required to include (4) A description of the reason for the a copy of the product’s current profes- permanent discontinuance or interrup- sional labeling. Form FDA–2253 is tion in manufacturing; and available on the Internet at http:// (5) The estimated duration of the www.fda.gov/opacom/morechoices/ interruption in manufacturing. fdaforms/cder.html. ( )( ) FDA will maintain a publicly (ii) Special reports. Upon written re- d 1 quest the agency may require that the available list of drugs that are deter- applicant submit the reports under this mined by FDA to be in shortage. This section at different times than those drug shortages list will include the fol- stated. lowing information: (iii) Notification of a permanent dis- (i) The names and NDC(s) for such continuance or an interruption in manu- drugs; facturing. (a) An applicant of a pre- (ii) The name of each applicant for scription drug product must notify such drugs; FDA in writing of a permanent dis- (iii) The reason for the shortage, as continuance of manufacture of the determined by FDA from the following drug product or an interruption in categories: Requirements related to manufacturing of the drug product complying with good manufacturing that is likely to lead to a meaningful practices; regulatory delay; shortage of disruption in supply of that drug in the an active ingredient; shortage of an in- United States if: active ingredient component; dis- (1) The drug product is life sup- continuation of the manufacture of the porting, life sustaining, or intended for drug; delay in shipping of the drug; de- use in the prevention or treatment of a mand increase for the drug; or other debilitating disease or condition, in- reason; and cluding any such drug used in emer- (iv) The estimated duration of the gency medical care or during surgery; shortage. and (2) FDA may choose not to make in- (2) The drug product is not a radio- formation collected to implement this pharmaceutical drug product. paragraph available on the drug short- (b) Notifications required by para- ages list or available under section graph (b)(3)(iii)(a) of this section must 506C(c) of the Federal Food, Drug, and be submitted to FDA electronically in Cosmetic Act (21 U.S.C. 356c(c)) if FDA a format that FDA can process, review, determines that disclosure of such in- and archive: formation would adversely affect the (1) At least 6 months prior to the public health (such as by increasing date of the permanent discontinuance the possibility of hoarding or other dis- or interruption in manufacturing; or ruption of the availability of the drug (2) If 6 months’ advance notice is not to patients). FDA will also not provide possible because the permanent dis- information on the public drug short- continuance or interruption in manu- ages list or under section 506C(c) of the facturing was not reasonably antici- Federal Food, Drug, and Cosmetic Act pated 6 months in advance, as soon as that is protected by 18 U.S.C. 1905 or 5 practicable thereafter, but in no case U.S.C. 552(b)(4), including trade secrets later than 5 business days after the and commercial or financial informa- permanent discontinuance or interruption that is considered confidential or tion in manufacturing occurs. privileged under § 20.61 of this chapter.

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(e) If an applicant fails to submit a changes in manufacturing so long as notification as required under para- the manufacturer expects to resume graph (b)(3)(iii)(a) of this section and in operations in a short period of time. accordance with paragraph (b)(3)(iii)(b) (iv) Withdrawal of approved drug prod- of this section, FDA will issue a letter uct from sale. (a) Within 30 calendar to the applicant informing it of such days of the withdrawal of an approved failure. drug from sale, applicants who are (1) Not later than 30 calendar days manufacturers, repackers, or relabelers after the issuance of such a letter, the subject to part 207 of this chapter must applicant must submit to FDA a writ- submit the following information ten response setting forth the basis for about the drug, in accordance with the noncompliance and providing the re- applicable requirements described in quired notification under paragraph §§ 207.61 and 207.65: (b)(3)(iii)(a) of this section and includ- (1) The National Drug Code (NDC); ing the information required under (2) The identity of the drug by estab- paragraph (b)(3)(iii)(c) of this section; lished name and by proprietary name, and if any; (2) Not later than 45 calendar days (3) The new drug application number after the issuance of a letter under or abbreviated application number; paragraph (b)(3)(iii)(e) of this section, (4) The date on which the drug is ex- FDA will make the letter and the ap- pected to be no longer in commercial plicant’s response to the letter public, distribution. FDA requests that the unless, after review of the applicant’s reason for withdrawal of the drug from response, FDA determines that the ap- sale be included with the information. plicant had a reasonable basis for not (b) Within 30 calendar days of the notifying FDA as required under para- withdrawal of an approved drug from graph (b)(3)(iii)(a) of this section. sale, applicants who are not subject to (f) The following definitions of terms part 207 of this chapter must submit apply to paragraph (b)(3)(iii) of this the information listed in paragraphs section: (b)(3)(iv)(a)(1) through (4) of this sec- Drug shortage or shortage means a pe- tion. The information must be sub- riod of time when the demand or pro- mitted either electronically or in writ- jected demand for the drug within the ing to the Drug Registration and List- United States exceeds the supply of the ing Office, Food and Drug Administra- drug. tion, Center for Drug Evaluation and Intended for use in the prevention or Research. treatment of a debilitating disease or con- (c) Reporting under paragraph dition means a drug product intended (b)(3)(iv)(a) of this section constitutes for use in the prevention or treatment compliance with the requirements of of a disease or condition associated § 207.57 of this chapter to update drug with mortality or morbidity that has a listing information with respect to the substantial impact on day-to-day func- withdrawal from sale. tioning. (c) General requirements—(1) Multiple Life supporting or life sustaining means applications. For all reports required by a drug product that is essential to, or this section, the applicant shall submit that yields information that is essen- the information common to more than tial to, the restoration or continuation one application only to the application of a bodily function important to the first approved, and shall not report sep- continuation of human life. arately on each application. The sub- Meaningful disruption means a change mission is required to identify all the in production that is reasonably likely applications to which the report ap- to lead to a reduction in the supply of plies. a drug by a manufacturer that is more (2) Patient identification. Applicants than negligible and affects the ability should not include in reports under of the manufacturer to fill orders or this section the names and addresses of meet expected demand for its product, individual patients; instead, the appli- and does not include interruptions in cant should code the patient names manufacturing due to matters such as whenever possible and retain the code routine maintenance or insignificant in the applicant’s files. The applicant

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shall maintain sufficient patient iden- (1) The applicant’s compliance with tification information to permit FDA, the requirement is unnecessary for the by using that information alone or agency to evaluate the NDA or compli- along with records maintained by the ance cannot be achieved; investigator of a study, to identify the (2) The applicant’s alternative sub- name and address of individual pa- mission satisfies the requirement; or tients; this will ordinarily occur only (3) The applicant’s submission other- when the agency needs to investigate wise justifies a waiver. the reports further or when there is (c) If FDA grants the applicant’s reason to believe that the reports do waiver request with respect to a re- not represent actual results obtained. quirement under §§ 314.50 through (d) Withdrawal of approval. If an ap- 314.81, the waived requirement will not plicant fails to make reports required constitute a basis for refusal to ap- under this section, FDA may withdraw prove an NDA under § 314.125. approval of the application and, thus, [50 FR 7493, Feb. 22, 1985, as amended at 50 prohibit continued marketing of the FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, drug product that is the subject of the 2002; 81 FR 69649, Oct. 6, 2016] application. (Collection of information requirements ap- Subpart C—Abbreviated proved by the Office of Management and Applications Budget under control number 0910–0001)

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, SOURCE: 57 FR 17983, Apr. 28, 1992, unless 1985, as amended at 50 FR 21238, May 23, 1985; otherwise noted. 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. § 314.92 Drug products for which ab- 5, 1999; 65 FR 64617, Oct. 30, 2000; 66 FR 10815, breviated applications may be sub- Feb. 20, 2001; 68 FR 69019, Dec. 11, 2003; 69 FR mitted. 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004; 72 FR 58999, Oct. 18, 2007; 74 FR 13113, Mar. 26, (a) Abbreviated applications are suit- 2009; 74 FR 37167, July 28, 2009; 76 FR 78539, able for the following drug products Dec. 19, 2011; 80 FR 38938, July 8, 2015; 81 FR within the limits set forth under 60221, Aug. 31, 2016] § 314.93: (1) Drug products that are the same § 314.90 Waivers. as a listed drug. A ‘‘listed drug’’ is de- (a) An applicant may ask the Food fined in § 314.3. For determining the and Drug Administration to waive suitability of an abbreviated new drug under this section any requirement application, the term ‘‘same as’’ means that applies to the applicant under identical in active ingredient(s), dosage §§ 314.50 through 314.81. An applicant form, strength, route of administra- may ask FDA to waive under tion, and conditions of use, except that § 314.126(c) any criteria of an adequate conditions of use for which approval and well-controlled study described in cannot be granted because of exclu- § 314.126(b). A waiver request under this sivity or an existing patent may be section is required to be submitted omitted. If a listed drug has been vol- with supporting documentation in an untarily withdrawn from or not offered NDA, or in an amendment or supple- for sale by its manufacturer, a person ment to an NDA. The waiver request is who wishes to submit an abbreviated required to contain one of the fol- new drug application for the drug shall lowing: comply with § 314.122. (1) An explanation why the appli- (2) [Reserved] cant’s compliance with the require- (3) Drug products that have been de- ment is unnecessary or cannot be clared suitable for an abbreviated new achieved; drug application submission by FDA (2) A description of an alternative through the petition procedures set submission that satisfies the purpose of forth under § 10.30 of this chapter and the requirement; or § 314.93. (3) Other information justifying a (b) FDA will publish in the list listed waiver. drugs for which abbreviated applica- (b) FDA may grant a waiver if it tions may be submitted. The list is finds one of the following: available from the Superintendent of

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Documents, U.S. Government Printing (1) The active ingredients of the pro- Office, Washington, DC 20402, 202–783– posed drug product are of the same 3238. pharmacological or therapeutic class as those of the reference listed drug. [57 FR 17983, Apr. 28, 1992, as amended at 64 (2) The drug product can be expected FR 401, Jan. 5, 1999] to have the same therapeutic effect as § 314.93 Petition to request a change the reference listed drug when adminis- from a listed drug. tered to patients for each condition of use in the reference listed drug’s label- (a) The only changes from a listed ing for which the applicant seeks ap- drug for which the agency will accept a proval. petition under this section are those (3) If the proposed drug product is a changes described in paragraph (b) of combination product with one different this section. Petitions to submit active ingredient, including a different ANDAs for other changes from a listed ester or salt, from the reference listed drug will not be approved. drug, that the different active ingre- (b) A person who wants to submit an dient has previously been approved in a ANDA for a drug product which is not listed drug or is a drug that does not identical to a listed drug in route of ad- meet the definition of ‘‘new drug’’ in ministration, dosage form, and section 201(p) of the Federal Food, strength, or in which one active ingre- Drug, and Cosmetic Act. dient is substituted for one of the ac- (e) No later than 90 days after the tive ingredients in a listed combina- date a petition that is permitted under tion drug, must first obtain permission paragraph (a) of this section is sub- from FDA to submit such an ANDA. mitted, FDA will approve or disapprove (c) To obtain permission to submit an the petition. ANDA for a change described in para- (1) FDA will approve a petition prop- graph (b) of this section, a person must erly submited under this section unless submit and obtain approval of a peti- it finds that: tion requesting the change. A person (i) Investigations must be conducted seeking permission to request such a to show the safety and effectiveness of change from a reference listed drug the drug product or of any of its active shall submit a petition in accordance ingredients, its route of administra- with § 10.20 of this chapter and in the tion, dosage form, or strength which format specified in § 10.30 of this chap- differs from the reference listed drug; ter. The petition shall contain the in- or formation specified in § 10.30 of this (ii) For a petition that seeks to chapter and any additional information change an active ingredient, the drug required by this section. If any provi- product that is the subject of the peti- sion of § 10.20 or § 10.30 of this chapter is tion is not a combination drug; or inconsistent with any provision of this (iii) For a combination drug product section, the provisions of this section that is the subject of the petition and apply. has an active ingredient different from (d) The petitioner shall identify a the reference listed drug: listed drug and include a copy of the (A) The drug product may not be ade- proposed labeling for the drug product quately evaluated for approval as safe that is the subject of the petition and and effective on the basis of the infor- a copy of the approved labeling for the mation required to be submitted under listed drug. The petitioner may, under § 314.94; or limited circumstances, identify more (B) The petition does not contain in- than one listed drug, for example, when formation to show that the different the proposed drug product is a com- active ingredient of the drug product is bination product that differs from the of the same pharmacological or thera- combination reference listed drug with peutic class as the ingredient of the regard to an active ingredient, and the reference listed drug that is to be different active ingredient is an active changed and that the drug product can ingredient of a listed drug. The peti- be expected to have the same thera- tioner shall also include information to peutic effect as the reference listed show that: drug when administered to patients for

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each condition of use in the listed the petition and the listed drug identi- drug’s labeling for which the applicant fied in the petition can no longer be seeks approval; or the basis for ANDA submission, irre- (C) The different active ingredient is spective of whether FDA has with- not an active ingredient in a listed drawn approval of the petition. A per- drug or a drug that meets the require- son seeking approval for such drug ments of section 201(p) of the Federal product must submit a new ANDA that Food, Drug, and Cosmetic Act; or identifies the pharmaceutically equiva- (D) The remaining active ingredients lent reference listed drug as the basis are not identical to those of the listed for ANDA submission and comply with combination drug; or applicable regulatory requirements. (iv) Any of the proposed changes from the listed drug would jeopardize [57 FR 17983, Apr. 28, 1992, as amended at 81 FR 69649, Oct. 6, 2016] the safe or effective use of the product so as to necessitate significant labeling § 314.94 Content and format of an changes to address the newly intro- ANDA. duced safety or effectiveness problem; or ANDAs are required to be submitted (v) FDA has determined that the ref- in the form and contain the informa- erence listed drug has been withdrawn tion required under this section. Three from sale for safety or effectiveness copies of the ANDA are required, an ar- reasons under § 314.161, or the reference chival copy, a review copy, and a field listed drug has been voluntarily with- copy. FDA will maintain guidance doc- drawn from sale and the agency has uments on the format and content of not determined whether the with- ANDAs to assist applicants in their drawal is for safety or effectiveness preparation. reasons; or (a) ANDAs. Except as provided in (vi) A drug product is approved in an paragraph (b) of this section, the appli- NDA for the change described in the cant must submit a complete archival petition. copy of the abbreviated new drug appli- (2) For purposes of this paragraph, cation that includes the following: ‘‘investigations must be conducted’’ (1) Application form. The applicant means that information derived from must submit a completed and signed animal or clinical studies is necessary application form that contains the in- to show that the drug product is safe or formation described under § 314.50(a)(1), effective. Such information may be (a)(3), (a)(4), and (a)(5). The applicant contained in published or unpublished must state whether the submission is reports. an ANDA under this section or a sup- (3) If FDA approves a petition sub- plement to an ANDA under § 314.97. mitted under this section, the agency’s (2) Table of contents. The archival response may describe what additional copy of the ANDA is required to con- information, if any, will be required to tain a table of contents that shows the support an ANDA for the drug product. volume number and page number of the FDA may, at any time during the contents of the submission. course of its review of an ANDA, re- (3) Basis for ANDA submission. An quest additional information required ANDA must refer to a listed drug. Ordi- to evaluate the change approved under narily, that listed drug will be the drug the petition. product selected by the Agency as the (f)(1) FDA may withdraw approval of reference standard for conducting bio- a petition if the agency receives any equivalence testing. The ANDA must information demonstrating that the contain: petition no longer satisfies the condi- (i) The name of the reference listed tions under paragraph (e) of this sec- drug, including its dosage form and tion. strength. For an ANDA based on an ap- (2) If, after approval of a petition and proved petition under § 10.30 of this before approval of an ANDA submitted chapter and § 314.93, the reference listed pursuant to the approved petition, a drug must be the same as the listed drug product is approved in an NDA for drug referenced in the approved peti- the change described in the petition, tion.

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(ii) A statement as to whether, ac- dient is an active ingredient of another cording to the information published in listed drug or of a drug that does not the list, the reference listed drug is en- meet the definition of ‘‘new drug’’ in titled to a period of marketing exclu- section 201(p) of the Federal Food, sivity under section 505(j)(5)(F) of the Drug, and Cosmetic Act, and such Federal Food, Drug, and Cosmetic Act. other information about the different (iii) For an ANDA based on an ap- active ingredient that FDA may re- proved petition under § 10.30 of this quire. chapter and § 314.93, a reference to the (B) A reference to the applicant’s an- FDA-assigned docket number for the notated proposed labeling and to the petition and a copy of FDA’s cor- currently approved labeling for the ref- respondence approving the petition. erence listed drug provided under para- (4) Conditions of use. (i) A statement graph (a)(8) of this section. that the conditions of use prescribed, (6) Route of administration, dosage recommended, or suggested in the la- form, and strength. (i) Information to beling proposed for the drug product show that the route of administration, have been previously approved for the dosage form, and strength of the drug reference listed drug. product are the same as those of the (ii) A reference to the applicant’s an- reference listed drug except for any dif- notated proposed labeling and to the ferences that have been the subject of currently approved labeling for the ref- an approved petition, as follows: erence listed drug provided under para- (A) A statement that the route of ad- graph (a)(8) of this section. ministration, dosage form, and (5) Active ingredients. (i) For a single- strength of the proposed drug product active-ingredient drug product, infor- are the same as those of the reference mation to show that the active ingre- listed drug. dient is the same as that of the ref- (B) A reference to the applicant’s an- erence single-active-ingredient listed notated proposed labeling and to the drug, as follows: currently approved labeling for the ref- (A) A statement that the active in- erence listed drug provided under para- gredient of the proposed drug product graph (a)(8) of this section. is the same as that of the reference (ii) If the route of administration, listed drug. dosage form, or strength of the drug (B) A reference to the applicant’s an- product differs from the reference list- notated proposed labeling and to the ed drug and the ANDA is submitted currently approved labeling for the ref- under an approved petition under erence listed drug provided under para- § 314.93, such information about the dif- graph (a)(8) of this section. ferent route of administration, dosage (ii) For a combination drug product, form, or strength that FDA may re- information to show that the active in- quire. gredients are the same as those of the (7) Bioequivalence. (i) Information reference listed drug except for any dif- that shows that the drug product is ferent active ingredient that has been bioequivalent to the reference listed the subject of an approved petition, as drug upon which the applicant relies. A follows: complete study report must be sub- (A) A statement that the active in- mitted for the bioequivalence study gredients of the proposed drug product upon which the applicant relies for ap- are the same as those of the reference proval. For all other bioequivalence listed drug, or if one of the active in- studies conducted on the same drug gredients differs from one of the active product formulation as defined in ingredients of the reference listed drug § 314.3(b), the applicant must submit ei- and the ANDA is submitted under the ther a complete or summary report. If approval of a petition under § 314.93 to a summary report of a bioequivalence vary such active ingredient, informa- study is submitted and FDA deter- tion to show that the other active in- mines that there may be bioequiva- gredients of the drug product are the lence issues or concerns with the prod- same as the other active ingredients of uct, FDA may require that the appli- the reference listed drug, information cant submit a complete report of the to show that the different active ingre- bioequivalence study to FDA; or

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(ii) If the ANDA is submitted pursu- sent regulations in part 50 of this chap- ant to a petition approved under ter. § 314.93, the results of any bio- (8) Labeling—(i) Listed drug labeling. A availability or bioequivalence testing copy of the currently approved labeling required by the Agency, or any other (including, if applicable, any Medica- information required by the Agency to tion Guide required under part 208 of show that the active ingredients of the this chapter) for the listed drug re- proposed drug product are of the same ferred to in the ANDA, if the ANDA re- pharmacological or therapeutic class lies on a reference listed drug. as those in the reference listed drug (ii) Copies of proposed labeling. Copies and that the proposed drug product can of the label and all labeling for the be expected to have the same thera- drug product including, if applicable, peutic effect as the reference listed any Medication Guide required under drug. If the proposed drug product con- part 208 of this chapter (4 copies of tains a different active ingredient than draft labeling or 12 copies of final the reference listed drug, FDA will con- printed labeling). sider the proposed drug product to have (iii) Statement on proposed labeling. A the same therapeutic effect as the ref- statement that the applicant’s pro- erence listed drug if the applicant proposed labeling including, if applicable, vides information demonstrating that: any Medication Guide required under (A) There is an adequate scientific part 208 of this chapter is the same as basis for determining that substitution the labeling of the reference listed drug of the specific proposed dose of the dif- except for differences annotated and ferent active ingredient for the dose of explained under paragraph (a)(8)(iv) of the member of the same pharma- this section. cological or therapeutic class in the (iv) Comparison of approved and pro- reference listed drug will yield a re- posed labeling. A side-by-side compari- sulting drug product whose safety and son of the applicant’s proposed labeling effectiveness have not been adversely including, if applicable, any Medica- affected. tion Guide required under part 208 of (B) The unchanged active ingredients this chapter with the approved labeling in the proposed drug product are bio- for the reference listed drug with all equivalent to those in the reference differences annotated and explained. listed drug. Labeling (including the container (C) The different active ingredient in label, package insert, and, if applica- the proposed drug product is bioequiva- ble, Medication Guide) proposed for the lent to an approved dosage form con- drug product must be the same as the taining that ingredient and approved labeling approved for the reference list- for the same indication as the proposed ed drug, except for changes required be- drug product or is bioequivalent to a cause of differences approved under a drug product offered for that indication petition filed under § 314.93 or because which does not meet the definition of the drug product and the reference list- ‘‘new drug’’ under section 201(p) of the ed drug are produced or distributed by Federal Food, Drug, and Cosmetic Act. different manufacturers. Such dif- (iii) For each in vivo or in vitro bio- ferences between the applicant’s pro- equivalence study contained in the posed labeling and labeling approved ANDA: for the reference listed drug may in- (A) A description of the analytical clude differences in expiration date, and statistical methods used in each formulation, bioavailability, or phar- study; and macokinetics, labeling revisions made (B) With respect to each study in- to comply with current FDA labeling volving human subjects, a statement guidelines or other guidance, or omis- that the study either was conducted in sion of an indication or other aspect of compliance with the institutional re- labeling protected by patent or ac- view board regulations in part 56 of corded exclusivity under section this chapter, or was not subject to the 505(j)(5)(F) of the Federal Food, Drug, regulations under § 56.104 or § 56.105 of and Cosmetic Act. this chapter, and that it was conducted (9) Chemistry, manufacturing, and con- in compliance with the informed controls. (i) The information required

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under § 314.50(d)(1), except that the in- vantage over or difference from the formation required under listed drug, e.g., by using a balanced § 314.50(d)(1)(ii)(c) must contain the pro- salt solution as a diluent as opposed to posed or actual master production an isotonic saline solution, or by mak- record, including a description of the ing a significant change in the pH or equipment, to be used for the manufac- other change that may raise questions ture of a commercial lot of the drug of irritability. product. (v) Inactive ingredient changes per- (ii) Inactive ingredients. Unless other- mitted in drug products intended for top- wise stated in paragraphs (a)(9)(iii) ical use. Generally, a drug product in- through (a)(9)(v) of this section, an ap- tended for topical use, solutions for plicant must identify and characterize aerosolization or nebulization, and the inactive ingredients in the pro- nasal solutions shall contain the same posed drug product and provide infor- inactive ingredients as the reference mation demonstrating that such inac- listed drug identified by the applicant tive ingredients do not affect the safe- under paragraph (a)(3) of this section. ty or efficacy of the proposed drug However, an ANDA may include dif- product. ferent inactive ingredients provided (iii) Inactive ingredient changes per- that the applicant identifies and char- mitted in drug products intended for par- acterizes the differences and provides enteral use. Generally, a drug product information demonstrating that the intended for parenteral use must con- differences do not affect the safety or tain the same inactive ingredients and efficacy of the proposed drug product. in the same concentration as the ref- (10) Samples. The information re- erence listed drug identified by the ap- quired under § 314.50(e)(1) and (e)(2)(i). plicant under paragraph (a)(3) of this Samples need not be submitted until section. However, an applicant may requested by FDA. seek approval of a drug product that (11) Other. The information required differs from the reference listed drug in under § 314.50(g). preservative, buffer, or antioxidant (12) Patent certification—(i) Patents provided that the applicant identifies claiming drug substance, drug product, or and characterizes the differences and method of use. (A) An appropriate pat- provides information demonstrating ent certification or statement with re- that the differences do not affect the spect to each patent issued by the U.S. safety or efficacy of the proposed drug Patent and Trademark Office that, in product. the opinion of the applicant and to the (iv) Inactive ingredient changes per- best of its knowledge, claims the ref- mitted in drug products intended for oph- erence listed drug or that claims a use thalmic or otic use. Generally, a drug of such listed drug for which the appli- product intended for ophthalmic or cant is seeking approval under section otic use must contain the same inac- 505(j) of the Federal Food, Drug, and tive ingredients and in the same con- Cosmetic Act and for which informa- centration as the reference listed drug tion is required to be filed under sec- identified by the applicant under para- tion 505(b) and (c) of the Federal Food, graph (a)(3) of this section. However, Drug, and Cosmetic Act and § 314.53. an applicant may seek approval of a For each such patent, the applicant drug product that differs from the ref- must provide the patent number and erence listed drug in preservative, buff- certify, in its opinion and to the best of er, substance to adjust tonicity, or its knowledge, one of the following cir- thickening agent provided that the ap- cumstances: plicant identifies and characterizes the (1) That the patent information has differences and provides information not been submitted to FDA. The appli- demonstrating that the differences do cant must entitle such a certification not affect the safety or efficacy of the ‘‘Paragraph I Certification’’; proposed drug product, except that, in (2) That the patent has expired. The a product intended for ophthalmic use, applicant must entitle such a certifi- an applicant may not change a buffer cation ‘‘Paragraph II Certification’’; or substance to adjust tonicity for the (3) The date on which the patent will purpose of claiming a therapeutic ad- expire. The applicant must entitle such

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a certification ‘‘Paragraph III Certifi- applicant is seeking approval does not cation’’; or include an indication or other condi- (4)(i) That the patent is invalid, un- tion of use that is covered by the meth- enforceable, or will not be infringed by od-of-use patent, a statement explain- the manufacture, use, or sale of the ing that the method-of-use patent does drug product for which the ANDA is not claim a proposed indication or submitted. The applicant must entitle other condition of use. such a certification ‘‘Paragraph IV Cer- (B) If the labeling of the drug product tification’’. This certification must be for which the applicant is seeking ap- submitted in the following form: proval includes an indication or other I, (name of applicant), certify that Patent condition of use that, according to the No. lllll (is invalid, unenforceable, or will patent information submitted under not be infringed by the manufacture, use, or section 505(b) or (c) of the Federal sale of) (name of proposed drug product) for Food, Drug, and Cosmetic Act and which this ANDA is submitted. § 314.53 or in the opinion of the appli- (ii) The certification must be accom- cant, is claimed by a method-of-use panied by a statement that the appli- patent, an applicable certification cant will comply with the require- under paragraph (a)(12)(i) of this sec- ments under § 314.95(a) with respect to tion. providing a notice to each owner of the (iv) [Reserved] patent or its representative and to the (v) Licensing agreements. If the ANDA NDA holder (or, if the NDA holder does is for a drug or method of using a drug not reside or maintain a place of busi- claimed by a patent and the applicant ness within the United States, its at- has a licensing agreement with the pat- torney, agent, or other authorized offi- ent owner, the applicant must submit a cial) for the listed drug, with the re- paragraph IV certification as to that quirements under § 314.95(b) with re- patent and a statement that the appli- spect to sending the notice, and with cant has been granted a patent license. the requirements under § 314.95(c) with If the patent owner consents to ap- respect to the content of the notice. proval of the ANDA (if otherwise eligi- (B) If the ANDA refers to a listed ble for approval) as of a specific date, drug that is itself a licensed generic the ANDA must contain a written product of a patented drug first ap- statement from the patent owner that proved under section 505(b) of the Fed- it has a licensing agreement with the eral Food, Drug, and Cosmetic Act, an applicant and that it consents to ap- appropriate patent certification or proval of the ANDA as of a specific statement under paragraph (a)(12)(i) date. and/or (iii) of this section with respect (vi) Untimely filing of patent informa- to each patent that claims the first-ap- tion. (A) If a patent on the listed drug proved patented drug or that claims a is issued and the holder of the approved use for such drug. NDA for the listed drug does not file (ii) No relevant patents. If, in the opin- with FDA the required information on ion of the applicant and to the best of the patent within 30 days of issuance of its knowledge, there are no patents de- the patent, an applicant who submitted scribed in paragraph (a)(12)(i) of this an ANDA for that drug that contained section, a certification in the following an appropriate patent certification or form: statement before the submission of the In the opinion and to the best knowledge of patent information is not required to (name of applicant), there are no patents submit a patent certification or state- that claim the listed drug referred to in this ment to address the patent or patent ANDA or that claim a use of the listed drug. information that is late-listed with re- (iii) Method-of-use patent. (A) If pat- spect to the pending ANDA. Except as ent information is submitted under provided in § 314.53(f)(1), an NDA hold- section 505(b) or (c) of the Federal er’s amendment to the description of Food, Drug, and Cosmetic Act and the approved method(s) of use claimed § 314.53 for a patent claiming a method by the patent will be considered un- of using the listed drug, and the label- timely filing of patent information un- ing for the drug product for which the less:

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(1) The amendment to the description certification, the ANDA will no longer of the approved method(s) of use be considered to contain the prior cer- claimed by the patent is submitted tification. within 30 days of patent issuance; (A) After finding of infringement. An (2) The amendment to the description applicant who has submitted a para- of the approved method(s) of use graph IV certification and is sued for claimed by the patent is submitted patent infringement must submit an within 30 days of approval of a cor- amendment to change its certification responding change to product labeling; if a court enters a final decision from or which no appeal has been or can be (3) The amendment to the description taken, or signs and enters a settlement of the approved method(s) of use order or consent decree in the action claimed by the patent is submitted that includes a finding that the patent within 30 days of a decision by the U.S. is infringed, unless the final decision, Patent and Trademark Office or by a settlement order, or consent decree Federal district court, the Court of Ap- also finds the patent to be invalid. In peals for the Federal Circuit, or the its amendment, the applicant must cer- U.S. Supreme Court that is specific to tify under paragraph (a)(12)(i)(A)(3) of the patent and alters the construction this section that the patent will expire of a method-of-use claim(s) of the pat- on a specific date or, with respect to a ent, and the amendment contains a patent claiming a method of use, the copy of the decision. applicant may instead provide a state- (B) An applicant whose ANDA is sub- ment under paragraph (a)(12)(iii) of mitted after the NDA holder’s un- this section if the applicant amends its timely filing of patent information, or ANDA such that the applicant is no whose pending ANDA was previously submitted but did not contain an ap- longer seeking approval for a method propriate patent certification or state- of use claimed by the patent. Once an ment at the time of the patent submis- amendment for the change has been sion, must submit a certification under submitted, the ANDA will no longer be paragraph (a)(12)(i) of this section and/ considered to contain a paragraph IV or a statement under paragraph certification to the patent. If a final (a)(12)(iii) of this section as to that pat- judgment finds the patent to be invalid ent. and infringed, an amended certification (vii) Disputed patent information. If an is not required. applicant disputes the accuracy or rel- (B) After request to remove a patent or evance of patent information sub- patent information from the list. If the mitted to FDA, the applicant may seek list reflects that an NDA holder has re- a confirmation of the correctness of quested that a patent or patent infor- the patent information in accordance mation be removed from the list and no with the procedures under § 314.53(f). ANDA applicant is eligible for 180-day Unless the patent information is with- exclusivity based on a paragraph IV drawn, the applicant must submit an certification to that patent, the patent appropriate certification or statement or patent information will be removed for each listed patent. and any applicant with a pending (viii) Amended certifications. A patent ANDA (including a tentatively ap- certification or statement submitted proved ANDA) who has made a certifi- under paragraphs (a)(12)(i) through (iii) cation with respect to such patent of this section may be amended at any must submit an amendment to with- time before the approval of the ANDA. draw its certification. In the amend- If an applicant with a pending ANDA ment, the applicant must state the rea- voluntarily makes a patent certifi- son for withdrawing the certification cation for an untimely filed patent, the or statement (that the patent has been applicant may withdraw the patent removed from the list). If the list recertification for the untimely filed pat- flects that an NDA holder has re- ent. An applicant must submit an quested that a patent or patent infor- amended certification as an amend- mation be removed from the list and ment to a pending ANDA. Once an one or more first applicants are eligi- amendment is submitted to change a ble for 180-day exclusivity based on a

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paragraph IV certification to that pat- statement as required by part 54 of this ent, the patent will remain listed until chapter. any 180-day exclusivity based on that (b) Drug products subject to the Drug patent has expired or has been extin- Efficacy Study Implementation (DESI) re- guished. After any applicable 180-day view. If the ANDA is for a duplicate of exclusivity has expired or has been ex- a drug product that is subject to FDA’s tinguished, the patent or patent infor- DESI review (a review of drug products mation will be removed and any appli- approved as safe between 1938 and 1962) cant with a pending ANDA (including a or other DESI-like review and the drug tentatively approved ANDA) who has product evaluated in the review is a made a certification with respect to listed drug, the applicant must comply such patent must submit an amend- with the provisions of paragraph (a) of ment to withdraw its certification. this section. Once an amendment to withdraw the (c) [Reserved] certification has been submitted, the (d) Format of an ANDA. (1) The appli- ANDA will no longer be considered to cant must submit a complete archival contain a paragraph IV certification to copy of the ANDA as required under the patent. If removal of a patent from paragraphs (a) and (c) of this section. the list results in there being no pat- FDA will maintain the archival copy ents listed for the listed drug identified during the review of the ANDA to per- in the ANDA, the applicant must submit individual reviewers to refer to in- mit an amended certification reflecting formation that is not contained in that there are no relevant patents. their particular technical sections of (C) Other amendments. (1) Except as the ANDA, to give other Agency per- provided in paragraphs (a)(12)(vi) and sonnel access to the ANDA for official (a)(12)(viii)(C)(2) of this section: business, and to maintain in one place (i) An applicant must amend a sub- a complete copy of the ANDA. mitted certification or statement if, at (i) Format of submission. An applicant any time before the date of approval of may submit portions of the archival the ANDA, the applicant learns that copy of the ANDA in any form that the the submitted certification or state- applicant and FDA agree is acceptable, ment is no longer accurate; and except as provided in paragraph (ii) An applicant must submit an ap- (d)(1)(ii) of this section. propriate patent certification or state- (ii) Labeling. The content of labeling ment under paragraph (a)(12)(i) and/or required under § 201.100(d)(3) of this (iii) of this section if, after submission chapter (commonly referred to as the of the ANDA, a new patent is issued by package insert or professional label- the U.S. Patent and Trademark Office ing), including all text, tables, and fig- that, in the opinion of the applicant ures, must be submitted to the agency and to the best of its knowledge, in electronic format as described in claims the reference listed drug or that paragraph (d)(1)(iii) of this section. claims an approved use for such ref- This requirement applies to the con- erence listed drug and for which infor- tent of labeling for the proposed drug mation is required to be filed under product only and is in addition to the section 505(b) and (c) of the Federal requirements of paragraph (a)(8)(ii) of Food, Drug, and Cosmetic Act and this section that copies of the for- § 314.53. For a paragraph IV certifi- matted label and all proposed labeling cation, the certification must not be be submitted. Submissions under this submitted earlier than the first work- paragraph must be made in accordance ing day after the day the patent is pub- with part 11 of this chapter, except for lished in the list. the requirements of § 11.10(a), (c) (2) An applicant is not required to through (h), and (k), and the cor- submit a supplement to change a sub- responding requirements of § 11.30. mitted certification when information (iii) Electronic format submissions. on a patent on the listed drug is sub- Electronic format submissions must be mitted after the approval of the ANDA. in a form that FDA can process, re- (13) Financial certification or disclosure view, and archive. FDA will periodi- statement. An ANDA must contain a fi- cally issue guidance on how to provide nancial certification or disclosure the electronic submission (e.g., method

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of transmission, media, file formats, designated delivery service, as defined preparation and organization of files). in paragraph (g) of this section to each (2) For ANDAs, the applicant must of the following persons: submit a review copy of the ANDA that (1) Each owner of the patent that is contains two separate sections. One the subject of the certification or the section must contain the information representative designated by the owner described under paragraphs (a)(2) to receive the notice. The name and ad- through (6) and (8) and (9) of this sec- dress of the patent owner or its rep- tion and section 505(j)(2)(A)(vii) of the resentative may be obtained from the Federal Food, Drug, and Cosmetic Act U.S. Patent and Trademark Office; and and a copy of the analytical procedures (2) The holder of the approved NDA and descriptive information needed by under section 505(b) of the Federal FDA’s laboratories to perform tests on Food, Drug, and Cosmetic Act for the samples of the proposed drug product listed drug that is claimed by the pat- and to validate the applicant’s analyt- ent and for which the applicant is seek- ical procedures. The other section must ing approval, or, if the NDA holder contain the information described does not reside or maintain a place of under paragraphs (a)(3), (7), and (8) of business within the United States, the this section. Each of the sections in the review copy is required to contain a NDA holder’s attorney, agent, or other copy of the application form described authorized official. The name and ad- under paragraph (a) of this section. dress of the NDA holder or its attor- (3) [Reserved] ney, agent, or authorized official may (4) The applicant may obtain from be obtained by sending a written or FDA sufficient folders to bind the ar- electronic communication to the Cen- chival, the review, and the field copies tral Document Room, Attn: Orange of the ANDA. Book Staff, Center for Drug Evaluation (5) The applicant must submit a field and Research, Food and Drug Adminis- copy of the ANDA that contains the tration, 5901–B Ammendale Rd., Belts- technical section described in para- ville, MD 20705–1266 or to the Orange graph (a)(9) of this section, a copy of Book Staff at the email address listed the application form required under on the Agency’s Web site at http:// paragraph (a)(1) of this section, and a www.fda.gov. certification that the field copy is a (3) This paragraph (a) does not apply true copy of the technical section de- to a method-of-use patent that does scribed in paragraph (a)(9) of this sec- not claim a use for which the applicant tion contained in the archival and re- is seeking approval. view copies of the ANDA. (4) An applicant may send notice by [57 FR 17983, Apr. 28, 1992; 57 FR 29353, July an alternative method only if FDA has 1, 1992, as amended at 58 FR 47352, Sept. 8, agreed in advance that the method will 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. produce an acceptable form of docu- 2, 1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, mentation. Jan. 5, 1999; 65 FR 56479, Sept. 19, 2000; 67 FR (b) Sending the notice. (1) Except as 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003; provided under paragraph (d) of this 69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16, 2009; 76 FR 13880, Mar. 15, 2011; 81 FR 69649, section, the applicant must send the Oct. 6, 2016] notice required by paragraph (a) of this section on or after the date it receives § 314.95 Notice of certification of inva- a paragraph IV acknowledgment letter lidity, unenforceability, or non- from FDA, but not later than 20 days infringement of a patent. after the date of the postmark on the (a) Notice of certification. For each paragraph IV acknowledgment letter. patent that claims the listed drug or The 20-day clock described in this para- that claims a use for such listed drug graph (b) begins on the day after the for which the applicant is seeking ap- date of the postmark on the paragraph proval and for which the applicant sub- IV acknowledgment letter. When the mits a paragraph IV certification, the 20th day falls on Saturday, Sunday, or applicant must send notice of such cer- a Federal holiday, the 20th day will be tification by registered or certified the next day that is not a Saturday, mail, return receipt requested, or by a Sunday, or Federal holiday.

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(2) Any notice required by paragraph (8) If the applicant alleges that the (a) of this section is invalid if it is sent patent will not be infringed and the ap- before the applicant’s receipt of a para- plicant seeks to preserve the option to graph IV acknowledgment letter, or be- later file a civil action for declaratory fore the first working day after the day judgment in accordance with section the patent is published in the list. The 505(j)(5)(C) of the Federal Food, Drug, applicant will not have complied with and Cosmetic Act, then the notice this paragraph (b) until it sends valid must be accompanied by an offer of notice. confidential access to the ANDA for (3) The applicant must submit to the sole and limited purpose of evalu- FDA an amendment to its ANDA that ating possible infringement of the pat- includes a statement certifying that ent that is the subject of the paragraph the notice has been provided to each IV certification. person identified under paragraph (a) of (9) If the applicant does not reside or this section and that the notice met have a place of business in the United the content requirements under para- States, the name and address of an graph (c) of this section. A copy of the agent in the United States authorized notice itself need not be submitted to to accept service of process for the ap- the Agency. plicant. (c) Contents of a notice. In the notice, (d) Amendment or supplement to an the applicant must cite section ANDA. (1) If, after receipt of a para- 505(j)(2)(B)(iv) of the Federal Food, graph IV acknowledgment letter or ac- Drug, and Cosmetic Act and the notice knowledgment letter, an applicant sub- must include, but is not limited to, the mits an amendment or supplement to following information: its ANDA that includes a paragraph IV (1) A statement that FDA has recertification, the applicant must send ceived an ANDA submitted by the ap- the notice required by paragraph (a) of plicant containing any required bio- this section at the same time that the availability or bioequivalence data or amendment or supplement to the information. ANDA is submitted to FDA, regardless (2) The ANDA number. of whether the applicant has already (3) A statement that the applicant has received the paragraph IV acknowl- given notice with respect to another edgment letter for the ANDA. such certification contained in the (4) The established name, if any, as ANDA or in an amendment or supple- defined in section 502(e)(3) of the Fed- ment to the ANDA. eral Food, Drug, and Cosmetic Act, of (2) If, before receipt of a paragraph IV the proposed drug product. acknowledgment letter, an applicant (5) The active ingredient, strength, submits an amendment to its ANDA and dosage form of the proposed drug that includes a paragraph IV certifi- product. cation, the applicant must send the no- (6) The patent number and expiration tice required by paragraph (a) of this date of each listed patent for the ref- section in accordance with the proce- erence listed drug alleged to be invalid, dures in paragraph (b) of this section. unenforceable, or not infringed. If an ANDA applicant’s notice of its (7) A detailed statement of the fac- paragraph IV certification is timely tual and legal basis of the applicant’s provided in accordance with paragraph opinion that the patent is not valid, (b) of this section and the applicant has unenforceable, or will not be infringed. not submitted a previous paragraph IV The applicant must include in the de- certification, FDA will base its deter- tailed statement: mination of whether the applicant is a (i) For each claim of a patent alleged first applicant on the date of submis- not to be infringed, a full and detailed sion of the amendment containing the explanation of why the claim is not in- paragraph IV certification. fringed. (3) An applicant that submits an (ii) For each claim of a patent al- amendment or supplement to seek ap- leged to be invalid or unenforceable, a proval of a different strength must pro- full and detailed explanation of the vide notice of any paragraph IV certifi- grounds supporting the allegation. cation in accordance with paragraph

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(d)(1) or (2) of this section, as applica- ‘‘designated delivery service’’ means ble. any delivery service provided by a (e) Documentation of timely sending trade or business that the Agency de- and receipt of notice. The applicant termines: must amend its ANDA to provide docu- (i) Is available to the general public mentation of the date of receipt of the throughout the United States; notice required under paragraph (a) of (ii) Records electronically to its this section by each person provided database, kept in the regular course of the notice. The amendment must be its business, or marks on the cover in submitted to FDA within 30 days after which any item referred to in this sec- the last date on which notice was re- tion is to be delivered, the date on ceived by a person described in para- which such item was given to such graph (a) of this section. The appli- trade or business for delivery; and cant’s amendment also must include (iii) Provides overnight or 2-day de- documentation that its notice was sent livery service throughout the United on a date that complies with the time- States. frame required by paragraph (b) or (d) (2) FDA may periodically issue guid- of this section, as applicable, and a ance regarding designated delivery dated printout of the entry for the ref- services. erence listed drug in FDA’s ‘‘Approved [81 FR 69651, Oct. 6, 2016, as amended at 84 FR Drug Products With Therapeutic 6673, Feb. 28, 2019] Equivalence Evaluations’’ (the list) that includes the patent that is the § 314.96 Amendments to an unap- subject of the paragraph IV certifi- proved ANDA. cation. FDA will accept, as adequate (a) ANDA. (1) An applicant may documentation of the date the notice amend an ANDA that is submitted was sent, a copy of the registered mail under § 314.94, but not yet approved, to receipt, certified mail receipt, or re- revise existing information or provide ceipt from a designated delivery serv- additional information. Amendments ice as defined in paragraph (g) of this containing bioequivalence studies must section. FDA will accept as adequate contain reports of all bioequivalence documentation of the date of receipt a studies conducted by the applicant on return receipt, signature proof of deliv- the same drug product formulation, un- ery by a designated delivery service, or less the information has previously a letter acknowledging receipt by the been submitted to FDA in the ANDA. A person provided the notice. An appli- complete study report must be sub- cant may rely on another form of docu- mitted for any bioequivalence study mentation only if FDA has agreed to upon which the applicant relies for ap- such documentation in advance. A copy proval. For all other bioequivalence of the notice itself need not be sub- studies conducted on the same drug mitted to the Agency. product formulation as defined in (f) Forty-five day period after receipt of § 314.3 of this chapter, the applicant notice. If the requirements of this sec- must submit either a complete or sum- tion are met, FDA will presume the no- mary report. If a summary report of a tice to be complete and sufficient, and bioequivalence study is submitted and it will count the day following the date FDA determines that there may be bio- of receipt of the notice by the patent equivalence issues or concerns with the owner or its representative and by the product, FDA may require that the ap- approved NDA holder or its attorney, plicant submit a complete report of the agent, or other authorized official as bioequivalence study to FDA. the first day of the 45-day period pro- (2) Submission of an amendment con- vided for in section 505(j)(5)(B)(iii) of taining significant data or information the Federal Food, Drug, and Cosmetic before the end of the initial review Act. FDA may, if the applicant pro- cycle constitutes an agreement be- vides a written statement to FDA that tween FDA and the applicant to extend a later date should be used, count from the initial review cycle only for the such later date. time necessary to review the signifi- (g) Designated delivery services. (1) For cant data or information and for no purposes of this section, the term more than 180 days.

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(b) Field copy. The applicant must the types of amendments described in submit a field copy of each amendment paragraph (d)(1) of this section. under § 314.94(a)(9). The applicant, other [57 FR 17983, Apr. 28, 1992, as amended at 58 than a foreign applicant, must include FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999; in its submission of each such amend- 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 16, ment to FDA a statement certifying 2009; 81 FR 69652, Oct. 6, 2016] that a field copy of the amendment has been sent to the applicant’s home FDA § 314.97 Supplements and other district office. changes to an approved ANDA. (c) Different listed drug. An applicant (a) General requirements. The appli- may not amend an ANDA to seek ap- cant must comply with the require- proval of a drug referring to a listed ments of §§ 314.70 and 314.71 regarding drug that is different from the ref- the submission of supplemental ANDAs erence listed drug identified in the and other changes to an approved ANDA. This paragraph (c) applies if, at ANDA. any time before the approval of the (b) Different listed drug. An applicant ANDA, a different listed drug is ap- may not supplement an ANDA to seek proved that is the pharmaceutical approval of a drug referring to a listed equivalent to the product in the ANDA drug that is different from the current and is designated as a reference listed reference listed drug identified in the ANDA. This paragraph (b) applies if drug. This paragraph (c) also applies if changes are proposed in a supplement changes are proposed in an amendment to the ANDA such that the proposed to the ANDA such that the proposed product is a pharmaceutical equivalent product is a pharmaceutical equivalent to a different listed drug than the ref- to a different listed drug than the reference listed drug identified in the erence listed drug identified in the ANDA. A change of reference listed ANDA. A change of the reference listed drug must be submitted in a new drug must be submitted in a new ANDA. However, notwithstanding the ANDA. However, notwithstanding the limitation described in this paragraph limitation described in this paragraph (b), an applicant may supplement the (c), an applicant may amend the ANDA ANDA to seek approval of a different to seek approval of a different strength. strength. [81 FR 69653, Oct. 6, 2016] (d)(1) Patent certification requirements. An amendment to an ANDA is required § 314.98 Postmarketing reports. to contain an appropriate patent cer- (a) Each applicant having an ap- tification or statement described in proved abbreviated new drug applica- § 314.94(a)(12) or a recertification for a tion under § 314.94 that is effective previously submitted paragraph IV cer- must comply with the requirements of tification if approval is sought for any § 314.80 regarding the reporting and rec- of the following types of amendments: ordkeeping of adverse drug experi- (i) To add a new indication or other ences. condition of use; (b) Each applicant must make the re- (ii) To add a new strength; ports required under § 314.81 and section (iii) To make other than minor 505(k) of the Federal Food, Drug, and changes in product formulation; or Cosmetic Act for each of its approved (iv) To change the physical form or abbreviated applications. crystalline structure of the active in- [79 FR 33089, June 10, 2014] gredient. (2) If the amendment to the ANDA § 314.99 Other responsibilities of an does not contain a patent certification applicant of an ANDA. or statement, the applicant must (a) An applicant must comply with verify that the proposed change de- the requirements of § 314.65 regarding scribed in the amendment is not one of withdrawal by the applicant of an unapproved ANDA and § 314.72 regarding a change in ownership of an ANDA.

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(b) An applicant may ask FDA to (2) If FDA finds that none of the rea- waive under this section any require- sons in paragraphs (d) and (e) of this ment that applies to the applicant section for refusing to file the NDA under §§ 314.92 through 314.99. The appli- apply, the Agency will file the NDA cant must comply with the require- and notify the applicant in writing. In ments for a waiver under § 314.90. If the case of a 505(b)(2) application that FDA grants the applicant’s waiver re- contains a paragraph IV certification, quest with respect to a requirement the applicant will be notified via a under §§ 314.92 through 314.99, the paragraph IV acknowledgment letter. waived requirement will not constitute The date of filing will be the date 60 a basis for refusal to approve an ANDA days after the date FDA received the under § 314.127. NDA. The date of filing begins the 180- day period described in section 505(c) of 81 FR 69653, Oct. 6, 2016] the Federal Food, Drug, and Cosmetic Act. This 180-day period is called the Subpart D—FDA Action on Appli- ‘‘filing clock.’’ cations and Abbreviated Ap- (3) If FDA refuses to file the NDA, plications the Agency will notify the applicant in writing and state the reason under SOURCE: 50 FR 7493, Feb. 22, 1985, unless paragraph (d) or (e) of this section for otherwise noted. Redesignated at 57 FR 17983, the refusal. If FDA refuses to file the Apr. 28, 1992. NDA under paragraph (d) of this section, the applicant may request in § 314.100 Timeframes for reviewing ap- writing within 30 days of the date of plications and abbreviated applications. the Agency’s notification an informal conference with the Agency about (a) Except as provided in paragraph whether the Agency should file the (c) of this section, within 180 days of NDA. If, following the informal con- receipt of an application for a new drug ference, the applicant requests that under section 505(b) of the act or an ab- FDA file the NDA (with or without breviated application for a new drug amendments to correct the defi- under section 505(j) of the act, FDA ciencies), the Agency will file the NDA will review it and send the applicant ei- over protest under paragraph (a)(2) of ther an approval letter under § 314.105 this section, notify the applicant in or a complete response letter under writing, and review it as filed. If the § 314.110. This 180-day period is called NDA is filed over protest, the date of the ‘‘initial review cycle.’’ filing will be the date 60 days after the (b) At any time before approval, an date the applicant requested the infor- applicant may withdraw an application mal conference. The applicant need not under § 314.65 or an abbreviated applica- resubmit a copy of an NDA that is filed tion under § 314.99 and later submit it over protest. If FDA refuses to file the again for consideration. NDA under paragraph (e) of this sec- (c) The initial review cycle may be tion, the applicant may amend the adjusted by mutual agreement between NDA and resubmit it, and the Agency FDA and an applicant or as provided in will make a determination under this §§ 314.60 and 314.96, as the result of a section whether it may be filed. major amendment. (b)(1) Receiving an ANDA. An ANDA [73 FR 39609, July 10, 2008] will be evaluated after it is submitted to determine whether the ANDA may § 314.101 Filing an NDA and receiving be received. Receipt of an ANDA means an ANDA. that FDA has made a threshold deter- (a) Filing an NDA. (1) Within 60 days mination that the abbreviated applica- after FDA receives an NDA, the Agen- tion is substantially complete. cy will determine whether the NDA (2) If FDA finds that none of the rea- may be filed. The filing of an NDA sons in paragraphs (d) and (e) of this means that FDA has made a threshold section for considering the ANDA not determination that the NDA is suffi- to have been received applies, the ciently complete to permit a sub- ANDA is substantially complete and stantive review. the Agency will receive the ANDA and

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notify the applicant in writing. If FDA conducted in compliance with the re- determines, upon evaluation, that an quirements set forth in part 58 of this ANDA was substantially complete as of chapter, or, for each study not con- the date it was submitted to FDA, FDA ducted in compliance with part 58 of will consider the ANDA to have been this chapter, a brief statement of the received as of the date of submission. reason for the noncompliance. In the case of an ANDA that contains a (7) The NDA or ANDA does not con- paragraph IV certification, the appli- tain a statement for each clinical cant will be notified via a paragraph IV study that the study was conducted in acknowledgment letter. compliance with the institutional re- (3) If FDA considers the ANDA not to view board regulations in part 56 of have been received under paragraph (d) this chapter, or was not subject to or (e) of this section, FDA will notify those regulations, and that it was con- the applicant of the refuse-to-receive ducted in compliance with the in- decision. The applicant may then: formed consent regulations in part 50 (i) Withdraw the ANDA under § 314.99; of this chapter, or, if the study was or subject to but was not conducted in (ii) Correct the deficiencies and re- compliance with those regulations, the submit the ANDA; or NDA or ANDA does not contain a brief (iii) Take no action, in which case statement of the reason for the non- FDA may consider the ANDA with- compliance. drawn after 1 year. (8) The drug product that is the sub- (c) [Reserved] ject of the submission is already cov- (d) NDA or ANDA deficiencies. FDA ered by an approved NDA or ANDA and may refuse to file an NDA or may not the applicant of the submission: consider an ANDA to be received if any (i) Has an approved NDA or ANDA for of the following applies: the same drug product; or (1) The NDA or ANDA does not con- (ii) Is merely a distributor and/or retain a completed application form. packager of the already approved drug (2) The NDA or ANDA is not sub- product. mitted in the form required under (9) The NDA is submitted as a § 314.50 or § 314.94. 505(b)(2) application for a drug that is a (3) The NDA or ANDA is incomplete duplicate of a listed drug and is eligible because it does not on its face contain for approval under section 505(j) of the information required under section Federal Food, Drug, and Cosmetic Act. 505(b) or section 505(j) of the Federal (e) Regulatory deficiencies. The Agen- Food, Drug, and Cosmetic Act and cy will refuse to file an NDA or will § 314.50 or § 314.94. In determining consider an ANDA not to have been re- whether an ANDA is incomplete on its ceived if any of the following applies: face, FDA will consider the nature (1) The drug product is subject to li- (e.g., major or minor) of the defi- censing by FDA under the Public ciencies, including the number of defi- Health Service Act (42 U.S.C. 201 et ciencies in the ANDA. seq.) and subchapter F of this chapter. (4) The applicant fails to submit a (2) Submission of a 505(b)(2) applica- complete environmental assessment, tion or an ANDA is not permitted which addresses each of the items spec- under section 505(c)(3)(E)(ii), ified in the applicable format under 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), § 25.40 of this chapter or fails to provide 505A(c)(1)(A)(i)(I), or 505E(a) of the Fed- sufficient information to establish that eral Food, Drug, and Cosmetic Act. the requested action is subject to cat- (f) Outcome of FDA review. (1) Within egorical exclusion under § 25.30 or § 25.31 180 days after the date of filing, plus of this chapter. the period of time the review period (5) The NDA or ANDA does not con- was extended (if any), FDA will either: tain an accurate and complete English (i) Approve the NDA; or translation of each part of the NDA or (ii) Issue a notice of opportunity for ANDA that is not in English. a hearing if the applicant asked FDA (6) The NDA or ANDA does not con- to provide it an opportunity for a hear- tain a statement for each nonclinical ing on an NDA in response to a com- laboratory study that the study was plete response letter.

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(2) Within 180 days after the date of consideration of the entire pending ap- receipt, plus the period of time the re- plication or abbreviated application by view clock was extended (if any), FDA agency managers as well as reviewing will either approve or disapprove the staff. Instead, major scientific issues ANDA. If FDA disapproves the ANDA, will ordinarily be addressed in a com- FDA will issue a notice of opportunity plete response letter. for hearing if the applicant asked FDA (c) Ninety-day conference. Approxi- to provide it an opportunity for a hear- mately 90 days after the agency re- ing on an ANDA in response to a com- ceives the application, FDA will pro- plete response letter. vide applicants with an opportunity to (3) This paragraph (f) does not apply meet with agency reviewing officials. to NDAs or ANDAs that have been withdrawn from FDA review by the ap- The purpose of the meeting will be to plicant. inform applicants of the general progress and status of their applica- [81 FR 69653, Oct. 6, 2016] tions, and to advise applicants of deficiencies that have been identified by § 314.102 Communications between FDA and applicants. that time and that have not already been communicated. This meeting will (a) General principles. During the be available on applications for all new course of reviewing an application or chemical entities and major new indi- an abbreviated application, FDA shall cations of marketed drugs. Such meet- communicate with applicants about scientific, medical, and procedural ings will be held at the applicant’s op- issues that arise during the review tion, and may be held by telephone if process. Such communication may mutually agreed upon. Such meetings take the form of telephone conversa- would not ordinarily be held on abbre- tions, letters, or meetings, whichever viated applications because they are is most appropriate to discuss the par- not submitted for new chemical enti- ticular issue at hand. Communications ties or new indications. shall be appropriately documented in (d) End-of-review conference. At the the application in accordance with conclusion of FDA’s review of an NDA § 10.65 of this chapter. Further details as designated by the issuance of a com- on the procedures for communication plete response letter, FDA will provide between FDA and applicants are con- the applicant with an opportunity to tained in a staff manual guide that is meet with agency reviewing officials. publicly available. The purpose of the meeting will be to (b) Notification of easily correctable de- discuss what further steps need to be ficiencies. FDA reviewers shall make taken by the applicant before the ap- every reasonable effort to commu- plication can be approved. Requests for nicate promptly to applicants easily such meetings must be directed to the correctable deficiencies found in an ap- director of the division responsible for plication or an abbreviated application reviewing the application. when those deficiencies are discovered, (e) Other meetings. Other meetings be- particularly deficiencies concerning chemistry, manufacturing, and con- tween FDA and applicants may be held, trols issues. The agency will also in- with advance notice, to discuss sci- form applicants promptly of its need entific, medical, and other issues that for more data or information or for arise during the review process. Re- technical changes in the application or quests for meetings shall be directed to the abbreviated application needed to the director of the division responsible facilitate the agency’s review. This for reviewing the application or abbre- early communication is intended to viated application. FDA will make permit applicants to correct such read- every attempt to grant requests for ily identified deficiencies relatively meetings that involve important issues early in the review process and to sub- and that can be scheduled at mutually mit an amendment before the review convenient times. However, ‘‘drop-in’’ period has elapsed. Such early commu- visits (i.e., an unannounced and un- nication would not ordinarily apply to scheduled visit by a company rep- major scientific issues, which require resentative) are discouraged except for

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urgent matters, such as to discuss an ing with the appropriate reviewing offi- important new safety issue. cials and management representatives in order to seek a resolution. Ordi- [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 73 FR 39609, July 10, narily, such meetings would be held 2008] first with the Division Director, then with the Office Director, and finally § 314.103 Dispute resolution. with the Center Director if the matter (a) General. FDA is committed to re- is still unresolved. Requests for such solving differences between applicants meetings shall be directed to the direc- and FDA reviewing divisions with re- tor of the division responsible for respect to technical requirements for ap- viewing the application or abrreviated plications or abbreviated applications application. FDA will make every at- as quickly and amicably as possible tempt to grant requests for meetings through the cooperative exchange of that involve important issues and that information and views. can be scheduled at mutually conven- (b) Administrative and procedural ient times. issues. When administrative or proce- (3) In requesting a meeting designed dural disputes arise, the applicant to resolve a scientific or medical dis- should first attempt to resolve the pute, applicants may suggest that FDA matter with the division responsible seek the advice of outside experts, in for reviewing the application or abbre- which case FDA may, in its discretion, viated application, beginning with the invite to the meeting one or more of its consumer safety officer assigned to the advisory committee members or other application or abbreviated application. consultants, as designated by the agen- If resolution is not achieved, the appli- cy. Applicants may also bring their cant may raise the matter with the own consultants. For major scientific person designated as ombudsman, and medical policy issues not resolved whose function shall be to investigate by informal meetings, FDA may refer what has happened and to facilitate a the matter to one of its standing advi- timely and equitable resolution. Appro- sory committees for its consideration priate issues to raise with the ombuds- and recommendations. man include resolving difficulties in [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, scheduling meetings, obtaining timely 1985, as amended at 57 FR 17989, Apr. 28, 1992; replies to inquiries, and obtaining 73 FR 39609, July 10, 2008] timely completion of pending reviews. Further details on this procedure are § 314.104 Drugs with potential for abuse. contained in a staff manual guide that is publicly available under FDA’s pub- The Food and Drug Administration lic information regulations in part 20. will inform the Drug Enforcement Ad- (c) Scientific and medical disputes. (1) ministration under section 201(f) of the Because major scientific issues are or- Controlled Substances Act (21 U.S.C. dinarily communicated to applicants 801) when an application or abbreviated in a complete response letter pursuant application is submitted for a drug to § 314.110, the ‘‘end-of-review con- that appears to have an abuse poten- ference’’ described in § 314.102(d) will tial. provide a timely forum for discussing [57 FR 17989, Apr. 28, 1992] and resolving, if possible, scientific and medical issues on which the applicant § 314.105 Approval of an NDA and an disagrees with the agency. In addition, ANDA. the ‘‘ninety-day conference’’ described (a) FDA will approve an NDA and in § 314.102(c) will provide a timely send the applicant an approval letter if forum for discussing and resolving, if none of the reasons in § 314.125 for re- possible, issues identified by that date. fusing to approve the NDA applies. (2) When scientific or medical dis- FDA will issue a tentative approval putes arise at other times during the letter if an NDA otherwise meets the review process, applicants should dis- requirements for approval under the cuss the matter directly with the re- Federal Food, Drug, and Cosmetic Act, sponsible reviewing officials. If nec- but cannot be approved because there essary, applicants may request a meet- is a 7-year period of orphan exclusivity

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for the listed drug under section 527 of mand flexibility in applying the stand- the Federal Food, Drug, and Cosmetic ards. Thus FDA is required to exercise Act and § 316.31 of this chapter, or if a its scientific judgment to determine 505(b)(2) application otherwise meets the kind and quantity of data and in- the requirements for approval under formation an applicant is required to the Federal Food, Drug, and Cosmetic provide for a particular drug to meet Act, but cannot be approved until the the statutory standards. FDA makes conditions in § 314.107(b)(3) are met; be- its views on drug products and classes cause there is a period of exclusivity of drugs available through guidance for the listed drug under § 314.108; be- documents, recommendations, and cause there is a period of pediatric ex- other statements of policy. clusivity for the listed drug under sec- (d) FDA will approve an ANDA and tion 505A of the Federal Food, Drug, send the applicant an approval letter if and Cosmetic Act; or because there is a none of the reasons in § 314.127 for re- period of exclusivity for the listed drug fusing to approve the ANDA applies. under section 505E of the Federal Food, FDA will issue a tentative approval Drug, and Cosmetic Act. A drug prod- letter if an ANDA otherwise meets the uct that is granted tentative approval requirements for approval under the is not an approved drug and will not be Federal Food, Drug, and Cosmetic Act, approved until FDA issues an approval but cannot be approved because there after any necessary additional review is a 7-year period of orphan exclusivity of the NDA. FDA’s tentative approval for the listed drug under section 527 of of a drug product is based on informa- the Federal Food, Drug, and Cosmetic tion available to FDA at the time of Act and § 316.31 of this chapter, or can- the tentative approval letter (i.e., in- not be approved until the conditions in formation in the 505(b)(2) application § 314.107(b)(3) or (c) are met; because and the status of current good manu- there is a period of exclusivity for the facturing practices of the facilities listed drug under § 314.108; because used in the manufacturing and testing there is a period of pediatric exclu- of the drug product) and is therefore sivity for the listed drug under section subject to change on the basis of new 505A of the Federal Food, Drug, and information that may come to FDA’s Cosmetic Act; or because there is a pe- attention. A new drug product may not riod of exclusivity for the listed drug be marketed until the date of approval. under section 505E of the Federal Food, (b) FDA will approve an NDA and Drug, and Cosmetic Act. A drug prod- issue the applicant an approval letter uct that is granted tentative approval on the basis of draft labeling if the is not an approved drug and will not be only deficiencies in the NDA concern approved until FDA issues an approval editorial or similar minor deficiencies after any necessary additional review in the draft labeling. Such approval of the ANDA. FDA’s tentative approval will be conditioned upon the applicant of a drug product is based on informa- incorporating the specified labeling tion available to FDA at the time of changes exactly as directed, and upon the tentative approval letter (i.e., in- the applicant submitting to FDA a formation in the ANDA and the status copy of the final printed labeling prior of current good manufacturing prac- to marketing. tices of the facilities used in the manu- (c) FDA will approve an NDA after it facturing and testing of the drug prod- determines that the drug meets the uct) and is therefore subject to change statutory standards for safety and ef- on the basis of new information that fectiveness, manufacturing and con- may come to FDA’s attention. A new trols, and labeling, and an ANDA after drug product may not be marketed it determines that the drug meets the until the date of approval. statutory standards for manufacturing and controls, labeling, and, where ap- [81 FR 69654, Oct. 6, 2016] plicable, bioequivalence. While the statutory standards apply to all drugs, § 314.106 Foreign data. the many kinds of drugs that are sub- (a) General. The acceptance of foreign ject to the statutory standards and the data in an application generally is gov- wide range of uses for those drugs de- erned by § 312.120 of this chapter.

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(b) As sole basis for marketing approval. 505(b)(2) application or ANDA may be An application based solely on foreign approved on the last applicable date. clinical data meeting U.S. criteria for (1) Timing of approval based on patent marketing approval may be approved certification or statement. If none of the if: (1) The foreign data are applicable reasons in § 314.125 or § 314.127, as appli- to the U.S. population and U.S. med- cable, for refusing to approve the ical practice; (2) the studies have been 505(b)(2) application or ANDA applies, performed by clinical investigators of and none of the reasons in paragraph recognized competence; and (3) the (d) of this section for delaying approval data may be considered valid without applies, the 505(b)(2) application or the need for an on-site inspection by ANDA may be approved as follows: FDA or, if FDA considers such an in- (i) Immediately, if the applicant cer- spection to be necessary, FDA is able tifies under § 314.50(i) or § 314.94(a)(12) to validate the data through an on-site that: inspection or other appropriate means. (A) The applicant is aware of a rel- Failure of an application to meet any evant patent but the patent informa- of these criteria will result in the ap- tion required under section 505(b) or (c) plication not being approvable based on of the Federal Food, Drug, and Cos- the foreign data alone. FDA will apply metic Act has not been submitted to this policy in a flexible manner accord- FDA; or ing to the nature of the drug and the (B) The relevant patent has expired; data being considered. or (c) Consultation between FDA and ap- (C) The relevant patent is invalid, plicants. Applicants are encouraged to unenforceable, or will not be infringed, meet with agency officials in a ‘‘pre- except as provided in paragraphs (b)(3) submission’’ meeting when approval and (c) of this section, and the 45-day based solely on foreign data will be period provided for in section sought. 505(c)(3)(C) and (j)(5)(B)(iii) of the Fed- [50 FR 7493, Feb. 22, 1985, as amended at 55 eral Food, Drug, and Cosmetic Act has FR 11580, Mar. 29, 1990] expired; or (D) There are no relevant patents. § 314.107 Date of approval of a (ii) Immediately, if the applicant 505(b)(2) application or ANDA. submits an appropriate statement (a) General. A drug product may be under § 314.50(i) or § 314.94(a)(12) explain- introduced or delivered for introduc- ing that a method-of-use patent does tion into interstate commerce when not claim an indication or other condi- the 505(b)(2) application or ANDA for tion of use for which the applicant is the drug product is approved. A seeking approval, except that if the ap- 505(b)(2) application or ANDA for a plicant also submits a paragraph IV drug product is approved on the date certification to the patent, then the FDA issues an approval letter under 505(b)(2) application or ANDA may be § 314.105 for the 505(b)(2) application or approved as provided in paragraph ANDA. (b)(1)(i)(C) of this section. (b) Effect of patent(s) on the listed (iii) On the date specified, if the ap- drug. As described in paragraphs (b)(1) plicant certifies under § 314.50(i) or and (2) of this section, the status of § 314.94(a)(12) that the relevant patent patents listed for the listed drug(s) re- will expire on a specified date. lied upon or reference listed drug, as (2) Patent information filed after sub- applicable, must be considered in de- mission of 505(b)(2) application or ANDA. termining the first possible date on If the holder of the approved NDA for which a 505(b)(2) application or ANDA the listed drug submits patent informa- can be approved. The criteria in para- tion required under § 314.53 after the graphs (b)(1) and (2) of this section will date on which the 505(b)(2) application be used to determine, for each relevant or ANDA was submitted to FDA, the patent, the date that patent will no 505(b)(2) applicant or ANDA applicant longer prevent approval. The first pos- must comply with the requirements of sible date on which the 505(b)(2) appli- § 314.50(i)(4) and (6) and § 314.94(a)(12)(vi) cation or ANDA can be approved will and (viii) regarding submission of an be calculated for each patent, and the appropriate patent certification or

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statement. If the applicant submits an the expiration of the 71⁄2 years from the amendment certifying under date of approval of the NDA for the § 314.50(i)(1)(i)(A)(4) or patented drug product. § 314.94(a)(12)(i)(A)(4) that the relevant (ii) Federal district court decision of in- patent is invalid, unenforceable, or will validity, unenforceability, or non-in- not be infringed, and complies with the fringement. If before the expiration of requirements of § 314.52 or § 314.95, the the 30-month period, or 71⁄2 years where 505(b)(2) application or ANDA may be applicable, the district court decides approved immediately upon submission that the patent is invalid, unenforce- of documentation of receipt of notice able, or not infringed (including any of paragraph IV certification under substantive determination that there § 314.52(e) or § 314.95(e). The 45-day pe- is no cause of action for patent in- riod provided for in section 505(c)(3)(C) fringement or invalidity), the 505(b)(2) and (j)(5)(B)(iii) of the Federal Food, application or ANDA may be approved Drug, and Cosmetic Act does not apply on: in these circumstances. (3) Disposition of patent litigation—(i) (A) The date on which the court en- Approval upon expiration of 30-month pe- ters judgment reflecting the decision; or riod or 71⁄2 years from date of listed drug approval. (A) Except as provided in (B) The date of a settlement order or paragraphs (b)(3)(ii) through (viii) of consent decree signed and entered by this section, if, with respect to patents the court stating that the patent that for which required information was is the subject of the certification is in- submitted under § 314.53 before the date valid, unenforceable, or not infringed. on which the 505(b)(2) application or (iii) Appeal of Federal district court ANDA was submitted to FDA (exclud- judgment of infringement. If before the ing an amendment or supplement to expiration of the 30-month period, or the 505(b)(2) application or ANDA), the 71⁄2 years where applicable, the district applicant certifies under § 314.50(i) or court decides that the patent has been § 314.94(a)(12) that the relevant patent infringed, and if the judgment of the is invalid, unenforceable, or will not be district court is appealed, the 505(b)(2) infringed, and the patent owner or its application or ANDA may be approved representative or the exclusive patent on: licensee brings suit for patent infringe- (A) The date on which the mandate is ment within 45 days of receipt of the issued by the court of appeals entering notice of certification from the appli- judgment that the patent is invalid, cant under § 314.52 or § 314.95, the unenforceable, or not infringed (includ- 505(b)(2) application or ANDA may be ing any substantive determination that approved 30 months after the later of there is no cause of action for patent the date of the receipt of the notice of infringement or invalidity); or certification by any owner of the listed (B) The date of a settlement order or patent or by the NDA holder (or its representative(s)) unless the court has consent decree signed and entered by extended or reduced the period because the court of appeals stating that the of a failure of either the plaintiff or de- patent that is the subject of the certifi- fendant to cooperate reasonably in ex- cation is invalid, unenforceable, or not pediting the action; or infringed. (B) If the patented drug product (iv) Affirmation or non-appeal of Fed- qualifies for 5 years of exclusive mar- eral district court judgment of infringe- keting under § 314.108(b)(2) and the pat- ment. If before the expiration of the 30- ent owner or its representative or the month period, or 71⁄2 years where appli- exclusive patent licensee brings suit cable, the district court decides that for patent infringement during the 1- the patent has been infringed, and if year period beginning 4 years after the the judgment of the district court is date of approval of the patented drug not appealed or is affirmed, the and within 45 days of receipt of the no- 505(b)(2) application or ANDA may be tice of certification from the applicant approved no earlier than the date spec- under § 314.52 or § 314.95, the 505(b)(2) ap- ified by the district court in an order plication or ANDA may be approved at under 35 U.S.C. 271(e)(4)(A).

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(v) Grant of preliminary injunction by a 505(b)(2) application or ANDA to be Federal district court. If before the expi- approved under paragraph (b)(3) of this ration of the 30-month period, or 71⁄2 section, the applicant must receive an years where applicable, the district approval letter from the Agency. Ten- court grants a preliminary injunction tative approval of an NDA or ANDA prohibiting the applicant from engag- does not constitute ‘‘approval’’ of an ing in the commercial manufacture or NDA or ANDA and cannot, absent an sale of the drug product until the court approval letter from the Agency, result decides the issues of patent validity in an approval under paragraph (b)(3) of and infringement, and if the court later this section. decides that: (c) Timing of approval of subsequent (A) The patent is invalid, unenforce- ANDA. (1) If an ANDA contains a para- able, or not infringed, the 505(b)(2) ap- graph IV certification for a relevant plication or ANDA may be approved as patent and the ANDA is not that of a provided in paragraph (b)(3)(ii) of this first applicant, the ANDA is regarded section; or as the ANDA of a subsequent applicant. (B) The patent is infringed, the The ANDA of a subsequent applicant 505(b)(2) application or ANDA may be will not be approved during the period approved as provided in paragraph when any first applicant is eligible for (b)(3)(iii) or (iv) of this section, which- 180-day exclusivity or during the 180- ever is applicable. day exclusivity period of a first appli- (vi) Written consent to approval by pat- cant. Any applicable 180-day exclu- ent owner or exclusive patent licensee. If sivity period cannot extend beyond the before the expiration of the 30-month expiration of the patent upon which period, or 71⁄2 years where applicable, the 180-day exclusivity period was the patent owner or the exclusive pat- based. ent licensee (or their representatives) (2) A first applicant must submit cor- agrees in writing that the 505(b)(2) ap- respondence to its ANDA notifying plication or ANDA may be approved FDA within 30 days of the date of its any time on or after the date of the first commercial marketing of its drug consent, approval may be granted on or product or the reference listed drug. If after that date. an applicant does not notify FDA, as (vii) Court order terminating 30-month required in this paragraph (c)(2), of this or 71⁄2-year period. If before the expira- date, the date of first commercial mar- tion of the 30-month period, or 71⁄2 keting will be deemed to be the date of years where applicable, the court en- the drug product’s approval. ters an order requiring the 30-month or (3) If FDA concludes that a first ap- 71⁄2-year period to be terminated, the plicant is not actively pursuing ap- 505(b)(2) application or ANDA may be proval of its ANDA, FDA may imme- approved in accordance with the diately approve an ANDA(s) of a subse- court’s order. quent applicant(s) if the ANDA(s) is (viii) Court order of dismissal without a otherwise eligible for approval. finding of infringement. If before the ex- (d) Delay due to exclusivity. The Agen- piration of the 30-month period, or 71⁄2 cy will also delay the approval of a years where applicable, the court(s) 505(b)(2) application or ANDA if delay enter(s) an order of dismissal, with or is required by the exclusivity provi- without prejudice, without a finding of sions in § 314.108; section 527 of the Fed- infringement in each pending suit for eral Food, Drug, and Cosmetic Act and patent infringement brought within 45 § 316.31 of this chapter; section 505A of days of receipt of the notice of para- the Federal Food, Drug, and Cosmetic graph IV certification sent by the Act; or section 505E of the Federal 505(b)(2) or ANDA applicant, the Food, Drug, and Cosmetic Act. When 505(b)(2) application or ANDA may be the approval of a 505(b)(2) application approved on or after the date of the or ANDA is delayed under this section order. and § 314.108; section 527 of the Federal (4) Tentative approval. FDA will issue Food, Drug, and Cosmetic Act and a tentative approval letter when ten- § 316.31 of this chapter; section 505A of tative approval is appropriate in ac- the Federal Food, Drug, and Cosmetic cordance with this section. In order for Act; or section 505E of the Federal

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Food, Drug, and Cosmetic Act, the (f) Forty-five day period after receipt of 505(b)(2) application or ANDA will be notice of paragraph IV certification—(1) approved on the latest of the days spec- Computation of 45-day time clock. The 45- ified under this section and § 314.108; day clock described in paragraph (b)(3) section 527 of the Federal Food, Drug, of this section as to each recipient re- and Cosmetic Act and § 316.31 of this quired to receive notice of paragraph chapter; section 505A of the Federal IV certification under § 314.52 or § 314.95 Food, Drug, and Cosmetic Act; or sec- begins on the day after the date of re- tion 505E of the Federal Food, Drug, ceipt of the applicant’s notice of para- and Cosmetic Act, as applicable. graph IV certification by the recipient. (e) Notification of court actions or writ- When the 45th day falls on Saturday, ten consent to approval. (1) The appli- Sunday, or a Federal holiday, the 45th cant must submit the following infor- day will be the next day that is not a mation to FDA, as applicable: Saturday, Sunday, or a Federal holi- (i) A copy of any judgment by the day. court (district court or mandate of the (2) Notification of filing of legal action. court of appeals) or settlement order or (i) The 505(b)(2) or ANDA applicant consent decree signed and entered by must notify FDA in writing within 14 the court (district court or court of ap- days of the filing of any legal action peals) finding a patent described in filed within 45 days of receipt of the no- paragraph (b)(3) of this section invalid, tice of paragraph IV certification by unenforceable, or not infringed, or find- any recipient. A 505(b)(2) applicant ing the patent valid and infringed; must send the notification to its NDA. An ANDA applicant must send the no- (ii) Written notification of whether tification to its ANDA. The notifica- or not any action by the court de- tion to FDA of the legal action must scribed in paragraph (e)(1)(i) of this include: section has been appealed within the (A) The 505(b)(2) application or ANDA time permitted for an appeal; number. (iii) A copy of any order entered by (B) The name of the 505(b)(2) or the court terminating the 30-month or ANDA applicant. 1 7 ⁄2-year period as described in para- (C) The established name of the drug graph (b)(3)(i), (ii), (vii), or (viii) of this product or, if no established name ex- section; ists, the name(s) of the active ingre- (iv) A copy of any written consent to dient(s), the drug product’s strength, approval by the patent owner or exclu- and dosage form. sive patent licensee described in para- (D) A statement that an action for graph (b)(3)(vi) of this section; patent infringement, identified by (v) A copy of any preliminary injunc- court, case number, and the patent tion described in paragraph (b)(3)(v) of number(s) of the patent(s) at issue in this section, and a copy of any subse- the action, has been filed in an appro- quent court order lifting the injunc- priate court on a specified date. tion; and (ii) A patent owner or NDA holder (or (vi) A copy of any court order pursu- its representative(s)) may also notify ant to 35 U.S.C. 271(e)(4)(A) ordering FDA of the filing of any legal action that a 505(b)(2) application or ANDA for patent infringement. The notice may be approved no earlier than the should contain the information and be date specified (irrespective of whether sent to the offices or divisions de- the injunction relates to a patent described in paragraph (f)(2)(i) of this sec- scribed in paragraph (b)(3) of this section. tion). (iii) If the 505(b)(2) or ANDA appli- (2) All information required by para- cant, the patent owner(s), the NDA graph (e)(1) of this section must be sent holder, or its representative(s) does not to the applicant’s NDA or ANDA, as ap- notify FDA in writing before the expi- propriate, within 14 days of the date of ration of the 45-day time period or the entry by the court, the date of appeal completion of the Agency’s review of or expiration of the time for appeal, or the 505(b)(2) application or ANDA, the date of written consent to ap- whichever occurs later, that a legal ac- proval, as applicable. tion for patent infringement was filed

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within 45 days of receipt of the notice 1962, or an application that was of paragraph IV certification, the ‘‘deemed approved’’ under section 505(b)(2) application or ANDA may be 107(c)(2) of Public Law 87–781. approved upon expiration of the 45-day Bioavailability study means a study to period (if the 505(b)(2) or ANDA appli- determine the bioavailability or the cant confirms that a legal action for pharmacokinetics of a drug. patent infringement has not been filed) Clinical investigation means any ex- or upon completion of the Agency’s re- periment other than a bioavailability view of the 505(b)(2) application or study in which a drug is administered ANDA, whichever is later. or dispensed to, or used on, human sub- (3) Waiver. If the patent owner or jects. NDA holder who is an exclusive patent Conducted or sponsored by the appli- licensee (or its representative(s)) cant with regard to an investigation waives its opportunity to file a legal means that before or during the inves- action for patent infringement within tigation, the applicant was named in 45 days of a receipt of the notice of cer- Form FDA–1571 filed with FDA as the tification and the patent owner or NDA sponsor of the investigational new drug holder who is an exclusive patent li- application under which the investiga- censee (or its representative(s)) sub- tion was conducted, or the applicant or mits to FDA a valid waiver before the the applicant’s predecessor in interest, 45 days elapse, the 505(b)(2) application provided substantial support for the in- or ANDA may be approved upon com- vestigation. To demonstrate ‘‘substan- pletion of the Agency’s review of the tial support,’’ an applicant must either NDA or ANDA. FDA will only accept a provide a certified statement from a waiver in the following form: certified public accountant that the ap- (Name of patent owner or NDA holder who is plicant provided 50 percent or more of an exclusive patent licensee or its representa- the cost of conducting the study or tive(s)) has received notice from (name of ap- provide an explanation why FDA plicant) under (section 505(b)(3) or 505(j)(2)(B) should consider the applicant to have of the Federal Food, Drug, and Cosmetic Act) conducted or sponsored the study if the and does not intend to file an action for pat- applicant’s financial contribution to ent infringement against (name of applicant) concerning the drug (name of drug) before the study is less than 50 percent or the (date on which 45 days elapse). (Name of patent applicant did not sponsor the inves- owner or NDA holder who is an exclusive patent tigational new drug. A predecessor in licensee) waives the opportunity provided by interest is an entity, e.g., a corpora- (section 505(c)(3)(C) or 505(j)(5)(B)(iii) of the tion, that the applicant has taken over, Federal Food, Drug, and Cosmetic Act) and merged with, or purchased, or from does not object to FDA’s approval of (name of which the applicant has purchased all applicant)’s (505(b)(2) application or ANDA) for (name of drug) with an approval date on or rights to the drug. Purchase of non- after the date of this submission. exclusive rights to a clinical investigation after it is completed is not suffi- (g) Conversion of approval to tentative cient to satisfy this definition. approval. If FDA issues an approval let- Essential to approval means, with re- ter in error or a court enters an order gard to an investigation, that there are requiring, in the case of an already ap- no other data available that could sup- proved 505(b)(2) application or ANDA, port approval of the NDA. that the date of approval be delayed, New chemical entity means a drug that FDA will convert the approval to a ten- contains no active moiety that has tative approval if appropriate. been approved by FDA in any other [81 FR 69655, Oct. 6, 2016] NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic § 314.108 New drug product exclu- Act. sivity. New clinical investigation means an in- (a) Definitions. The definitions in vestigation in humans the results of § 314.3 and the following definitions of which have not been relied on by FDA terms apply to this section: to demonstrate substantial evidence of Approved under section 505(b) means effectiveness of a previously approved an NDA submitted under section 505(b) drug product for any indication or of and approved on or after October 10, safety for a new patient population and

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do not duplicate the results of another under section 505(b) of the Federal investigation that was relied on by the Food, Drug, and Cosmetic Act; and agency to demonstrate the effective- (iv) Contained reports of new clinical ness or safety in a new patient popu- investigations (other than bio- lation of a previously approved drug availability studies) conducted or spon- product. For purposes of this section, sored by the applicant that were essen- data from a clinical investigation pre- tial to approval of the application, for viously submitted for use in the com- a period of 3 years after the date of ap- prehensive evaluation of the safety of a proval of the application, the Agency drug product but not to support the ef- will not approve a 505(b)(2) application fectiveness of the drug product would or an ANDA for the conditions of ap- be considered new. proval of the NDA, or an ANDA sub- (b) Submission of and timing of ap- mitted pursuant to an approved peti- proval of a 505(b)(2) application or ANDA. tion under section 505(j)(2)(C) of the (1) [Reserved] Federal Food, Drug, and Cosmetic Act (2) If a drug product that contains a that relies on the information sup- new chemical entity was approved porting the conditions of approval of after September 24, 1984, in an NDA an original NDA. submitted under section 505(b) of the (5) If a supplemental NDA: Federal Food, Drug, and Cosmetic Act, (i) Was approved after September 24, no person may submit a 505(b)(2) appli- 1984; and cation or ANDA under section 505(j) of (ii) Contained reports of new clinical the Federal Food, Drug, and Cosmetic investigations (other than bio- Act for a drug product that contains availability studies) that were con- the same active moiety as in the new ducted or sponsored by the applicant chemical entity for a period of 5 years that were essential to approval of the from the date of approval of the first supplemental NDA, for a period of 3 approved NDA, except that the 505(b)(2) years after the date of approval of the application or ANDA may be submitted supplemental application, the Agency after 4 years if it contains a certifi- will not approve a 505(b)(2) application cation of patent invalidity or non- or an ANDA for a change, or an ANDA infringement described in submitted pursuant to an approved pe- § 314.50(i)(1)(i)(A)(4) or tition under section 505(j)(2)(C) of the § 314.94(a)(12)(i)(A)(4). Federal Food, Drug, and Cosmetic Act (3) The approval of a 505(b)(2) applica- that relies on the information sup- tion or ANDA described in paragraph porting a change approved in the sup- (b)(2) of this section will occur as pro- plemental NDA. vided in § 314.107(b)(1) or (2), unless the [59 FR 50368, Oct. 3, 1994, as amended at 81 FR owner of a patent that claims the drug, 69657, Oct. 6, 2016] the patent owner’s representative, or exclusive licensee brings suit for pat- § 314.110 Complete response letter to ent infringement against the applicant the applicant. during the 1-year period beginning 48 (a) Complete response letter. FDA will months after the date of approval of send the applicant a complete response the NDA for the new chemical entity letter if the agency determines that we and within 45 days after receipt of the will not approve the application or ab- notice described at § 314.52 or § 314.95, in breviated application in its present which case, approval of the 505(b)(2) ap- form for one or more of the reasons plication or ANDA will occur as pro- given in § 314.125 or § 314.127, respec- vided in § 314.107(b)(3). tively. (4) If an NDA: (1) Description of specific deficiencies. A (i) Was submitted under section complete response letter will describe 505(b) of the Federal Food, Drug, and all of the specific deficiencies that the Cosmetic Act; agency has identified in an application (ii) Was approved after September 24, or abbreviated application, except as 1984; stated in paragraph (a)(3) of this sec- (iii) Was for a drug product that con- tion. tains an active moiety that has been (2) Complete review of data. A com- previously approved in another NDA plete response letter reflects FDA’s

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complete review of the data submitted the date FDA receives the resubmis- in an original application or abbre- sion. viated application (or, where appro- (v) A minor resubmission of an abbre- priate, a resubmission) and any amend- viated application constitutes an ments that the agency has reviewed. agreement by the applicant to start a The complete response letter will iden- new review cycle beginning on the date tify any amendments that the agency FDA receives the resubmission. has not yet reviewed. (2) Withdrawal. Withdraw the applica- (3) Inadequate data. If FDA deter- tion or abbreviated application. A deci- mines, after an application is filed or sion to withdraw an application or ab- an abbreviated application is received, breviated application is without preju- that the data submitted are inadequate dice to a subsequent submission. to support approval, the agency might (3) Request opportunity for hearing. issue a complete response letter with- Ask the agency to provide the appli- out first conducting required inspec- cant an opportunity for a hearing on tions and/or reviewing proposed prod- the question of whether there are uct labeling. grounds for denying approval of the ap- (4) Recommendation of actions for application or abbreviated application proval. When possible, a complete re- under section 505(d) or (j)(4) of the act, sponse letter will recommend actions respectively. The applicant must sub- that the applicant might take to place mit the request to the Associate Direc- the application or abbreviated applicator for Policy, Center for Drug Evalua- tion in condition for approval. tion and Research, Food and Drug Ad- (b) Applicant actions. After receiving ministration, 10903 New Hampshire a complete response letter, the appli- Ave., Silver Spring, MD 20993. Within cant must take one of following ac- 60 days of the date of the request for an tions: opportunity for a hearing, or within a (1) Resubmission. Resubmit the appli- different time period to which FDA and cation or abbreviated application, ad- the applicant agree, the agency will ei- dressing all deficiencies identified in ther approve the application or abbre- the complete response letter. viated application under § 314.105, or (i) A resubmission of an application refuse to approve the application under or efficacy supplement that FDA clas- § 314.125 or abbreviated application sifies as a Class 1 resubmission con- under § 314.127 and give the applicant stitutes an agreement by the applicant written notice of an opportunity for a to start a new 2-month review cycle be- hearing under § 314.200 and section ginning on the date FDA receives the 505(c)(1)(B) or (j)(5)(c) of the act on the resubmission. question of whether there are grounds (ii) A resubmission of an application for denying approval of the application or efficacy supplement that FDA clas- or abbreviated application under sec- sifies as a Class 2 resubmission con- tion 505(d) or (j)(4) of the act, respec- stitutes an agreement by the applicant tively. to start a new 6-month review cycle be- (c) Failure to take action. (1) An appli- ginning on the date FDA receives the cant agrees to extend the review period resubmission. under section 505(c)(1) or (j)(5)(A) of the (iii) A resubmission of an NDA sup- act until it takes any of the actions plement other than an efficacy supple- listed in paragraph (b) of this section. ment constitutes an agreement by the For an application or abbreviated ap- applicant to start a new review cycle plication, FDA may consider an appli- the same length as the initial review cant’s failure to take any of such ac- cycle for the supplement (excluding tions within 1 year after issuance of a any extension due to a major amend- complete response letter to be a re- ment of the initial supplement), begin- quest by the applicant to withdraw the ning on the date FDA receives the re- application, unless the applicant has submission. requested an extension of time in (iv) A major resubmission of an ab- which to resubmit the application. breviated application constitutes an FDA will grant any reasonable request agreement by the applicant to start a for such an extension. FDA may con- new 6-month review cycle beginning on sider an applicant’s failure to resubmit

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the application within the extended termines that the withdrawal of the time period or to request an additional listed drug was not for safety or effec- extension to be a request by the appli- tiveness reasons. cant to withdraw the application. (d) Certain drug products approved (2) If FDA considers an applicant’s for safety and effectiveness that were failure to take action in accordance no longer marketed on September 24, with paragraph (c)(1) of this section to 1984, are not included in the list. Any be a request to withdraw the applica- person who wishes to obtain marketing tion, the agency will notify the appli- approval for such a drug product under cant in writing. The applicant will an abbreviated new drug application have 30 days from the date of the noti- must petition FDA for a determination fication to explain why the application whether the drug product was with- should not be withdrawn and to request drawn from the market for safety or ef- an extension of time in which to resub- fectiveness reasons and request that mit the application. FDA will grant the list be amended to include the drug any reasonable request for an exten- product. A person seeking such a deter- sion. If the applicant does not respond mination shall use the petition proce- to the notification within 30 days, the dures established in § 10.30 of this chap- application will be deemed to be with- ter. The petitioner shall include in the drawn. petition information to show that the [73 FR 39609, July 10, 2008] drug product was approved for safety and effectiveness and all evidence § 314.120 [Reserved] available to the petitioner concerning the reason that marketing of the drug § 314.122 Submitting an abbreviated product ceased. application for, or a 505(j)(2)(C) petition that relies on, a listed drug [57 FR 17990, Apr. 28, 1992; 57 FR 29353, July that is no longer marketed. 1, 1992] (a) An abbreviated new drug applica- § 314.125 Refusal to approve an NDA. tion that refers to, or a petition under section 505(j)(2)(C) of the act and (a) The Food and Drug Administra- § 314.93 that relies on, a listed drug that tion will refuse to approve the NDA has been voluntarily withdrawn from and for a new drug give the applicant sale in the United States must be ac- written notice of an opportunity for a companied by a petition seeking a de- hearing under § 314.200 on the question termination whether the listed drug of whether there are grounds for deny- was withdrawn for safety or effective- ing approval of the NDA under section ness reasons. The petition must be sub- 505(d) of the Federal Food, Drug, and mitted under §§ 10.25(a) and 10.30 of this Cosmetic Act, if: chapter and must contain all evidence (1) FDA sends the applicant a com- available to the petitioner concerning plete response letter under § 314.110; the reasons for the withdrawal from (2) The applicant requests an oppor- sale. tunity for hearing for a new drug on (b) When a petition described in para- the question of whether the NDA is ap- graph (a) of this section is submitted, provable; and the agency will consider the evidence (3) FDA finds that any of the reasons in the petition and any other evidence given in paragraph (b) of this section before the agency, and determine apply. whether the listed drug is withdrawn (b) FDA may refuse to approve an from sale for safety or effectiveness NDA for any of the following reasons, reasons, in accordance with the proce- unless the requirement has been dures in § 314.161. waived under § 314.90: (c) An abbreviated new drug applica- (1) The methods to be used in, and tion described in paragraph (a) of this the facilities and controls used for, the section will be disapproved, under manufacture, processing, packing, or § 314.127(a)(11), and a 505(j)(2)(C) peti- holding of the drug substance or the tion described in paragraph (a) of this drug product are inadequate to pre- section will be disapproved, under serve its identity, strength, quality, § 314.93(e)(1)(iv), unless the agency de- purity, stability, and bioavailability.

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(2) The investigations required under drug product do not comply with the section 505(b) of the Federal Food, current good manufacturing practice Drug, and Cosmetic Act do not include regulations in parts 210 and 211. adequate tests by all methods reason- (14) The NDA does not contain an ex- ably applicable to show whether or not planation of the omission of a report of the drug is safe for use under the condi- any investigation of the drug product tions prescribed, recommended, or sug- sponsored by the applicant, or an ex- gested in its proposed labeling. planation of the omission of other in- (3) The results of the tests show that formation about the drug pertinent to the drug is unsafe for use under the an evaluation of the NDA that is re- conditions prescribed, recommended, ceived or otherwise obtained by the ap- or suggested in its proposed labeling or plicant from any source. the results do not show that the drug (15) A nonclinical laboratory study product is safe for use under those con- that is described in the NDA and that ditions. is essential to show that the drug is (4) There is insufficient information safe for use under the conditions pre- about the drug to determine whether scribed, recommended, or suggested in the product is safe for use under the its proposed labeling was not con- conditions prescribed, recommended, ducted in compliance with the good or suggested in its proposed labeling. laboratory practice regulations in part (5) There is a lack of substantial evi- 58 of this chapter and no reason for the dence consisting of adequate and well- noncompliance is provided or, if it is, controlled investigations, as defined in the differences between the practices § 314.126, that the drug product will used in conducting the study and the have the effect it purports or is rep- good laboratory practice regulations do resented to have under the conditions not support the validity of the study. of use prescribed, recommended, or (16) Any clinical investigation in- suggested in its proposed labeling. volving human subjects described in (6) The proposed labeling is false or the NDA, subject to the institutional misleading in any particular. (7) The NDA contains an untrue review board regulations in part 56 of statement of a material fact. this chapter or informed consent regu- (8) The drug product’s proposed label- lations in part 50 of this chapter, was ing does not comply with the require- not conducted in compliance with ments for labels and labeling in part those regulations such that the rights 201. or safety of human subjects were not (9) The NDA does not contain bio- adequately protected. availability or bioequivalence data re- (17) The applicant or contract required under part 320 of this chapter. search organization that conducted a (10) A reason given in a letter refus- bioavailability or bioequivalence study ing to file the NDA under § 314.101(d), if described in § 320.38 or § 320.63 of this the deficiency is not corrected. chapter that is contained in the NDA (11) The drug will be manufactured in refuses to permit an inspection of fa- whole or in part in an establishment cilities or records relevant to the study that is not registered and not exempt by a properly authorized officer or em- from registration under section 510 of ployee of the Department of Health and the Federal Food, Drug, and Cosmetic Human Services or refuses to submit Act and part 207. reserve samples of the drug products (12) The applicant does not permit a used in the study when requested by properly authorized officer or employee FDA. of the Department of Health and (18) For a new drug, the NDA failed Human Services an adequate oppor- to contain the patent information re- tunity to inspect the facilities, con- quired by section 505(b)(1) of the Fed- trols, and any records relevant to the eral Food, Drug, and Cosmetic Act. NDA. (19) The 505(b)(2) application failed to (13) The methods to be used in, and contain a patent certification or state- the facilities and controls used for, the ment with respect to each listed patent manufacture, processing, packing, or for a drug product approved in an NDA holding of the drug substance or the that:

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(i) Is pharmaceutically equivalent to contain a description of the proposed the drug product for which the original methods of analysis, and the study re- 505(b)(2) application is submitted; and port should contain a description of the (ii) Was approved before the original methods of analysis ultimately used. If 505(b)(2) application was submitted. the protocol does not contain a descrip- (c) For drugs intended to treat life- tion of the proposed methods of anal- threatening or severely-debilitating ill- ysis, the study report should describe nesses that are developed in accordance how the methods used were selected. with §§ 312.80 through 312.88 of this (2) The study uses a design that per- chapter, the criteria contained in para- mits a valid comparison with a control graphs (b) (3), (4), and (5) of this section to provide a quantitative assessment of shall be applied according to the con- drug effect. The protocol for the study siderations contained in § 312.84 of this and report of results should describe chapter. the study design precisely; for example, duration of treatment periods, whether [50 FR 7493, Feb. 22, 1985, as amended at 53 FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28, treatments are parallel, sequential, or 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan. crossover, and whether the sample size 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766, is predetermined or based upon some Mar. 6, 2009; 81 FR 60221, Aug. 31, 2016; 81 FR interim analysis. Generally, the fol- 69658, Oct. 6, 2016] lowing types of control are recognized: (i) Placebo concurrent control. The test § 314.126 Adequate and well-controlled drug is compared with an inactive studies. preparation designed to resemble the (a) The purpose of conducting clin- test drug as far as possible. A placebo- ical investigations of a drug is to dis- controlled study may include addi- tinguish the effect of a drug from other tional treatment groups, such as an ac- influences, such as spontaneous change tive treatment control or a dose-com- in the course of the disease, placebo ef- parison control, and usually includes fect, or biased observation. The charac- randomization and blinding of patients teristics described in paragraph (b) of or investigators, or both. this section have been developed over a (ii) Dose-comparison concurrent con- period of years and are recognized by trol. At least two doses of the drug are the scientific community as the essen- compared. A dose-comparison study tials of an adequate and well-con- may include additional treatment trolled clinical investigation. The Food groups, such as placebo control or ac- and Drug Administration considers tive control. Dose-comparison trials these characteristics in determining usually include randomization and whether an investigation is adequate blinding of patients or investigators, or and well-controlled for purposes of sec- both. tion 505 of the act. Reports of adequate (iii) No treatment concurrent control. and well-controlled investigations pro- Where objective measurements of effec- vide the primary basis for determining tiveness are available and placebo ef- whether there is ‘‘substantial evi- fect is negligible, the test drug is com- dence’’ to support the claims of effec- pared with no treatment. No treatment tiveness for new drugs. Therefore, the concurrent control trials usually in- study report should provide sufficient clude randomization. details of study design, conduct, and (iv) Active treatment concurrent con- analysis to allow critical evaluation trol. The test drug is compared with and a determination of whether the known effective therapy; for example, characteristics of an adequate and where the condition treated is such well-controlled study are present. that administration of placebo or no (b) An adequate and well-controlled treatment would be contrary to the in- study has the following characteristics: terest of the patient. An active treat- (1) There is a clear statement of the ment study may include additional objectives of the investigation and a treatment groups, however, such as a summary of the proposed or actual placebo control or a dose-comparison methods of analysis in the protocol for control. Active treatment trials usu- the study and in the report of its re- ally include randomization and blind- sults. In addition, the protocol should ing of patients or investigators, or

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both. If the intent of the trial is to used to accomplish this, such as blind- show similarity of the test and control ing. drugs, the report of the study should (6) The methods of assessment of sub- assess the ability of the study to have jects’ response are well-defined and re- detected a difference between treat- liable. The protocol for the study and ments. Similarity of test drug and ac- the report of results should explain the tive control can mean either that both variables measured, the methods of ob- drugs were effective or that neither servation, and criteria used to assess was effective. The analysis of the study response. should explain why the drugs should be (7) There is an analysis of the results considered effective in the study, for of the study adequate to assess the ef- example, by reference to results in pre- fects of the drug. The report of the vious placebo-controlled studies of the study should describe the results and active control drug. the analytic methods used to evaluate (v) Historical control. The results of them, including any appropriate statis- treatment with the test drug are com- tical methods. The analysis should as- pared with experience historically de- sess, among other things, the com- rived from the adequately documented parability of test and control groups natural history of the disease or condi- with respect to pertinent variables, and tion, or from the results of active the effects of any interim data anal- treatment, in comparable patients or yses performed. populations. Because historical control (c) The Director of the Center for populations usually cannot be as well Drug Evaluation and Research may, on assessed with respect to pertinent vari- the Director’s own initiative or on the ables as can concurrent control popu- petition of an interested person, waive lations, historical control designs are in whole or in part any of the criteria usually reserved for special cir- in paragraph (b) of this section with re- cumstances. Examples include studies spect to a specific clinical investiga- of diseases with high and predictable tion, either prior to the investigation mortality (for example, certain malig- or in the evaluation of a completed nancies) and studies in which the effect study. A petition for a waiver is re- of the drug is self-evident (general an- quired to set forth clearly and con- esthetics, drug metabolism). cisely the specific criteria from which (3) The method of selection of sub- waiver is sought, why the criteria are jects provides adequate assurance that not reasonably applicable to the par- they have the disease or condition ticular clinical investigation, what al- being studied, or evidence of suscepti- ternative procedures, if any, are to be, bility and exposure to the condition or have been employed, and what re- against which prophylaxis is directed. sults have been obtained. The petition (4) The method of assigning patients is also required to state why the clin- to treatment and control groups mini- ical investigations so conducted will mizes bias and is intended to assure yield, or have yielded, substantial evi- comparability of the groups with re- dence of effectiveness, notwithstanding spect to pertinent variables such as nonconformance with the criteria for age, sex, severity of disease, duration which waiver is requested. of disease, and use of drugs or therapy (d) For an investigation to be consid- other than the test drug. The protocol ered adequate for approval of a new for the study and the report of its re- drug, it is required that the test drug sults should describe how subjects were be standardized as to identity, assigned to groups. Ordinarily, in a strength, quality, purity, and dosage concurrently controlled study, assign- form to give significance to the results ment is by randomization, with or of the investigation. without stratification. (e) Uncontrolled studies or partially (5) Adequate measures are taken to controlled studies are not acceptable as minimize bias on the part of the sub- the sole basis for the approval of jects, observers, and analysts of the claims of effectiveness. Such studies data. The protocol and report of the carefully conducted and documented, study should describe the procedures may provide corroborative support of

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well-controlled studies regarding effi- (2) That the different active ingre- cacy and may yield valuable data re- dient is an active ingredient of a listed garding safety of the test drug. Such drug or a drug that does not meet the studies will be considered on their mer- requirements of section 201(p) of the its in the light of the principles listed Federal Food, Drug, and Cosmetic Act; here, with the exception of the require- or ment for the comparison of the treated (B) No petition to submit an ANDA subjects with controls. Isolated case re- for the drug product with the different ports, random experience, and reports active ingredient was approved under lacking the details which permit sci- § 314.93. entific evaluation will not be consid- (4)(i) If the ANDA is for a drug prod- ered. uct whose route of administration, dos- [50 FR 7493, Feb. 22, 1985, as amended at 50 age form, or strength purports to be FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, the same as that of the listed drug re- 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. ferred to in the ANDA, information 4, 2002] submitted in the abbreviated new drug application is insufficient to show that § 314.127 Refusal to approve an ANDA. the route of administration, dosage (a) FDA will refuse to approve an form, or strength is the same as that of ANDA for a new drug under section the reference listed drug; or 505(j) of the Federal Food, Drug, and (ii) If the ANDA is for a drug product Cosmetic Act for any of the following whose route of administration, dosage reasons, unless the requirement has form, or strength is different from that been waived under § 314.99: of the listed drug referred to in the ap- (1) The methods used in, or the facili- plication, no petition to submit an ties and controls used for, the manu- ANDA for the drug product with the facture, processing, and packing of the different route of administration, dos- drug product are inadequate to ensure age form, or strength was approved and preserve its identity, strength, under § 314.93. quality, and purity. (5) If the ANDA was submitted under (2) Information submitted with the the approval of a petition under § 314.93, ANDA is insufficient to show that each the ANDA did not contain the informa- of the proposed conditions of use has tion required by FDA with respect to been previously approved for the listed the active ingredient, route of adminis- drug referred to in the ANDA. tration, dosage form, or strength that (3)(i) If the reference listed drug has is not the same as that of the reference only one active ingredient, information listed drug. submitted with the ANDA is insuffi- (6)(i) Information submitted in the cient to show that the active ingre- ANDA is insufficient to show that the dient is the same as that of the ref- drug product is bioequivalent to the erence listed drug; listed drug referred to in the ANDA; or (ii) If the reference listed drug has (ii) If the ANDA was submitted under more than one active ingredient, infor- a petition approved under § 314.93, in- mation submitted with the ANDA is information submitted in the ANDA is sufficient to show that the active in- insufficient to show that the active ingredients are the same as the active ingredients of the drug product are of the gredients of the reference listed drug; same pharmacological or therapeutic or class as those of the reference listed (iii) If the reference listed drug has drug and that the drug product can be more than one active ingredient and if expected to have the same therapeutic the ANDAis for a drug product that has effect as the reference listed drug when an active ingredient different from the administered to patients for each con- reference listed drug: dition of use approved for the reference (A) Information submitted with the listed drug. ANDA is insufficient to show: (7) Information submitted in the (1) That the other active ingredients ANDA is insufficient to show that the are the same as the active ingredients labeling proposed for the drug is the of the reference listed drug; or same as the labeling approved for the

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listed drug referred to in the ANDA ex- (1) A change in an inactive ingredient cept for changes required because of so that the product does not comply differences approved in a petition with an official compendium. under § 314.93 or because the drug prod- (2) A change in composition to in- uct and the reference listed drug are clude an inactive ingredient that has produced or distributed by different not been previously approved in a drug manufacturers or because aspects of product for human use by the same the listed drug’s labeling are protected route of administration. by patent, or by exclusivity, and such (3) A change in the composition of a differences do not render the proposed parenteral drug product to include an drug product less safe or effective than inactive ingredient that has not been the listed drug for all remaining, non- previously approved in a parenteral protected conditions of use. drug product. (4) A change in composition of a drug (8)(i) Information submitted in the product for ophthalmic use to include ANDA or any other information avail- an inactive ingredient that has not able to FDA shows that: been previously approved in a drug for (A) The inactive ingredients of the ophthalmic use. drug product are unsafe for use, as de- (5) The use of a delivery or a modified scribed in paragraph (a)(8)(ii) of this release mechanism never before ap- section, under the conditions pre- proved for the drug. scribed, recommended, or suggested in (6) A change in composition to in- the labeling proposed for the drug prod- clude a significantly greater content of uct; or one or more inactive ingredients than (B) The composition of the drug prod- previously used in the drug product. uct is unsafe, as described in paragraph (7) If the drug product is intended for (a)(8)(ii) of this section, under the con- topical administration, a change in the ditions prescribed, recommended, or properties of the vehicle or base that suggested in the proposed labeling be- might increase absorption of certain cause of the type or quantity of inac- potentially toxic active ingredients tive ingredients included or the man- thereby affecting the safety of the drug ner in which the inactive ingredients product, or a change in the lipophilic are included. properties of a vehicle or base, e.g., a (ii)(A) FDA will consider the inactive change from an oleaginous to a water ingredients or composition of a drug soluble vehicle or base. product unsafe and refuse to approve (B) FDA will consider an inactive in- an ANDA under paragraph (a)(8)(i) of gredient in, or the composition of, a this section if, on the basis of informa- drug product intended for parenteral use to be unsafe and will refuse to ap- tion available to the agency, there is a prove the ANDA unless it contains the reasonable basis to conclude that one same inactive ingredients, other than or more of the inactive ingredients of preservatives, buffers, and anti- the proposed drug or its composition oxidants, in the same concentration as raises serious questions of safety or ef- the listed drug, and, if it differs from ficacy. From its experience with re- the listed drug in a preservative, buff- viewing inactive ingredients, and from er, or antioxidant, the ANDA contains other information available to it, FDA sufficient information to demonstrate may identify changes in inactive ingre- that the difference does not affect the dients or composition that may ad- safety or efficacy of the drug product. versely affect a drug product’s safety (C) FDA will consider an inactive in- or efficacy. The inactive ingredients or gredient in, or the composition of, a composition of a proposed drug product drug product intended for ophthalmic will be considered to raise serious ques- or otic use unsafe and will refuse to ap- tions of safety or efficacy if the prod- prove the ANDA unless it contains the uct incorporates one or more of these same inactive ingredients, other than changes. Examples of the changes that preservatives, buffers, substances to may raise serious questions of safety or adjust tonicity, or thickening agents, efficacy include, but are not limited to, in the same concentration as the listed the following: drug, and if it differs from the listed

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drug in a preservative, buffer, sub- Health and Human Services or refuses stance to adjust tonicity, or thickening to submit reserve samples of the drug agent, the ANDA contains sufficient products used in the study when re- information to demonstrate that the quested by FDA. difference does not affect the safety or efficacy of the drug product and the la- [57 FR 17991, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 FR 25927, Apr. 28, beling does not claim any therapeutic 1993; 67 FR 77672, Dec. 19, 2002; 81 FR 69658, advantage over or difference from the Oct. 6, 2016] listed drug. (9) Approval of the listed drug re- § 314.150 Withdrawal of approval of an ferred to in the ANDA has been with- application or abbreviated applica- drawn or suspended for grounds de- tion. scribed in § 314.150(a) or FDA has pub- (a) The Food and Drug Administra- lished a notice of opportunity for hear- tion will notify the applicant, and, if ing to withdraw approval of the ref- appropriate, all other persons who erence listed drug under § 314.150(a). manufacture or distribute identical, re- (10) Approval of the listed drug related, or similar drug products as deferred to in the ANDA has been with- fined in §§ 310.6 and 314.151(a) of this drawn under § 314.151 or FDA has pro- chapter and for a new drug afford an posed to withdraw approval of the ref- opportunity for a hearing on a proposal erence listed drug under § 314.151(a). to withdraw approval of the applica- (11) FDA has determined that the ref- tion or abbreviated new drug applica- erence listed drug has been withdrawn tion under section 505(e) of the act and from sale for safety or effectiveness under the procedure in § 314.200, if any reasons under § 314.161, or the reference of the following apply: listed drug has been voluntarily withdrawn from sale and the agency has (1) The Secretary of Health and not determined whether the with- Human Services has suspended the ap- drawal is for safety or effectiveness proval of the application or abbre- reasons, or approval of the reference viated application for a new drug on a listed drug has been suspended under finding that there is an imminent haz- § 314.153, or the agency has issued an ard to the public health. FDA will initial decision proposing to suspend promptly afford the applicant an expe- the reference listed drug under dited hearing following summary sus- § 314.153(a)(1). pension on a finding of imminent haz- (12) The abbreviated new drug appli- ard to health. cation does not meet any other re- (2) FDA finds: quirement under section 505(j)(2)(A) of (i) That clinical or other experience, the Federal Food, Drug, and Cosmetic tests, or other scientific data show Act. that the drug is unsafe for use under (13) The abbreviated new drug appli- the conditions of use upon the basis of cation contains an untrue statement of which the application or abbreviated material fact. application was approved; or (14) For an ANDA submitted pursu- (ii) That new evidence of clinical ex- ant to an approved petition under perience, not contained in the applica- § 10.30 of this chapter and § 314.93, an tion or not available to FDA until after NDA subsequently has been approved the application or abbreviated applica- for the change described in the ap- tion was approved, or tests by new proved petition. methods, or tests by methods not (b) FDA may refuse to approve an deemed reasonably applicable when the ANDA for a new drug if the applicant application or abbreviated application or contract research organization that was approved, evaluated together with conducted a bioavailability or bio- the evidence available when the appli- equivalence study described in § 320.63 cation or abbreviated application was of this chapter that is contained in the approved, reveal that the drug is not ANDA refuses to permit an inspection shown to be safe for use under the con- of facilities or records relevant to the ditions of use upon the basis of which study by a properly authorized officer the application or abbreviated applica- or employee of the Department of tion was approved; or

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(iii) Upon the basis of new informa- application or abbreviated application tion before FDA with respect to the was approved, the labeling of the drug, drug, evaluated together with the evi- based on a fair evaluation of all mate- dence available when the application rial facts, is false or misleading in any or abbreviated application was ap- particular, and the labeling was not proved, that there is a lack of substan- corrected by the applicant within a tial evidence from adequate and well- reasonable time after receipt of writ- controlled investigations as defined in ten notice from the agency. § 314.126, that the drug will have the ef- (4) That the applicant has failed to fect it is purported or represented to comply with the notice requirements of have under the conditions of use pre- section 510(j)(2) of the act. scribed, recommended, or suggested in its labeling; or (5) That the applicant has failed to (iv) That the application or abbre- submit bioavailability or bioequiva- viated application contains any untrue lence data required under part 320 of statement of a material fact; or this chapter. (v) That the patent information pre- (6) The application or abbreviated ap- scribed by section 505(c) of the act was plication does not contain an expla- not submitted within 30 days after the nation of the omission of a report of receipt of written notice from FDA any investigation of the drug product specifying the failure to submit such sponsored by the applicant, or an ex- information; or planation of the omission of other in- (b) FDA may notify the applicant, formation about the drug pertinent to and, if appropriate, all other persons an evaluation of the application or ab- who manufacture or distribute iden- breviated application that is received tical, related, or similar drug products or otherwise obtained by the applicant as defined in § 310.6, and for a new drug from any source. afford an opportunity for a hearing on (7) That any nonclinical laboratory a proposal to withdraw approval of the study that is described in the applica- application or abbreviated new drug tion or abbreviated application and application under section 505(e) of the that is essential to show that the drug act and under the procedure in § 314.200, is safe for use under the conditions pre- if the agency finds: scribed, recommended, or suggested in (1) That the applicant has failed to establish a system for maintaining re- its labeling was not conducted in com- quired records, or has repeatedly or de- pliance with the good laboratory prac- liberately failed to maintain required tice regulations in part 58 of this chap- records or to make required reports ter and no reason for the noncompli- under section 505(k) or 507(g) of the act ance was provided or, if it was, the dif- and § 314.80, § 314.81, or § 314.98, or that ferences between the practices used in the applicant has refused to permit ac- conducting the study and the good lab- cess to, or copying or verification of, oratory practice regulations do not its records. support the validity of the study. (2) That on the basis of new informa- (8) Any clinical investigation involv- tion before FDA, evaluated together ing human subjects described in the ap- with the evidence available when the plication or abbreviated application, application or abbreviated application subject to the institutional review was approved, the methods used in, or board regulations in part 56 of this the facilities and controls used for, the chapter or informed consent regula- manufacture, processing, and packing tions in part 50 of this chapter, was not of the drug are inadequate to ensure conducted in compliance with those and preserve its identity, strength, regulations such that the rights or quality, and purity and were not made safety of human subjects were not ade- adequate within a reasonable time quately protected. after receipt of written notice from the agency. (9) That the applicant or contract re- (3) That on the basis of new informa- search organization that conducted a tion before FDA, evaluated together bioavailability or bioequivalence study with the evidence available when the described in § 320.38 or § 320.63 of this

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chapter that is contained in the appli- withdraw approval of the application cation or abbreviated application re- or abbreviated application in a notice fuses to permit an inspection of facili- published in the FEDERAL REGISTER ties or records relevant to the study by that contains a brief summary of the a properly authorized officer or em- agency’s and the applicant’s views of ployee of the Department of Health and the reasons for withdrawal. Human Services or refuses to submit [57 FR 17993, Apr. 28, 1992, as amended at 58 reserve samples of the drug products FR 25927, Apr. 28, 1993; 64 FR 402, Jan. 5, 1999] used in the study when requested by FDA. § 314.151 Withdrawal of approval of an (10) That the labeling for the drug abbreviated new drug application product that is the subject of the ab- under section 505(j)(5) of the act. breviated new drug application is no (a) Approval of an abbreviated new longer consistent with that for the list- drug application approved under ed drug referred to in the abbreviated § 314.105(d) may be withdrawn when the new drug application, except for dif- agency withdraws approval, under ferences approved in the abbreviated § 314.150(a) or under this section, of the new drug application or those dif- approved drug referred to in the abbre- ferences resulting from: viated new drug application. If the (i) A patent on the listed drug issued agency proposed to withdraw approval after approval of the abbreviated new of a listed drug under § 314.150(a), the drug application; or holder of an approved application for (ii) Exclusivity accorded to the listed the listed drug has a right to notice drug after approval of the abbreviated and opportunity for hearing. The pub- new drug application that do not lished notice of opportunity for hearing render the drug product less safe or ef- will identify all drug products approved fective than the listed drug for any re- under § 314.105(d) whose applications maining, nonprotected condition(s) of are subject to withdrawal under this use. section if the listed drug is withdrawn, (c) FDA will withdraw approval of an and will propose to withdraw such application or abbreviated application drugs. Holders of approved applications if the applicant requests its withdrawal for the identified drug products will be because the drug subject to the appli- provided notice and an opportunity to cation or abbreviated application is no respond to the proposed withdrawal of longer being marketed, provided none their applications as described in para- of the conditions listed in paragraphs graphs (b) and (c) of this section. (a) and (b) of this section applies to the (b)(1) The published notice of oppor- drug. FDA will consider a written re- tunity for hearing on the withdrawal of quest for a withdrawal under this para- the listed drug will serve as notice to graph to be a waiver of an opportunity holders of identified abbreviated new for hearing otherwise provided for in drug applications of the grounds for this section. Withdrawal of approval of the proposed withdrawal. an application or abbreviated applica- (2) Holders of applications for drug tion under this paragraph is without products identified in the notice of op- prejudice to refiling. portunity for hearing may submit writ- (d) FDA may notify an applicant that ten comments on the notice of oppor- it believes a potential problem associ- tunity for hearing issued on the pro- ated with a drug is sufficiently serious posed withdrawal of the listed drug. If that the drug should be removed from an abbreviated new drug application the market and may ask the applicant holder submits comments on the notice to waive the opportunity for hearing of opportunity for hearing and a hear- otherwise provided for under this sec- ing is granted, the abbreviated new tion, to permit FDA to withdraw ap- drug application holder may partici- proval of the application or abbre- pate in the hearing as a nonparty par- viated application for the product, and ticipant as provided for in § 12.89 of this to remove voluntarily the product from chapter. the market. If the applicant agrees, the (3) Except as provided in paragraphs agency will not make a finding under (c) and (d) of this section, the approval paragraph (b) of this section, but will of an abbreviated new drug application

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for a drug product identified in the no- scribed in § 314.150(a). The final decision tice of opportunity for hearing on the shall be in writing and shall constitute withdrawal of a listed drug will be final agency action, reviewable in a ju- withdrawn when the agency has com- dicial proceeding. pleted the withdrawal of approval of (8) Documents in the record will be the listed drug. publicly available in accordance with (c)(1) If the holder of an application § 10.20(j) of this chapter. Documents for a drug identified in the notice of op- available for examination or copying portunity for hearing has submitted will be placed on public display in the timely comments but does not have an Division of Dockets Management opportunity to participate in a hearing (HFA–305), Food and Drug Administra- because a hearing is not requested or is tion, room. 1–23, 12420 Parklawn Dr., settled, the submitted comments will Rockville, MD 20857, promptly upon re- be considered by the agency, which will ceipt in that office. issue an initial decision. The initial de- (d) If the agency determines, based cision will respond to the comments, upon information submitted by the and contain the agency’s decision holder of an abbreviated new drug ap- whether there are grounds to withdraw plication, that the grounds for with- approval of the listed drug and of the drawal of the listed drug are not appli- abbreviated new drug applications on cable to a drug identified in the notice which timely comments were sub- of opportunity for hearing, the final de- mitted. The initial decision will be cision will state that the approval of sent to each abbreviated new drug ap- the abbreviated new drug application plication holder that has submitted for such drug is not withdrawn. comments. (2) Abbreviated new drug application [57 FR 17994, Apr. 28, 1992] holders to whom the initial decision was sent may, within 30 days of the § 314.152 Notice of withdrawal of ap- issuance of the initial decision, submit proval of an application or abbre- written objections. viated application for a new drug. (3) The agency may, at its discretion, If the Food and Drug Administration hold a limited oral hearing to resolve withdraws approval of an application dispositive factual issues that cannot or abbreviated application for a new be resolved on the basis of written sub- drug, FDA will publish a notice in the missions. FEDERAL REGISTER announcing the (4) If there are no timely objections withdrawal of approval. If the applica- to the initial decision, it will become tion or abbreviated application was final at the expiration of 30 days. withdrawn for grounds described in (5) If timely objections are sub- § 314.150(a) or § 314.151, the notice will mitted, they will be reviewed and re- announce the removal of the drug from sponded to in a final decision. the list of approved drugs published (6) The written comments received, under section 505(j)(6) of the act and the initial decision, the evidence relied shall satisfy the requirement of on in the comments and in the initial § 314.162(b). decision, the objections to the initial decision, and, if a limited oral hearing [57 FR 17994, Apr. 28, 1992] has been held, the transcript of that hearing and any documents submitted § 314.153 Suspension of approval of an abbreviated new drug application. therein, shall form the record upon which the agency shall make a final (a) Suspension of approval. The ap- decision. proval of an abbreviated new drug ap- (7) Except as provided in paragraph plication approved under § 314.105(d) (d) of this section, any abbreviated new shall be suspended for the period stated drug application whose holder sub- when: mitted comments on the notice of op- (1) The Secretary of the Department portunity for hearing shall be with- of Health and Human Services, under drawn upon the issuance of a final deci- the imminent hazard authority of sec- sion concluding that the listed drug tion 505(e) of the act or the authority should be withdrawn for grounds as de- of this paragraph, suspends approval of

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a listed drug referred to in the abbre- (3) Comments and information re- viated new drug application, for the pe- ceived within 30 days of the issuance of riod of the suspension; the initial decision will be considered (2) The agency, in the notice de- by the agency and responded to in a scribed in paragraph (b) of this section, final decision. or in any subsequent written notice (4) The agency may, in its discretion, given an abbreviated new drug applica- hold a limited oral hearing to resolve tion holder by the agency, concludes dispositive factual issues that cannot that the risk of continued marketing be resolved on the basis of written sub- and use of the drug is inappropriate, pending completion of proceedings to missions. withdraw or suspend approval under (5) If the final decision affirms the § 314.151 or paragraph (b) of this sec- agency’s initial decision that the listed tion; or drug was withdrawn for reasons of safe- (3) The agency, under the procedures ty or effectiveness, the decision will be set forth in paragraph (b) of this sec- published in the FEDERAL REGISTER in tion, issues a final decision stating the compliance with § 314.152, and will, ex- determination that the abbreviated ap- cept as provided in paragraph (b)(6) of plication is suspended because the list- this section, suspend approval of all ab- ed drug on which the approval of the breviated new drug applications identi- abbreviated new drug application de- fied under paragraph (b)(1) of this sec- pends has been withdrawn from sale for tion and remove from the list the listed reasons of safety or effectiveness or has drug and any drug whose approval was been suspended under paragraph (b) of suspended under this paragraph. The this section. The suspension will take notice will satisfy the requirement of effect on the date stated in the decision § 314.162(b). The agency’s final decision and will remain in effect until the and copies of materials on which it re- agency determines that the marketing lies will also be filed with the Division of the drug has resumed or that the withdrawal is not for safety or effec- of Dockets Management (address in tiveness reasons. paragraph (b)(1) of this section). (b) Procedures for suspension of abbre- (6) If the agency determines in its viated new drug applications when a list- final decision that the listed drug was ed drug is voluntarily withdrawn for safe- withdrawn for reasons of safety or ef- ty or effectiveness reasons. (1) If a listed fectiveness but, based upon informa- drug is voluntarily withdrawn from tion submitted by the holder of an ab- sale, and the agency determines that breviated new drug application, also the withdrawal from sale was for rea- determines that the reasons for the sons of safety or effectiveness, the withdrawal of the listed drug are not agency will send each holder of an ap- relevant to the safety and effectiveness proved abbreviated new drug applica- of the drug subject to such abbreviated tion that is subject to suspension as a new drug application, the final decision result of this determination a copy of will state that the approval of such ab- the agency’s initial decision setting breviated new drug application is not forth the reasons for the determina- suspended. tion. The initial decision will also be placed on file with the Division of (7) Documents in the record will be Dockets Management (HFA–305), Food publicly available in accordance with and Drug Administration, room 1–23, § 10.20(j) of this chapter. Documents 12420 Parklawn Dr., Rockville, MD available for examination or copying 20857. will be placed on public display in the (2) Each abbreviated new drug appli- Division of Dockets Management (ad- cation holder will have 30 days from dress in paragraph (b)(1) of this sec- the issuance of the initial decision to tion) promptly upon receipt in that of- present, in writing, comments and in- fice. formation bearing on the initial decision. If no comments or information is [57 FR 17995, Apr. 28, 1992] received, the initial decision will become final at the expiration of 30 days.

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§ 314.160 Approval of an application or act, FDA will initiate a proceeding in abbreviated application for which accordance with § 314.153(b). approval was previously refused, (e) A drug that the agency deter- suspended, or withdrawn. mines is withdrawn for safety or effec- Upon the Food and Drug Administra- tiveness reasons will be removed from tion’s own initiative or upon request of the list, under § 314.162. The drug may an applicant, FDA may, on the basis of be relisted if the agency has evidence new data, approve an application or ab- that marketing of the drug has re- breviated application which it had pre- sumed or that the withdrawal is not for viously refused, suspended, or with- safety or effectiveness reasons. A de- drawn approval. FDA will publish a no- termination that the drug is not with- tice in the FEDERAL REGISTER announc- drawn for safety or effectiveness rea- ing the approval. sons may be made at any time after its removal from the list, upon the agen- [57 FR 17995, Apr. 28, 1992] cy’s initiative, or upon the submission § 314.161 Determination of reasons for of a petition under §§ 10.25(a) and 10.30 voluntary withdrawal of a listed of this chapter. If the agency deter- drug. mines that the drug is not withdrawn (a) A determination whether a listed for safety or effectiveness reasons, the drug that has been voluntarily with- agency shall publish a notice of this de- drawn from sale was withdrawn for termination in the FEDERAL REGISTER. safety or effectiveness reasons may be The notice will also announce that the made by the agency at any time after drug is relisted, under § 314.162(c). The the drug has been voluntarily with- notice will also serve to reinstate ap- drawn from sale, but must be made: proval of all suspended abbreviated new (1) Prior to approving an abbreviated drug applications that referred to the new drug application that refers to the listed drug. listed drug; [57 FR 17995, Apr. 28, 1992] (2) Whenever a listed drug is voluntarily withdrawn from sale and abbre- § 314.162 Removal of a drug product viated new drug applications that re- from the list. ferred to the listed drug have been ap- (a) FDA will remove a previously approved; and proved new drug product from the list (3) When a person petitions for such a for the period stated when: determination under §§ 10.25(a) and 10.30 (1) The agency withdraws or suspends of this chapter. approval of a new drug application or (b) Any person may petition under an abbreviated new drug application §§ 10.25(a) and 10.30 of this chapter for a under § 314.150(a) or § 314.151 or under determination whether a listed drug the imminent hazard authority of sec- has been voluntarily withdrawn for tion 505(e) of the act, for the same pe- safety or effectiveness reasons. Any riod as the withdrawal or suspension of such petition must contain all evidence the application; or available to the petitioner concerning (2) The agency, in accordance with the reason that the drug is withdrawn the procedures in § 314.153(b) or § 314.161, from sale. issues a final decision stating that the (c) If the agency determines that a listed drug was withdrawn from sale listed drug is withdrawn from sale for for safety or effectiveness reasons, or safety or effectiveness reasons, the suspended under § 314.153(b), until the agency will, except as provided in para- agency determines that the withdrawal graph (d) of this section, publish a no- from the market has ceased or is not tice of the determination in the FED- for safety or effectiveness reasons. ERAL REGISTER. (b) FDA will publish in the FEDERAL (d) If the agency determines under REGISTER a notice announcing the re- paragraph (a) of this section that a moval of a drug from the list. listed drug is withdrawn from sale for (c) At the end of the period specified safety and effectiveness reasons and in paragraph (a)(1) or (a)(2) of this sec- there are approved abbreviated new tion, FDA will relist a drug that has drug applications that are subject to been removed from the list. The agency suspension under section 505(j)(5) of the will publish in the FEDERAL REGISTER a

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notice announcing the relisting of the (2) FDA will publish the notice in the drug. FEDERAL REGISTER and will state that the applicant, and other persons sub- [57 FR 17996, Apr. 28, 1992] ject to the notice under § 310.6, who wishes to participate in a hearing, has § 314.170 Adulteration and misbranding of an approved drug. 30 days after the date of publication of the notice to file a written notice of All drugs, including those the Food participation and request for hearing. and Drug Administration approves The applicant, or other persons subject under section 505 of the act and this to the notice under § 310.6, who fails to part, are subject to the adulteration file a written notice of participation and misbranding provisions in sections and request for hearing within 30 days, 501, 502, and 503 of the act. FDA is au- waives the opportunity for a hearing. thorized to regulate approved new (3) It is the responsibility of every drugs by regulations issued through in- manufacturer and distributor of a drug formal rulemaking under sections 501, product to review every notice of op- 502, and 503 of the act. portunity for a hearing published in [50 FR 7493, Feb. 22, 1985. Redesignated at 57 the FEDERAL REGISTER to determine FR 17983, Apr. 28, 1992, and amended at 64 FR whether it covers any drug product 402, Jan. 5, 1999] that person manufactures or distrib- utes. Any person may request an opin- Subpart E—Hearing Procedures for ion of the applicability of a notice to a specific product that may be identical, New Drugs related, or similar to a product listed in a notice by writing to the Division SOURCE: 50 FR 7493, Feb. 22, 1985, unless of New Drugs and Labeling Compli- otherwise noted. Redesignated at 57 FR 17983, ance, Office of Compliance, Center for Apr. 28, 1992. Drug Evaluation and Research, Food and Drug Administration, 10903 New § 314.200 Notice of opportunity for Hampshire Ave., Silver Spring, MD hearing; notice of participation and request for hearing; grant or denial 20993–0002. A person shall request an of hearing. opinion within 30 days of the date of publication of the notice to be eligible (a) Notice of opportunity for hearing. for an opportunity for a hearing under The Director of the Center for Drug the notice. If a person requests an opin- Evaluation and Research, Food and ion, that person’s time for filing an ap- Drug Administration, will give the appearance and request for a hearing and plicant, and all other persons who man- supporting studies and analyses begins ufacture or distribute identical, re- on the date the person receives the lated, or similar drug products as de- opinion from FDA. fined in § 310.6 of this chapter, notice (b) FDA will provide the notice of op- and an opportunity for a hearing on the portunity for a hearing to applicants Center’s proposal to refuse to approve and to other persons subject to the no- an application or to withdraw the ap- tice under § 310.6, as follows: proval of an application or abbreviated (1) To any person who has submitted application under section 505(e) of the an application or abbreviated applica- act. The notice will state the reasons tion, by delivering the notice in person for the action and the proposed or by sending it by registered or cer- grounds for the order. tified mail to the last address shown in (1) The notice may be general (that the application or abbreviated applica- is, simply summarizing in a general tion. way the information resulting in the (2) To any person who has not sub- notice) or specific (that is, either refer- mitted an application or abbreviated ring to specific requirements in the application but who is subject to the statute and regulations with which notice under § 310.6 of this chapter, by there is a lack of compliance, or pro- publication of the notice in the FED- viding a detailed description and anal- ERAL REGISTER. ysis of the specific facts resulting in (c)(1) Notice of participation and re- the notice). quest for a hearing, and submission of

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studies and comments. The applicant, or (c)(1)(ii) of this section the studies (in- any other person subject to the notice cluding all protocols and underlying under § 310.6, who wishes to participate raw data) on which the person relies to in a hearing, shall file with the Divi- justify a hearing with respect to the sion of Dockets Management (HFA– drug product. Except, a person who re- 305), Food and Drug Administration, quests a hearing on the refusal to ap- 5630 Fishers Lane, rm. 1061, Rockville, prove an application is not required to MD 20852, (i) within 30 days after the submit additional studies and analyses date of the publication of the notice (or if the studies upon which the person re- of the date of receipt of an opinion relies have been submitted in the appli- quested under paragraph (a)(3) of this cation and in the format and con- section) a written notice of participa- taining the summaries required under tion and request for a hearing and (ii) § 314.50. within 60 days after the date of publi- (1) If the grounds for FDA’s proposed cation of the notice, unless a different action concern the effectiveness of the period of time is specified in the notice drug, each request for hearing is re- of opportunity for a hearing, the stud- quired to be supported only by ade- ies on which the person relies to justify quate and well-controlled clinical stud- a hearing as specified in paragraph (d) ies meeting all of the precise require- of this section. The applicant, or other ments of § 314.126 and, for combination person, may incorporate by reference drug products, § 300.50, or by other stud- the raw data underlying a study if the ies not meeting those requirements for data were previously submitted to FDA which a waiver has been previously as part of an application, abbreviated granted by FDA under § 314.126. Each application, or other report. person requesting a hearing shall sub- (2) FDA will not consider data or mit all adequate and well-controlled analyses submitted after 60 days in de- clinical studies on the drug product, in- termining whether a hearing is war- cluding any unfavorable analyses, ranted unless they are derived from views, or judgments with respect to the well-controlled studies begun before studies. No other data, information, or the date of the notice of opportunity studies may be submitted. for hearing and the results of the stud- (2) The submission is required to in- ies were not available within 60 days clude a factual analysis of all the stud- after the date of publication of the no- ies submitted. If the grounds for FDA’s tice. Nevertheless, FDA may consider proposed action concern the effective- other studies on the basis of a showing ness of the drug, the analysis is re- by the person requesting a hearing of quired to specify how each study ac- inadvertent omission and hardship. cords, on a point-by-point basis, with The person requesting a hearing shall each criterion required for an adequate list in the request for hearing all stud- well-controlled clinical investigation ies in progress, the results of which the established under § 314.126 and, if the person intends later to submit in sup- product is a combination drug product, port of the request for a hearing. The with each of the requirements for a person shall submit under paragraph combination drug established in (c)(1)(ii) of this section a copy of the § 300.50, or the study is required to be complete protocol, a list of the partici- accompanied by an appropriate waiver pating investigators, and a brief status previously granted by FDA. If a study report of the studies. concerns a drug or dosage form or con- (3) Any other interested person who dition of use or mode of administration is not subject to the notice of oppor- other than the one in question, that tunity for a hearing may also submit fact is required to be clearly stated. comments on the proposal to withdraw Any study conducted on the final mar- approval of the application or abbre- keted form of the drug product is re- viated application. The comments are quired to be clearly identified. requested to be submitted within the (3) Each person requesting a hearing time and under the conditions specified shall submit an analysis of the data in this section. upon which the person relies, except (d) The person requesting a hearing is that the required information relating required to submit under paragraph either to safety or to effectiveness may

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be omitted if the notice of opportunity clearly and a waiver obtained under § 314.126 for hearing does not raise any issue is required to be submitted. with respect to that aspect of the drug; IV. A statement signed by the person re- information on compliance with § 300.50 sponsible for such submission that it includes in full (or incorporates by reference as may be omitted if the drug product is permitted in § 314.200(c)(2)) all studies and in- not a combination drug product. A fi- formation specified in § 314.200(d). nancial certification or disclosure (WARNING: A willfully false statement is a statement or both as required by part criminal offense, 18 U.S.C. 1001.) 54 of this chapter must accompany all clinical data submitted. FDA can most (e) Contentions that a drug product is efficiently consider submissions made not subject to the new drug requirements. in the following format. A notice of opportunity for a hearing encompasses all issues relating to the I. Safety data. legal status of each drug product sub- A. Animal safety data. ject to it, including identical, related, 1. Individual active components. and similar drug products as defined in a. Controlled studies. b. Partially controlled or uncontrolled § 310.6. A notice of appearance and re- studies. quest for a hearing under paragraph 2. Combinations of the individual active (c)(1)(i) of this section is required to components. contain any contention that the prod- a. Controlled studies. uct is not a new drug because it is gen- b. Partially controlled or uncontrolled erally recognized as safe and effective studies. within the meaning of section 201(p) of B. Human safety data. 1. Individual active components. the act, or because it is exempt from a. Controlled studies. part or all of the new drug provisions b. Partially controlled or uncontrolled of the act under the exemption for studies. products marketed before June 25, 1938, c. Documented case reports. contained in section 201(p) of the act or d. Pertinent marketing experiences that under section 107(c) of the Drug may influence a determination about the Amendments of 1962, or for any other safety of each individual active component. reason. Each contention is required to 2. Combinations of the individual active components. be supported by a submission under a. Controlled studies. paragraph (c)(1)(ii) of this section and b. Partially controlled or uncontrolled the Commissioner of Food and Drugs studies. will make an administrative deter- c. Documented case reports. mination on each contention. The fail- d. Pertinent marketing experiences that ure of any person subject to a notice of may influence a determination about the opportunity for a hearing, including safety of each individual active component. any person who manufactures or dis- II. Effectiveness data. A. Individual active components: Con- tributes an identical, related, or simi- trolled studies, with an analysis showing lar drug product as defined in § 310.6, to clearly how each study satisfies, on a point- submit a notice of participation and re- by-point basis, each of the criteria required quest for hearing or to raise all such by § 314.126. contentions constitutes a waiver of any B. Combinations of individual active com- contentions not raised. ponents. (1) A contention that a drug product 1. Controlled studies with an analysis is generally recognized as safe and ef- showing clearly how each study satisfies on a point-by-point basis, each of the criteria fective within the meaning of section required by § 314.126. 201(p) of the act is required to be sup- 2. An analysis showing clearly how each reported by submission of the same quan- quirement of § 300.50 has been satisfied. tity and quality of scientific evidence III. A summary of the data and views set- that is required to obtain approval of ting forth the medical rationale and purpose an application for the product, unless for the drug and its ingredients and the sci- FDA has waived a requirement for ef- entific basis for the conclusion that the drug fectiveness (under § 314.126) or safety, and its ingredients have been proven safe or both. The submission should be in and/or effective for the intended use. If there is an absence of controlled studies in the ma- the format and with the analyses re- terial submitted or the requirements of any quired under paragraph (d) of this sec- element of § 300.50 or § 314.126 have not been tion. A person who fails to submit the fully met, that fact is required to be stated required scientific evidence required

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under paragraph (d) waives the conten- should be submitted to support the state- tion. General recognition of safety and ment. effectiveness shall ordinarily be based III. Marketing. upon published studies which may be A. A copy of each pertinent document or corroborated by unpublished studies record to establish the exact date the drug was initially marketed. and other data and information. B. A statement whether such marketing (2) A contention that a drug product has at any subsequent time been discon- is exempt from part or all of the new tinued. If such marketing has been discon- drug provisions of the act under the ex- tinued, the exact date of each such dis- emption for products marketed before continuance should be submitted, together June 25, 1938, contained in section with a copy of each pertinent document or 201(p) of the act, or under section 107(c) record to establish each such date. of the Drug Amendments of 1962, is re- IV. Verification. quired to be supported by evidence of A statement signed by the person respon- past and present quantitative for- sible for such submission, that all appropriate records have been searched and to the mulas, labeling, and evidence of mar- best of that person’s knowledge and belief it keting. A person who makes such a includes a true and accurate presentation of contention should submit the formulas, the facts. labeling, and evidence of marketing in (WARNING: A willfully false statement is a the following format. criminal offense, 18 U.S.C. 1001.) I. Formulation. (3) The Food and Drug Administra- A. A copy of each pertinent document or tion will not find a drug product, in- record to establish the exact quantitative cluding any active ingredient, which is formulation of the drug (both active and inactive ingredients) on the date of initial identical, related, or similar, as de- marketing of the drug. scribed in § 310.6, to a drug product, in- B. A statement whether such formulation cluding any active ingredient for which has at any subsequent time been changed in an application is or at any time has any manner. If any such change has been been effective or deemed approved, or made, the exact date, nature, and rationale approved under section 505 of the act, for each change in formulation, including to be exempt from part or all of the any deletion or change in the concentration new drug provisions of the act. of any active ingredient and/or inactive ingredient, should be stated, together with a (4) A contention that a drug product copy of each pertinent document or record to is not a new drug for any other reason establish the date and nature of each such is required to be supported by submis- change, including, but not limited to, the sion of the factual records, data, and formula which resulted from each such information that are necessary and ap- change. If no such change has been made, a propriate to support the contention. copy of representative documents or records (5) It is the responsibility of every showing the formula at representative points in time should be submitted to support the person who manufactures or distrib- statement. utes a drug product in reliance upon a II. Labeling. ‘‘grandfather’’ provision of the act to A. A copy of each pertinent document or maintain files that contain the data record to establish the identity of each item and information necessary fully to doc- of written, printed, or graphic matter used ument and support that status. as labeling on the date the drug was initially (f) Separation of functions. Separation marketed. of functions commences upon receipt of B. A statement whether such labeling has at any subsequent time been discontinued or a request for hearing. The Director of changed in any manner. If such discontinu- the Center for Drug Evaluation and Re- ance or change has been made, the exact search, Food and Drug Administration, date, nature, and rationale for each dis- will prepare an analysis of the request continuance or change and a copy of each and a proposed order ruling on the pertinent document or record to establish matter. The analysis and proposed each such discontinuance or change should order, the request for hearing, and any be submitted, including, but not limited to, proposed order denying a hearing and the labeling which resulted from each such discontinuance or change. If no such dis- response under paragraph (g) (2) or (3) continuance or change has been made, a copy of this section will be submitted to the of representative documents or records show- Office of the Commissioner of Food and ing labeling at representative points in time Drugs for review and decision. When

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the Center for Drug Evaluation and Re- refusal to approve the application or search recommends denial of a hearing abbreviated application or the with- on all issues on which a hearing is re- drawal of approval of the application or quested, no representative of the Cen- abbreviated application; for example, ter will participate or advise in the re- no adequate and well-controlled clin- view and decision by the Commis- ical investigations meeting each of the sioner. When the Center for Drug Eval- precise elements of § 314.126 and, for a uation and Research recommends that combination drug product, § 300.50 of a hearing be granted on one or more this chapter, showing effectiveness issues on which a hearing is requested, have been identified. Any order enter- separation of functions terminates as ing summary judgment is required to to those issues, and representatives of set forth the Commissioner’s findings the Center may participate or advise in and conclusions in detail and is re- the review and decision by the Com- quired to specify why each study sub- missioner on those issues. The Com- mitted fails to meet the requirements missioner may modify the text of the of the statute and regulations or why issues, but may not deny a hearing on the request for hearing does not raise a those issues. Separation of functions genuine and substantial issue of fact. continues with respect to issues on (2) When following a general notice of which the Center for Drug Evaluation opportunity for a hearing (as defined in and Research has recommended denial paragraph (a)(1) of this section) the Di- of a hearing. The Commissioner will rector of the Center for Drug Evalua- neither evaluate nor rule on the Cen- tion and Research concludes that sum- ter’s recommendation on such issues mary judgment against a person re- and such issues will not be included in questing a hearing should be consid- the notice of hearing. Participants in ered, the Director will serve upon the the hearing may make a motion to the person requesting a hearing by reg- presiding officer for the inclusion of istered mail a proposed order denying a any such issue in the hearing. The rul- hearing. This person has 60 days after ing on such a motion is subject to re- receipt of the proposed order to review in accordance with § 12.35(b). Fail- spond with sufficient data, informa- ure to so move constitutes a waiver of the right to a hearing on such an issue. tion, and analyses to demonstrate that Separation of functions on all issues there is a genuine and substantial issue resumes upon issuance of a notice of of fact which justifies a hearing. hearing. The Office of the General (3) When following a general or spe- Counsel, Department of Health and cific notice of opportunity for a hear- Human Services, will observe the same ing a person requesting a hearing sub- separation of functions. mits data or information of a type re- (g) Summary judgment. A person who quired by the statute and regulations, requests a hearing may not rely upon and the Director of the Center for Drug allegations or denials but is required to Evaluation and Research concludes set forth specific facts showing that that summary judgment against the there is a genuine and substantial issue person should be considered, the Direc- of fact that requires a hearing with re- tor will serve upon the person by reg- spect to a particular drug product spec- istered mail a proposed order denying a ified in the request for hearing. hearing. The person has 60 days after (1) Where a specific notice of oppor- receipt of the proposed order to re- tunity for hearing (as defined in para- spond with sufficient data, informa- graph (a)(1) of this section) is used, the tion, and analyses to demonstrate that Commissioner will enter summary there is a genuine and substantial issue judgment against a person who re- of fact which justifies a hearing. quests a hearing, making findings and (4) If review of the data, information, conclusions, denying a hearing, if it and analyses submitted show that the conclusively appears from the face of grounds cited in the notice are not the data, information, and factual valid, for example, that substantial analyses in the request for the hearing evidence of effectiveness exists, the that there is no genuine and substan- Commissioner will enter summary tial issue of fact which precludes the judgment for the person requesting the

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hearing, and rescind the notice of op- hearing under § 314.200(g), the record portunity for hearing. certified by the Commissioner is re- (5) If the Commissioner grants a quired to include the requests for hear- hearing, it will begin within 90 days ing together with the data and infor- after the expiration of the time for re- mation submitted and the Commis- questing the hearing unless the parties sioner’s findings and conclusion. otherwise agree in the case of denial of (b) A manufacturer or distributor of approval, and as soon as practicable in an identical, related, or similar drug the case of withdrawal of approval. product under § 310.6 may seek judicial (6) The Commissioner will grant a review of an order withdrawing ap- hearing if there exists a genuine and proval of a new drug application, substantial issue of fact or if the Com- whether or not a hearing has been held, missioner concludes that a hearing in a United States court of appeals would otherwise be in the public inter- under section 505(h) of the act. est. (7) If the manufacturer or distributor Subpart F [Reserved] of an identical, related, or similar drug product requests and is granted a hear- Subpart G—Miscellaneous ing, the hearing may consider whether Provisions the product is in fact identical, related, or similar to the drug product named in the notice of opportunity for a hear- SOURCE: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. Redesignated at 57 FR 17983, ing. Apr. 28, 1992. (8) A request for a hearing, and any subsequent grant or denial of a hear- § 314.410 Imports and exports of new ing, applies only to the drug products drugs. named in such documents. (a) Imports. (1) A new drug may be im- (h) FDA will issue a notice with- ported into the United States if: (i) It drawing approval and declaring all is the subject of an approved applica- products unlawful for drug products tion under this part; or (ii) it complies subject to a notice of opportunity for a with the regulations pertaining to in- hearing, including any identical, re- vestigational new drugs under part 312; lated, or similar drug product under and it complies with the general regu- § 310.6, for which an opportunity for a lations pertaining to imports under hearing is waived or for which a hear- subpart E of part 1. ing is denied. The Commissioner may (2) A drug substance intended for use defer or stay the action pending a rul- in the manufacture, processing, or re- ing on any related request for a hear- packing of a new drug may be imported ing or pending any related hearing or into the United States if it complies other administrative or judicial pro- with the labeling exemption in § 201.122 ceeding. pertaining to shipments of drug sub- [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, stances in domestic commerce. 1985, as amended at 50 FR 21238, May 23, 1985; (b) Exports. (1) A new drug may be ex- 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, ported if it is the subject of an ap- 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, proved application under this part or it Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 68 FR complies with the regulations per- 24879, May 9, 2003; 69 FR 48775, Aug. 11, 2004; taining to investigational new drugs 74 FR 13113, Mar. 26, 2009] under part 312. (2) A new drug substance that is cov- § 314.201 Procedure for hearings. ered by an application approved under Parts 10 through 16 apply to hearings this part for use in the manufacture of relating to new drugs under section 505 an approved drug product may be ex- (d) and (e) of the act. ported by the applicant or any person listed as a supplier in the approved ap- § 314.235 Judicial review. plication, provided the drug substance (a) The Commissioner of Food and intended for export meets the speci- Drugs will certify the transcript and fication of, and is shipped with a copy record. In any case in which the Com- of the labeling required for, the ap- missioner enters an order without a proved drug product.

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(3) Insulin or an antibiotic drug may (b) An investigational new drug ap- be exported without regard to the re- plication or an application, abbre- quirements in section 802 of the act if viated application, amendment, or sup- the insulin or antibiotic drug meets plement may incorporate by reference the requirements of section 801(e)(1) of all or part of the contents of any drug the act. master file in support of the submis- [50 FR 7493, Feb. 22, 1985. Redesignated at 57 sion if the holder authorizes the incor- FR 17983, Apr. 28, 1992, and amended at 64 FR poration in writing. Each incorpora- 402, Jan. 5, 1999; 69 FR 18766, Apr. 8, 2004] tion by reference is required to describe the incorporated material by § 314.420 Drug master files. name, reference number, volume, and (a) A drug master file is a submission page number of the drug master file. of information to the Food and Drug (c) A drug master file is required to Administration by a person (the drug be submitted in two copies. The agency master file holder) who intends it to be has prepared guidance that provides in- used for one of the following purposes: formation about how to prepare a well- To permit the holder to incorporate organized drug master file. If the drug the information by reference when the master file holder adds, changes, or de- holder submits an investigational new letes any information in the file, the drug application under part 312 or sub- holder shall notify in writing, each per- mits an application or an abbreviated son authorized to reference that infor- application or an amendment or sup- mation. Any addition, change, or dele- plement to them under this part, or to tion of information in a drug master permit the holder to authorize other file (except the list required under persons to rely on the information to paragraph (d) of this section) is re- support a submission to FDA without quired to be submitted in two copies the holder having to disclose the information to the person. FDA ordinarily and to describe by name, reference neither independently reviews drug number, volume, and page number the master files nor approves or dis- information affected in the drug mas- approves submissions to a drug master ter file. file. Instead, the agency customarily (d) The drug master file is required to reviews the information only in the contain a complete list of each person context of an application under part currently authorized to incorporate by 312 or this part. A drug master file may reference any information in the file, contain information of the kind re- identifying by name, reference number, quired for any submission to the agen- volume, and page number the informa- cy, including information about the tion that each person is authorized to following: incorporate. If the holder restricts the (1) [Reserved] authorization to particular drug prod- (2) Drug substance, drug substance ucts, the list is required to include the intermediate, and materials used in name of each drug product and the ap- their preparation, or drug product; plication number, if known, to which (3) Packaging materials; the authorization applies. (4) Excipient, colorant, flavor, es- (e) The public availability of data sence, or materials used in their prepa- and information in a drug master file, ration; including the availability of data and (5) FDA-accepted reference informa- information in the file to a person au- tion. (A person wishing to submit in- thorized to reference the file, is deter- formation and supporting data in a mined under part 20 and § 314.430. drug master file (DMF) that is not covered by Types II through IV DMF’s [50 FR 7493, Feb. 22, 1985, as amended at 50 must first submit a letter of intent to FR 21238, May 23, 1985; 53 FR 33122, Aug. 30, the Drug Master File Staff, Food and 1988; 55 FR 28380, July 11, 1990; 65 FR 1780, Drug Administration, 5901–B Jan. 12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR Ammendale Rd., Beltsville, MD 20705– 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004] 1266.) FDA will then contact the person to discuss the proposed submission.

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§ 314.430 Availability for public disclo- (2) Notwithstanding paragraph (d)(1) sure of data and information in an of this section, FDA will make avail- application or abbreviated applica- able to the public upon request the in- tion. formation in the investigational new (a) The Food and Drug Administra- drug application that was required to tion will determine the public avail- be filed in Docket Number 95S–0158 in ability of any part of an application or the Division of Dockets Management abbreviated application under this sec- (HFA–305), Food and Drug Administra- tion and part 20 of this chapter. For tion, 5630 Fishers Lane, rm. 1061, Rock- purposes of this section, the applica- ville, MD 20852, for investigations in- tion or abbreviated application involving an exception from informed cludes all data and information sub- consent under § 50.24 of this chapter. mitted with or incorporated by ref- Persons wishing to request this infor- erence in the application or abbre- mation shall submit a request under viated application, including investiga- the Freedom of Information Act. tional new drug applications, drug (e) After FDA sends an approval let- master files under § 314.420, supple- ter to the applicant, the following data ments submitted under § 314.70 or and information in the application or § 314.97, reports under § 314.80 or § 314.98, abbreviated application are imme- and other submissions. For purposes of diately available for public disclosure, this section, safety and effectiveness unless the applicant shows that ex- data include all studies and tests of a traordinary circumstances exist. A list drug on animals and humans and all of approved applications and abbre- studies and tests of the drug for iden- viated applications, entitled ‘‘Approved tity, stability, purity, potency, and Drug Products with Therapeutic bioavailability. Equivalence Evaluations,’’ is available (b) FDA will not publicly disclose the from the Government Printing Office, existence of an application or abbre- Washington, DC 20402. This list is up- viated application before an approval dated monthly. letter is sent to the applicant under (1) [Reserved] § 314.105 or tentative approval letter is (2) If the application applies to a new sent to the applicant under § 314.107, drug, all safety and effectiveness data unless the existence of the application previously disclosed to the public as or abbreviated application has been previously publicly disclosed or ac- set forth in § 20.81 and a summary or knowledged. summaries of the safety and effective- (c) If the existence of an unapproved ness data and information submitted application or abbreviated application with or incorporated by reference in has not been publicly disclosed or ac- the application. The summaries do not knowledged, no data or information in constitute the full reports of investiga- the application or abbreviated applications under section 505(b)(1) of the act tion is available for public disclosure. (21 U.S.C. 355(b)(1)) on which the safety (d)(1) If the existence of an applica- or effectiveness of the drug may be ap- tion or abbreviated application has proved. The summaries consist of the been publicly disclosed or acknowl- following: edged before the agency sends an ap- (i) For an application approved be- proval letter to the applicant, no data fore July 1, 1975, internal agency or information contained in the appli- records that describe safety and effec- cation or abbreviated application is tiveness data and information, for ex- available for public disclosure before ample, a summary of the basis for ap- the agency sends an approval letter, proval or internal reviews of the data but the Commissioner may, in his or and information, after deletion of the her discretion, disclose a summary of following: selected portions of the safety and ef- (a) Names and any information that fectiveness data that are appropriate would identify patients or test subjects for public consideration of a specific or investigators. pending issue; for example, for consid- (b) Any inappropriate gratuitous eration of an open session of an FDA comments unnecessary to an objective advisory committee. analysis of the data and information.

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(ii) For an application approved on or upon request, at the time any one of after July 1, 1975, a Summary Basis of the following events occurs unless ex- Approval (SBA) document that con- traordinary circumstances are shown: tains a summary of the safety and ef- (1) No work is being or will be under- fectiveness data and information eval- taken to have the application ap- uated by FDA during the drug approval proved. process. The SBA is prepared in one of (2) A final determination is made the following ways: that the application is not approvable (a) Before approval of the applica- and all legal appeals have been ex- tion, the applicant may prepare a draft hausted. SBA which the Center for Drug Evalua- (3) Approval of the application is tion and Research will review and may withdrawn and all legal appeals have revise. The draft may be submitted been exhausted. with the application or as an amend- (4) A final determination has been ment. made that the drug is not a new drug. (b) The Center for Drug Evaluation (5) For applications submitted under and Research may prepare the SBA. section 505(b) of the act, the effective (3) A protocol for a test or study, un- date of the approval of the first abbre- less it is shown to fall within the ex- viated application submitted under emption established for trade secrets section 505(j) of the act which refers to and confidential commercial informa- such drug, or the date on which the ap- tion in § 20.61. proval of an abbreviated application (4) Adverse reaction reports, product under section 505(j) of the act which re- experience reports, consumer com- fers to such drug could be made effec- plaints, and other similar data and in- tive if such an abbreviated application formation after deletion of the fol- had been submitted. lowing: (6) For abbreviated applications sub- (i) Names and any information that mitted under section 505(j) of the act, would identify the person using the when FDA sends an approval letter to product. the applicant. (ii) Names and any information that (g) The following data and informa- would identify any third party involved tion in an application or abbreviated with the report, such as a physician or application are not available for public hospital or other institution. disclosure unless they have been pre- (5) A list of all active ingredients and viously disclosed to the public as set any inactive ingredients previously forth in § 20.81 of this chapter or they disclosed to the public as set forth in relate to a product or ingredient that § 20.81. has been abandoned and they do not (6) An assay procedure or other ana- represent a trade secret or confidential lytical procedure, unless it serves no commercial or financial information regulatory or compliance purpose and under § 20.61 of this chapter: is shown to fall within the exemption (1) Manufacturing methods or proc- established for trade secrets and con- esses, including quality control proce- fidential commercial information in dures. § 20.61. (2) Production, sales distribution, (7) All correspondence and written and similar data and information, ex- summaries of oral discussions between cept that any compilation of that data FDA and the applicant relating to the and information aggregated and pre- application, under the provisions of pared in a way that does not reveal part 20. data or information which is not avail- (f) All safety and effectiveness data able for public disclosure under this and information which have been sub- provision is available for public disclo- mitted in an application and which sure. have not previously been disclosed to (3) Quantitative or semiquantitative the public are available to the public, formulas.

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(h) The compilations of information an application under paragraph (b) of specified in § 20.117 are available for this section, should be directed to the public disclosure. Associate Director for Policy (HFD–5). (4) The field copy of an application, [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, an abbreviated application, amend- 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, ments, supplements, resubmissions, re- Oct. 2, 1996; 64 FR 26698, May 13, 1998; 64 FR quests for waivers, and other cor- 402, Jan. 5, 1999; 66 FR 1832, Jan. 10, 2001; 68 respondence about an application and FR 24879, May 9, 2003; 69 FR 18766, Apr. 8, an abbreviated application shall be 2004; 73 FR 39610, July 10, 2008] sent to the applicant’s home FDA district office, except that a foreign appli- § 314.440 Addresses for applications cant shall send the field copy to the ap- and abbreviated applications. propriate address identified in para- (a) Applicants shall send applica- graphs (a)(1) and (a)(2) of this section. tions, abbreviated applications, and (b) Applicants shall send applications other correspondence relating to mat- and other correspondence relating to ters covered by this part, except for matters covered by this part for the products listed in paragraph (b) of this drug products listed below to the Food section, to the appropriate office iden- and Drug Administration, Center for tified below: Biologics Evaluation and Research, (1) Except as provided in paragraph Document Control Center, 10903 New (a)(4) of this section, an application Hampshire Ave., Bldg. 71, Rm. G112, under § 314.50 or § 314.54 submitted for Silver Spring, MD 20993–0002, except ap- filing should be directed to the Central plicants shall send a request for an op- Document Room, 5901–B Ammendale portunity for a hearing under § 314.110 Rd., Beltsville, MD 20705–1266. Appli- on the question of whether there are cants may obtain information about grounds for denying approval of an ap- folders for binding applications on the plication to the Center for Biologics Internet at http://www.fda.gov/cder/ Evaluation and Research, ATTN: Di- ddms/binders.htm. After FDA has filed rector, at the same address. the application, the agency will inform (1) Ingredients packaged together the applicant which division is respon- with containers intended for the collec- sible for the application. Amendments, tion, processing, or storage of blood supplements, resubmissions, requests and blood components; for waivers, and other correspondence (2) Plasma volume expanders and hy- about an application that has been droxyethyl starch for leukapheresis; filed should be addressed to 5901–B (3) Blood component processing solu- Ammendale Rd., Beltsville, MD 20705– tions and shelf life extenders; and 1266, to the attention of the appro- (4) Oxygen carriers. priate division. (2) Except as provided in paragraph [50 FR 7493, Feb. 22, 1985, as amended at 50 (a)(4) of this section, an abbreviated ap- FR 21238, May 23, 1985; 55 FR 11581, Mar. 29, 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, plication under § 314.94, and amend- Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR ments, supplements, and resubmissions 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005; should be directed to the Central Docu- 73 FR 39610, July 10, 2008; 74 FR 13113, Mar. ment Room, Center for Drug Evalua- 26, 2009; 75 FR 37295, June 29, 2010; 80 FR tion and Research, Food and Drug Ad- 18091, Apr. 3, 2015; 84 FR 6673, Feb. 28, 2019] ministration, 5901–B Ammendale Rd., Beltsville, MD 20705–1266. This includes § 314.445 Guidance documents. items sent by parcel post or overnight (a) FDA has made available guidance courier service. Correspondence not as- documents under § 10.115 of this chapter sociated with an abbreviated applica- to help you to comply with certain re- tion also should be addressed to 5901–B quirements of this part. Ammendale Rd., Beltsville, MD 20705– (b) The Center for Drug Evaluation 1266. and Research (CDER) maintains a list (3) A request for an opportunity for a of guidance documents that apply to hearing under § 314.110 on the question CDER’s regulations. The list is main- of whether there are grounds for deny- tained on the Internet and is published ing approval of an application, except annually in the FEDERAL REGISTER. A

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request for a copy of the CDER list must also be adequate and well-con- should be directed to the Office of trolled. The applicant shall carry out Training and Communications, Divi- any such studies with due diligence. sion of Drug Information, Center for Drug Evaluation and Research, Food § 314.520 Approval with restrictions to and Drug Administration, 10903 New assure safe use. Hampshire Ave., Silver Spring, MD (a) If FDA concludes that a drug 20993–0002. product shown to be effective can be safely used only if distribution or use [65 FR 56480, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009] is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the drug prod- Subpart H—Accelerated Approval uct, such as: of New Drugs for Serious or (1) Distribution restricted to certain Life-Threatening Illnesses facilities or physicians with special training or experience; or SOURCE: 57 FR 58958, Dec. 11, 1992, unless (2) Distribution conditioned on the otherwise noted. performance of specified medical procedures. § 314.500 Scope. (b) The limitations imposed will be This subpart applies to certain new commensurate with the specific safety drug products that have been studied concerns presented by the drug prod- for their safety and effectiveness in uct. treating serious or life-threatening illnesses and that provide meaningful § 314.530 Withdrawal procedures. therapeutic benefit to patients over ex- (a) For new drugs approved under isting treatments (e.g., ability to treat §§ 314.510 and 314.520, FDA may with- patients unresponsive to, or intolerant draw approval, following a hearing as of, available therapy, or improved pa- provided in part 15 of this chapter, as tient response over available therapy). modified by this section, if: [57 FR 58958, Dec. 11, 1992, as amended at 64 (1) A postmarketing clinical study FR 402, Jan. 5, 1999] fails to verify clinical benefit; (2) The applicant fails to perform the § 314.510 Approval based on a surro- required postmarketing study with due gate endpoint or on an effect on a diligence; clinical endpoint other than sur- (3) Use after marketing demonstrates vival or irreversible morbidity. that postmarketing restrictions are in- FDA may grant marketing approval adequate to assure safe use of the drug for a new drug product on the basis of product; adequate and well-controlled clinical (4) The applicant fails to adhere to trials establishing that the drug prod- the postmarketing restrictions agreed uct has an effect on a surrogate end- upon; point that is reasonably likely, based (5) The promotional materials are on epidemiologic, therapeutic, patho- false or misleading; or physiologic, or other evidence, to pre- (6) Other evidence demonstrates that dict clinical benefit or on the basis of the drug product is not shown to be an effect on a clinical endpoint other safe or effective under its conditions of than survival or irreversible morbidity. use. Approval under this section will be (b) Notice of opportunity for a hearing. subject to the requirement that the ap- The Director of the Center for Drug plicant study the drug further, to Evaluation and Research will give the verify and describe its clinical benefit, applicant notice of an opportunity for where there is uncertainty as to the re- a hearing on the Center’s proposal to lation of the surrogate endpoint to withdraw the approval of an applica- clinical benefit, or of the observed clin- tion approved under § 314.510 or § 314.520. ical benefit to ultimate outcome. Post- The notice, which will ordinarily be a marketing studies would usually be letter, will state generally the reasons studies already underway. When re- for the action and the proposed quired to be conducted, such studies grounds for the order.

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(c) Submission of data and information. § 314.540 Postmarketing safety report- (1) If the applicant fails to file a writing. ten request for a hearing within 15 days Drug products approved under this of receipt of the notice, the applicant program are subject to the post- waives the opportunity for a hearing. marketing recordkeeping and safety (2) If the applicant files a timely re- reporting applicable to all approved quest for a hearing, the agency will drug products, as provided in §§ 314.80 publish a notice of hearing in the FED- ERAL REGISTER in accordance with and 314.81. §§ 12.32(e) and 15.20 of this chapter. § 314.550 Promotional materials. (3) An applicant who requests a hearing under this section must, within 30 For drug products being considered days of receipt of the notice of oppor- for approval under this subpart, unless tunity for a hearing, submit the data otherwise informed by the agency, ap- and information upon which the appli- plicants must submit to the agency for cant intends to rely at the hearing. consideration during the preapproval (d) Separation of functions. Separation review period copies of all promotional of functions (as specified in § 10.55 of materials, including promotional label- this chapter) will not apply at any ing as well as advertisements, intended point in withdrawal proceedings under for dissemination or publication within this section. 120 days following marketing approval. (e) Procedures for hearings. Hearings After 120 days following marketing ap- held under this section will be con- proval, unless otherwise informed by ducted in accordance with the provi- the agency, the applicant must submit sions of part 15 of this chapter, with promotional materials at least 30 days the following modifications: prior to the intended time of initial (1) An advisory committee duly con- dissemination of the labeling or initial stituted under part 14 of this chapter publication of the advertisement. will be present at the hearing. The committee will be asked to review the § 314.560 Termination of requirements. issues involved and to provide advice and recommendations to the Commis- If FDA determines after approval sioner of Food and Drugs. that the requirements established in (2) The presiding officer, the advisory § 314.520, § 314.530, or § 314.550 are no committee members, up to three rep- longer necessary for the safe and effec- resentatives of the applicant, and up to tive use of a drug product, it will so no- three representatives of the Center tify the applicant. Ordinarily, for drug may question any person during or at products approved under § 314.510, these the conclusion of the person’s presen- requirements will no longer apply when tation. No other person attending the FDA determines that the required hearing may question a person making postmarketing study verifies and de- a presentation. The presiding officer scribes the drug product’s clinical ben- may, as a matter of discretion, permit efit and the drug product would be ap- questions to be submitted to the pre- propriate for approval under tradi- siding officer for response by a person tional procedures. For drug products making a presentation. approved under § 314.520, the restric- (f) Judicial review. The Commis- tions would no longer apply when FDA sioner’s decision constitutes final determines that safe use of the drug agency action from which the appli- product can be assured through appro- cant may petition for judicial review. priate labeling. FDA also retains the Before requesting an order from a discretion to remove specific post- court for a stay of action pending re- approval requirements upon review of a view, an applicant must first submit a petition submitted by the sponsor in petition for a stay of action under § 10.35 of this chapter. accordance with § 10.30. [57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999]

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Subpart I—Approval of New Drugs the toxicity of the substance and its When Human Efficacy Studies prevention or substantial reduction by Are Not Ethical or Feasible the product; (2) The effect is demonstrated in more than one animal species expected SOURCE: 67 FR 37995, May 31, 2002, unless otherwise noted. to react with a response predictive for humans, unless the effect is dem- § 314.600 Scope. onstrated in a single animal species This subpart applies to certain new that represents a sufficiently well- drug products that have been studied characterized animal model for pre- for their safety and efficacy in amelio- dicting the response in humans; rating or preventing serious or life- (3) The animal study endpoint is threatening conditions caused by expo- clearly related to the desired benefit in sure to lethal or permanently disabling humans, generally the enhancement of toxic biological, chemical, radio- survival or prevention of major mor- logical, or nuclear substances. This bidity; and subpart applies only to those new drug (4) The data or information on the ki- products for which: Definitive human netics and pharmacodynamics of the efficacy studies cannot be conducted product or other relevant data or infor- because it would be unethical to delib- mation, in animals and humans, allows erately expose healthy human volun- selection of an effective dose in hu- teers to a lethal or permanently dis- mans. abling toxic biological, chemical, radi- (b) Approval under this subpart will ological, or nuclear substance; and be subject to three requirements: field trials to study the product’s effec- (1) Postmarketing studies. The appli- tiveness after an accidental or hostile cant must conduct postmarketing exposure have not been feasible. This studies, such as field studies, to verify subpart does not apply to products that and describe the drug’s clinical benefit can be approved based on efficacy and to assess its safety when used as standards described elsewhere in FDA’s indicated when such studies are fea- regulations (e.g., accelerated approval sible and ethical. Such postmarketing based on surrogate markers or clinical studies would not be feasible until an endpoints other than survival or irre- exigency arises. When such studies are versible morbidity), nor does it address feasible, the applicant must conduct the safety evaluation for the products such studies with due diligence. Appli- to which it does apply. cants must include as part of their ap- § 314.610 Approval based on evidence plication a plan or approach to post- of effectiveness from studies in ani- marketing study commitments in the mals. event such studies become ethical and (a) FDA may grant marketing ap- feasible. proval for a new drug product for which (2) Approval with restrictions to ensure safety has been established and for safe use. If FDA concludes that a drug which the requirements of § 314.600 are product shown to be effective under met based on adequate and well-con- this subpart can be safely used only if trolled animal studies when the results distribution or use is restricted, FDA of those animal studies establish that will require such postmarketing re- the drug product is reasonably likely strictions as are needed to ensure safe to produce clinical benefit in humans. use of the drug product, commensurate In assessing the sufficiency of animal with the specific safety concerns pre- data, the agency may take into ac- sented by the drug product, such as: count other data, including human (i) Distribution restricted to certain data, available to the agency. FDA will facilities or health care practitioners rely on the evidence from studies in with special training or experience; animals to provide substantial evi- (ii) Distribution conditioned on the dence of the effectiveness of these performance of specified medical proce- products only when: dures, including medical followup; and (1) There is a reasonably well-under- (iii) Distribution conditioned on stood pathophysiological mechanism of specified recordkeeping requirements.

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(3) Information to be provided to patient sons for the action and the proposed recipients. For drug products or specific grounds for the order. indications approved under this sub- (c) Submission of data and information. part, applicants must prepare, as part (1) If the applicant fails to file a writ- of their proposed labeling, labeling to ten request for a hearing within 15 days be provided to patient recipients. The of receipt of the notice, the applicant patient labeling must explain that, for waives the opportunity for a hearing. ethical or feasibility reasons, the (2) If the applicant files a timely re- drug’s approval was based on efficacy quest for a hearing, the agency will studies conducted in animals alone and publish a notice of hearing in the FED- must give the drug’s indication(s), di- ERAL REGISTER in accordance with rections for use (dosage and adminis- §§ 12.32(e) and 15.20 of this chapter. tration), contraindications, a descrip- (3) An applicant who requests a hear- tion of any reasonably foreseeable ing under this section must, within 30 risks, adverse reactions, anticipated days of receipt of the notice of oppor- benefits, drug interactions, and any other relevant information required by tunity for a hearing, submit the data FDA at the time of approval. The pa- and information upon which the appli- tient labeling must be available with cant intends to rely at the hearing. the product to be provided to patients (d) Separation of functions. Separation prior to administration or dispensing of functions (as specified in § 10.55 of of the drug product for the use ap- this chapter) will not apply at any proved under this subpart, if possible. point in withdrawal proceedings under this section. § 314.620 Withdrawal procedures. (e) Procedures for hearings. Hearings (a) Reasons to withdraw approval. For held under this section will be con- new drugs approved under this subpart, ducted in accordance with the provi- FDA may withdraw approval, following sions of part 15 of this chapter, with a hearing as provided in part 15 of this the following modifications: chapter, as modified by this section, if: (1) An advisory committee duly con- (1) A postmarketing clinical study stituted under part 14 of this chapter fails to verify clinical benefit; will be present at the hearing. The (2) The applicant fails to perform the committee will be asked to review the postmarketing study with due dili- issues involved and to provide advice gence; and recommendations to the Commis- (3) Use after marketing demonstrates sioner of Food and Drugs. that postmarketing restrictions are in- (2) The presiding officer, the advisory adequate to ensure safe use of the drug committee members, up to three rep- product; resentatives of the applicant, and up to (4) The applicant fails to adhere to three representatives of CDER may the postmarketing restrictions applied question any person during or at the at the time of approval under this sub- conclusion of the person’s presen- part; tation. No other person attending the (5) The promotional materials are hearing may question a person making false or misleading; or a presentation. The presiding officer (6) Other evidence demonstrates that may, as a matter of discretion, permit the drug product is not shown to be questions to be submitted to the pre- safe or effective under its conditions of siding officer for response by a person use. making a presentation. (b) Notice of opportunity for a hearing. (f) Judicial review. The Commissioner The Director of the Center for Drug of Food and Drugs’ decision constitutes Evaluation and Research (CDER) will final agency action from which the ap- give the applicant notice of an oppor- plicant may petition for judicial re- tunity for a hearing on CDER’s pro- view. Before requesting an order from a posal to withdraw the approval of an court for a stay of action pending re- application approved under this sub- view, an applicant must first submit a part. The notice, which will ordinarily petition for a stay of action under be a letter, will state generally the rea- § 10.35 of this chapter.

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§ 314.630 Postmarketing safety report- 315.3 General factors relevant to safety and ing. effectiveness. 315.4 Indications. Drug products approved under this 315.5 Evaluation of effectiveness. subpart are subject to the post- 315.6 Evaluation of safety. marketing recordkeeping and safety reporting requirements applicable to AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, all approved drug products, as provided 355, 371, 374, 379e; sec. 122, Pub. L. 105–115, 111 in §§ 314.80 and 314.81. Stat. 2322 (21 U.S.C. 355 note). SOURCE: 64 FR 26667, May 17, 1999, unless § 314.640 Promotional materials. otherwise noted. For drug products being considered for approval under this subpart, unless § 315.1 Scope. otherwise informed by the agency, ap- The regulations in this part apply to plicants must submit to the agency for radiopharmaceuticals intended for in consideration during the preapproval vivo administration for diagnostic and review period copies of all promotional monitoring use. They do not apply to materials, including promotional label- radiopharmaceuticals intended for ing as well as advertisements, intended therapeutic purposes. In situations for dissemination or publication within where a particular radiopharma- 120 days following marketing approval. ceutical is proposed for both diagnostic After 120 days following marketing ap- and therapeutic uses, the radiopharma- proval, unless otherwise informed by ceutical must be evaluated taking into the agency, the applicant must submit account each intended use. promotional materials at least 30 days prior to the intended time of initial § 315.2 Definition. dissemination of the labeling or initial For purposes of this part, diagnostic publication of the advertisement. radiopharmaceutical means: § 314.650 Termination of requirements. (a) An article that is intended for use in the diagnosis or monitoring of a dis- If FDA determines after approval ease or a manifestation of a disease in under this subpart that the require- humans and that exhibits spontaneous ments established in §§ 314.610(b)(2), disintegration of unstable nuclei with 314.620, and 314.630 are no longer nec- the emission of nuclear particles or essary for the safe and effective use of photons; or a drug product, FDA will so notify the applicant. Ordinarily, for drug products (b) Any nonradioactive reagent kit or approved under § 314.610, these require- nuclide generator that is intended to ments will no longer apply when FDA be used in the preparation of such arti- determines that the postmarketing cle as defined in paragraph (a) of this study verifies and describes the drug section. product’s clinical benefit. For drug products approved under § 314.610, the § 315.3 General factors relevant to safety and effectiveness. restrictions would no longer apply when FDA determines that safe use of FDA’s determination of the safety the drug product can be ensured and effectiveness of a diagnostic radio- through appropriate labeling. FDA also pharmaceutical includes consideration retains the discretion to remove spe- of the following: cific postapproval requirements upon (a) The proposed use of the diagnostic review of a petition submitted by the radiopharmaceutical in the practice of sponsor in accordance with § 10.30 of medicine, this chapter. (b) The pharmacological and toxicological activity of the diagnostic PART 315—DIAGNOSTIC radiopharmaceutical (including any RADIOPHARMACEUTICALS carrier or ligand component of the diagnostic radiopharmaceutical), and Sec. (c) The estimated absorbed radiation 315.1 Scope. dose of the diagnostic radiopharma- 315.2 Definition. ceutical.

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§ 315.4 Indications. lish the effectiveness of the diagnostic radiopharmaceutical for the claim. (a) For diagnostic radiopharmaceuticals, the categories of proposed (b) The accuracy and usefulness of indications for use include, but are not the diagnostic information is deter- limited to, the following: mined by comparison with a reliable assessment of actual clinical status. A (1) Structure delineation; reliable assessment of actual clinical (2) Functional, physiological, or bio- status may be provided by a diagnostic chemical assessment; standard or standards of demonstrated (3) Disease or pathology detection or accuracy. In the absence of such diag- assessment; and nostic standard(s), the actual clinical (4) Diagnostic or therapeutic patient status must be established in another management. manner, e.g., patient followup. (b) Where a diagnostic radiopharmaceutical is not intended to provide dis- § 315.6 Evaluation of safety. ease-specific information, the proposed indications for use may refer to a bio- (a) Factors considered in the safety chemical, physiological, anatomical, or assessment of a diagnostic radio- pathological process or to more than pharmaceutical include, among others, one disease or condition. the following: (1) The radiation dose; § 315.5 Evaluation of effectiveness. (2) The pharmacology and toxicology of the radiopharmaceutical, including (a) The effectiveness of a diagnostic any radionuclide, carrier, or ligand; radiopharmaceutical is assessed by evaluating its ability to provide useful (3) The risks of an incorrect diag- clinical information related to its pro- nostic determination; posed indications for use. The method (4) The adverse reaction profile of the of this evaluation varies depending drug; upon the proposed indication(s) and (5) Results of human experience with may use one or more of the following the radiopharmaceutical for other uses; criteria: and (1) The claim of structure delineation (6) Results of any previous human ex- is established by demonstrating in a perience with the carrier or ligand of defined clinical setting the ability to the radiopharmaceutical when the locate anatomical structures and to same chemical entity as the carrier or characterize their anatomy. ligand has been used in a previously (2) The claim of functional, physio- studied product. logical, or biochemical assessment is (b) The assessment of the adverse re- established by demonstrating in a de- action profile includes, but is not lim- fined clinical setting reliable measure- ited to, an evaluation of the potential ment of function(s) or physiological, of the diagnostic radiopharmaceutical, biochemical, or molecular process(es). including the carrier or ligand, to elic- (3) The claim of disease or pathology it the following: detection or assessment is established (1) Allergic or hypersensitivity re- by demonstrating in a defined clinical sponses, setting that the diagnostic radio- (2) Immunologic responses, pharmaceutical has sufficient accuracy (3) Changes in the physiologic or bio- in identifying or characterizing the dis- chemical function of the target and ease or pathology. nontarget tissues, and (4) The claim of diagnostic or thera- (4) Clinically detectable signs or peutic patient management is estab- symptoms. lished by demonstrating in a defined (c)(1) To establish the safety of a di- clinical setting that the test is useful agnostic radiopharmaceutical, FDA in diagnostic or therapeutic patient may require, among other information, management. the following types of data: (5) For a claim that does not fall (i) Pharmacology data, within the indication categories identi- (ii) Toxicology data, fied in § 315.4, the applicant or sponsor (iii) Clinical adverse event data, and should consult FDA on how to estab- (iv) Radiation safety assessment.

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(2) The amount of new safety data re- 316.23 Timing of requests for orphan-drug quired will depend on the characteris- designation; designation of already ap- tics of the product and available infor- proved drugs. mation regarding the safety of the di- 316.24 Deficiency letters and granting orphan-drug designation. agnostic radiopharmaceutical, and its 316.25 Refusal to grant orphan-drug designa- carrier or ligand, obtained from other tion. studies and uses. Such information 316.26 Amendment to orphan-drug designa- may include, but is not limited to, the tion. dose, route of administration, fre- 316.27 Change in ownership of orphan-drug quency of use, half-life of the ligand or designation. carrier, half-life of the radionuclide, 316.28 Publication of orphan-drug designa- and results of clinical and preclinical tions. studies. FDA will establish categories 316.29 Revocation of orphan-drug designa- of diagnostic radiopharmaceuticals tion. based on defined characteristics rel- 316.30 Annual reports of holder of orphan- drug designation. evant to risk and will specify the amount and type of safety data that Subpart D—Orphan-Drug Exclusive are appropriate for each category (e.g., Approval required safety data may be limited for diagnostic radiopharmaceuticals with 316.31 Scope of orphan-drug exclusive ap- a well established, low-risk profile). proval. Upon reviewing the relevant product 316.34 FDA recognition of exclusive ap- characteristics and safety information, proval. 316.36 Insufficient quantities of orphan FDA will place each diagnostic radio- drugs. pharmaceutical into the appropriate safety risk category. Subpart E—Open Protocols for (d) Radiation safety assessment. The Investigations radiation safety assessment must establish the radiation dose of a diag- 316.40 Treatment use of a designated orphan nostic radiopharmaceutical by radi- drug. ation dosimetry evaluations in humans Subpart F—Availability of Information and appropriate animal models. The maximum tolerated dose need not be 316.50 Guidance documents. established. 316.52 Availability for public disclosure of data and information in requests and ap- PART 316—ORPHAN DRUGS plications. AUTHORITY: 21 U.S.C. 360aa, 360bb, 360cc, Subpart A—General Provisions 360dd, 371. Sec. SOURCE: 57 FR 62085, Dec. 29, 1992, unless 316.1 Scope of this part. otherwise noted. 316.2 Purpose. EDITORIAL NOTE: Nomenclature changes to 316.3 Definitions. part 316 appear at 69 FR 13717, Mar. 24, 2004. 316.4 Address for submissions.

Subpart B—Written Recommendations for Subpart A—General Provisions Investigations of Orphan Drugs § 316.1 Scope of this part. 316.10 Content and format of a request for (a) This part implements sections 525, written recommendations. 316.12 Providing written recommendations. 526, 527, and 528 of the act and provides 316.14 Refusal to provide written rec- procedures to encourage and facilitate ommendations. the development of drugs for rare diseases or conditions, including biologi- Subpart C—Designation of an Orphan cal products and antibiotics. This part Drug sets forth the procedures and requirements for: 316.20 Content and format of a request for orphan-drug designation. (1) Submissions to FDA of: 316.21 Verification of orphan-drug status. (i) Requests for recommendations for 316.22 Permanent-resident agent for foreign investigations of drugs for rare dis- sponsor. eases or conditions;

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(ii) Requests for designation of a drug that provided by an approved drug for a rare disease or condition; and (that is otherwise the same drug) in (iii) Requests for gaining exclusive one or more of the following ways: approval for a drug for a rare disease or (i) Greater effectiveness than an ap- condition. proved drug (as assessed by effect on a (2) Allowing a sponsor to provide an clinically meaningful endpoint in ade- investigational drug under a treatment quate and well controlled clinical protocol to patients who need the drug trials). Generally, this would represent for treatment of a rare disease or con- the same kind of evidence needed to dition. support a comparative effectiveness (b) This part does not apply to food, claim for two different drugs; in most medical devices, or drugs for veteri- cases, direct comparative clinical nary use. trials would be necessary; or (c) References in this part to regu- (ii) Greater safety in a substantial latory sections of the Code of Federal portion of the target populations, for Regulations are to chapter I of title 21, example, by the elimination of an in- unless otherwise noted. gredient or contaminant that is associ- [57 FR 62085, Dec. 29, 1992, as amended at 78 ated with relatively frequent adverse FR 35132, June 12, 2013] effects. In some cases, direct comparative clinical trials will be necessary; or § 316.2 Purpose. (iii) In unusual cases, where neither The purpose of this part is to estab- greater safety nor greater effectiveness lish standards and procedures for deter- has been shown, a demonstration that mining eligibility for the benefits pro- the drug otherwise makes a major con- vided for in section 2 of the Orphan tribution to patient care. Drug Act, including written rec- (4) Director means the Director of ommendations for investigations of or- FDA’s Office of Orphan Products Devel- phan drugs, a 7-year period of exclusive opment. marketing, and treatment use of inves- (5) FDA means the Food and Drug tigational orphan drugs. This part is Administration. also intended to satisfy Congress’ re- (6) Holder means the sponsor in whose quirements that FDA promulgate pro- name an orphan drug is designated and cedures for the implementation of sec- approved. tions 525(a) and 526(a) of the act. (7) IND means an investigational new drug application under part 312 of this § 316.3 Definitions. chapter. (a) The definitions and interpreta- (8) Manufacturer means any person or tions contained in section 201 of the act agency engaged in the manufacture of apply to those terms when used in this a drug that is subject to investigation part. and approval under the act or the bio- (b) The following definitions of terms logics provisions of the Public Health apply to this part: Service Act (42 U.S.C. 262–263). (1) Act means the Federal Food, Drug, (9) Marketing application means an ap- and Cosmetic Act as amended by sec- plication for approval of a new drug tion 2 of the Orphan Drug Act (sections filed under section 505(b) of the act or 525–528 (21 U.S.C. 360aa–360dd)). an application for a biologics license (2) Active moiety means the molecule submitted under section 351 of the Pub- or ion, excluding those appended por- lic Health Service Act (42 U.S.C. 262). tions of the molecule that cause the (10) Orphan drug means a drug in- drug to be an ester, salt (including a tended for use in a rare disease or con- salt with hydrogen or coordination dition as defined in section 526 of the bonds), or other noncovalent derivative act. (such as a complex, chelate, or clath- (11) Orphan-drug designation means rate) of the molecule, responsible for FDA’s act of granting a request for des- the physiological or pharmacological ignation under section 526 of the act. action of the drug substance. (12) Orphan-drug exclusive approval or (3) Clinically superior means that a exclusive approval means that, effective drug is shown to provide a significant on the date of FDA approval as stated therapeutic advantage over and above in the approval letter of a marketing

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application for a sponsor of a des- structures, would not cause the drugs ignated orphan drug, no approval will to be considered different unless the be given to a subsequent sponsor of the differences were shown to be clinically same drug for the same use or indica- superior. tion for 7 years, except as otherwise (B) Two polysaccharide drugs would provided by law or in this part. A des- be considered the same if they had ignated drug will receive orphan-drug identical saccharide repeating units, exclusive approval only if the same even if the number of units were to drug has not already been approved for vary and even if there were postpolym- the same use or indication. erization modifications, unless the sub- (13) Orphan subset of a non-rare disease sequent drug could be shown to be or condition (‘‘orphan subset’’) means clinically superior. that use of the drug in a subset of per- (C) Two polynucleotide drugs con- sons with a non-rare disease or condi- sisting of two or more distinct nucleo- tion may be appropriate but use of the tides would be considered the same if drug outside of that subset (in the re- they had an identical sequence of pu- maining persons with the non-rare dis- rine and pyrimidine bases (or their de- ease or condition) would be inappro- rivatives) bound to an identical sugar priate owing to some property(ies) of backbone (ribose, deoxyribose, or modi- the drug, for example, drug toxicity, fications of these sugars), unless the mechanism of action, or previous clin- subsequent drug were shown to be ical experience with the drug. clinically superior. (14) Same drug means: (D) Closely related, complex partly (i) If it is a drug composed of small definable drugs with similar thera- molecules, a drug that contains the peutic intent, such as two live viral same active moiety as a previously ap- vaccines for the same indication, would proved drug and is intended for the be considered the same unless the sub- same use as the previously approved sequent drug was shown to be clini- drug, even if the particular ester or cally superior. salt (including a salt with hydrogen or coordination bonds) or other (15) Sponsor means the entity that as- noncovalent derivative such as a com- sumes responsibility for a clinical or plex, chelate or clathrate has not been nonclinical investigation of a drug, in- previously approved, except that if the cluding the responsibility for compli- subsequent drug can be shown to be ance with applicable provisions of the clinically superior to the first drug, it act and regulations. A sponsor may be will not be considered to be the same an individual, partnership, corporation, drug. or Government agency and may be a (ii) If it is a drug composed of large manufacturer, scientific institution, or molecules (macromolecules), a drug an investigator regularly and lawfully that contains the same principal mo- engaged in the investigation of drugs. lecular structural features (but not For purposes of the Orphan Drug Act, necessarily all of the same structural FDA considers the real party or parties features) and is intended for the same in interest to be a sponsor. use as a previously approved drug, ex- [57 FR 62085, Dec. 29, 1992, as amended at 64 cept that, if the subsequent drug can be FR 402, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; shown to be clinically superior, it will 78 FR 35132, June 12, 2013] not be considered to be the same drug. This criterion will be applied as follows § 316.4 Address for submissions. to different kinds of macromolecules: All correspondence and requests for (A) Two protein drugs would be con- FDA action under the provisions of sidered the same if the only differences this rule should be addressed as fol- in structure between them were due to lows: Office of Orphan Products Devel- post-translational events or infidelity opment, Food and Drug Administra- of translation or transcription or were tion, Bldg. 32, Rm. 5271, 10903 New minor differences in amino acid se- Hampshire Ave., Silver Spring, MD quence; other potentially important 20993. differences, such as different glycosyl- ation patterns or different tertiary [78 FR 35133, June 12, 2013]

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Subpart B—Written Recommenda- (iii) So far as is known or can be de- tions for Investigations of Or- termined, all indications previously or phan Drugs currently under investigation anywhere; § 316.10 Content and format of a re- (iv) All adverse regulatory actions quest for written recommendations. taken by the United States or foreign (a) A sponsor’s request for written authorities. recommendations from FDA con- (8) The basis for concluding that the cerning the nonclinical and clinical in- drug is for a disease or condition that vestigations necessary for approval of a is rare in the United States, including marketing application shall be sub- the following: mitted in the form and contain the in- (i) The size and other known demo- formation required in this section. graphic characteristics of the patient FDA may require the sponsor to subpopulation affected and the source of mit information in addition to that this information. specified in paragraph (b) of this sec- (ii) For drugs intended for diseases or tion if FDA determines that the spon- conditions affecting 200,000 or more sor’s initial request does not contain people in the United States, or for a adequate information on which to base vaccine, diagnostic drug, or preventive recommendations. drug that would be given to 200,000 or (b) A sponsor shall submit two copies more persons per year, a summary of of a completed, dated, and signed re- the sponsor’s basis for believing that quest for written recommendations the disease or condition described in that contains the following: paragraph (b)(6) of this section occurs (1) The sponsor’s name and address. so infrequently that there is no reason- (2) A statement that the sponsor is able expectation that the costs of drug requesting written recommendations development and marketing will be re- on orphan-drug development under sec- covered in future sales of the drug in tion 525 of the act. the United States. The estimated costs (3) The name of the sponsor’s pri- and sales data should be submitted as mary contact person and/or resident provided for in § 316.21(c). agent, and the person’s title, address, (9) A summary and analysis of avail- and telephone number. able data on the pharmacologic effects (4) The generic name and trade name, of the drug. if any, of the drug and a list of the drug (10) A summary and analysis of avail- product’s components or description of able nonclinical and clinical data perti- the drug product’s formulation, and nent to the drug and the disease to be chemical and physical properties. studied including copies of pertinent (5) The proposed dosage form and published reports. When a drug pro- route of administration. posed for orphan drug designation is in- (6) A description of the disease or tended to treat a life-threatening or se- condition for which the drug is pro- verely debilitating illness, especially posed to be investigated and the pro- where no satisfactory alternative ther- posed indication or indications for use apy exists, the sponsor may wish vol- for such disease or condition. untarily to provide this information. A (7) Current regulatory and marketing sponsor of such a drug may be entitled status and history of the drug product, to expeditious development, evalua- including: tion, and marketing under 21 CFR part (i) Whether the product is the subject 312, subpart E. of an IND or a marketing application (11) An explanation of how the data (if the product is the subject of an IND summarized and analyzed under para- or a marketing application, the IND or graphs (b)(9) and (b)(10) of this section marketing application numbers should support the rationale for use of the be stated and the investigational or ap- drug in the rare disease or condition. proved indication or indications for use (12) A definition of the population specified); from which subjects will be identified (ii) Known marketing experience or for clinical trials, if known. investigational status outside the (13) A detailed outline of any proto- United States; cols under which the drug has been or

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is being studied for the rare disease or (2) There is insufficient information condition and a summary and analysis about: of any available data from such stud- (i) The drug to identify the active ies. moiety and its physical and chemical (14) The sponsor’s proposal as to the properties, if these characteristics can scope of nonclinical and clinical inves- be determined; or tigations needed to establish the safety (ii) The disease or condition to deter- and effectiveness of the drug. mine that the disease or condition is (15) Detailed protocols for each pro- rare in the United States; or posed United States or foreign clinical (iii) The reasons for believing that investigation, if available. the drug may be useful for treating the (16) Specific questions to be ad- rare disease or condition with that dressed by FDA in its recommenda- drug; or tions for nonclinical laboratory studies (iv) The regulatory and marketing and clinical investigations. history of the drug to determine the [57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, scope and type of investigations that 1993] have already been conducted on the drug for the rare disease or condition; § 316.12 Providing written rec- or ommendations. (v) The plan of study for establishing (a) FDA will provide the sponsor with the safety and effectiveness of the drug written recommendations concerning for treatment of the rare disease or the nonclinical laboratory studies and condition. clinical investigations necessary for (3) The specific questions for which approval of a marketing application if the sponsor seeks the advice of the none of the reasons described in § 316.14 agency are unclear or are not suffi- for refusing to do so applies. ciently specific. (b) When a sponsor seeks written rec- (4) On the basis of the information ommendations at a stage of drug devel- submitted and on other information opment at which advice on any clinical available to the agency, FDA deter- investigations, or on particular inves- mines that the disease or condition for tigations would be premature, FDA’s which the drug is intended is not rare response may be limited to written rec- in the United States. ommendations concerning only non- (5) On the basis of the information clinical laboratory studies, or only cer- submitted and on other information tain of the clinical studies (e.g., Phase available to the agency, FDA deter- 1 studies as described in § 312.21 of this mines that there is an inadequate basis chapter). Prior to providing written for permitting investigational use of recommendations for the clinical in- the drug under part 312 of this chapter vestigations required to achieve mar- for the rare disease or condition. keting approval, FDA may require that (6) The request for information con- the results of the nonclinical labora- tains an untrue statement of material tory studies or completed early clinical fact. studies be submitted to FDA for agen- (b) A refusal to provide written rec- cy review. ommendations will be in writing and will include a statement of the reason § 316.14 Refusal to provide written rec- for FDA’s refusal. Where practicable, ommendations. FDA will describe the information or (a) FDA may refuse to provide writ- material it requires or the conditions ten recommendations concerning the the sponsor must meet for FDA to pro- nonclinical laboratory studies and clin- vide recommendations. ical investigations necessary for ap- (c) Within 90 days after the date of a proval of a marketing application for letter from FDA requesting additional any of the following reasons: information or material or setting (1) The information required to be forth the conditions that the sponsor is submitted by § 316.10(b) has not been asked to meet, the sponsor shall either: submitted, or the information sub- (1) Provide the information or mate- mitted is incomplete. rial or amend the request for written

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recommendations to meet the condi- (3) A description of the rare disease tions sought by FDA; or or condition for which the drug is being (2) Withdraw the request for written or will be investigated, the proposed recommendations. FDA will consider a use of the drug, and the reasons why sponsor’s failure to respond within 90 such therapy is needed. days to an FDA letter requesting infor- (4) A description of the drug, to in- mation or material or setting forth clude the identity of the active moiety conditions to be met to be a with- if it is a drug composed of small mol- drawal of the request for written rec- ecules, or of the principal molecular ommendations. structural features if it is composed of macromolecules; its physical and Subpart C—Designation of an chemical properties, if these character- Orphan Drug istics can be determined; and a discussion of the scientific rationale to es- § 316.20 Content and format of a re- tablish a medically plausible basis for quest for orphan-drug designation. the use of the drug for the rare disease (a) A sponsor that submits a request or condition, including all relevant for orphan-drug designation of a drug data from in vitro laboratory studies, for a specified rare disease or condition preclinical efficacy studies conducted shall submit each request in the form in an animal model for the human dis- and containing the information re- ease or condition, and clinical experi- quired in paragraph (b) of this section. ence with the drug in the rare disease A sponsor may request orphan-drug or condition that are available to the designation of a previously unapproved sponsor, whether positive, negative, or drug, or of a new use for an already inconclusive. Animal toxicology stud- marketed drug. In addition, a sponsor ies are generally not relevant to a re- of a drug that is otherwise the same quest for orphan-drug designation. Cop- drug as an already approved drug may ies of pertinent unpublished and pub- seek and obtain orphan-drug designa- lished papers are also required. tion for the subsequent drug for the (5) Where the sponsor of a drug that same rare disease or condition if it can is otherwise the same drug as an al- present a plausible hypothesis that its ready approved drug seeks orphan-drug drug may be clinically superior to the designation for the subsequent drug for first drug. More than one sponsor may the same rare disease or condition, an receive orphan-drug designation of the explanation of why the proposed vari- same drug for the same rare disease or ation may be clinically superior to the condition, but each sponsor seeking or- first drug. phan-drug designation must file a complete request for designation as pro- (6) Where a sponsor requests orphan- vided in paragraph (b) of this section. drug designation for a drug for only a (b) A sponsor shall submit two copies subset of persons with a particular dis- of a completed, dated, and signed re- ease or condition that otherwise affects quest for designation that contains the 200,000 or more people (‘‘orphan sub- following: set’’), a demonstration that, due to one (1) A statement that the sponsor re- or more properties of the drug, the requests orphan-drug designation for a maining persons with such disease or rare disease or condition, which shall condition would not be appropriate be identified with specificity. candidates for use of the drug. (2) The name and address of the spon- (7) A summary of the regulatory sta- sor; the name of the sponsor’s primary tus and marketing history of the drug contact person and/or resident agent in the United States and in foreign including title, address, telephone countries, e.g., IND and marketing ap- number, and email address; the generic plication status and dispositions, what and trade name, if any, of the drug, or, uses are under investigation and in if neither is available, the chemical what countries; for what indication is name or a meaningful descriptive name the drug approved in foreign countries; of the drug; and the name and address what adverse regulatory actions have of the source of the drug if it is not been taken against the drug in any manufactured by the sponsor. country.

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(8) Documentation, with appended States who have been diagnosed as hav- authoritative references, to dem- ing the disease or condition at the time onstrate that: of the submission of the request for or- (i) The disease or condition for which phan-drug designation. To document the drug is intended affects fewer than the number of persons in the United 200,000 people in the United States or, States who have the disease or condi- if the drug is a vaccine, diagnostic tion for which the drug is to be devel- drug, or preventive drug, the persons to oped, the sponsor shall submit to FDA whom the drug will be administered in evidence showing: the United States are fewer than 200,000 (1) The estimated prevalence of the per year as specified in § 316.21(b), or disease or condition for which the drug (ii) For a drug intended for diseases is being developed, together with a list or conditions affecting 200,000 or more of the sources (including dates of infor- people, or for a vaccine, diagnostic mation provided and literature cita- drug, or preventive drug to be adminis- tions) for the estimate; tered to 200,000 or more persons per (2) Upon request by FDA, the esti- year in the United States, there is no mated prevalence of any other disease reasonable expectation that costs of re- or condition for which the drug has al- search and development of the drug for ready been approved or for which the the indication can be recovered by drug is currently being developed, to- sales of the drug in the United States gether with an explanation of the bases as specified in § 316.21(c). of these estimates; and (c) Any of the information previously (3) The estimated number of people provided by the sponsor to FDA under to whom the drug will be administered subpart B of this part may be ref- annually if the drug is a vaccine or is erenced by specific page or location if a drug intended for diagnosis or pre- it duplicates information required else- vention of a rare disease or condition, where in this section. together with an explanation of the [57 FR 62085, Dec. 29, 1992, as amended at 78 bases of these estimates (including FR 35133, June 12, 2013] dates of information provided and literature citations). § 316.21 Verification of orphan-drug (c) When submitting documentation status. that there is no reasonable expectation (a) So that FDA can determine that costs of research and development whether a drug qualifies for orphan- of the drug for the disease or condition drug designation under section 526(a) of can be recovered by sales of the drug in the act, the sponsor shall include in its the United States, the sponsor shall request to FDA for orphan-drug des- submit to FDA: ignation under § 316.20 either: (1) Data on all costs that the sponsor (1) Documentation as described in has incurred in the course of devel- paragraph (b) of this section that the oping the drug for the U.S. market. number of people affected by the dis- These costs shall include, but are not ease or condition for which the drug is limited to, nonclinical laboratory stud- to be developed is fewer than 200,000 ies, clinical studies, dosage form devel- persons; or opment, record and report mainte- (2) Documentation as described in nance, meetings with FDA, determina- paragraph (c) of this section that dem- tion of patentability, preparation of onstrates that there is no reasonable designation request, IND/marketing ap- expectation that the sales of the drug plication preparation, distribution of will be sufficient to offset the costs of the drug under a ‘‘treatment’’ protocol, developing the drug for the U.S. mar- licensing costs, liability insurance, and ket and the costs of making the drug overhead and depreciation. Further- available in the United States. more, the sponsor shall demonstrate (b) For the purpose of documenting the reasonableness of the cost data. that the number of people affected by For example, if the sponsor has in- the disease or condition for which the curred costs for clinical investigations, drug is to be developed is less than the sponsor shall provide information 200,000 persons, ‘‘prevalence’’ is defined on the number of investigations, the as the number of persons in the United years in which they took place, and on

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the scope, duration, and number of pa- that the sponsor has incurred in the tients that were involved in each inves- past and expects to incur during the tigation. first 7 years that the drug is marketed. (2) If the drug was developed wholly (6) An estimate of and justification or in part outside the United States, in for the expected revenues from sales of addition to the documentation listed in the drug in the United States during paragraph (c)(1) of this section: its first 7 years of marketing. The jus- (i) Data on and justification for all tification should assume that the total costs that the sponsor has incurred market for the drug is equal to the outside of the United States in the prevalence of the disease or condition course of developing the drug for the that the drug will be used to treat. The U.S. market. The justification, in addi- justification should include: tion to demonstrating the reasonable- (i) An estimate of the expected mar- ness of the cost data, must also explain ket share of the drug in each of the the method that was used to determine first 7 years that it is marketed, to- which portion of the foreign develop- gether with an explanation of the basis ment costs should be applied to the for that estimate; U.S. market, and what percent these (ii) A projection of and justification costs are of total worldwide develop- for the price at which the drug will be ment costs. Any data submitted to for- sold; and eign government authorities to support (iii) Comparisons with sales of simi- drug pricing determinations must be larly situated drugs, where available. included with this information. (7) The name of each country where (ii) Data that show which foreign de- the drug has already been approved for velopment costs were recovered marketing for any indication, the dates through cost recovery procedures that of approval, the indication for which are allowed during drug development in the drug is approved, and the annual some foreign countries. For example, if sales and number of prescriptions in the sponsor charged patients for the each country since the first approval drug during clinical investigations, the date. revenues collected by the sponsor must (8) A report of an independent cer- be reported to FDA. tified public accountant in accordance (3) In cases where the drug has al- with Statement on Standards for At- ready been approved for marketing for testation established by the American any indication or in cases where the Institute of Certified Public Account- drug is currently under investigation ants on agreed upon procedures per- for one or more other indications (in formed with respect to the data esti- addition to the indication for which or- mates and justifications submitted phan-drug designation is being sought), pursuant to this section. Cost data a clear explanation of and justification shall be determined in accordance with for the method that is used to appor- generally accepted accounting prin- tion the development costs among the ciples. various indications. (d) A sponsor that is requesting or- (4) A statement of and justification phan-drug designation for a drug de- for any development costs that the signed to treat a disease or condition sponsor expects to incur after the sub- that affects 200,000 or more persons mission of the designation request. In shall, at FDA’s request, allow FDA or cases where the extent of these future FDA-designated personnel to examine development costs are not clear, the at reasonable times and in a reasonable sponsor should request FDA’s advice manner all relevant financial records and assistance in estimating the scope and sales data of the sponsor and man- of nonclinical laboratory studies and ufacturer. clinical investigations and other data [57 FR 62085, Dec. 29, 1992, as amended at 78 that are needed to support marketing FR 35133, June 12, 2013] approval. Based on these recommendations, a cost estimate should be pre- § 316.22 Permanent-resident agent for pared. foreign sponsor. (5) A statement of and justification Every foreign sponsor that seeks or- for production and marketing costs phan-drug designation shall name a

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permanent resident of the United reasonable requests for an extension. States as the sponsor’s agent upon In the event FDA denies a request for whom service of all processes, notices, an extension of time, FDA may con- orders, decisions, requirements, and sider the designation request volun- other communications may be made on tarily withdrawn. In the event FDA behalf of the sponsor. Notifications of considers a designation request volun- changes in such agents or changes of tarily withdrawn, FDA will so notify address of agents should preferably be the sponsor in writing. provided in advance, but not later than (b) FDA will grant the request for or- 60 days after the effective date of such phan-drug designation if none of the changes. The permanent-resident agent reasons described in § 316.25 for requir- may be an individual, firm, or domestic ing or permitting refusal to grant such corporation and may represent any a request applies. number of sponsors. The name of the (c) When a request for orphan-drug permanent-resident agent, address, designation is granted, FDA will notify telephone number, and email address the sponsor in writing and will pub- shall be provided to: Office of Orphan licize the orphan-drug designation in Products Development, Food and Drug accordance with § 316.28. Administration, Bldg. 32, rm. 5271, 10903 (d) A sponsor may voluntarily with- New Hampshire Ave., Silver Spring, draw an orphan-drug designation re- MD 20993. quest or an orphan-drug designation at any time after the request is submitted [78 FR 35133, June 12, 2013] or granted, respectively, by submitting a written request for withdrawal to § 316.23 Timing of requests for orphan- drug designation; designation of al- FDA. FDA will acknowledge such with- ready approved drugs. drawal in a letter to the sponsor. Any benefits attendant to designation (such (a) A sponsor may request orphan- as orphan-exclusive approval) will drug designation at any time in its cease once designation is voluntarily drug development process prior to the withdrawn, from the date of FDA’s ac- time that sponsor submits a marketing knowledgement letter. If a sponsor vol- application for the drug for the same untarily withdraws designation, FDA rare disease or condition. will publicize such withdrawal in ac- (b) A sponsor may request orphan- cordance with § 316.28. drug designation of an already approved drug for an unapproved use [57 FR 62085, Dec. 29, 1992, as amended at 78 without regard to whether the prior FR 35133, June 12, 2013] marketing approval was for a rare dis- § 316.25 Refusal to grant orphan-drug ease or condition. designation. [78 FR 35133, June 12, 2013] (a) FDA will refuse to grant a request for orphan-drug designation if any of § 316.24 Deficiency letters and grant- the following reasons apply: ing orphan-drug designation. (1) The drug is not intended for a rare (a) FDA will send a deficiency letter disease or condition because: to the sponsor if the request for or- (i) There is insufficient evidence to phan-drug designation lacks informa- support the estimate that the drug is tion required under §§ 316.20 and 316.21, intended for treatment of a disease or or contains inaccurate or incomplete condition in fewer than 200,000 people information. FDA may consider a des- in the United States, or that the drug ignation request voluntarily with- is intended for use in prevention or in drawn if the sponsor fails to respond to diagnosis in fewer than 200,000 people the deficiency letter within 1 year of annually in the United States; or issuance of the deficiency letter, unless (ii) Where the drug is intended for within that same timeframe the spon- prevention, diagnosis, or treatment of sor requests in writing an extension of a disease or condition affecting 200,000 time to respond. This request must in- or more people in the United States, clude the reason(s) for the requested the sponsor has failed to demonstrate extension and the length of time of the that there is no reasonable expectation requested extension. FDA will grant all that development and production costs

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will be recovered from sales of the drug § 316.21(a)(1) or (a)(2) upon which the for such disease or condition in the drug was originally designated. United States. A sponsor’s failure to [78 FR 35134, June 12, 2013] comply with § 316.21 shall constitute a failure to make the demonstration re- § 316.27 Change in ownership of or- quired in this paragraph. phan-drug designation. (2) There is insufficient information (a) A sponsor may transfer ownership about the drug, or the disease or condi- of or any beneficial interest in the or- tion for which it is intended, to estab- phan-drug designation of a drug to a lish a medically plausible basis for ex- new sponsor. At the time of the trans- pecting the drug to be effective in the fer, the new and former owners are re- prevention, diagnosis, or treatment of quired to submit the following infor- that disease or condition. mation to FDA: (3) The drug is otherwise the same (1) The former owner or assignor of drug as an already approved drug for rights shall submit a letter or other the same rare disease or condition and document that states that all or some the sponsor has not submitted a medi- rights to the orphan-drug designation cally plausible hypothesis for the pos- of the drug have been transferred to sible clinical superiority of the subse- the new owner or assignee and that a quent drug. complete copy of the request for orphan-drug designation, including any (b) FDA may refuse to grant a re- amendments to the request, supple- quest for orphan-drug designation if ments to the granted request, and cor- the request for designation contains an respondence relevant to the orphan- untrue statement of material fact or drug designation, has been provided to omits material information or if the the new owner or assignee. request is otherwise ineligible under (2) The new owner or assignee of this part. rights shall submit a statement accept- [57 FR 62085, Dec. 29, 1992, as amended at 78 ing orphan-drug designation and a let- FR 35133, June 12, 2013] ter or other document containing the following: § 316.26 Amendment to orphan-drug (i) The date that the change in own- designation. ership or assignment of rights is effec- (a) At any time prior to approval of a tive; marketing application for a designated (ii) A statement that the new owner orphan drug, the sponsor holding des- has a complete copy of the request for ignation may apply for an amendment orphan-drug designation including any to the designated use if the proposed amendments to the request, supple- change is due to new and unexpected ments to the granted request, and correspondence relevant to the orphan- findings in research on the drug, infor- drug designation; and mation arising from FDA recommenda- (iii) A specific description of the tions, or unforeseen developments in rights that have been assigned and treatment or diagnosis of the disease those that have been reserved. This or condition. may be satisfied by the submission of (b) FDA will grant the amendment if either a list of rights assigned and re- it finds that the initial designation reserved or copies of all relevant agree- quest was made in good faith and that ments between assignors and assignees; the amendment is intended to conform and the orphan-drug designation to the re- (iv) The name and address of a new sults of unanticipated research find- primary contact person or resident ings, to unforeseen developments in the agent. treatment or diagnosis of the disease (b) No sponsor may relieve itself of or condition, or to changes based on responsibilities under the Orphan Drug FDA recommendations, and that, as of Act or under this part by assigning the date of the submission of the rights to another person without: amendment request, the amendment (1) Assuring that the sponsor or the would not result in exceeding the prev- assignee will carry out such respon- alence or cost recovery thresholds in sibilities; or

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(2) Obtaining prior permission from lation) becomes more than 200,000 per- FDA. sons. (d) If FDA revokes orphan-drug des- [57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993] ignation, FDA will publicize that the drug is no longer designated in accord- § 316.28 Publication of orphan-drug ance with § 316.28(e). designations. [57 FR 62085, Dec. 29, 1992, as amended at 78 Each month FDA will update a pub- FR 35134, June 12, 2013] licly available cumulative posting of all drugs designated as orphan drugs. § 316.30 Annual reports of holder of orphan-drug designation. These postings will contain the following information: Within 14 months after the date on (a) The name and address of the spon- which a drug was designated as an or- sor; phan drug and annually thereafter (b) The generic name and trade name, until marketing approval, the sponsor if any, or, if neither is available, the of a designated drug shall submit a chemical name or a meaningful de- brief progress report to the FDA Office scriptive name of the drug; of Orphan Products Development on (c) The date of the granting of or- the drug that includes: phan-drug designation; (a) A short account of the progress of (d) The designated use in the rare dis- drug development including a review of ease or condition; and preclinical and clinical studies initi- (e) If the drug loses designation after ated, ongoing, and completed and a August 12, 2013, the date of it no longer short summary of the status or results of such studies. having designation. (b) A description of the investiga- [78 FR 35134, June 12, 2013] tional plan for the coming year, as well as any anticipated difficulties in devel- § 316.29 Revocation of orphan-drug opment, testing, and marketing; and designation. (c) A brief discussion of any changes (a) FDA may revoke orphan-drug des- that may affect the orphan-drug status ignation for any drug if the agency of the product. For example, for prod- finds that: ucts nearing the end of the approval (1) The request for designation con- process, sponsors should discuss any tained an untrue statement of material disparity between the probable mar- fact; or keting indication and the designated (2) The request for designation omit- indication as related to the need for an ted material information required by amendment to the orphan-drug des- this part; or ignation pursuant to § 316.26. (3) FDA subsequently finds that the drug in fact had not been eligible for Subpart D—Orphan-drug orphan-drug designation at the time of Exclusive Approval submission of the request therefor. (b) For an approved drug, revocation § 316.31 Scope of orphan-drug exclu- of orphan-drug designation also sus- sive approval. pends or withdraws the sponsor’s exclu- (a) FDA may approve a sponsor’s sive marketing rights for the drug but marketing application for a designated not the approval of the drug’s mar- orphan drug for use in the rare disease keting application. or condition for which the drug was (c) Where a drug has been designated designated, or for select indication(s) as an orphan drug because the preva- or use(s) within the rare disease or con- lence of a disease or condition (or, in dition for which the drug was des- the case of vaccines, diagnostic drugs, ignated. Unless FDA previously ap- or preventive drugs, the target popu- proved the same drug for the same use lation) is under 200,000 in the United or indication, FDA will not approve an- States at the time of designation, its other sponsor’s marketing application designation will not be revoked on the for the same drug for the same use or ground that the prevalence of the dis- indication before the expiration of 7 ease or condition (or the target popu- years from the date of such approval as

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stated in the approval letter from FDA, same drug has not already been ap- except that such a marketing applica- proved for the same use or indication. tion can be approved sooner if, and at The written notice will inform the such time as, any of the following oc- sponsor of the requirements for main- curs: taining orphan-drug exclusive approval (1) Withdrawal of exclusive approval for the full 7-year term of exclusive ap- or revocation of orphan-drug designa- proval. tion by FDA under any provision of (b) When a marketing application is this part; or approved under section 505 of the Fed- (2) Withdrawal for any reason of the eral Food, Drug, and Cosmetic Act (21 marketing application for the drug in U.S.C. 355) for a designated orphan question; or drug that qualifies for exclusive ap- (3) Consent by the holder of exclusive proval, FDA will publish in its publica- approval to permit another marketing tion entitled ‘‘Approved Drug Products application to gain approval; or With Therapeutic Equivalence Evalua- (4) Failure of the holder of exclusive tions’’ information identifying the approval to assure a sufficient quantity sponsor, the drug, and the date of ter- of the drug under section 527 of the act mination of the orphan-drug exclusive and § 316.36. approval. A subscription to this publi- (b) Orphan-drug exclusive approval cation and its monthly cumulative sup- protects only the approved indication plements is available from the Super- or use of a designated drug. If such ap- intendent of Documents, Government proval is limited to only particular in- Printing Office, Washington, DC 20402– dication(s) or uses(s) within the rare 9325, and is also available online at disease or condition for which the drug http://www.accessdata.fda.gov/scripts/ was designated, FDA may later ap- cder/ob/default.cfm. prove the drug for additional indica- (c) If a drug is otherwise the same tion(s) or uses(s) within the rare dis- drug as a previously approved drug for ease or condition not protected by the the same use or indication, FDA will exclusive approval. If the sponsor who not recognize orphan-drug exclusive obtains approval for these new indica- approval if the sponsor fails to dem- tion(s) or uses(s) has orphan-drug des- onstrate upon approval that the drug is ignation for the drug for the rare dis- clinically superior to the previously ease or condition, FDA will recognize a approved drug. new orphan-drug exclusive approval for these new (not previously approved) in- [78 FR 35135, June 12, 2013] dication(s) or use(s) from the date of approval of the drug for such new indi- § 316.36 Insufficient quantities of or- cation(s) or use(s). phan drugs. (c) If a sponsor’s marketing applica- (a) Under section 527 of the act, tion for a drug product is determined whenever the Director has reason to not to be approvable because approval believe that the holder of exclusive ap- is barred under section 527 of the Fed- proval cannot assure the availability of eral Food, Drug, and Cosmetic Act sufficient quantities of an orphan drug until the expiration of the period of ex- to meet the needs of patients with the clusive marketing of another drug, disease or condition for which the drug FDA will so notify the sponsor in writ- was designated, the Director will so no- ing. tify the holder of this possible insuffi- [57 FR 62085, Dec. 29, 1992, as amended at 78 ciency and will offer the holder one of FR 35134, June 12, 2013] the following options, which must be exercised by a time that the Director § 316.34 FDA recognition of exclusive specifies: approval. (1) Provide the Director in writing, or (a) FDA will send the sponsor (or, the orally, or both, at the Director’s dis- permanent-resident agent, if applica- cretion, views and data as to how the ble) timely written notice recognizing holder can assure the availability of exclusive approval once the marketing sufficient quantities of the orphan drug application for a designated orphan- within a reasonable time to meet the drug product has been approved, if the needs of patients with the disease or

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condition for which the drug was des- New Hampshire Ave., Silver Spring, ignated; or MD 20993. (2) Provide the Director in writing [78 FR 35135, June 12, 2013] the holder’s consent for the approval of other marketing applications for the § 316.52 Availability for public disclo- same drug before the expiration of the sure of data and information in re- 7-year period of exclusive approval. quests and applications. (b) If, within the time that the Direc- (a) FDA will not publicly disclose the tor specifies, the holder fails to consent existence of a request for orphan-drug to the approval of other marketing ap- designation under section 526 of the act plications and if the Director finds that prior to final FDA action on the re- the holder has not shown that it can quest unless the existence of the re- assure the availability of sufficient quest has been previously publicly dis- quantities of the orphan drug to meet closed or acknowledged. the needs of patients with the disease (b) Whether or not the existence of a or condition for which the drug was pending request for designation has designated, the Director will issue a been publicly disclosed or acknowl- written order withdrawing the drug edged, no data or information in the re- product’s exclusive approval. This quest are available for public disclo- order will embody the Director’s find- sure prior to final FDA action on the ings and conclusions and will con- request. stitute final agency action. An order (c) Upon final FDA action on a re- withdrawing the sponsor’s exclusive quest for designation, FDA will deter- marketing rights may issue whether or mine the public availability of data not there are other sponsors that can and information in the request in ac- assure the availability of alternative cordance with part 20 and § 314.430 of sources of supply. Once withdrawn this chapter and other applicable stat- under this section, exclusive approval utes and regulations. may not be reinstated for that drug. (d) In accordance with § 316.28, FDA will make a cumulative list of all orphan drug designations available to the Subpart E—Open Protocols for public and update such list monthly. Investigations (e) FDA will not publicly disclose the existence of a pending marketing appli- § 316.40 Treatment use of a designated cation for a designated orphan drug for orphan drug. the use for which the drug was des- Prospective investigators seeking to ignated unless the existence of the ap- obtain treatment use of designated or- plication has been previously publicly phan drugs may do so as provided in disclosed or acknowledged. subpart I of this chapter. (f) FDA will determine the public availability of data and information [74 FR 40945, Aug. 13, 2009] contained in pending and approved marketing applications for a des- Subpart F—Availability of ignated orphan drug for the use for Information which the drug was designated in accordance with part 20 and § 314.430 of § 316.50 Guidance documents. this chapter and other applicable stat- FDA’s Office of Orphan Products De- utes and regulations. velopment will maintain and make publicly available a list of guidance PART 317—QUALIFYING documents that apply to the regula- PATHOGENS tions in this part. The list is maintained on the Internet and is published Sec. annually in the FEDERAL REGISTER. A 317.1 [Reserved] request for a copy of the list should be 317.2 List of qualifying pathogens that have directed to the Office of Orphan Prod- the potential to pose a serious threat to ucts Development, Food and Drug Ad- public health. ministration, Bldg. 32, rm. 5271, 10903 AUTHORITY: 21 U.S.C. 355f, 371.

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SOURCE: 79 FR 32480, June 5, 2014, unless 320.27 Guidelines on the design of a mul- otherwise noted. tiple-dose in vivo bioavailability study. 320.28 Correlation of bioavailability with an § 317.1 [Reserved] acute pharmacological effect or clinical evidence. § 317.2 List of qualifying pathogens 320.29 Analytical methods for an in vivo that have the potential to pose a se- bioavailability or bioequivalence study. rious threat to public health. 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- The term ‘‘qualifying pathogen’’ in view of protocols by the Food and Drug section 505E(f) of the Federal Food, Administration. Drug, and Cosmetic Act is defined to 320.31 Applicability of requirements regard- mean any of the following: ing an ‘‘Investigational New Drug Appli- (a) Acinetobacter species. cation.’’ (b) Aspergillus species. 320.32 Procedures for establishing or amend- (c) Burkholderia cepacia complex. ing a bioequivalence requirement. 320.33 Criteria and evidence to assess actual (d) Campylobacter species. or potential bioequivalence problems. (e) Candida species. 320.34 Requirements for batch testing and (f) Clostridium difficile. certification by the Food and Drug Ad- (g) Coccidioides species. ministration. (h) Cryptococcus species. 320.35 Requirements for in vitro testing of (i) Enterobacteriaceae. each batch. (j) Enterococcus species. 320.36 Requirements for maintenance of records of bioequivalence testing. (k) Helicobacter pylori. 320.38 Retention of bioavailability samples. (l) Mycobacterium tuberculosis com- 320.63 Retention of bioequivalence samples. plex. (m) Neisseria gonorrhoeae. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371. (n) Neisseria meningitidis. (o) Non-tuberculous mycobacteria Subpart A—General Provisions species. (p) Pseudomonas species. § 320.1 Definitions. (q) Staphylococcus aureus. The definitions contained in § 314.3 of (r) Streptococcus agalactiae. this chapter apply to those terms when (s) Streptococcus pneumoniae. used in this part. (t) Streptococcus pyogenes. [81 FR 69658, Oct. 6, 2016] (u) Vibrio cholerae. Subpart B—Procedures for Deter- PART 320—BIOAVAILABILITY AND mining the Bioavailability or BIOEQUIVALENCE REQUIREMENTS Bioequivalence of Drug Prod- ucts Subpart A—General Provisions

Sec. SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth- 320.1 Definitions. erwise noted.

Subpart B—Procedures for Determining the § 320.21 Requirements for submission Bioavailability or Bioequivalence of of bioavailability and bioequiva- Drug Products lence data. 320.21 Requirements for submission of bio- (a) Any person submitting a full new availability and bioequivalence data. drug application to the Food and Drug 320.22 Criteria for waiver of evidence of in Administration (FDA) shall include in vivo bioavailability or bioequivalence. the application either: 320.23 Basis for measuring in vivo bio- (1) Evidence measuring the in vivo availability or demonstrating bioequiva- bioavailability of the drug product that lence. is the subject of the application; or 320.24 Types of evidence to measure bio- (2) Information to permit FDA to availability or establish bioequivalence. waive the submission of evidence meas- 320.25 Guidelines for the conduct of an in vivo bioavailability study. uring in vivo bioavailability. 320.26 Guidelines on the design of a single- (b) Any person submitting an abbre- dose in vivo bioavailability or bioequiva- viated new drug application to FDA lence study. shall include in the application either:

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(1) Evidence demonstrating that the (1) The application is otherwise ap- drug product that is the subject of the provable. abbreviated new drug application is (2) The application agrees to submit, bioequivalent to the reference listed within the time specified by FDA, ei- drug (defined in § 314.3(b) of this chap- ther: ter). A complete study report must be (i) Evidence measuring the in vivo submitted for the bioequivalence study bioavailability and demonstrating the upon which the applicant relies for ap- in vivo bioequivalence of the drug proval. For all other bioequivalence product that is the subject of the appli- studies conducted on the same drug cation; or product formulation, the applicant (ii) Information to permit FDA to must submit either a complete or sum- waive measurement of in vivo bio- mary report. If a summary report of a availability. bioequivalence study is submitted and (e) Evidence measuring the in vivo FDA determines that there may be bio- bioavailability and demonstrating the equivalence issues or concerns with the in vivo bioequivalence of a drug prod- product, FDA may require that the ap- uct shall be obtained using one of the plicant submit a complete report of the approaches for determining bio- bioequivalence study to FDA; or availability set forth in § 320.24. (2) Information to show that the drug (f) Information to permit FDA to product is bioequivalent to the ref- waive the submission of evidence meas- erence listed drug which would permit uring the in vivo bioavailability or FDA to waive the submission of evi- demonstrating the in vivo bioequiva- dence demonstrating in vivo bioequivalence shall meet the criteria set forth lence as provided in paragraph (f) of in § 320.22. this section. (g) Any person holding an approved (c) Any person submitting a supple- full or abbreviated new drug applica- mental application to FDA shall in- tion shall submit to FDA a supple- clude in the supplemental application mental application containing new evi- the evidence or information set forth dence measuring the in vivo bio- in paragraphs (a) and (b) of this section availability or demonstrating the in if the supplemental application pro- vivo bioequivalence of the drug product poses any of the following changes: that is the subject of the application if (1) A change in the manufacturing notified by FDA that: site or a change in the manufacturing (1) There are data demonstrating process, including a change in product that the dosage regimen in the labeling formulation or dosage strength, beyond is based on incorrect assumptions or the variations provided for in the ap- facts regarding the pharmacokinetics proved application. of the drug product and that following (2) A change in the labeling to pro- this dosage regimen could potentially vide for a new indication for use of the result in subtherapeutic or toxic levels; drug product, if clinical studies are re- or quired to support the new indication for use. (2) There are data measuring signifi- (3) A change in the labeling to pro- cant intra-batch and batch-to-batch vide for a new dosage regimen or for an variability, e.g., plus or minus 25 per- additional dosage regimen for a special cent, in the bioavailability of the drug patient population, e.g., infants, if clin- product. ical studies are required to support the (h) The requirements of this section new or additional dosage regimen. regarding the submission of evidence (d) FDA may approve a full new drug measuring the in vivo bioavailability application, or a supplemental applica- or demonstrating the in vivo bio- tion proposing any of the changes set equivalence apply only to a full or ab- forth in paragraph (c) of this section, breviated new drug application or a that does not contain evidence of in supplemental application for a finished vivo bioavailability or information to dosage formulation. permit waiver of the requirement for in [57 FR 17998, Apr. 28, 1992, as amended at 67 vivo bioavailability data, if all of the FR 77672, Dec. 19, 2002; 74 FR 2862, Jan. 16, following conditions are met. 2009]

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§ 320.22 Criteria for waiver of evidence or nebulization, a nasal solution, or of in vivo bioavailability or bio- similar other solubilized form; and equivalence. (ii) Contains an active drug ingre- (a) Any person submitting a full or dient in the same concentration and abbreviated new drug application, or a dosage form as a drug product that is supplemental application proposing the subject of an approved full new any of the changes set forth in drug application or abbreviated new § 320.21(c), may request FDA to waive drug application; and the requirement for the submission of (iii) Contains no inactive ingredient evidence measuring the in vivo bio- or other change in formulation from availability or demonstrating the in the drug product that is the subject of vivo bioequivalence of the drug product the approved full new drug application that is the subject of the application. or abbreviated new drug application An applicant shall submit a request for that may significantly affect absorp- waiver with the application. Except as tion of the active drug ingredient or provided in paragraph (f) of this sec- active moiety for products that are tion, FDA shall waive the requirement systemically absorbed, or that may sig- for the submission of evidence of in nificantly affect systemic or local vivo bioavailability or bioequivalence availability for products intended to if the drug product meets any of the act locally. provisions of paragraphs (b), (c), (d), or (c) FDA shall waive the requirement (e) of this section. for the submission of evidence meas- (b) For certain drug products, the in uring the in vivo bioavailability or vivo bioavailability or bioequivalence demonstrating the in vivo bioequiva- of the drug product may be self-evi- lence of a solid oral dosage form (other dent. FDA shall waive the requirement than a delayed release or extended re- for the submission of evidence obtained lease dosage form) of a drug product in vivo measuring the bioavailability determined to be effective for at least or demonstrating the bioequivalence of one indication in a Drug Efficacy these drug products. A drug product’s Study Implementation notice or which in vivo bioavailability or bioequiva- is identical, related, or similar to such lence may be considered self-evident a drug product under § 310.6 of this based on other data in the application chapter unless FDA has evaluated the if the product meets one of the fol- drug product under the criteria set lowing criteria: forth in § 320.33, included the drug product in the Approved Drug Products (1) The drug product: with Therapeutic Equivalence Evalua- (i) Is a parenteral solution intended tions List, and rated the drug product solely for administration by injection, as having a known or potential bio- or an ophthalmic or otic solution; and equivalence problem. A drug product so (ii) Contains the same active and in- rated reflects a determination by FDA active ingredients in the same con- that an in vivo bioequivalence study is centration as a drug product that is the required. subject of an approved full new drug (d) For certain drug products, bio- application or abbreviated new drug availability may be measured or bio- application. equivalence may be demonstrated by (2) The drug product: evidence obtained in vitro in lieu of in (i) Is administered by inhalation as a vivo data. FDA shall waive the require- gas, e.g., a medicinal or an inhalation ment for the submission of evidence anesthetic; and obtained in vivo measuring the bio- (ii) Contains an active ingredient in availability or demonstrating the bio- the same dosage form as a drug product equivalence of the drug product if the that is the subject of an approved full drug product meets one of the fol- new drug application or abbreviated lowing criteria: new drug application. (1) [Reserved] (3) The drug product: (2) The drug product is in the same (i) Is a solution for application to the dosage form, but in a different skin, an oral solution, elixir, syrup, strength, and is proportionally similar tincture, a solution for aerosolization in its active and inactive ingredients to

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another drug product for which the § 320.23 Basis for measuring in vivo same manufacturer has obtained ap- bioavailability or demonstrating proval and the conditions in para- bioequivalence. graphs (d)(2)(i) through (d)(2)(iii) of (a)(1) The in vivo bioavailability of a this section are met: drug product is measured if the prod- (i) The bioavailability of this other uct’s rate and extent of absorption, as drug product has been measured; determined by comparison of measured (ii) Both drug products meet an ap- parameters, e.g., concentration of the propriate in vitro test approved by active drug ingredient in the blood, FDA; and urinary excretion rates, or pharma- (iii) The applicant submits evidence cological effects, do not indicate a sig- showing that both drug products are nificant difference from the reference proportionally similar in their active material’s rate and extent of absorp- and inactive ingredients. tion. For drug products that are not intended to be absorbed into the blood- (iv) Paragraph (d) of this section does stream, bioavailability may be as- not apply to delayed release or ex- sessed by scientifically valid measure- tended release products. ments intended to reflect the rate and (3) The drug product is, on the basis extent to which the active ingredient of scientific evidence submitted in the or active moiety becomes available at application, shown to meet an in vitro the site of action. test that has been correlated with in (2) Statistical techniques used must vivo data. be of sufficient sensitivity to detect (4) The drug product is a reformu- differences in rate and extent of ab- lated product that is identical, except sorption that are not attributable to for a different color, flavor, or preserv- subject variability. ative that could not affect the bio- (3) A drug product that differs from availability of the reformulated prod- the reference material in its rate of ab- uct, to another drug product for which sorption, but not in its extent of ab- the same manufacturer has obtained sorption, may be considered to be bio- approval and the following conditions available if the difference in the rate of are met: absorption is intentional, is appro- (i) The bioavailability of the other priately reflected in the labeling, is not product has been measured; and essential to the attainment of effective (ii) Both drug products meet an ap- body drug concentrations on chronic propriate in vitro test approved by use, and is considered medically insig- FDA. nificant for the drug product. (e) FDA, for good cause, may waive a (b)(1) Two drug products will be con- requirement for the submission of evi- sidered bioequivalent drug products if dence of in vivo bioavailability or bio- they are pharmaceutical equivalents or equivalence if waiver is compatible pharmaceutical alternatives whose with the protection of the public rate and extent of absorption do not health. For full new drug applications, show a significant difference when ad- FDA may defer a requirement for the ministered at the same molar dose of submission of evidence of in vivo bio- the active moiety under similar experi- availability if deferral is compatible mental conditions, either single dose or with the protection of the public multiple dose. Some pharmaceutical health. equivalents or pharmaceutical alternatives may be equivalent in the ex- (f) FDA, for good cause, may require tent of their absorption but not in evidence of in vivo bioavailability or their rate of absorption and yet may be bioequivalence for any drug product if considered bioequivalent because such the agency determines that any dif- differences in the rate of absorption are ference between the drug product and a intentional and are reflected in the la- listed drug may affect the bio- beling, are not essential to the attain- availability or bioequivalence of the ment of effective body drug concentra- drug product. tions on chronic use, and are consid- [57 FR 17998, Apr. 28, 1992, as amended at 67 ered medically insignificant for the FR 77673, Dec. 19, 2002] particular drug product studied.

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(2) For drug products that are not in- systemic distribution within the body; tended to be absorbed into the blood- or stream, bioequivalence may be dem- (ii) An in vitro test that has been onstrated by scientifically valid meth- correlated with and is predictive of ods that are expected to detect a sig- human in vivo bioavailability data; or nificant difference between the drug (2) An in vivo test in humans in and the listed drug in safety and thera- which the urinary excretion of the ac- peutic effect. tive moiety, and, when appropriate, its [57 FR 17999, Apr. 28, 1992, as amended at 67 active metabolite(s), are measured as a FR 77673, Dec. 19, 2002, 81 FR 69658, Oct. 6, function of time. The intervals at 2016] which measurements are taken should ordinarily be as short as possible so § 320.24 Types of evidence to measure bioavailability or establish bio- that the measure of the rate of elimi- equivalence. nation is as accurate as possible. De- pending on the nature of the drug prod- (a) Bioavailability may be measured or bioequivalence may be dem- uct, this approach may be applicable to onstrated by several in vivo and in the category of dosage forms described vitro methods. FDA may require in in paragraph (b)(1)(i) of this section. vivo or in vitro testing, or both, to This method is not appropriate where measure the bioavailability of a drug urinary excretion is not a significant product or establish the bioequivalence mechanism of elimination. of specific drug products. Information (3) An in vivo test in humans in on bioequivalence requirements for which an appropriate acute pharma- specific products is included in the cur- cological effect of the active moiety, rent edition of FDA’s publication ‘‘Ap- and, when appropriate, its active me- proved Drug Products with Thera- tabolite(s), are measured as a function peutic Equivalence Evaluations’’ and of time if such effect can be measured any current supplement to the publica- with sufficient accuracy, sensitivity, tion. The selection of the method used and reproducibility. This approach is to meet an in vivo or in vitro testing applicable to the category of dosage requirement depends upon the purpose forms described in paragraph (b)(1)(i) of of the study, the analytical methods this section only when appropriate available, and the nature of the drug methods are not available for measure- product. Applicants shall conduct bio- ment of the concentration of the moi- availability and bioequivalence testing ety, and, when appropriate, its active using the most accurate, sensitive, and metabolite(s), in biological fluids or ex- reproducible approach available among cretory products but a method is avail- those set forth in paragraph (b) of this able for the measurement of an appro- section. The method used must be ca- priate acute pharmacological effect. pable of measuring bioavailability or This approach may be particularly ap- establishing bioequivalence, as appro- plicable to dosage forms that are not priate, for the product being tested. intended to deliver the active moiety (b) The following in vivo and in vitro to the bloodstream for systemic dis- approaches, in descending order of accuracy, sensitivity, and reproduc- tribution. ibility, are acceptable for determining (4) Well-controlled clinical trials that the bioavailability or bioequivalence of establish the safety and effectiveness a drug product. of the drug product, for purposes of (1)(i) An in vivo test in humans in measuring bioavailability, or appro- which the concentration of the active priately designed comparative clinical ingredient or active moiety, and, when trials, for purposes of demonstrating appropriate, its active metabolite(s), in bioequivalence. This approach is the whole blood, plasma, serum, or other least accurate, sensitive, and reproduc- appropriate biological fluid is meas- ible of the general approaches for ured as a function of time. This ap- measuring bioavailability or dem- proach is particularly applicable to onstrating bioequivalence. For dosage dosage forms intended to deliver the forms intended to deliver the active active moiety to the bloodstream for moiety to the bloodstream for systemic

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distribution, this approach may be con- In some situations, an in vivo bio- sidered acceptable only when analyt- availability study in humans may pref- ical methods cannot be developed to erably and more properly be done in permit use of one of the approaches suitable patients. Critically ill patients outlined in paragraphs (b)(1)(i) and shall not be included in an in vivo bio- (b)(2) of this section, when the ap- availability study unless the attending proaches described in paragraphs physician determines that there is a (b)(1)(ii), (b)(1)(iii), and (b)(3) of this potential benefit to the patient. section are not available. This ap- (b) Basic design. The basic design of proach may also be considered suffi- an in vivo bioavailability study is de- ciently accurate for measuring bio- termined by the following: availability or demonstrating bio- (1) The scientific questions to be an- equivalence of dosage forms intended swered. to deliver the active moiety locally, (2) The nature of the reference mate- e.g., topical preparations for the skin, rial and the dosage form to be tested. eye, and mucous membranes; oral dos- (3) The availability of analytical age forms not intended to be absorbed, methods. e.g., an antacid or radiopaque medium; (4) Benefit-risk considerations in re- and bronchodilators administered by gard to testing in humans. inhalation if the onset and duration of (c) Comparison to a reference material. pharmacological activity are defined. In vivo bioavailability testing of a drug (5) A currently available in vitro test product shall be in comparison to an acceptable to FDA (usually a dissolu- appropriate reference material unless tion rate test) that ensures human in some other approach is more appro- vivo bioavailability. priate for valid scientific reasons. (6) Any other approach deemed ade- (d) Previously unmarketed active drug quate by FDA to measure bio- ingredients or therapeutic moieties. (1) An availability or establish bioequiva- in vivo bioavailability study involving lence. a drug product containing an active (c) FDA may, notwithstanding prior drug ingredient or therapeutic moiety requirements for measuring bio- that has not been approved for mar- availability or establishing bioequiva- keting can be used to measure the fol- lence, require in vivo testing in hu- lowing pharmacokinetic data: mans of a product at any time if the (i) The bioavailability of the formu- agency has evidence that the product: lation proposed for marketing; and (1) May not produce therapeutic ef- (ii) The essential pharmacokinetic fects comparable to a pharmaceutical characteristics of the active drug in- equivalent or alternative with which it gredient or therapeutic moiety, such as is intended to be used interchangeably; the rate of absorption, the extent of ab- (2) May not be bioequivalent to a sorption, the half-life of the thera- pharmaceutical equivalent or alter- peutic moiety in vivo, and the rate of native with which it is intended to be excretion and/or metabolism. Dose pro- used interchangeably; or portionality of the active drug ingre- (3) Has greater than anticipated po- dient or the therapeutic moiety needs tential toxicity related to pharmaco- to be established after single-dose ad- kinetic or other characteristics. ministration and in certain instances [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July after multiple-dose administration. 1, 1992, as amended at 67 FR 77673, Dec. 19, This characterization is a necessary 2002] part of the investigation of the drug to support drug labeling. § 320.25 Guidelines for the conduct of (2) The reference material in such a an in vivo bioavailability study. bioavailability study should be a solu- (a) Guiding principles. (1) The basic tion or suspension containing the same principle in an in vivo bioavailability quantity of the active drug ingredient study is that no unnecessary human re- or therapeutic moiety as the formula- search should be done. tion proposed for marketing. (2) An in vivo bioavailability study is (3) The reference material should be generally done in a normal adult popu- administered by the same route as the lation under standardized conditions. formulation proposed for marketing

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unless an alternative or additional (iii) The drug product’s steady-state route is necessary to answer the sci- performance is equivalent to a cur- entific question under study. For ex- rently marketed nonextended release ample, in the case of an active drug in- or extended release drug product that gredient or therapeutic moiety that is contains the same active drug ingre- poorly absorbed after oral administra- dient or therapeutic moiety and that is tion, it may be necessary to compare subject to an approved full new drug the oral dosage form proposed for mar- application. keting with the active drug ingredient (iv) The drug product’s formulation or therapeutic moiety administered in provides consistent pharmacokinetic solution both orally and intravenously. performance between individual dosage (e) New formulations of active drug in- units. gredients or therapeutic moieties approved (2) The reference material(s) for such for marketing. (1) An in vivo bio- a bioavailability study shall be chosen availability study involving a drug to permit an appropriate scientific product that is a new dosage form, or a evaluation of the extended release new salt or ester of an active drug in- claims made for the drug product. The gredient or therapeutic moiety that reference material shall be one of the has been approved for marketing can following or any combination thereof: be used to: (i) A solution or suspension of the ac- (i) Measure the bioavailability of the tive drug ingredient or therapeutic new formulation, new dosage form, or moiety. new salt or ester relative to an appropriate reference material; and (ii) A currently marketed noncon- (ii) Define the pharmacokinetic pa- trolled release drug product containing rameters of the new formulation, new the same active drug ingredient or dosage form, or new salt or ester to es- therapeutic moiety and administered tablish dosage recommendation. according to the dosage recommenda- (2) The selection of the reference ma- tions in the labeling of the noncon- terial(s) in such a bioavailability study trolled release drug product. depends upon the scientific questions (iii) A currently marketed extended to be answered, the data needed to es- release drug product subject to an ap- tablish comparability to a currently proved full new drug application con- marketed drug product, and the data taining the same active drug ingre- needed to establish dosage rec- dient or therapeutic moiety and admin- ommendations. istered according to the dosage rec- (3) The reference material should be ommendations in the labeling proposed taken from a current batch of a drug for the extended release drug product. product that is the subject of an ap- (iv) A reference material other than proved new drug application and that one set forth in paragraph (f)(2) (i), (ii) contains the same active drug ingre- or (iii) of this section that is appro- dient or therapeutic moiety, if the new priate for valid scientific reasons. formulation, new dosage form, or new (g) Combination drug products. (1) Gen- salt or ester is intended to be com- erally, the purpose of an in vivo bio- parable to or to meet any comparative availability study involving a combina- labeling claims made in relation to the tion drug product is to determine if the drug product that is the subject of an rate and extent of absorption of each approved new drug application. active drug ingredient or therapeutic (f) Extended release formulations. (1) moiety in the combination drug prod- The purpose of an in vivo bio- uct is equivalent to the rate and extent availability study involving a drug of absorption of each active drug ingre- product for which an extended release dient or therapeutic moiety adminis- claim is made is to determine if all of tered concurrently in separate single- the following conditions are met: ingredient preparations. (i) The drug product meets the ex- (2) The reference material in such a tended release claims made for it. bioavailability study should be two or (ii) The bioavailability profile estab- more currently marketed, single-ingre- lished for the drug product rules out dient drug products each of which con- the occurrence of any dose dumping. tains one of the active drug ingredients

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or therapeutic moieties in the com- § 320.26 Guidelines on the design of a bination drug product. The Food and single-dose in vivo bioavailability Drug Administration may, for valid or bioequivalence study. scientific reasons, specify that the ref- (a) Basic principles. (1) An in vivo bio- erence material shall be a combination availability or bioequivalence study drug product that is the subject of an should be a single-dose comparison of approved new drug application. the drug product to be tested and the (3) The Food and Drug Administra- appropriate reference material con- tion may permit a bioavailability ducted in normal adults. study involving a combination drug (2) The test product and the reference product to determine the rate and ex- material should be administered to tent of absorption of selected, but not subjects in the fasting state, unless all, active drug ingredients or thera- some other approach is more appro- peutic moieties in the combination priate for valid scientific reasons. drug product. The Food and Drug Ad- (b) Study design. (1) A single-dose ministration may permit this deter- study should be crossover in design, mination if the pharmacokinetics and unless a parallel design or other design the interactions of the active drug in- is more appropriate for valid scientific gredients or therapeutic moieties in reasons, and should provide for a drug the combination drug product are well elimination period. known and the therapeutic activity of (2) Unless some other approach is ap- the combination drug product is gen- propriate for valid scientific reasons, erally recognized to reside in only one the drug elimination period should be of the active drug ingredients or thera- either: (i) At least three times the half-life peutic moieties, e.g., ampicillin in an of the active drug ingredient or thera- ampicillin-probenecid combination peutic moiety, or its metabolite(s), drug product. measured in the blood or urine; or (h) Use of a placebo as the reference (ii) At least three times the half-life material. Where appropriate or where of decay of the acute pharmacological necessary to demonstrate the sensi- effect. tivity of the test, the reference mate- (c) Collection of blood samples. (1) rial in a bioavailability study may be a When comparison of the test product placebo if: and the reference material is to be (1) The study measures the thera- based on blood concentration time peutic or acute pharmacological effect curves, unless some other approach is of the active drug ingredient or thera- more appropriate for valid scientific peutic moiety; or reasons, blood samples should be taken (2) The study is a clinical trial to es- with sufficient frequency to permit an tablish the safety and effectiveness of estimate of both: the drug product. (i) The peak concentration in the (i) Standards for test drug product and blood of the active drug ingredient or reference material. (1) Both the drug therapeutic moiety, or its metabo- product to be tested and the reference lite(s), measured; and material, if it is another drug product, (ii) The total area under the curve for shall be shown to meet all compendial a time period at least three times the or other applicable standards of iden- half-life of the active drug ingredient tity, strength, quality, and purity, in- or therapeutic moiety, or its metabo- cluding potency and, where applicable, lite(s), measured. content uniformity, disintegration (2) In a study comparing oral dosage times, and dissolution rates. forms, the sampling times should be identical. (2) Samples of the drug product to be (3) In a study comparing an intra- tested shall be manufactured using the venous dosage form and an oral dosage same equipment and under the same form, the sampling times should be conditions as those used for full-scale those needed to describe both: production. (i) The distribution and elimination [42 FR 1648, Jan. 7, 1977, as amended at 67 FR phase of the intravenous dosage form; 77674, Dec. 19, 2002] and

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(ii) The absorption and elimination reflected in the proposed labeling of phase of the oral dosage form. the test product. (4) In a study comparing drug deliv- (3) A multiple-dose study may be re- ery systems other than oral or intra- quired to determine the bioavailability venous dosage forms with an appro- of a drug product in the following cir- priate reference standard, the sampling cumstances: times should be based on valid sci- (i) There is a difference in the rate of entific reasons. absorption but not in the extent of ab- (d) Collection of urine samples. When sorption. comparison of the test product and the (ii) There is excessive variability in reference material is to be based on cu- bioavailability from subject to subject. mulative urinary excretion-time (iii) The concentration of the active curves, unless some other approach is drug ingredient or therapeutic moiety, more appropriate for valid scientific or its metabolite(s), in the blood re- reasons, samples of the urine should be sulting from a single dose is too low for collected with sufficient frequency to accurate determination by the analyt- permit an estimate of the rate and ex- ical method. tent of urinary excretion of the active (iv) The drug product is an extended drug ingredient or therapeutic moiety, release dosage form. or its metabolite(s), measured. (b) Study design. (1) A multiple-dose (e) Measurement of an acute pharma- study should be crossover in design, cological effect. (1) When comparison of unless a parallel design or other design the test product and the reference ma- is more appropriate for valid scientific terial is to be based on acute pharma- reasons, and should provide for a drug cological effect-time curves, measure- elimination period if steady-state con- ments of this effect should be made ditions are not achieved. with sufficient frequency to permit a (2) A multiple-dose study is not re- reasonable estimate of the total area quired to be of crossover design if the under the curve for a time period at study is to establish dose proportion- least three times the half-life of decay ality under a multiple-dose regimen or of the pharmacological effect, unless to establish the pharmacokinetic pro- some other approach is more appro- file of a new drug product, a new drug priate for valid scientific reasons. delivery system, or an extended release (2) The use of an acute pharma- dosage form. cological effect to determine bio- (3) If a drug elimination period is re- availability may further require dem- quired, unless some other approach is onstration of dose-related response. In more appropriate for valid scientific such a case, bioavailability may be de- reasons, the drug elimination period termined by comparison of the dose-re- should be either: sponse curves as well as the total area (i) At least five times the half-life of under the acute pharmacological ef- the active drug ingredient or thera- fect-time curves for any given dose. peutic moiety, or its active metabo- [42 FR 1648, Jan. 7, 1977, as amended at 67 FR lite(s), measured in the blood or urine; 77674, Dec. 19, 2002] or (ii) At least five times the half-life of § 320.27 Guidelines on the design of a decay of the acute pharmacological ef- multiple-dose in vivo bioavailability fect. study. (c) Achievement of steady-state condi- (a) Basic principles. (1) In selected cir- tions. Whenever a multiple-dose study cumstances it may be necessary for the is conducted, unless some other ap- test product and the reference material proach is more appropriate for valid to be compared after repeated adminis- scientific reasons, sufficient doses of tration to determine steady-state lev- the test product and reference material els of the active drug ingredient or should be administered in accordance therapeutic moiety in the body. with the labeling to achieve steady- (2) The test product and the reference state conditions. material should be administered to (d) Collection of blood or urine samples. subjects in the fasting or nonfasting (1) Whenever comparison of the test state, depending upon the conditions product and the reference material is

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to be based on blood concentration- onstrate a maximum effect and a lack time curves at steady state, appro- of significant difference between the priate dosage administration and sam- test product and the reference mate- pling should be carried out to docu- rial. ment attainment of steady state. [42 FR 1648, Jan. 7, 1977, as amended at 67 FR (2) Whenever comparison of the test 77674, Dec. 19, 2002] product and the reference material is to be based on cumulative urinary ex- § 320.28 Correlation of bioavailability cretion-time curves at steady state, ap- with an acute pharmacological ef- propriate dosage administration and fect or clinical evidence. sampling should be carried out to docu- Correlation of in vivo bioavailability ment attainment of steady state. data with an acute pharmacological ef- (3) A more complete characterization fect or clinical evidence of safety and of the blood concentration or urinary effectiveness may be required if needed excretion rate during the absorption to establish the clinical significance of and elimination phases of a single dose a special claim, e.g., in the case of an administered at steady-state is encour- extended release preparation. aged to permit estimation of the total [42 FR 1648, Jan. 7, 1977, as amended at 67 FR area under concentration-time curves 77674, Dec. 19, 2002] or cumulative urinary excretion-time curves and to obtain pharmacokinetic § 320.29 Analytical methods for an in information, e.g., half-life or blood vivo bioavailability or bioequiva- clearance, that is essential in pre- lence study. paring adequate labeling for the drug (a) The analytical method used in an product. in vivo bioavailability or bioequiva- (e) Steady-state parameters. (1) In cer- lence study to measure the concentra- tain instances, e.g., in a study involv- tion of the active drug ingredient or ing a new drug entity, blood clearances therapeutic moiety, or its active me- at steady-state obtained in a multiple- tabolite(s), in body fluids or excretory dose study should be compared to blood products, or the method used to meas- clearances obtained in a single-dose ure an acute pharmacological effect study to support adequate dosage rec- shall be demonstrated to be accurate ommendations. and of sufficient sensitivity to meas- (2) In a linear system, the area under ure, with appropriate precision, the ac- the blood concentration-time curve tual concentration of the active drug during a dosing interval in a multiple- ingredient or therapeutic moiety, or its dose steady-state study is directly pro- active metabolite(s), achieved in the portional to the fraction of the dose ab- body. sorbed and is equal to the cor- (b) When the analytical method is responding ‘‘zero to infinity’’ area not sensitive enough to measure accu- under the curve for a single-dose study. rately the concentration of the active Therefore, when steady-state condi- drug ingredient or therapeutic moiety, tions are achieved, a comparison of or its active metabolite(s), in body blood concentrations during a dosing fluids or excretory products produced interval may be used to define the frac- by a single dose of the test product, tion of the active drug ingredient or two or more single doses may be given therapeutic moiety absorbed. together to produce higher concentra- (3) Other methods based on valid sci- tion if the requirements of § 320.31 are entific reasons should be used to deter- met. mine the bioavailability of a drug prod- [42 FR 1648, Jan. 7, 1977, as amended at 67 FR uct having dose-dependent kinetics 77674, Dec. 19, 2002] (non-linear system). (f) Measurement of an acute pharma- § 320.30 Inquiries regarding bio- cological effect. When comparison of the availability and bioequivalence re- test product and the reference material quirements and review of protocols is to be based on acute pharma- by the Food and Drug Administra- cological effect-time curves, measure- tion. ments of this effect should be made (a) The Commissioner of Food and with sufficient frequency to dem- Drugs strongly recommends that, to

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avoid the conduct of an improper study chemical entity shall submit an IND if and unnecessary human research, any the study is one of the following: person planning to conduct a bio- (1) A single-dose study in normal sub- availability or bioequivalence study jects or patients where either the max- submit the proposed protocol for the imum single or total daily dose exceeds study to FDA for review prior to the that specified in the labeling of the initiation of the study. drug product that is the subject of an (b) FDA may review a proposed pro- approved new drug application or ab- tocol for a bioavailability or bioequiva- breviated new drug application. lence study and will offer advice with (2) A multiple-dose study in normal respect to whether the following condi- subjects or patients where either the tions are met: single or total daily dose exceeds that (1) The design of the proposed bio- specified in the labeling of the drug availability or bioequivalence study is product that is the subject of an ap- appropriate. proved new drug application or abbre- (2) The reference material to be used viated new drug application. in the bioavailability or bioequivalence (3) A multiple-dose study on an ex- study is appropriate. tended release product on which no sin- (3) The proposed chemical and statis- gle-dose study has been completed. tical analytical methods are adequate. (c) The provisions of parts 50, 56, and (c)(1) General inquiries relating to in 312 of this chapter are applicable to vivo bioavailability requirements and any bioavailability or bioequivalence methodology shall be submitted to the study in humans conducted under an Food and Drug Administration, Center IND. for Drug Evaluation and Research, Of- (d) A bioavailability or bioequiva- fice of Clinical Pharmacology, 10903 lence study in humans other than one New Hampshire Ave., Silver Spring, described in paragraphs (a) through (c) MD 20993–0002. of this section is exempt from the re- (2) General inquiries relating to bio- quirements of part 312 of this chapter if equivalence requirements and method- the following conditions are satisfied: ology shall be submitted to the Food (1) If the study is one described under and Drug Administration, Center for § 320.38(b) or § 320.63, the person con- Drug Evaluation and Research, Divi- ducting the study, including any con- sion of Bioequivalence (HFD–650), 7500 tract research organization, must re- Standish Pl., Rockville, MD 20855–2773. tain reserve samples of any test article [57 FR 18000, Apr. 28, 1992, as amended at 67 and reference standard used in the FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26, study and release the reserve samples 2009] to FDA upon request, in accordance with, and for the period specified in, § 320.31 Applicability of requirements § 320.38; regarding an ‘‘Investigational New (2) An in vivo bioavailability or bio- Drug Application.’’ equivalence study in humans must be (a) Any person planning to conduct conducted in compliance with the re- an in vivo bioavailability or bioequiva- quirements for institutional review set lence study in humans shall submit an forth in part 56 of this chapter, and in- ‘‘Investigational New Drug Applica- formed consent set forth in part 50 of tion’’ (IND) if: this chapter; and (1) The test product contains a new (3) The person conducting the study, chemical entity as defined in including any contract research orga- § 314.108(a) of this chapter; or nization, must notify FDA and all par- (2) The study involves a radioactively ticipating investigators of any serious labeled drug product; or adverse event, as defined in § 312.32(a), (3) The study involves a cytotoxic observed during the conduct of the drug product. study as soon as possible but in no case (b) Any person planning to conduct a later than 15 calendar days after be- bioavailability or bioequivalence study coming aware of its occurrence. Each in humans using a drug product that report must be submitted on FDA contains an already approved, non-new Form 3500A or in an electronic format

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that FDA can process, review, and ar- (2) May not be bioequivalent drug chive. FDA will periodically issue guid- products based on the criteria set forth ance on how to provide the electronic in § 320.33; or submission (e.g., method of trans- (3) May not be bioequivalent drug mission, media, file formats, prepara- products because they are members of tion and organization of files). Each re- a class of drug products that have close port must bear prominent identifica- structural similarity and similar phys- tion of its contents, i.e., ‘‘bio- icochemical or pharmacokinetic prop- availability/bioequivalence safety re- erties to other drug products in the port.’’ The person conducting the same class that FDA finds are not bio- study, including any contract research equivalent drug products. organization, must also notify FDA of (b) FDA shall include in a proposed any fatal or life-threatening adverse rule to establish a bioequivalence re- event from the study as soon as pos- quirement the evidence and criteria set sible but in no case later than 7 cal- forth in § 320.33 that are to be consid- endar days after becoming aware of its ered in determining whether to issue occurrence. Each notification under the proposal. If the rulemaking is pro- this paragraph must be submitted to posed in response to a petition, FDA the Director, Office of Generic Drugs in shall include in the proposal a sum- the Center for Drug Evaluation and Re- mary and analysis of the relevant in- search at FDA. Relevant followup information that was submitted in the formation to a bioavailability/bio- petition as well as other available in- equivalence safety report must be sub- formation to support the establishment mitted as soon as the information is of a bioequivalence requirement. available and must be identified as (c) FDA, on its own initiative or in such, i.e., ‘‘Followup bioavailability/ response to a petition by an interested bioequivalence safety report.’’ Upon re- person, may propose and promulgate quest from FDA, the person conducting an amendment to a bioequivalence re- the study, including any contract requirement established under this sub- search organization, must submit to part. FDA any additional data or information that the agency deems necessary, [57 FR 18000, Apr. 28, 1992] as soon as possible, but in no case later than 15 calendar days after receiving § 320.33 Criteria and evidence to as- the request. sess actual or potential bioequivalence problems. [57 FR 18000, Apr. 28, 1992, as amended at 58 The Commissioner of Food and Drugs FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, 2002; 75 FR 59963, Sept. 29, 2010] shall consider the following factors, when supported by well-documented § 320.32 Procedures for establishing or evidence, to identify specific pharma- amending a bioequivalence require- ceutical equivalents and pharma- ment. ceutical alternatives that are not or (a) The Food and Drug Administra- may not be bioequivalent drug prod- tion, on its own initiative or in re- ucts. sponse to a petition by an interested (a) Evidence from well-controlled person, may propose and promulgate a clinical trials or controlled observa- regulation to establish a bioequiva- tions in patients that such drug prod- lence requirement for a product not ucts do not give comparable thera- subject to section 505(j) of the act if it peutic effects. finds there is well-documented evi- (b) Evidence from well-controlled dence that specific pharmaceutical bioequivalence studies that such prod- equivalents or pharmaceutical alter- ucts are not bioequivalent drug prod- natives intended to be used inter- ucts. changeably for the same therapeutic (c) Evidence that the drug products effect: exhibit a narrow therapeutic ratio, (1) Are not bioequivalent drug prod- e.g., there is less than a 2-fold dif- ucts; or ference in median lethal dose (LD50) 217

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and median effective dose (ED50) val- sorbed in large part in a particular seg- ues, or have less than a 2-fold dif- ment of the gastrointestinal tract or is ference in the minimum toxic con- absorbed from a localized site. centrations and minimum effective (2) The degree of absorption of the ac- concentrations in the blood, and safe tive drug ingredient, therapeutic moi- and effective use of the drug products ety, or its precursor is poor, e.g., less requires careful dosage titration and than 50 percent, ordinarily in compari- patient monitoring. son to an intravenous dose, even when (d) Competent medical determination it is administered in pure form, e.g., in that a lack of bioequivalence would solution. have a serious adverse effect in the (3) There is rapid metabolism of the treatment or prevention of a serious therapeutic moiety in the intestinal disease or condition. wall or liver during the process of ab- (e) Physicochemical evidence that: sorption (first-pass metabolism) so the (1) The active drug ingredient has a therapeutic effect and/or toxicity of low solubility in water, e.g., less than 5 such drug product is determined by the milligrams per 1 milliliter, or, if dis- rate as well as the degree of absorp- solution in the stomach is critical to tion. absorption, the volume of gastric fluids (4) The therapeutic moiety is rapidly required to dissolve the recommended metabolized or excreted so that rapid dose far exceeds the volume of fluids dissolution and absorption are required present in the stomach (taken to be 100 for effectiveness. milliliters for adults and prorated for (5) The active drug ingredient or infants and children). therapeutic moiety is unstable in spe- (2) The dissolution rate of one or cific portions of the gastrointestinal more such products is slow, e.g., less tract and requires special coatings or than 50 percent in 30 minutes when formulations, e.g., buffers, enteric tested using either a general method coatings, and film coatings, to assure specified in an official compendium or adequate absorption. a paddle method at 50 revolutions per (6) The drug product is subject to minute in 900 milliliters of distilled or dose dependent kinetics in or near the deionized water at 37 °C, or differs sig- therapeutic range, and the rate and ex- nificantly from that of an appropriate tent of absorption are important to reference material such as an identical bioequivalence. drug product that is the subject of an approved full new drug application. [42 FR 1635, Jan. 7, 1977. Redesignated and (3) The particle size and/or surface amended at 57 FR 18001, Apr. 28, 1992; 81 FR area of the active drug ingredient is 17066, Mar. 28, 2016] critical in determining its bioavailability. § 320.34 Requirements for batch test- (4) Certain physical structural char- ing and certification by the Food and Drug Administration. acteristics of the active drug ingredient, e.g., polymorphic forms, con- (a) If the Commissioner determines forms, solvates, complexes, and crystal that individual batch testing by the modifications, dissolve poorly and this Food and Drug Administration is nec- poor dissolution may affect absorption. essary to assure that all batches of the (5) Such drug products have a high same drug product meet an appropriate ratio of excipients to active ingredi- in vitro test, he shall include in the ents, e.g., greater than 5 to 1. bioequivalence requirement a require- (6) Specific inactive ingredients, e.g., ment for manufacturers to submit sam- hydrophilic or hydrophobic excipients ples of each batch to the Food and and lubricants, either may be required Drug Administration and to withhold for absorption of the active drug ingre- distribution of the batch until notified dient or therapeutic moiety or, alter- by the Food and Drug Administration natively, if present, may interfere with that the batch may be introduced into such absorption. interstate commerce. (f) Pharmacokinetic evidence that: (b) The Commissioner will ordinarily (1) The active drug ingredient, thera- terminate a requirement for a manu- peutic moiety, or its precursor is ab- facturer to submit samples for batch

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testing on a finding that the manufac- ployee to have access to and copy and turer has produced four consecutive verify these records. batches that were tested by the Food [42 FR 1635, Jan. 7, 1977. Redesignated at 57 and Drug Administration and found to FR 18001, Apr. 28, 1992, as amended at 63 FR meet the bioequivalence requirement, 5252, Feb. 2, 1998] unless the public health requires that batch testing be extended to additional § 320.38 Retention of bioavailability batches. samples. [42 FR 1635, Jan. 7, 1977. Redesignated at 57 (a) The applicant of an application or FR 18001, Apr. 28, 1992] supplemental application submitted under section 505 of the Federal Food, § 320.35 Requirements for in vitro test- Drug, and Cosmetic Act, or, if bio- ing of each batch. availability testing was performed If a bioequivalence requirement under contract, the contract research specifies a currently available in vitro organization shall retain an appro- test or an in vitro bioequivalence priately identified reserve sample of standard comparing the drug product the drug product for which the appli- to a reference standard, the manufac- cant is seeking approval (test article) turer shall conduct the test on a sam- and of the reference standard used to ple of each batch of the drug product to perform an in vivo bioavailability assure batch-to-batch uniformity. study in accordance with and for the studies described in paragraph (b) of [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992] this section that is representative of each sample of the test article and ref- § 320.36 Requirements for mainte- erence standard provided by the appli- nance of records of bioequivalence cant for the testing. testing. (b) Reserve samples shall be retained (a) All records of in vivo or in vitro for the following test articles and ref- tests conducted on any marketed batch erence standards and for the studies de- of a drug product to assure that the scribed: product meets a bioequivalence re- (1) If the formulation of the test arti- quirement shall be maintained by the cle is the same as the formulation(s) manufacturer for at least 2 years after used in the clinical studies dem- the expiration date of the batch and onstrating substantial evidence of safe- submitted to the Food and Drug Ad- ty and effectiveness for the test arti- ministration on request. cle’s claimed indications, a reserve (b) Any person who contracts with sample of the test article used to con- another party to conduct a bioequiva- duct an in vivo bioavailability study lence study from which the data are in- comparing the test article to a ref- tended to be submitted to FDA as part erence oral solution, suspension, or in- of an application submitted under part jection. 314 of this chapter shall obtain from (2) If the formulation of the test arti- the person conducting the study suffi- cle differs from the formulation(s) used cient accurate financial information to in the clinical studies demonstrating allow the submission of complete and substantial evidence of safety and ef- accurate financial certifications or dis- fectiveness for the test article’s closure statements required under part claimed indications, a reserve sample 54 of this chapter and shall maintain of the test article and of the reference that information and all records relat- standard used to conduct an in vivo ing to the compensation given for that bioequivalence study comparing the study and all other financial interest test article to the formulation(s) (ref- information required under part 54 of erence standard) used in the clinical this chapter for 2 years after the date studies. of approval of the application. The per- (3) For a new formulation, new dos- son maintaining these records shall, age form, or a new salt or ester of an upon request for any properly author- active drug ingredient or therapeutic ized officer or employee of the Food moiety that has been approved for mar- and Drug Administration, at reason- keting, a reserve sample of the test ar- able time, permit such officer or em- ticle and of the reference standard used

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to conduct an in vivo bioequivalence as used in the specific bioavailability study comparing the test article to a or bioequivalence study identified by marketed product (reference standard) the agency. The assurance shall be exe- that contains the same active drug in- cuted by an individual authorized to gredient or therapeutic moiety. act for the applicant or contract re- (c) Each reserve sample shall consist search organization in releasing the re- of a sufficient quantity to permit FDA serve samples to FDA. to perform five times all of the release (h) A contract research organization tests required in the application or may contract with an appropriate, supplemental application. independent third party to provide (d) Each reserve sample shall be adequately identified so that the reserve storage of reserve samples provided sample can be positively identified as that the sponsor of the study has been having come from the same sample as notified in writing of the name and ad- used in the specific bioavailability dress of the facility at which the re- study. serve samples will be stored. (e) Each reserve sample shall be (i) If a contract research organization stored under conditions consistent conducting a bioavailability or bio- with product labeling and in an area equivalence study that requires reserve segregated from the area where testing sample retention under this section or is conducted and with access limited to § 320.63 goes out of business, it shall authorized personnel. Each reserve transfer its reserve samples to an ap- sample shall be retained for a period of propriate, independent third party, and at least 5 years following the date on shall notify in writing the sponsor of which the application or supplemental the study of the transfer and provide application is approved, or, if such ap- the study sponsor with the name and plication or supplemental application address of the facility to which the re- is not approved, at least 5 years fol- serve samples have been transferred. lowing the date of completion of the bioavailability study in which the sam- [58 FR 25927, Apr. 28, 1993, as amended at 64 ple from which the reserve sample was FR 402, Jan. 5, 1999] obtained was used. (f) Authorized FDA personnel will or- § 320.63 Retention of bioequivalence dinarily collect reserve samples di- samples. rectly from the applicant or contract The applicant of an abbreviated ap- research organization at the storage plication or a supplemental application site during a preapproval inspection. If submitted under section 505 of the Fed- authorized FDA personnel are unable eral Food, Drug, and Cosmetic Act, or, to collect samples, FDA may require if bioequivalence testing was per- the applicant or contract research or- formed under contract, the contract re- ganization to submit the reserve sam- search organization shall retain re- ples to the place identified in the agen- serve samples of any test article and cy’s request. If FDA has not collected or requested delivery of a reserve sam- reference standard used in conducting ple, or if FDA has not collected or re- an in vivo or in vitro bioequivalence quested delivery of any portion of a re- study required for approval of the ab- serve sample, the applicant or contract breviated application or supplemental research organization shall retain the application. The applicant or contract sample or remaining sample for the 5- research organization shall retain the year period specified in paragraph (e) reserve samples in accordance with, of this section. and for the period specified in, § 320.38 (g) Upon release of the reserve sam- and shall release the reserve samples to ples to FDA, the applicant or contract FDA upon request in accordance with research organization shall provide a § 320.38. written assurance that, to the best knowledge and belief of the individual [58 FR 25928, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999] executing the assurance, the reserve samples came from the same samples

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PART 328—OVER-THE-COUNTER of age and over, the amount of alcohol DRUG PRODUCTS INTENDED FOR in the product shall not exceed 10 per- ORAL INGESTION THAT CONTAIN cent. ALCOHOL (c) For any OTC drug product intended for oral ingestion and labeled for use by children 6 to under 12 years Subpart A—General Provisions of age, the amount of alcohol in the Sec. product shall not exceed 5 percent. 328.1 Scope. (d) For any OTC drug product in- 328.3 Definitions. tended for oral ingestion and labeled Subpart B—Ingredients for use by children under 6 years of age, the amount of alcohol in the prod- 328.10 Alcohol. uct shall not exceed 0.5 percent. (e) The Food and Drug Administra- Subpart C—Labeling tion will grant an exemption from 328.50 Principal display panel of all OTC paragraphs (b), (c), and (d) of this sec- drug products intended for oral ingestion tion where appropriate, upon petition that contain alcohol. under the provisions of § 10.30 of this AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, chapter. Appropriate cause, such as a 701 of the Federal Food, Drug, and Cosmetic specific solubility or manufacturing Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371). problem, must be adequately docu- SOURCE: 60 FR 13595, Mar. 13, 1995, unless mented in the petition. Decisions with otherwise noted. respect to requests for exemption shall be maintained in a permanent file for EDITORIAL NOTE: Nomenclature changes to part 328 appear at 69 FR 13717, Mar. 24, 2004. public review by the Division of Dock- ets Management (HFA–305), Food and Drug Administration, 5630 Fishers Subpart A—General Provisions Lane, rm. 1061, Rockville, MD 20852. § 328.1 Scope. (f) Ipecac syrup is exempt from the provisions of paragraph (d) of this sec- Reference in this part to regulatory tion. sections of the Code of Federal Regula- (g) The following drugs are tempo- tions are to chapter I of title 21 unless rarily exempt from the provisions of otherwise noted. paragraphs (b), (c), and (d) of this sec- § 328.3 Definitions. tion: (1) Aromatic Cascara Fluidextract. As used in this part: (a) Alcohol means the substance (2) Cascara Sagrada Fluidextract. known as ethanol, ethyl alcohol, or Al- (3) Orally ingested homeopathic drug cohol, USP. products. (b) Inactive ingredient means any com- [60 FR 13595, Mar. 13, 1995, as amended at 61 ponent of a product other than an ac- FR 58630, Nov. 18, 1996; 68 FR 24879, May 9, tive ingredient as defined in § 210.3(b)(7) 2003] of this chapter. Subpart C—Labeling Subpart B—Ingredients § 328.50 Principal display panel of all § 328.10 Alcohol. OTC drug products intended for (a) Any over-the-counter (OTC) drug oral ingestion that contain alcohol. product intended for oral ingestion (a) The amount (percentage) of alco- shall not contain alcohol as an inactive hol present in a product shall be stated ingredient in concentrations that ex- in terms of percent volume of absolute ceed those established in this part, un- alcohol at 60 °F (15.56 °C) in accordance less a specific exemption, as provided with § 201.10(d)(2) of this chapter. in paragraph (e) or (f) of this section, (b) A statement expressing the has been approved. amount (percentage) of alcohol present (b) For any OTC drug product in- in a product shall appear prominently tended for oral ingestion and labeled and conspicuously on the ‘‘principal for use by adults and children 12 years display panel,’’ as defined in § 201.60 of

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this chapter. For products whose prin- PART 329—NONPRESCRIPTION cipal display panel is on the immediate HUMAN DRUG PRODUCTS SUB- container label and that are not mar- JECT TO SECTION 760 OF THE keted in another retail package (e.g., FEDERAL FOOD, DRUG, AND an outer box), the statement of the per- COSMETIC ACT centage of alcohol present in the product shall appear prominently and conspicuously on the ‘‘principal display AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, panel’’ of the immediate container 355, 371, 379aa. label. SOURCE: 79 FR 33089, June 10, 2014, unless (c) For products whose principal dis- otherwise noted. play panel is on the retail package and § 329.100 Postmarketing reporting of the retail package is not the imme- adverse drug events under section diate container, the statement of the 760 of the Federal Food, Drug, and percentage of alcohol present in the Cosmetic Act. product shall also appear on the immediate container label; it may appear (a) Reporting requirements. Reports of anywhere on that label in accord with serious adverse events required by section 760 of the Federal Food, Drug, and section 502(e) of the Federal Food, Cosmetic Act (FD&C Act) must include Drug, and Cosmetic Act. the information specified in this sec- (d) The statement expressing the tion, as applicable. Except as provided amount (percentage) of alcohol present in paragraph (c)(2) of this section, in the product shall be in a size reason- these reports must be submitted to the ably related to the most prominent Agency in electronic format as de- printed matter on the panel or label on scribed in paragraph (c)(1) of this sec- which it appears, and shall be in lines tion. generally parallel to the base on which (b) Contents of reports. For purposes of the package rests as it is designed to be reporting serious adverse events under displayed. section 760 of the FD&C Act, an indi- (e) For a product to state in its label- vidual case safety report (ICSR) con- ing that it is ‘‘alcohol free,’’ it must stitutes the MedWatch form required contain no alcohol (0 percent). to be submitted by section 760(d) of the (f) For any OTC drug product in- FD&C Act. ICSRs include the following tended for oral ingestion containing information: over 5 percent alcohol and labeled for (1) Patient information. use by adults and children 12 years of (i) Patient identification code; (ii) Patient age at the time of adverse age and over, the labeling shall contain drug experience, or date of birth; the following statement in the direc- (iii) Patient gender; and tions section: ‘‘Consult a physician for (iv) Patient weight. use in children under 12 years of age.’’ (2) Adverse event. (g) For any OTC drug product in- (i) Outcome attributed to adverse tended for oral ingestion containing drug event; over 0.5 percent alcohol and labeled for (ii) Date of adverse drug event; use by children ages 6 to under 12 years (iii) Date of ICSR submission; of age, the labeling shall contain the (iv) Description of adverse drug event following statement in the directions (including a concise medical nar- section: ‘‘Consult a physician for use in rative); children under 6 years of age.’’ (v) Adverse drug event term(s); (h) When the direction regarding age (vi) Description of relevant tests, in- in paragraph (e) or (f) of this section cluding dates and laboratory data; and differs from an age-limiting direction (vii) Other relevant patient history, including preexisting medical condi- contained in any OTC drug monograph tions. in this chapter, the direction con- (3) Suspect medical product(s). taining the more stringent age limita- (i) Name; tion shall be used. (ii) Dose, frequency, and route of administration used;

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(iii) Therapy dates; granted on a limited basis for good (iv) Diagnosis for use (indication); cause shown. FDA will issue guidance (v) Whether the product is a com- on requesting a waiver of the require- bination product as defined in § 3.2(e) of ments in paragraph (c)(1) of this sec- this chapter; tion. (vi) Whether the product is a pre- (d) Patient privacy. The responsible scription or nonprescription product; person should not include in reports (vii) Whether adverse drug event under this section the names and ad- abated after drug use stopped or dose dresses of individual patients; instead, reduced; the responsible person should assign a (viii) Whether adverse drug event re- unique code for identification of the appeared after reintroduction of drug; patient. The responsible person should (ix) Lot number; include the name of the reporter from (x) Expiration date; whom the information was received as (xi) National Drug Code (NDC) num- part of the initial reporter informa- ber; and tion, even when the reporter is the pa- (xii) Concomitant medical products tient. The names of patients, health and therapy dates. care professionals, hospitals, and geo- (4) Initial reporter information. graphical identifiers in adverse drug (i) Name, address, and telephone event reports are not releasable to the number; public under FDA’s public information (ii) Whether the initial reporter is a regulations in part 20 of this chapter. health care professional; and (iii) Occupation, if a health care pro- PART 330—OVER-THE-COUNTER fessional. (5) Responsible person (as defined in (OTC) HUMAN DRUGS WHICH section 760(b) of the FD&C Act) informa- ARE GENERALLY RECOGNIZED tion. AS SAFE AND EFFECTIVE AND (i) Name and contact office address; NOT MISBRANDED (ii) Telephone number; (iii) Report source, such as sponta- Subpart A—General Provisions neous; (iv) Date the report was received by Sec. responsible person; 330.1 General conditions for general recognition as safe, effective and not mis- (v) Whether the ICSR is a 15-day re- branded. port; 330.2 Pregnancy-nursing warning. (vi) Whether the ICSR is an initial 330.3 Imprinting of solid oral dosage form report or followup report; and drug products. (vii) Unique case identification num- 330.5 Drug categories. ber, which must be the same in the initial report and any subsequent fol- Subpart B—Administrative Procedures lowup report(s). (c) Electronic format for submissions. (1) 330.10 Procedures for classifying OTC drugs as generally recognized as safe and effec- Each report required to be submitted tive and not misbranded, and for estab- to FDA under section 760 of the FD&C lishing monographs. Act, accompanied by a copy of the 330.11 NDA deviations from applicable label on or within the retail package of monograph. the drug and any other documentation 330.12 Status of over-the-counter (OTC) (as ICSR attachments), must be in an drugs previously reviewed under the electronic format that FDA can proc- Drug Efficacy Study (DESI). ess, review, and archive. FDA will issue 330.13 Conditions for marketing ingredients guidance on how to provide the elec- recommended for over-the-counter (OTC) tronic submission (e.g., method of use under the OTC drug review. transmission, media, file formats, prep- 330.14 Additional criteria and procedures for classifying OTC drugs as generally recog- aration, and organization of files). nized as safe and effective and not mis- (2) The responsible person may re- branded. quest, in writing, a temporary waiver 330.15 Timelines for FDA review and action of the requirements in paragraph (c)(1) on time and extent applications and safe- of this section. These waivers will be ty and effectiveness data submissions.

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AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, statements describing only those indi- 360, 360fff–6, 371. cations for use that have been estab- SOURCE: 39 FR 11741, Mar. 29, 1974, unless lished in an applicable monograph, sub- otherwise noted. ject to the provisions of section 502 of EDITORIAL NOTE: Nomenclature changes to the act relating to misbranding and the part 330 appear at 69 FR 13717, Mar. 24, 2004. prohibition in section 301(d) of the act against the introduction or delivery for Subpart A—General Provisions introduction into interstate commerce of unapproved new drugs in violation of § 330.1 General conditions for general section 505(a) of the act. Any other la- recognition as safe, effective and beling under this subchapter and sub- not misbranded. chapter C et seq. of this chapter shall be An over-the-counter (OTC) drug list- stated in the exact language where ed in this subchapter is generally rec- exact language has been established ognized as safe and effective and is not and identified by quotation marks in misbranded if it meets each of the con- an applicable OTC drug monograph or ditions contained in this part and each by regulation (e.g., § 201.63 of this chap- of the conditions contained in any ap- ter), except as provided in paragraphs plicable monograph. Any product (i) and (j) of this section. which fails to conform to each of the (d) The advertising for the product conditions contained in this part and prescribes, recommends, or suggests its in an applicable monograph is liable to use only under the conditions stated in regulatory action. the labeling. (a) The product is manufactured in (e) The product contains only suit- compliance with current good manu- able inactive ingredients which are facturing practices, as established by safe in the amounts administered and parts 210 and 211 of this chapter. do not interfere with the effectiveness (b) The establishment(s) in which the of the preparation or with suitable drug product is manufactured is reg- tests or assays to determine if the istered, and the drug product is listed, product meets its professed standards in compliance with part 207 of this of identity, strength, quality, and pu- chapter. It is requested but not re- rity. Color additives may be used only quired that the number assigned to the in accordance with section 721 of the product pursuant to part 207 of this act and subchapter A of this chapter. chapter appear on all drug labels and in (f) The product container and con- all drug labeling. If this number is tainer components meet the require- used, it shall be placed in the manner ments of § 211.94 of this chapter. set forth in part 207 of this chapter. (g) The labeling for all drugs contains (c)(1) The product is labeled in com- the general warning: ‘‘Keep out of pliance with chapter V of the Federal reach of children.’’ [highlighted in bold Food, Drug, and Cosmetic Act (the act) type]. The labeling of drugs shall also and subchapter C et seq. of this chapter, state as follows: For drugs used by oral including the format and content re- administration, ‘‘In case of overdose, quirements in § 201.66 of this chapter. get medical help or contact a Poison An OTC drug product that is not in Control Center right away’’; for drugs compliance with chapter V and sub- used topically, rectally, or vaginally chapter C, including § 201.66 of this and not intended for oral ingestion, ‘‘If chapter, is subject to regulatory ac- swallowed, get medical help or contact tion. For purposes of § 201.61(b) of this a Poison Control Center right away’’; chapter, the statement of identity of and for drugs used topically and in- the product shall be the term or phrase tended for oral use, ‘‘If more than used used in the applicable OTC drug mono- for’’ (insert intended use, e.g., pain) ‘‘is graph established in this part. accidentally swallowed, get medical (2) The ‘‘Uses’’ section of the label help or contact a Poison Control Cen- and labeling of the product shall con- ter right away.’’ The Food and Drug tain the labeling describing the ‘‘Indi- Administration will grant an exemp- cations’’ that have been established in tion from these general warnings where an applicable OTC drug monograph or appropriate upon petition, which shall alternative truthful and nonmisleading be maintained in a permanent file for

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public review by the Division of Dock- (24) ‘‘Drowsiness’’ or ‘‘the drowsiness ets Management, Food and Drug Ad- effect’’. ministration, 5630 Fishers Lane, rm. (25) ‘‘Drowsiness may occur’’ or ‘‘you 1061, Rockville, MD 20852. may get drowsy’’. (h) Where no maximum daily dosage (26) ‘‘Enlargement of the’’ or ‘‘an en- limit for an active ingredient is estab- larged’’. lished in this part, it is used in a prod- (27) ‘‘Especially in children’’ or espe- uct at a level that does not exceed the cially children’’. amount reasonably required to achieve (28) ‘‘Exceed’’ or ‘‘use more than’’ or its intended effect. ‘‘go beyond’’. (i) The following terms may be used (29) ‘‘Exceed recommended dosage’’ interchangeably in the labeling of OTC or ‘‘use more than directed’’. drug products, provided such use does (30) ‘‘Excessive’’ or ‘‘too much’’. not alter the meaning of the labeling (31) ‘‘Excitability may occur’’ or that has been established and identi- ‘‘you may get excited’’. fied in an applicable monograph or by (32) ‘‘Experience’’ or ‘‘feel’’. regulation. The following terms shall (33) ‘‘For relief of’’ or ‘‘relieves’’. not be used to change in any way the (34) ‘‘For temporary reduction of’’ or title, headings, and subheadings re- ‘‘temporarily reduces’’. quired under § 201.66(c)(1) through (c)(9) (35) ‘‘For the temporary relief of’’ or of this chapter: ‘‘temporarily relieves’’. (1) ‘‘Abdominal’’ or ‘‘stomach’’ (in (36) ‘‘For the treatment of’’ or context only). ‘‘treats’’. (2) ‘‘Administer’’ or ‘‘give’’. (37) ‘‘Frequently’’ or ‘‘often’’. (3) ‘‘Aggravate(s)’’ or ‘‘make(s) (38) ‘‘Give to’’ or ‘‘use in’’. worse’’. (39) ‘‘Immediately’’ or ‘‘right away’’ (4) ‘‘Application of this product’’ or or ‘‘directly’’. ‘‘applying’’. (40) ‘‘Immediately’’ or ‘‘as soon as’’. (5) ‘‘Are uncertain’’ or ‘‘do not (41) ‘‘Immediately following’’ or know’’. ‘‘right after’’. (6) ‘‘Ask’’ or ‘‘consult’’ or ‘‘contact’’. (42) ‘‘Improve(s)’’ or ‘‘get(s) better’’ (7) ‘‘Asking’’ or ‘‘consulting’’. or ‘‘make(s) better’’. (8) ‘‘Assistance’’ or ‘‘help’’ or ‘‘aid’’. (43) ‘‘Increased’’ or ‘‘more’’. (44) ‘‘Increase your risk of’’ or (9) ‘‘Associated with’’ or ‘‘due to’’ or ‘‘cause’’. ‘‘caused by’’. (45) ‘‘Indication(s)’’ or ‘‘Use(s)’’. (10) ‘‘Avoid contact with eyes’’ or ‘‘do (46) ‘‘Inhalation’’ or ‘‘puff’’. not get into eyes’’. (47) ‘‘In persons who’’ or ‘‘if you’’ or (11) ‘‘Avoid inhaling’’ or ‘‘do not in- ‘‘if the child’’. hale’’. (48) ‘‘Instill’’ or ‘‘put’’. (12) ‘‘Before a doctor is consulted’’ or (49) ‘‘Is (are) accompanied by’’ or ‘‘without first consulting your doctor’’ ‘‘you also have’’ (in context only) or or ‘‘consult your doctor before’’. ‘‘(optional: that) occur(s) with’’. (13) ‘‘Beverages’’ or ‘‘drinks’’. (50) ‘‘Longer’’ or ‘‘more’’. (14) ‘‘Clean’’ or ‘‘cleanse’’. (51) ‘‘Lung’’ or ‘‘pulmonary’’. (15) ‘‘Consulting’’ or ‘‘advising’’. (52) ‘‘Medication(s)’’ or ‘‘medicine(s)’’ (16) ‘‘Continue(s)’’ or ‘‘persist(s)’’ or or ‘‘drug(s)’’. ‘‘is persistent’’ or ‘‘do(es) not go away’’ (53) ‘‘Nervousness, dizziness, or sleep- or ‘‘last(s)’’. lessness occurs’’ or ‘‘you get nervous, (17) ‘‘Daily’’ or ‘‘every day’’. dizzy, or sleepless’’. (18) ‘‘Develop(s)’’ or ‘‘begin(s)’’ or (54) ‘‘Not to exceed’’ or ‘‘do not ex- ‘‘occur(s)’’. ceed’’ or ‘‘not more than’’. (19) ‘‘Difficulty’’ or ‘‘trouble’’. (55) ‘‘Obtain(s)’’ or ‘‘get(s)’’. (20) ‘‘Difficulty in urination’’ or (56) ‘‘Passages’’ or ‘‘passageways’’ or ‘‘trouble urinating’’. ‘‘tubes’’. (21) ‘‘Discard’’ or ‘‘throw away’’. (57) ‘‘Perforation of’’ or ‘‘hole in’’. (22) ‘‘Discontinue’’ or ‘‘stop’’ or (58) ‘‘Persistent’’ or ‘‘that does not go ‘‘quit’’. away’’ or ‘‘that continues’’ or ‘‘that (23) ‘‘Doctor’’ or ‘‘physician’’. lasts’’.

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(59) ‘‘Per day’’ or ‘‘daily’’. (14) ‘‘Or as directed by a doctor’’. (60) ‘‘Presently’’ or ‘‘now’’. (15) ‘‘Such as’’. (61) ‘‘Produce(s)’’ or ‘‘cause(s)’’. (16) ‘‘Such as occurs with’’. (62) ‘‘Prompt(ly)’’ or ‘‘quick(ly)’’ or (17) ‘‘Tends to’’. ‘‘right away’’. (18) ‘‘This product’’. (63) ‘‘Reduce’’ or ‘‘minimize’’. (19) ‘‘Unless directed by a doctor’’. (64) ‘‘Referred to as’’ or ‘‘of’’. (20) ‘‘While taking this product’’ or (65) ‘‘Sensation’’ or ‘‘feeling’’. ‘‘before taking this product’’. (66) ‘‘Solution’’ or ‘‘liquid’’. (21) ‘‘Within’’. (67) ‘‘Specifically’’ or ‘‘definitely’’. [39 FR 11741, Mar. 29, 1974, as amended at 40 (68) ‘‘Take’’ or ‘‘use’’ or ‘‘give’’. FR 11718, Mar. 13, 1975; 40 FR 13496, Mar. 27, (69) ‘‘Tend(s) to recur’’ or ‘‘reoc- 1975; 42 FR 15674, Mar. 22, 1977; 46 FR 8459, cur(s)’’ or ‘‘return(s)’’ or ‘‘come(s) Jan. 27, 1981; 50 FR 8996, Mar. 6, 1985; 51 FR back’’. 16266, May 1, 1986; 55 FR 11581, Mar. 29, 1990; (70) ‘‘To avoid contamination’’ or 59 FR 4000, Jan. 28, 1994; 59 FR 14365, Mar. 28, ‘‘avoid contamination’’ or ‘‘do not con- 1994; 64 FR 13294, Mar. 17, 1999; 68 FR 24879, May 9, 2003] taminate’’. (71) ‘‘To help’’ or ‘‘helps’’. § 330.2 Pregnancy-nursing warning. (72) ‘‘Unless directed by a doctor’’ or ‘‘except under the advice of a doctor’’ A pregnancy-nursing warning for or ‘‘unless told to do so by a doctor’’. OTC drugs is set forth under § 201.63 of (73) ‘‘Use caution’’ or ‘‘be careful’’. this chapter. (74) ‘‘Usually’’ or ‘‘generally’’ (in con- [47 FR 54758, Dec. 3, 1982] text only). (75) ‘‘You’’ (‘‘Your’’) or ‘‘the child’’ § 330.3 Imprinting of solid oral dosage (‘‘the child’s’’). form drug products. (76) ‘‘You also have’’ or ‘‘occurs A requirement to imprint an identi- with’’. fication code on solid oral dosage form (77) ‘‘When practical’’ or ‘‘if pos- drug products is set forth under part sible’’. 206 of this chapter. (78) ‘‘Whether’’ or ‘‘if’’. [58 FR 47959, Sept. 13, 1993] (79) ‘‘Worsen(s)’’ or ‘‘get(s) worse’’ or ‘‘make(s) worse’’. § 330.5 Drug categories. (j) The following connecting terms Monographs promulgated pursuant to may be deleted from the labeling of the provisions of this part shall be es- OTC drug products, provided such dele- tablished in this part 330 and following tion does not alter the meaning of the parts and shall cover the following des- labeling that has been established and ignated categories: identified in an applicable monograph (a) Antacids. or by regulation. The following terms (b) Laxatives. shall not be used to change in any way (c) Antidiarrheal products. the specific title, headings, and sub- (d) Emetics. headings required under § 201.66(c)(1) (e) Antiemetics. through (c)(9) of this chapter: (f) Antiperspirants. (l) ‘‘And’’. (g) Sunburn prevention and treat- (2) ‘‘As may occur with’’. ment products. (3) ‘‘Associated’’ or ‘‘to be associ- (h) Vitamin-mineral products. ated’’. (i) Antimicrobial products. (4) ‘‘Consult a doctor’’. (j) Dandruff products. (5) ‘‘Discontinue use’’. (k) Oral hygiene aids. (6) ‘‘Drug Interaction Precaution’’. (l) Hemorrhoidal products. (7) ‘‘Due to’’. (m) Hematinics. (8) ‘‘Except under the advice and su- (n) Bronchodilator and antiasthmatic pervision of a physician’’. products. (9) ‘‘If this occurs’’. (o) Analgesics. (10) ‘‘In case of’’. (p) Sedatives and sleep aids. (11) ‘‘Notice’’. (q) Stimulants. (12) ‘‘Or’’. (r) Antitussives. (13) ‘‘Occurring with’’. (s) Allergy treatment products.

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(t) Cold remedies. a published notice, and falling within (u) Antirheumatic products. the confidentiality provisions of 18 (v) Ophthalmic products. U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. (w) Contraceptive products. 331(j), shall be handled by the advisory (x) Miscellaneous dermatologic prod- review panel and the Food and Drug ucts. Administration as confidential until (y) Dentifrices and dental products publication of a proposed monograph such as analgesics, antiseptics, etc. and the full report(s) of the panel or (z) Miscellaneous (all other OTC until the Commissioner places the pan- drugs not falling within one of the el’s recommendations on public display above therapeutic categories). at the office of the Division of Dockets Management. Thirty days thereafter Subpart B—Administrative such data and information shall be Procedures made publicly available and may be viewed at the office of the Division of § 330.10 Procedures for classifying Dockets Management of the Food and OTC drugs as generally recognized Drug Administration, except to the ex- as safe and effective and not mis- tent that the person submitting it branded, and for establishing mono- demonstrates that it still falls within graphs. the confidentiality provisions of one or For purposes of classifying over-the- more of those statutes. To be consid- counter (OTC) drugs as drugs generally ered, eight copies of the data and/or recognized among qualified experts as views on any marketed drug within the safe and effective for use and as not class must be submitted, preferably misbranded drugs, the following regu- bound, indexed, and on standard sized lations shall apply: paper (approximately 81⁄2 × 11 inches). (a) Procedure for establishing OTC drug When requested, abbreviated submis- monographs—(1) Advisory review panels. sions should be sent. All submissions The Commissioner shall appoint advi- must be in the following format: sory review panels of qualified experts to evaluate the safety and effectiveness OTC DRUG REVIEW INFORMATION of OTC drugs, to review OTC drug la- I. Label(s) and all labeling (preferably beling, and to advise him on the pro- mounted and filed with the other data—fac- mulgation of monographs establishing simile labeling is acceptable in lieu of actual container labeling). conditions under which OTC drugs are II. A statement setting forth the quan- generally recognized as safe and effec- tities of active ingredients of the drug. tive and not misbranded. A single advi- III. Animal safety data. sory review panel shall be established A. Individual active components. for each designated category of OTC 1. Controlled studies. drugs and every OTC drug category 2. Partially controlled or uncontrolled will be considered by a panel. The studies. B. Combinations of the individual active members of a panel shall be qualified components. experts (appointed by the Commis- 1. Controlled studies. sioner) and may include persons from 2. Partially controlled or uncontrolled lists submitted by organizations rep- studies. resenting professional, consumer, and C. Finished drug product. industry interests. The Commissioner 1. Controlled studies. shall designate the chairman of each 2. Partially controlled or uncontrolled studies. panel. Summary minutes of all meet- IV. Human safety data. ings shall be made. A. Individual active components. (2) Request for data and views. The 1. Controlled studies. Commissioner will publish a notice in 2. Partially controlled or uncontrolled the FEDERAL REGISTER requesting in- studies. terested persons to submit, for review 3. Documented case reports. Identify ex- and evaluation by an advisory review pected or frequently reported side effects. 4. Pertinent marketing experiences that panel, published and unpublished data may influence a determination as to the and information pertinent to a des- safety of each individual active component. ignated category of OTC drugs. Data 5. Pertinent medical and scientific lit- and information submitted pursuant to erature.

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B. Combinations of the individual active controlled studies in the material submitted, components. an explanation as to why such studies are 1. Controlled studies. not considered necessary must be included. 2. Partially controlled or uncontrolled VII. An official United States Pharma- studies. copeia (USP)–National Formulary (NF) drug 3. Documented case reports. Identify ex- monograph for the active ingredient(s) or bo- pected or frequently reported side effects. tanical drug substance(s), or a proposed 4. Pertinent marketing experiences that standard for inclusion in an article to be rec- may influence a determination as to the ognized in an official USP-NF drug mono- safety of combinations of the individual ac- graph for the active ingredient(s) or botan- tive components. ical drug substance(s). Include information 5. Pertinent medical and scientific lit- showing that the official or proposed erature. compendial monograph for the active ingre- C. Finished drug product. dient or botanical drug substance is con- 1. Controlled studies. sistent with the active ingredient or botan- 2. Partially controlled or uncontrolled ical drug substance used in the studies estab- studies. lishing safety and effectiveness and with the 3. Documented case reports. Identify ex- active ingredient or botanical drug sub- pected or frequently reported side effects. 4. Pertinent marketing experiences that stance marketed in the OTC product(s) to a may influence a determination as to the material extent and for a material time. If safety of the finished drug product. differences exist, explain why. 5. Pertinent medical and scientific lit- (3) Deliberations of an advisory review erature. panel. An advisory review panel will V. Efficacy data. A. Individual active components. meet as often and for as long as is ap- 1. Controlled studies. propriate to review the data submitted 2. Partially controlled or uncontrolled to it and to prepare a report containing studies. its conclusions and recommendations 3. Documented case reports. Identify ex- to the Commissioner with respect to pected or frequently reported side effects. the safety and effectiveness of the 4. Pertinent marketing experiences that may influence a determination on the effi- drugs in a designated category of OTC cacy of each individual active component. drugs. A panel may consult any indi- 5. Pertinent medical and scientific lit- vidual or group. Any interested person erature. may request an opportunity to present B. Combinations of the individual active oral views to the panel; such request components. may be granted or denied by the panel. 1. Controlled studies. Such requests for oral presentations 2. Partially controlled or uncontrolled studies. should be in written form including a 3. Documented case reports. Identify ex- summarization of the data to be pre- pected or frequently reported side effects. sented to the panel. Any interested 4. Pertinent marketing experiences that person may present written data and may influence a determination on the effi- views which shall be considered by the cacy of combinations of the individual active panel. This information shall be pre- components. sented to the panel in the format set 5. Pertinent medical and scientific literature. forth in paragraph (a)(2) of this section C. Finished drug product. and within the time period established 1. Controlled studies. for the drug category in the notice for 2. Partially controlled or uncontrolled review by a panel. studies. (4) Standards for safety, effectiveness, 3. Documented case reports. Identify ex- and labeling. The advisory review panel, pected or frequently reported side effects. 4. Pertinent marketing experiences that in reviewing the data submitted to it may influence a determination on the effi- and preparing its conclusions and rec- cacy of the finished drug product. ommendations, and the Commissioner, 5. Pertinent medical and scientific lit- in reviewing the conclusions and rec- erature. ommendations of the panel and the VI. A summary of the data and views set- published proposed, tentative, and the ting forth the medical rationale and purpose final monographs, shall apply the fol- (or lack thereof) for the drug and its ingredients and the scientific basis (or lack thereof) lowing standards to determine general for the conclusion that the drug and its in- recognition that a category of OTC gredients have been proven safe and effective drugs is safe and effective and not mis- for the intended use. If there is an absence of branded:

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(i) Safety means a low incidence of any of the individual active ingredi- adverse reactions or significant side ef- ents; and when the combination, when fects under adequate directions for use used under adequate directions for use and warnings against unsafe use as and warnings against unsafe use, pro- well as low potential for harm which vides rational concurrent therapy for a may result from abuse under condi- significant proportion of the target tions of widespread availability. Proof population. of safety shall consist of adequate tests (v) Labeling shall be clear and truth- by methods reasonably applicable to ful in all respects and may not be false show the drug is safe under the pre- or misleading in any particular. It scribed, recommended, or suggested shall state the intended uses and re- conditions of use. This proof shall in- sults of the product; adequate direc- clude results of significant human ex- tions for proper use; and warnings perience during marketing. General against unsafe use, side effects, and ad- recognition of safety shall ordinarily verse reactions in such terms as to be based upon published studies which render them likely to be read and un- may be corroborated by unpublished derstood by the ordinary individual, in- studies and other data. cluding individuals of low comprehen- (ii) Effectiveness means a reasonable sion, under customary conditions of expectation that, in a significant pro- purchase and use. portion of the target population, the (vi) A drug shall be permitted for pharmacological effect of the drug, OTC sale and use by the laity unless, when used under adequate directions because of its toxicity or other poten- for use and warnings against unsafe tial for harmful effect or because of the use, will provide clinically significant method or collateral measures nec- relief of the type claimed. Proof of ef- essary to its use, it may safely be sold fectiveness shall consist of controlled and used only under the supervision of clinical investigations as defined in a practitioner licensed by law to ad- § 314.126(b) of this chapter, unless this minister such drugs. requirement is waived on the basis of a (5) Advisory review panel report to the showing that it is not reasonably appli- Commissioner. An advisory review panel cable to the drug or essential to the va- may submit to the Commissioner a re- lidity of the investigation and that an port containing its conclusions and alternative method of investigation is recommendations with respect to the adequate to substantiate effectiveness. conditions under which OTC drugs fall- Investigations may be corroborated by ing within the category covered by the partially controlled or uncontrolled panel are generally recognized as safe studies, documented clinical studies by and effective and not misbranded. In- qualified experts, and reports of signifi- cluded within this report shall be: cant human experience during mar- (i) A recommended monograph or keting. Isolated case reports, random monographs covering the category of experience, and reports lacking the de- OTC drugs and establishing conditions tails which permit scientific evalua- under which the drugs involved are tion will not be considered. General generally recognized as safe and effec- recognition of effectiveness shall ordi- tive and not misbranded (Category I). narily be based upon published studies This monograph may include any con- which may be corroborated by unpub- ditions relating to active ingredients, lished studies and other data. labeling indications, warnings and ade- (iii) The benefit-to-risk ratio of a quate directions for use, prescription drug shall be considered in determining or OTC status, and any other condi- safety and effectiveness. tions necessary and appropriate for the (iv) An OTC drug may combine two safety and effectiveness of drugs cov- or more safe and effective active ingre- ered by the monograph. dients and may be generally recognized (ii) A statement of active ingredi- as safe and effective when each active ents, labeling claims or other state- ingredient makes a contribution to the ments, or other conditions reviewed claimed effect(s); when combining of and excluded from the monograph on the active ingredients does not de- the basis of the panel’s determination crease the safety or effectiveness of that they would result in the drug’s

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not being generally recognized as safe Management of the Food and Drug Ad- and effective or would result in mis- ministration written comments in trip- branding (Category II). licate. Comments may be accompanied (iii) A statement of active ingredi- by a memorandum or brief in support ents, labeling claims or other state- thereof. All comments may be reviewed ments, or other conditions reviewed at the office of the Division of Dockets and excluded from the monograph on Management between the hours of 9 the basis of the panel’s determination a.m. and 4 p.m., Monday through Fri- that the available data are insufficient day. Within 30 days after the final day to classify such condition under either for submission of comments, reply paragraph (a)(5) (i) or (ii) of this sec- comments may be filed with the Divi- tion and for which further testing is sion of Dockets Management; these therefore required (Category III). The comments shall be utilized to reply to report may recommend the type of fur- comments made by other interested ther testing required and the time pe- persons and not to reiterate a position. riod within which it might reasonably The Commissioner may satisfy this re- be concluded. quirement by publishing in the FED- (6) Proposed monograph. After review- ERAL REGISTER a proposed order sum- ing the conclusions and recommenda- marizing the full report of the advisory tions of the advisory review panel, the review panel, containing its conclu- Commissioner shall publish in the FED- sions and recommendations, to obtain ERAL REGISTER a proposed order con- full public comment before under- taining: taking his own evaluation and decision (i) A monograph or monographs es- on the matters involved. tablishing conditions under which a (7) Tentative final monograph. (i) After category of OTC drugs or a specific or reviewing all comments, reply com- specific OTC drugs are generally recog- ments, and any new data and informa- nized as safe and effective and not mis- tion or, alternatively, after reviewing a branded (Category I). panel’s recommendations, the Commis- (ii) A statement of the conditions ex- sioner shall publish in the FEDERAL cluded from the monograph on the REGISTER a tentative order containing basis of the Commissioner’s determina- a monograph establishing conditions tion that they would result in the under which a category of OTC drugs drug’s not being generally recognized or specific OTC drugs are generally rec- as safe and effective or would result in ognized as safe and effective and not misbranding (Category II). misbranded. Within 90 days, any inter- (iii) A statement of the conditions ested person may file with the Division excluded from the monograph on the of Dockets Management, Food and basis of the Commissioner’s determina- Drug Administration, written com- tion that the available data are insuffi- ments or written objections specifying cient to classify such conditions under with particularity the omissions or ad- either paragraph (a)(6)(i) or (ii) of this ditions requested. These objections are section (Category III). to be supported by a brief statement of (iv) The full report(s) of the panel to the grounds therefor. A request for an the Commissioner. The proposed order oral hearing may accompany such ob- shall specify a reasonable period of jections. time within which conditions falling (ii) The Commissioner may also pub- within paragraph (a)(6)(iii) of this sec- lish in the FEDERAL REGISTER a sepa- tion may be continued in marketed rate tentative order containing a state- products while the data necessary to ment of those active ingredients re- support them are being obtained for viewed and proposed to be excluded evaluation by the Food and Drug Ad- from the monograph on the basis of the ministration. The summary minutes of Commissioner’s determination that the panel meetings shall be made avail- they would result in a drug product not able to interested persons upon re- being generally recognized as safe and quest. Any interested person may, effective or would result in mis- within 90 days after publication of the branding. This order may be published proposed order in the FEDERAL REG- when no substantive comments in op- ISTER, file with the Division of Dockets position to the panel report or new

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data and information were received by (9) Final monograph. After reviewing the Food and Drug Administration the objections, the entire administra- under paragraph (a)(6)(iv) of this sec- tive record including all new data and tion or when the Commissioner has information and comments, and consid- evaluated and concurs with a panel’s ering the arguments made at any oral recommendation that a condition be hearing, the Commissioner shall pub- excluded from the monograph. Within lish in the FEDERAL REGISTER a final 90 days, any interested person may file order containing a monograph estab- with the Division of Dockets Manage- lishing conditions under which a cat- ment, Food and Drug Administration, egory of OTC drugs or a specific or spe- written objections specifying with par- cific OTC drugs are generally recog- ticularity the provision of the ten- nized as safe and effective and not mis- tative order to which objection is branded. The monograph shall become made. These objections are to be sup- effective as specified in the order. ported by a brief statement of the (10) Administrative record. (i) All data grounds therefor. A request for an oral and information to be considered in hearing may accompany such objec- any proceeding pursuant to this sections. tion shall be submitted in response to (iii) Within 12 months after pub- the request for data and views pursu- lishing a tentative order pursuant to ant to paragraph (a)(2) of this section, paragraph (a)(7)(i) of this section, any interested person may file with the Di- in response to any other notice pub- vision of Dockets Management, Food lished in the FEDERAL REGISTER, or ac- and Drug Administration, new data cepted by the panel during its delibera- and information to support a condition tions pursuant to paragraph (a)(3) of excluded from the monograph in the this section or submitted to the Divi- tentative order. sion of Dockets Management as part of (iv) Within 60 days after the final day the comments during the 90-day period for submission of new data and infor- and 30-day rebuttal comment period mation, comments on the new data and permitted pursuant to paragraph (a)(6) information may be filed with the Divi- of this section or submitted to the Di- sion of Dockets Management, Food and vision of Dockets Management during Drug Administration. the 12-month period or as part of the (v) New data and information sub- comments during the 60-day period permitted after the time specified in this mitted pursuant to paragraph (a)(7) of paragraph but prior to the establish- this section. ment of a final monograph will be con- (ii) The Commissioner shall make all sidered as a petition to amend the decisions and issue all orders pursuant monograph and will be considered by to this section solely on the basis of the Commissioner only after a final the administrative record, and shall monograph has been published in the not consider data or information not FEDERAL REGISTER unless the included as part of the administrative Commisisoner finds that good cause record. has been shown that warrants earlier (iii) The administrative record shall consideration. consist solely of the following mate- (8) Oral hearing before the Commis- rial: All notices and orders published in sioner. After reviewing objections filed the FEDERAL REGISTER, all data and in response to the tentative final views submitted in response to the re- monograph, the Commissioner, if he quest published pursuant to paragraph finds reasonable grounds in support (a)(2) of this section, in response to any thereof, shall by notice in the FEDERAL other notice published in the FEDERAL REGISTER schedule an oral hearing. The REGISTER, or accepted by the panel notice scheduling an oral hearing shall during its deliberations pursuant to specify the length of the hearing and paragraph (a)(3) of this section, all how the time shall be divided among minutes of panel meetings, the panel the parties requesting the hearing. The report(s), all comments and rebuttal hearing shall be conducted by the Com- missioner and may not be delegated. comments submitted on the proposed

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monograph and all new data and infor- between the hours of 9 a.m. and 4 p.m., mation submitted pursuant to para- Monday through Friday. After review- graph (a)(6) of this section, all objec- ing the comments, the Commissioner tions submitted on the tentative final shall publish a final order amending monograph and all new data and infor- the monograph established under the mation and comments submitted pur- provisions of paragraph (a)(9) of this suant to paragraph (a)(7) of this sec- section or withdraw the proposal if tion, the complete record of any oral comments opposing the amendment public hearing conducted pursuant to are persuasive. A new drug application paragraph (a)(8) of this section, all may be submitted in lieu of, or in addi- other comments requested at any time tion to, a petition under this para- by the Commissioner, all data and in- graph. formation for which the Commissioner (ii) A new drug application may be has reopened the administrative submitted in lieu of a petition to record, and all other material that the amend the OTC drug monograh only if Commissioner includes in the adminis- the drug product with the condition trative record as part of the basis for that is the subject of the new drug ap- the Commissioner’s decision. plication has not been marketed on an (11) Court appeal. The monograph interim basis (such as under the provi- contained in the final order constitutes sions of paragraph (a)(6)(iii) of this sec- final agency action from which appeal tion), all clinical testing has been con- lies to the courts. The Food and Drug ducted pursuant to a new drug applica- Administration will request consolida- tion plan, and no marketing of the tion of all appeals in a single court. product with the condition for which Upon court appeal, the Commissioner approval is sought is undertaken prior may, at his discretion, stay the effec- to approval of the new drug applica- tive date for part or all of the mono- tion. The Food and Drug Administra- graph pending appeal and final court tion shall handle a new drug applica- adjudication. tion as a petition for amendment of a (12) Amendment of monographs. (i) The monograph, and shall review it on that Commissioner may propose on the basis, if the provisions of this para- Commissioner’s own initiative to graph preclude approval of a new drug amend or repeal any monograph estab- application but permit the granting of lished pursuant to this section. Any in- such a petition. terested person may petition the Com- (b) Regulatory action. Any product missioner for such proposal pursuant which fails to conform to an applicable to § 10.30 of this chapter. The Commis- monograph after its effective date is sioner may deny the petition if the liable to regulatory action. Commissioner finds a lack of safety or (c) Information and data submitted effectiveness employing the standards under this section shall include, with in paragraph (a)(4) of this section (in respect to each nonclinical laboratory which case the appeal provisions of study contained in the application, ei- paragraph (a)(11) of this section shall ther a statement that the study was apply), or the Commissioner may pub- conducted in compliance with the good lish a proposed amendment or repeal in laboratory practice regulations set the FEDERAL REGISTER if the Commis- forth in part 58 of this chapter, or, if sioner finds general recognition of safe- the study was not conducted in compli- ty and effectiveness employing the ance with such regulations, a brief standards in paragraph (a)(4) of this statement of the reason for the non- section. Any interested person may, compliance. within 90 days after publication of the (d) [Reserved] proposed order in the FEDERAL REG- (e) Institutional review and informed ISTER, file with the Division of Dockets consent. Information and data sub- Management, Food and Drug Adminis- mitted under this section after July 27, tration, written comments in trip- 1981, shall include statements regard- licate. Comments may be accompanied ing each clinical investigation involv- by a memorandum or brief in support ing human subjects, from which the in- thereof. All comments may be reviewed formation and data are derived, that it in the Division of Dockets Management either was conducted in compliance

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with the requirements for institutional viewed by the National Academy of review set forth in part 56 of this chap- Sciences-National Research Council ter, or was not subject to such require- Drug Efficacy Study Group. Only the ments in accordance with §§ 56.104 or evaluations and comments of the pan- 56.105, and that it was conducted in els were published, with no conclusions compliance with the requirements for of the Commissioner of Food and informed consent set forth in part 50 of Drugs. Those publications were for the this chapter. purpose of giving interested persons (f) Financial certification or disclosure the benefit of the Academy’s opinions. statement. Any clinical data submitted For those products, and also for OTC under this section must be accom- drug products previously published panied by financial certifications or with the Commissioner’s conclusions disclosure statements or both as re- (except for the products listed in para- quired by part 54 of this chapter. graphs (b) (1) and (2) of this section, all requests for data, revised labeling, re- [39 FR 11741, Mar. 29, 1974, as amended at 39 FR 39556, Nov. 8, 1974; 42 FR 19141, Apr. 12, quests for new drug applications, ab- 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460, breviated new drug applications, updat- 8955, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; ing supplements, data to support less 46 FR 21360, Apr. 10, 1981; 46 FR 47738, Sept. than effective claims, if any, etc., are 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR 11581, deferred, and such OTC drug products Mar. 29, 1990; 63 FR 5253, Feb. 2, 1998; 67 FR are instead subject to the OTC drug re- 3073, Jan. 23, 2002] view in their appropriate classes pursuant to the procedures established in § 330.11 NDA deviations from applica- this subpart. ble monograph. (1) The requirements of the following A new drug application requesting DESI announcements are not deferred approval of an OTC drug deviating in (the reference document may also per- any respect from a monograph that has tain to prescription drugs): become final shall be in the form re- (i) Certain Surgical Sutures (DESI quired by § 314.50 of this chapter, but 4725), published in the FEDERAL REG- shall include a statement that the ISTER of November 11, 1971 (36 FR product meets all conditions of the ap- 21612). plicable monograph except for the devi- (ii) Absorbable Dusting Powder ation for which approval is requested (DESI 6264), published in the FEDERAL and may omit all information except REGISTER of May 25, 1971 (36 FR 9475). that pertinent to the deviation. (iii) Certain Insulin Preparations [39 FR 11741, Mar. 29, 1974, as amended at 55 (DESI 4286), published in the FEDERAL FR 11581, Mar. 29, 1990] REGISTER of April 9, 1971 (36 FR 6842). (iv) Sulfo-Van Ointment (DESI 2230), § 330.12 Status of over-the-counter published in the FEDERAL REGISTER of (OTC) drugs previously reviewed October 8, 1970 (35 FR 15860). under the Drug Efficacy Study (v) Antiperspirants and Deodorants (DESI). Containing Neomycin Sulfate (DESI (a) There were 420 OTC drugs re- 11048) for which an order revoking pro- viewed in the Drug Efficacy Study (a visions for certification or release was review of drugs introduced to the mar- published in the FEDERAL REGISTER of ket through new drug procedures be- December 5, 1972 (37 FR 25820) and has tween 1938 and 1962). A careful review been stayed by the filing of objections. has been made of the reports on these (vi) Thorexin Cough Medicine (DESI drugs to determine those drugs for 11160) for which a notice of opportunity which implementation may be deferred for hearing was published in the FED- without significant risk to the public ERAL REGISTER of February 2, 1973 (38 health, pending review by appropriate FR 3210). OTC drug advisory review panels and (vii) Antibiotic susceptibility discs promulgation of a monograph. (DESI 90235) for which an order pro- (b) On and after April 20, 1972, a num- viding for certain discs to be certified ber of notices were published in the and removing provisions for certifi- FEDERAL REGISTER concerning pre- cation of other discs was published in viously unpublished OTC drugs re- the FEDERAL REGISTER of September

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30, 1972 (37 FR 20525) and has been (vi) Drugs Containing Rutin, Quer- stayed by the filing of objections no- cetin, Hesperidin, or any Bioflavonoids tice of which was published in the FED- (DESI 5960), for which notice of with- ERAL REGISTER of March 15, 1973 (38 FR drawal of approval of new drug applica- 7007). tions was published in the FEDERAL (2) Deferral of requirements is not ap- REGISTER of July 3, 1970 (35 FR 10872, propriate when an announcement has 10873) and October 17, 1970 (35 FR 16332). been published and has been followed A further notice of opportunity for by a final order classifying a drug ei- hearing with respect to the drugs cov- ther as lacking substantial evidence of ered by the October 17, 1970 FEDERAL effectiveness or as not shown to be REGISTER notice will be published at a safe. These products will be removed later date. from the market, if they have not al- (vii) Antibiotics in Combination with ready been removed. Regulatory action Other Drugs for Nasal Use (DESI 7561), will also be undertaken against iden- for which an order revoking provision tical, similar and related products (21 for certification was published in the CFR 310.6). Deferral of requirements is FEDERAL REGISTER of August 6, 1971 (36 not appropriate for the following (the FR 14469) and confirmed in the FED- referenced document may also pertain ERAL REGISTER of October 28, 1971 (36 to prescription drugs): FR 20686). (i) Certain Sulfonamide-Deconges- (viii) Antibiotic Troches (DESI 8328), tant Nasal Preparation (DESI 4850), for for which an order revoking provision which notice of withdrawal of approval for certification was published in the of new drug applications was published FEDERAL REGISTER of July 14, 1971 (36 FR 13089) and confirmed in the FED- in the FEDERAL REGISTER of October 24, 1970 (35 FR 16605, 16606). ERAL REGISTER of October 9, 1971 (36 FR 19695). (ii) Eskay’s Theranates, containing (ix) Certain Drugs Containing Oxy- strychnine, sodium, and calcium glyc- phenisatin or Oxyphenisatin Acetate erophosphates, thiamine hydro- (DESI 10732), for which notices of with- chloride, alcohol, and phosphoric acid drawal of approval of new drug applica- (DESI 2220), for which notice of with- tions were published in the FEDERAL drawal of approval of the new drug ap- REGISTER of February 1, 1972 (37 FR plication was published in the FEDERAL 2460), and March 9, 1973 (38 FR 6419). REGISTER of February 18, 1971 (36 FR (x) Curad Medicated Adhesive Ban- 3152). dage containing tyrothricin-nitrofu- (iii) The following topical drugs razone (DESI 6898), for which an order (DESI 1726), for which notice of with- revoking provision for certification drawal of new drug applications was was published March 14, 1972 (37 FR published in the FEDERAL REGISTER of 5294), and confirmed in the FEDERAL August 28, 1971 (36 FR 17368): REGISTER of July 6, 1972 (37 FR 13254). (a) Rhulitol Solution, containing tan- (xi) Candette Cough Gel (DESI 11562), nic acid, chlorobutanol, phenol, cam- for which notice of withdrawal of ap- phor, alum, and isopropyl alcohol. proval of the new drug application was (b) Zirnox Topical Lotion, containing published in the FEDERAL REGISTER of phenyitoloxamine citrate and zir- November 19, 1972 (37 FR 25249). conium oxide. (xii) Certain OTC Multiple-Vitamin (iv) Menacyl Tablets, containing as- Preparations for Oral Use containing pirin, menadione, and ascorbic acid excessive amounts of vitamin D and/or (DESI 6363), for which notice of with- vitamin A (DESI 97), for which notice drawal of approval of the new drug ap- of withdrawal of approval of the new plication was published in the FEDERAL drug applications was published in the REGISTER of July 23, 1970 (35 FR 11827). FEDERAL REGISTER of November 29, 1972 (v) Curad Medicated Adhesive Ban- (37 FR 25249). dage containing sulfathiazole (DESI (xiii) Certain Sulfonamide-Con- 4964), for which notice of withdrawal of taining Preparations for Topical Oph- approval of the new drug application thalmic or Otic Use (DESI 368, for was published in the FEDERAL REG- which a notice of withdrawal of ap- ISTER of December 31, 1969 (34 FR 20441). proval was published in the FEDERAL

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REGISTER of February 2, 1973 (38 FR or contribute any added safety ques- 3208). tions. (xiv) Those parts of the publication (4) Changes in the components or entitled ‘‘Certain Mouthwash and Gar- composition of the drug which may gle Preparations’’ (DESI 2855) per- reasonably be concluded to improve the taining to Tyrolaris Mouthwash, con- safety of the drug, without diminishing taining tyrothricin, panthenol, and al- its effectiveness. cohol, for which an order revoking pro- (e) The forbearance from legal action vision for certification was published for lack of grandfather protection is an in the FEDERAL REGISTER of February interim procedure designed to encour- 2, 1967 (32 FR 1172) prior to the drug ef- age appropriate change in formulation ficacy study implementation. and/or labeling during the time period (c) Manufacturers and distributors required to review the various classes should take notice that the informa- of OTC drugs. At such time as an appli- tion on OTC drugs provided by the cable OTC drug monograph becomes ef- Drug Efficacy Study review is valuable fective, the interim procedure will information as to the deficiencies in automatically be terminated and any the data available to support indica- appropriate regulatory action will be tions for use. They are encouraged to initiated. perform studies to obtain adequate evidence of effectiveness for the review of § 330.13 Conditions for marketing in- OTC drugs which is already in progress. gredients recommended for over- In the interim it is in the public inter- the-counter (OTC) use under the est that manufacturers and distribu- OTC drug review. tors of all OTC drugs effect changes in (a) Before the publication in the FED- their formulations and/or labeling to ERAL REGISTER of an applicable pro- bring the products into conformity posed monograph, an OTC drug product with current medical knowledge and that contains: (1) An active ingredient experience. limited, on or after May 11, 1972, to pre- (d) Manufacturers and distributors of scription use for the indication and OTC drugs may be reluctant to make route of administration under consider- appropriate formulation and/or label- ation by an OTC advisory review panel, ing changes for fear of losing the pro- and not thereafter exempted from such tection of the so-called ‘‘grandfather’’ limitation pursuant to § 310.200 of this provisions of the 1938 Federal Food, chapter, or Drug, and Cosmetic Act (sec. 201(p)(1)) (2) An active ingredient at a dosage and the 1962 amendments to the act level higher than that available in an (sec. 107(c) of those amendments). To OTC drug product on December 4, 1975, encourage and facilitate prompt shall be regarded as a new drug within changes, the Food and Drug Adminis- the meaning of section 201(p) of the act tration will not take legal action for which an approved new drug appli- against any OTC drug, other than those cation is required. not deferred, based on a charge that (b)(1) An OTC drug product that con- the product is a new drug and not tains: (i) An active ingredient limited, grandfathered under the act as a result on or after May 11, 1972, to prescription of the changes if the changes in formu- use for the indication and route of ad- lation and/or labeling are of the fol- ministration under consideration by an lowing kind: OTC advisory review panel, and not (1) The addition to the labeling of thereafter exempted from such limita- warning, contraindications, side ef- tion pursuant to § 310.200 of this chap- fects, and/or precaution information. ter, or (2) The deletion from the labeling of (ii) An active ingredient at a dosage false, misleading, or unsupported indi- level higher than that available in an cations for use or claims of effective- OTC drug product on December 4, 1975, ness. which ingredient and/or dosage level is (3) Changes in the components or classified by the panel in category I composition of the drug that will give (conditions subject to § 330.10(a)(6)(i)) increased assurance that the drug will shall be regarded as a new drug within have its intended effect, yet not raise the meaning of section 201(p) of the act

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for which an approved new drug appli- (iii) A new drug application for the cation is required if marketed for OTC product has been approved. use prior to the date of publication in (d) An OTC drug product that con- the FEDERAL REGISTER of a proposed tains: (1) An active ingredient limited, monograph. on or after May 11, 1972, to prescription (2) An OTC drug product covered by use for the indication and route of ad- paragraph (b)(1) of this section which is ministration under consideration by an marketed after the date of publication OTC advisory review panel, and not in the FEDERAL REGISTER of a proposed thereafter exempted from such limita- monograph but prior to the effective tion pursuant to § 310.200 of this chap- date of a final monograph shall be sub- ter, or ject to the risk that the Commissioner (2) An active ingredient at a dosage may not accept the panel’s rec- level higher than that available in any ommendation and may instead adopt a OTC drug product on December 4, 1975, different position that may require re- which ingredient and/or dosage level is labeling, recall, or other regulatory ac- classified by the panel in category III tion. The Commissioner may state (conditions subject to § 330.10(a)(6)(iii)), such position at any time by notice in may be marketed only after: the FEDERAL REGISTER, either sepa- (i) The Center for Drug Evaluation rately or as part of another document; and Research or the Commissioner ten- appropriate regulatory action will tatively determines that the ingredient commence immediately and will not is generally recognized as safe and ef- await publication of a final monograph. fective, and the Commissioner states Marketing of such a product with a for- by notice in the FEDERAL REGISTER mulation or labeling not in accord with (separately or as part of another docu- a proposed monograph or tentative ment) that marketing under specified final monograph also may result in conditions will be permitted; regulatory action against the product, (ii) The ingredient is determined by the marketer, or both. the Commissioner to be generally rec- (c) An OTC drug product that con- ognized as safe and effective and is in- tains: (1) An active ingredient limited, cluded in the appropriate published on or after May 11, 1972, to prescription OTC drug final monograph; or use for the indication and route of ad- (iii) A new drug application for the ministration under consideration by an product has been approved. OTC advisory review panel, and not (e) This section applies only to condi- thereafter exempted from such limitations under consideration as part of the tion pursuant to § 310.200 of this chap- OTC drug review initiated on May 11, ter, or 1972, and evaluated under the proce- (2) An active ingredient at a dosage dures set forth in § 330.10. Section level higher than that available in any 330.14(h) applies to the marketing of all OTC drug product on December 4, 1975, conditions under consideration and which ingredient and/or dosage level is evaluated using the criteria and proce- classified by the panel in category II dures set forth in § 330.14. (conditions subject to § 330.10(a)(6)(ii)), may be marketed only after: [41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982; 50 FR 8996, Mar. 6, (i) The Center for Drug Evaluation 1985; 55 FR 11581, Mar. 29, 1990; 67 FR 3074, and Research or the Commissioner ten- Jan. 23, 2002] tatively determines that the ingredient is generally recognized as safe and ef- § 330.14 Additional criteria and proce- fective, and the Commissioner states dures for classifying OTC drugs as by notice in the FEDERAL REGISTER generally recognized as safe and ef- (separately or as part of another docu- fective and not misbranded. ment) that marketing under specified This section sets forth additional cri- conditions will be permitted; teria and procedures by which over- (ii) The ingredient is determined by the-counter (OTC) drugs initially mar- the Commissioner to be generally rec- keted in the United States after the ognized as safe and effective and is in- OTC drug review began in 1972 and OTC cluded in the appropriate published drugs without any U.S. marketing ex- OTC drug final monograph; or perience can be considered in the OTC

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drug monograph system. This section (6) Sponsor means the person that also addresses conditions regulated as submitted a time and extent applica- a cosmetic or dietary supplement in a tion (TEA) under paragraph (c) of this foreign country that would be regu- section. lated as OTC drugs in the United (7) Time and extent application (TEA) States. Section 330.15 sets forth means a submission by a sponsor under timelines for FDA review and action. paragraph (c) of this section, which (a) Definitions. The definitions and in- will be evaluated by the agency to de- terpretations contained in section 201 termine eligibility of a condition for of the Federal Food, Drug, and Cos- consideration in the OTC drug mono- metic Act and the following definitions graph system. of terms apply to this section and to (b) Criteria. To be considered for in- § 330.15. clusion in the OTC drug monograph (1) Botanical drug substance means a system, the condition must meet the drug substance derived from one or following criteria: more plants, algae, or macroscopic (1) The condition must be marketed fungi, but does not include a highly pu- for OTC purchase by consumers. If the rified or chemically modified substance condition is marketed in another coun- derived from such a source. try in a class of OTC drug products (2) Condition means an active ingre- that may be sold only in a pharmacy, dient or botanical drug substance (or a with or without the personal involve- combination of active ingredients or ment of a pharmacist, it must be estab- botanical drug substances), dosage lished that this marketing restriction form, dosage strength, or route of ad- does not indicate safety concerns about ministration, marketed for a specific the condition’s toxicity or other poten- OTC use, except as excluded in para- tiality for harmful effect, the method graph (b)(2) of this section. of its use, or the collateral measures (3) Date of filing means the date of the necessary to its use. notice from FDA stating that FDA has (2) The condition must have been made a threshold determination that marketed OTC for a minimum of 5 con- the safety and effectiveness data sub- tinuous years in the same country and mission is sufficiently complete to per- in sufficient quantity, as determined in mit a substantive review; or, if the sub- paragraphs (c)(2)(ii), (c)(2)(iii), and mission is filed over protest in accord- (c)(2)(iv) of this section. Depending on ance with paragraph (j)(3) of this sec- the condition’s extent of marketing in tion, the date of filing is the date of only one country with 5 continuous the notice from FDA stating that FDA years of marketing, marketing in more has filed the submission over protest than one country may be necessary. (this date will be no later than 30 days (c) Time and extent application. Cer- after the request that FDA file the sub- tain information must be provided mission over protest). when requesting that a condition sub- (4) Feedback letter means a letter ject to this section be considered for issued by the agency in accordance inclusion in the OTC drug monograph with paragraph (g)(4) of this section system. The following information that informs the sponsor and other in- must be provided in the format of a terested persons who have submitted time and extent application (TEA): data under paragraph (f) of this section (1) Basic information about the con- that a condition is initially determined dition that includes a description of not to be generally recognized as safe the active ingredient(s) or botanical and effective (GRASE). drug substance(s), pharmacologic (5) Safety and effectiveness data sub- class(es), intended OTC use(s), OTC mission means a data package sub- strength(s) and dosage form(s), route(s) mitted by a sponsor or other interested of administration, directions for use, person that includes safety and effec- and the applicable existing OTC drug tiveness data and information under monograph(s) under which the condi- paragraph (f) of this section and that is tion would be marketed or the request represented by the submitter as being a and rationale for creation of a new OTC complete submission. drug monograph(s).

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(i) A detailed chemical description of effect, the method of its use, or the col- the active ingredient(s) that includes a lateral measures necessary to its use. full description of the drug substance, (ii) The cumulative total number of including its physical and chemical dosage units (e.g., tablets, capsules, characteristics, the method of syn- ounces) sold for each dosage form of thesis (or isolation) and purification of the condition. Manufacturers or sup- the drug substance, and any specifica- pliers of OTC active ingredients may tions and analytical methods necessary provide dosage unit information as the to ensure the identity, strength, qual- total weight of active ingredient sold. ity, and purity of the drug substance. List the various package sizes for each (ii) For a botanical drug substance(s), dosage form in which the condition is a detailed description of the botanical marketed OTC. Provide an estimate of ingredient (including proper identifica- the minimum number of potential con- tion of the plant, plant part(s), alga, or sumer exposures to the condition using macroscopic fungus used; a certificate one of the following calculations: of authenticity; and information on the (A) Divide the total number of dosage grower/supplier, growing conditions, units sold by the number of dosage harvest location and harvest time); a units in the largest package size mar- qualitative description (including the keted, or name, appearance, physical/chemical (B) Divide the total weight of the ac- properties, chemical constituents, active ingredient sold by the total weight tive constituent(s) (if known), and bio- of the active ingredient in the largest logical activity (if known)); a quan- package size marketed. titative description of the chemical constituents, including the active con- (iii) A description of the population stituent(s) or other chemical marker(s) demographics (percentage of various (if known and measurable); the type of racial/ethnic groups) and the source(s) manufacturing process (e.g., aqueous from which this information has been extraction, pulverization); and infor- compiled, to ensure that the condi- mation on any further processing of tion’s use(s) can be reasonably extrapo- the botanical substance (e.g., addition lated to the U.S. population. of excipients or blending). (iv) If the use pattern (i.e., how often (iii) Reference to the current edition it is to be used (according to the label) of the U.S. Pharmacopeia (USP)–Na- and for how long) varies between coun- tional Formulary (NF) or foreign com- tries based on the condition’s pack- pendiums may help satisfy the require- aging and labeling, or changes in use ments in this section. pattern have occurred over time in one (2) A list of all countries in which the or more countries, describe the use pat- condition has been marketed. Include tern for each country and explain why the following information for each there are differences or changes. country. (For a condition that has been (v) A description of the country’s sys- marketed OTC in 5 or more countries tem for identifying adverse drug expe- with a minimum of 5 continuous years riences, especially those found in OTC of marketing in at least one country, marketing experience, including meth- the sponsor may submit information in od of collection if applicable. accordance with paragraph (c)(4) of this (3) A statement of how long the con- section): dition has been marketed in each coun- (i) How the condition has been mar- try and how long the current product keted (e.g., OTC general sales direct- labeling has been in use, accompanied to-consumer; sold only in a pharmacy, by a copy of the current product label- with or without the personal involve- ing. All labeling that is not in English ment of a pharmacist; dietary supple- must be translated to English in ac- ment; or cosmetic). If the condition has cordance with § 10.20(c)(2) of this chap- been marketed as a nonprescription ter. State whether the current product pharmacy-only product, establish that labeling has or has not been author- this marketing restriction does not in- ized, accepted, or approved by a regu- dicate safety concerns about its tox- latory body in each country where the icity or other potentiality for harmful condition is marketed.

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(4) For a condition that has been a decision is made on the eligibility of marketed OTC in five or more coun- the condition for consideration in the tries with a minimum of 5 continuous OTC drug monograph system. If the years of marketing in at least one condition is found eligible, the TEA country, the sponsor may select at will be placed on public display in the least five of these countries from which Division of Dockets Management after to submit information in accord with deletion of information deemed con- paragraphs (c)(2)(i) through (c)(2)(iv) of fidential under 18 U.S.C. 1905, 5 U.S.C. this section. Selected countries must 552(b), or 21 U.S.C. 331(j). Sponsors include the country with a minimum of must identify information that is con- 5 continuous years of OTC marketing, sidered confidential under these statu- countries that have the longest dura- tory provisions. If the condition is not tion of marketing, and countries hav- found eligible, the TEA will not be ing the most support for extent of mar- placed on public display, but a letter keting, i.e., a large volume of sales from the agency to the sponsor stating with cultural diversity among users of why the condition was not found ac- the product. If the condition meets ceptable will be placed on public dis- these criteria in countries listed in sec- play in the Division of Dockets Man- tion 802(b)(1)(A) of the Federal Food, agement. Drug, and Cosmetic Act, some of these (e) Notice of eligibility. If the condition countries should be included among the is found eligible, the agency will pub- five selected. Sponsors should provide lish a notice of eligibility in the FED- information from more than five coun- ERAL REGISTER and provide the sponsor tries if they believe that it is needed to and other interested parties an oppor- support eligibility. Sponsors should ex- tunity to submit data to demonstrate plain the basis for the countries se- safety and effectiveness. When the no- lected in the TEA. tice of eligibility is published, the (5) A list of all countries where the agency will place the TEA on public condition is marketed only as a pre- display in the Division of Dockets Man- scription drug and the reasons why its agement. marketing is restricted to prescription (f) Safety and effectiveness data submis- in these countries. sion. The notice of eligibility will re- (6) A list of all countries in which the quest a safety and effectiveness data condition has been withdrawn from submission that includes published and marketing or in which an application unpublished data to demonstrate the for OTC marketing approval has been safety and effectiveness of the condi- denied. Include the reasons for such tion for its intended OTC use(s), as well withdrawal or application denial. as the submission of any other relevant (7) The information requested in data and views. These data will be sub- paragraphs (c)(2), (c)(2)(i) through mitted to a docket established in the (c)(2)(iv), and (c)(3) of this section must Division of Dockets Management and be provided in a table format. The la- will be publicly available for viewing beling required by paragraph (c)(3) of at that office, except data deemed con- this section must be attached to the fidential under 18 U.S.C. 1905, 5 U.S.C. table. 552(b), or 21 U.S.C. 331(j). Data consid- (8) For OTC drugs that have been ered confidential under these provi- marketed for more than 5 years in the sions must be clearly identified. Any United States under a new drug appli- proposed compendial standards for the cation, the information requested in condition will not be considered con- paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), fidential. The safety and effectiveness (c)(3), and (c)(5) of this section need not data submission must be sufficiently be provided. complete to be filed by the agency (d) Submission of information; confiden- under paragraph (j)(2) of this section. tiality. The sponsor must submit three Safety and effectiveness data and other copies of the TEA to the Central Docu- information submitted under this para- ment Room, 5630 Fishers Lane, rm. graph are subject to the requirements 1061, Rockville, MD 20852. The Food and in § 330.10(c), (e), and (f). The safety and Drug Administration will handle the effectiveness data submission must in- TEA as confidential until such time as clude the following:

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(1) All data and information listed in agency will publish a notice of pro- § 330.10(a)(2) under the outline ‘‘OTC posed rulemaking to include the condi- Drug Review Information,’’ items III tion in § 310.502 of this chapter. through VII. (5) Interested parties will have an op- (2) All serious adverse drug experi- portunity to submit comments and new ences as defined in §§ 310.305 and 314.80 data. The agency will subsequently of this chapter, from each country publish a final rule (or reproposal if where the condition has been or is cur- necessary) in the FEDERAL REGISTER. rently marketed as a prescription drug (h) Marketing. A condition submitted or as an OTC drug or product. Provide under this section for consideration in individual adverse drug experience re- the OTC drug monograph system may ports (FDA Form 3500A or equivalent) be marketed in accordance with an ap- along with a summary of all serious ad- plicable final OTC drug monograph(s) verse drug experiences and expected or only after the agency determines that frequently reported side effects for the the condition is generally recognized as condition. Individual reports that are safe and effective and includes it in the not in English must be translated to appropriate OTC drug final mono- English in accordance with § 10.20(c)(2) graph(s), and the condition complies of this chapter. with paragraph (i) of this section. (g) Administrative procedures. The When an OTC drug monograph has not agency may use an advisory review been finalized and finalization is not panel to evaluate the safety and effec- imminent, after the agency has evalu- tiveness data in accord with the provi- ated the comments to a proposed rule sions of § 330.10(a)(3). Alternatively, the to include a new condition in a ten- agency may evaluate the data in con- tative final monograph as generally junction with the advisory review recognized as safe and effective and the panel or on its own without using an agency has not changed its position as advisory review panel. The agency will a result of the comments, and the con- use the safety, effectiveness, and label- dition complies with paragraph (i) of ing standards in § 330.10(a)(4)(i) through this section, the agency may publish a (a)(4)(vi) in evaluating the data. notice of enforcement policy that al- (1) If the agency uses an advisory review panel to evaluate the data, the lows marketing to begin pending com- panel may submit its recommendations pletion of the final monograph subject in its official minutes of meeting(s) or to the risk that the agency may, prior by a report under the provisions of to or in the final monograph, adopt a § 330.10(a)(5). different position that could require re- (2) The agency may act on an advi- labeling, recall, or other regulatory ac- sory review panel’s recommendations tion. using the procedures in §§ 330.10(a)(2) (i) Compendial monograph. Any active and 330.10(a)(6) through (a)(10). ingredient or botanical drug substance (3) If the condition is initially deter- included in a final OTC drug mono- mined to be generally recognized as graph or the subject of an enforcement safe and effective for OTC use in the notice described in paragraph (h) of United States, the agency will propose this section must be recognized in an to include it in an appropriate OTC official USP-NF drug monograph that drug monograph(s), either by amending sets forth its standards of identity, an existing monograph(s) or estab- strength, quality, and purity. Sponsors lishing a new monograph(s), if nec- must include an official or proposed essary. compendial monograph as part of the (4) If the condition is initially deter- safety and effectiveness data submis- mined not to be GRASE for OTC use in sion listed in § 330.10(a)(2) under item the United States, the agency will in- VII of the outline entitled ‘‘OTC DRUG form the sponsor and other interested REVIEW INFORMATION.’’ persons who have submitted data of its (j) Filing determination. (1) After FDA determination by feedback letter, a receives a safety and effectiveness data copy of which will be placed on public submission, the agency will determine display in the docket established in the whether the submission may be filed. Division of Dockets Management. The The filing of a submission means that

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FDA has made a threshold determina- (4) FDA may refuse to file a safety tion that the submission is sufficiently and effectiveness data submission if complete to permit a substantive re- any of the following applies: view. (i) The submission is incomplete be- (2) If FDA finds that none of the rea- cause it does not contain information sons in paragraph (j)(4) of this section required under paragraph (f) of this for refusing to file the safety and effec- section. If the submission does not con- tiveness data submission apply, the tain required information because such agency will file the submission and no- information or data are not relevant to tify the submitter in writing. FDA will the condition, the submission must post a copy of the notice to the docket. clearly identify and provide an expla- The date of filing begins the FDA nation for the omission. timelines described in § 330.15(c)(3) and (ii) The submission is not organized (4). Data submitted after the date of or formatted in a manner to enable the filing will be considered before the agency to readily determine whether it issuance of a notice of proposed rule- is sufficiently complete to permit a making if there is adequate time for substantive review. review; otherwise, the data will be con- (iii) The submission does not contain sidered as comments to the proposed a signed statement that the submission rule after issuance of a notice of pro- represents a complete safety and effec- posed rulemaking. tiveness data submission and that the (3) If FDA refuses to file the safety submission includes all the safety and and effectiveness data submission, the effectiveness data and information agency will notify the submitter in available to the submitter at the time writing and state the reason(s) under of the submission, whether positive or paragraph (j)(4) of this section for the negative. refusal. The submitter may request in writing, within 30 days of the date of (iv) The submission does not contain the agency’s notification, a meeting an analysis and summary of the data with the agency about whether the and other supporting information, or- agency should file the submission, and ganized by clinical or nonclinical area, FDA will convene the meeting within such as clinical efficacy data, clinical 30 days of the request. If, within 120 safety data, clinical pharmacology, ad- days after the meeting, the submitter verse event reports, animal toxicology, requests that FDA file the submission chemistry data, and compendial status. (with or without correcting the defi- (v) The submission does not contain a ciencies), the agency will file the safe- supporting document summarizing the ty and effectiveness data submission strategy used for literature searches, over protest under paragraph (j)(2) of including search terms, sources, dates this section, notify the submitter in accessed, and years reviewed. writing and post a copy to the docket, (vi) The submission does not contain and review the submission as filed. The a reference list of supporting informa- submitter must have a meeting before tion, such as published literature, un- requesting that FDA file the submis- published information, abstracts and sion over protest but need not resubmit case reports, and a copy of the sup- a copy of a safety and effectiveness porting information. data submission that is filed over pro- (vii) The submission includes data or test. A safety and effectiveness data information relevant for making a submission and the corresponding GRASE determination marked as con- TEA-eligible condition are both not fidential without a statement that the deemed under consideration if FDA re- information may be released to the fuses to file the safety and effective- public. ness data submission, and it is not filed (viii) The submission does not con- over protest; the condition remains eli- tain a complete environmental assess- gible for consideration and the sponsor ment under § 25.40 of this chapter or or any interested person can pursue fails to provide sufficient information consideration of the condition in the to establish that the requested action future by submitting a new safety and is subject to categorical exclusion effectiveness data submission. under § 25.30 or § 25.31 of this chapter.

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(ix) The submission does not contain notice of eligibility or a safety and ef- a statement for each nonclinical lab- fectiveness data submission that has oratory study that the study was con- been accepted for filing and posted to ducted in compliance with the require- the docket) will remain in the public ments set forth in part 58 of this chap- docket. If the condition has been found ter, or, if it was not conducted in com- eligible through issuance of a notice of pliance with part 58 of this chapter, a eligibility, the condition remains eligi- brief statement of the reason for the ble for consideration and the sponsor noncompliance. or any interested person can pursue (x) The submission does not contain a consideration of the condition in the statement for each clinical investiga- future by submitting a new safety and tion involving human subjects that the effectiveness data submission. investigation was conducted in compli- (4) If FDA withdraws consideration of ance with the institutional review a submission under paragraph (k)(1) of board regulations in part 56 of this this section, the timelines under chapter, or was not subject to those § 330.15(c) will no longer apply as of the regulations, and that the investigation date of withdrawal, and the submission was conducted in compliance with the will not be included in the metrics informed consent regulations in part 50 under § 330.15(b). of this chapter. (xi) The submission does not include [67 FR 3074, Jan. 23, 2002, as amended at 81 financial certification or disclosure FR 84475, Nov. 23, 2016] statements, or both, as required by part 54 of this chapter, accompanying § 330.15 Timelines for FDA review and action on time and extent applica- any clinical data submitted. tions and safety and effectiveness (k) Withdrawal of consideration. (1) data submissions. Notwithstanding paragraph (g) of this section, FDA may withdraw consider- (a) Applicability. This section applies ation of a TEA submission or a safety to the review of a condition in a time and effectiveness data submission if: and extent application (TEA) sub- (i) The person that submitted the mitted under § 330.14 for consideration submission requests that its submis- in the over-the-counter (OTC) drug sion be withdrawn from consideration; monograph system. This section does or not apply to: (ii) FDA deems the submission to be (1) A sunscreen active ingredient or withdrawn from consideration due to combination of sunscreen active ingre- the submitter’s failure to respond to dients, and other conditions for such communications from FDA. ingredients; or (2) Before FDA deems a submission (2) A non-sunscreen active ingredient withdrawn under paragraph (k)(1)(ii) of or combination of non-sunscreen active this section, FDA will notify the per- ingredients, and other conditions for son that submitted the submission. If, such ingredients submitted in a TEA within 90 days from the date of the no- under § 330.14 before November 27, 2014, tice from FDA, the submitter requests subject to section 586F(a)(1)(C) of the that FDA not withdraw consideration Federal Food, Drug, and Cosmetic Act. of the submission, FDA will not deem (b) Metrics. FDA will maintain and the submission to be withdrawn. update annually, a publicly available (3) If FDA withdraws consideration of posting of metrics for the review of a submission under paragraph (k)(1) of TEAs and safety and effectiveness data this section, FDA will post a notice of submissions that are subject to the withdrawal to the docket, except in the timelines in this section. The posting case of a TEA submission that is with- will contain the following information drawn from consideration before for tracking the extent to which the issuance of a notice of eligibility, in timelines set forth in paragraph (c) of which case, the notice of withdrawal this section were met during the pre- will only be provided to the sponsor. vious calendar year. Information that has been posted to (1) Number and percent of eligibility the public docket for the condition at notices or ineligibility letters issued the time of the withdrawal (such as a within 180 days of submission of a TEA;

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(2) Number and percent of filing de- PART 331—ANTACID PRODUCTS terminations issued within 90 days of FOR OVER-THE-COUNTER (OTC) submission of a safety and effective- HUMAN USE ness data submission; (3) If applicable, number and percent Subpart A—General Provisions of feedback letters issued within 730 days from the date of filing; Sec. 331.1 Scope. (4) Number and percent of notices for proposed rulemaking issued within Subpart B—Active Ingredients 1,095 days from the date of filing; 331.10 Antacid active ingredients. (5) Number and percent of final rules 331.11 Listing of specific active ingredients. issued within 912 days of closing of the 331.15 Combination with nonantacid active docket of the proposed rulemaking; and ingredients. (6) Total number of TEAs submitted under § 330.14. Subpart C—Testing Procedures (c) Timelines for FDA review and ac- 331.20 Determination of percent contribution. FDA will review and take an action of active ingredients. tion within the following timelines: 331.21 Test Modifications. (1) Within 180 days of submission of a Subpart D—Labeling TEA under § 330.14(c), FDA will issue a notice of eligibility or post to the 331.30 Labeling of antacid products. docket a letter of ineligibility, in ac- 331.80 Professional labeling. cordance with § 330.14(d) and (e). AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (2) Within 90 days of submission of a 360, 371. safety and effectiveness data submis- SOURCE: 39 FR 19874, June 4, 1974, unless sion, in accordance with § 330.14(j), FDA otherwise noted. will issue a filing determination. The date of filing begins the FDA timelines Subpart A—General Provisions in paragraphs (c)(3) and (4) of this section. § 331.1 Scope. (3) Within 730 days from the date of An over-the-counter antacid product filing, if the condition is initially de- in a form suitable for oral administra- termined not to be GRASE for OTC use tion is generally recognized as safe and in the United States, FDA will inform effective and is not misbranded if it the sponsor and other interested per- meets each of the following conditions sons who have submitted data of its de- and each of the general conditions es- termination by feedback letter in ac- tablished in § 330.1 of this chapter. cordance with § 330.14(g)(4). (4) Within 1,095 days from the date of Subpart B—Active Ingredients filing of a safety and effectiveness data § 331.10 Antacid active ingredients. submission, FDA will issue a notice of proposed rulemaking to either: (a) The active antacid ingredients of (i) Include the condition in an appro- the product consist of one or more of priate OTC monograph(s), either by the ingredients permitted in § 331.11 amending an existing monograph(s) or within any maximum daily dosage limit established, each ingredient is in- establishing a new monograph(s), if cluded at a level that contributes at necessary; or least 25 percent of the total acid neu- (ii) Include the condition in § 310.502 tralizing capacity of the product, and of this chapter. the finished product contains at least 5 (5) Within 912 days of the closing of meq of acid neutralizing capacity as the docket of the proposed rulemaking measured by the procedure provided in under paragraph (c)(4) of this section, the United States Pharmacopeia 23/Na- FDA will issue a final rule. tional Formulary 18. The method es- [81 FR 84477, Nov. 23, 2016] tablished in § 331.20 shall be used to determine the percent contribution of each antacid active ingredient.

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(b) This section does not apply to an (6) Magnesium hydroxide. antacid ingredient specifically added as (7) Magnesium oxide. a corrective to prevent a laxative or (8) Magnesium trisilicate. constipating effect. (h) Milk solids, dried. [39 FR 19874, June 4, 1974, as amended at 61 (i) Phosphate-containing active in- FR 4822, Feb. 8, 1996] gredients: (1) Aluminum phosphate; maximum § 331.11 Listing of specific active in- daily dosage limit 8 grams. gredients. (2) Mono or dibasic calcium salt; (a) Aluminum-containing active in- maximum daily dosage limit 2 grams. gredients: (3) Tricalcium phosphate; maximum (1) Basic aluminum carbonate gel. daily dosage limit 24 grams. (2) Aluminum hydroxide (or as aluminum hydroxide-hexitol stabilized (j) Potassium-containing active in- polymer, aluminum hydroxide-magne- gredients: sium carbonate codried gel, aluminum (1) Potassium bicarbonate (or car- hydroxide-magnesium trisilicate bonate when used as a component of an codried gel, aluminum-hydroxide su- effervescent preparation); maximum crose powder hydrated). daily dosage limit 200 mEq. of bicar- (3) Dihydroxyaluminum amino- bonate ion for persons up to 60 years acetate and dihydroxyaluminum ami- old and 100 mEq. of bicarbonate ion for noacetic acid. persons 60 years or older. (4) Aluminum phosphate gel when (2) Sodium potassium tartrate. used as part of an antacid combination (k) Sodium-containing active ingre- product and contributing at least 25 dients: percent of the total acid neutralizing (1) Sodium bicarbonate (or carbonate capacity; maximum daily dosage limit when used as a component of an effer- is 8 grams. vescent preparation); maximum daily (5) Dihydroxyaluminum sodium car- dosage limit 200 mEq. of sodium for bonate. persons up to 60 years old and 100 mEq. (b) Bicarbonate-containing active in- of sodium for persons 60 years or older, gredients: Bicarbonate ion; maximum and 200 mEq. of bicarbonate ion for per- daily dosage limit 200 mEq. for persons sons up to 60 years old and 100 mEq. of up to 60 years old and 100 mEq. for persons 60 years or older. bicarbonate ion for persons 60 years or (c) Bismuth-containing active ingre- older. That part of the warning re- dients: quired by § 330.1(g), which states, ‘‘Keep (1) Bismuth aluminate. this and all drugs out of the reach of (2) Bismuth carbonate. children’’ is not required on a product (3) Bismuth subcarbonate. which contains only sodium bicarbon- (4) Bismuth subgallate. ate powder and which is intended pri- (5) Bismuth subnitrate. marily for other than drug uses. (d) Calcium-containing active ingre- (2) Sodium potassium tartrate. dients: Calcium, as carbonate or phos- (l) Silicates: phate; maximum daily dosage limit 160 (1) Magnesium aluminosilicates. mEq. calcium (e.g., 8 grams calcium (2) Magnesium trisilicate. carbonate). (m) Tartrate-containing active ingre- (e) Citrate-containing active ingredi- dients. Tartaric acid or its salts; max- ents: Citrate ion, as citric acid or salt; imum daily dosage limit 200 mEq. (15 maximum daily dosage limit 8 grams. grams) of tartrate. (f) Glycine (aminoacetic acid). (g) Magnesium-containing active in- [39 FR 19874, June 4, 1974, as amended at 51 gredients: FR 27763, Aug. 1, 1986; 55 FR 19859, May 11, (1) Hydrate magnesium aluminate ac- 1990] tivated sulfate. (2) Magaldrate. § 331.15 Combination with nonantacid (3) Magnesium aluminosilicates. active ingredients. (4) Magnesium carbonate. (a) An antacid may contain any gen- (5) Magnesium glycinate. erally recognized as safe and effective

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nonantacid laxative ingredient to cor- submitted will be subject to the disclo- rect for constipation caused by the ant- sure rules in part 20 of this chapter. acid. No labeling claim of the laxative [61 FR 4823, Feb. 8, 1996] effect may be used for such a product. (b) An antacid may contain any generally recognized as safe and effective Subpart D—Labeling analgesic ingredient(s), if it is indicated for use solely for the concurrent § 331.30 Labeling of antacid products. symptoms involved, e.g., headache and (a) Statement of identity. The labeling acid indigestion, and is marketed in a of the product contains the established form intended for ingestion as a solu- name of the drug, if any, and identifies tion. the product as an ‘‘antacid.’’ (c) An antacid may contain any gen- (b) Indications. The labeling of the erally recognized as safe and effective product states, under the heading ‘‘In- antiflatulent ingredient if it is indi- dications,’’ the following: ‘‘For the re- cated for use solely for the concurrent lief of’’ (optional, any or all of the fol- symptoms of gas associated with heart- lowing:) ‘‘heartburn,’’ ‘‘sour stomach,’’ burn, sour stomach or acid indigestion. and/or ‘‘acid indigestion’’ (which may be followed by the optional statement:) Subpart C—Testing Procedures ‘‘and upset stomach associated with’’ (optional, as appropriate) ‘‘this symp- § 331.20 Determination of percent con- tom’’ or ‘‘these symptoms.’’ Other tribution of active ingredients. truthful and nonmisleading statements, describing only the indications To determine the percent contribu- for use that have been established and tion of an antacid active ingredient, listed in this paragraph (b), may also place an accurately weighed amount of be used, as provided in § 330.1(c)(2) of the antacid active ingredient equal to this chapter, subject to the provisions the amount present in a unit dose of of section 502 of the act relating to the product into a 250-milliliter (mL) misbranding and the prohibition in sec- beaker. If wetting is desired, add not tion 301(d) of the act against the intro- more than 5 mL of alcohol (neutralized duction or delivery for introduction to an apparent pH of 3.5), and mix to into interstate commerce of unap- wet the sample thoroughly. Add 70 mL proved new drugs in violation of sec- of water, and mix on a magnetic stirrer tion 505(a) of the act. at 300 ±30 r.p.m. for 1 minute. Analyze the acid neutralizing capacity of the (c) Warnings. The labeling of the sample according to the procedure pro- product contains the following warn- vided in the United States Pharma- ings, under the heading ‘‘Warnings’’, copeia 23/National Formulary 18 and which may be combined but not rear- calculate the percent contribution of ranged to eliminate duplicative words the antacid active ingredient in the or phrases if the resulting warning is total product as follows: clear and understandable: Percent contribution = (Total mEq. (1) ‘‘Do not take more than (max- Antacid Active Ingredient × 100)/(Total imum recommended daily dosage, bro- mEq. Antacid Product). ken down by age groups if appropriate, expressed in units such as tablets or [61 FR 4823, Feb. 8, 1996] teaspoonfuls) in a 24–hour period, or use the maximum dosage of this prod- § 331.21 Test modifications. uct for more than 2 weeks, except The formulation or mode of adminis- under the advice and supervision of a tration of certain products may require physician.’’ a modification of the United States (2) For products which cause con- Pharmacopeia 23/National Formulary stipation in 5 percent or more of per- 18 acid neutralizing capacity test. Any sons who take the maximum rec- proposed modification and the data to ommended dosage: ‘‘May cause con- support it shall be submitted as a peti- stipation.’’ tion under the rules established in (3) For products which cause laxation § 10.30 of this chapter. All information in 5 percent or more of persons who

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take the maximum recommended dos- any of the labeling statements in this age: ‘‘May have laxative effect.’’ section. (4) For products containing more [39 FR 19874, June 4, 1974, as amended at 47 than 5 gm per day lactose in a max- FR 38484, Aug. 31, 1982; 51 FR 16266, May 1, imum daily dosage: ‘‘Do not use this 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, product except under advice and super- Mar. 13, 1987; 55 FR 11581, Mar. 29, 1990; 58 FR vision of a physician if you are allergic 45208, Aug. 26, 1993; 59 FR 60556, Nov. 25, 1994; to milk or milk products.’’ 61 FR 17806, Apr. 22, 1996; 64 FR 13295, Mar. 17, 1999; 69 FR 13734, Mar. 24, 2004] (d) Drug interaction precaution. The labeling of the product contains the § 331.80 Professional labeling. following statement ‘‘Ask a doctor or (a) The labeling of the product pro- pharmacist before use if you are [bul- vided to health professionals (but not 1 let] presently taking a prescription to the general public): drug. Antacids may interact with cer- (1) Shall contain the neutralizing ca- tain prescription drugs.’’ pacity of the product as calculated (e) Directions for use. The labeling of using the procedure set forth in United the product contains the recommended States Pharmacopeia 23/National For- dosage, under the heading ‘‘Direc- mulary 18 expressed in terms of the tions’’, per time interval (e.g., every 4 dosage recommended per minimum hours) or time period (e.g., 4 times a time interval or, if the labeling rec- day) broken down by age groups if ap- ommends more than one dosage, in propriate, followed by ‘‘or as directed terms of the minimum dosage rec- by a physician.’’ ommended per minimum time interval. (f) Exemption from the general acci- (2) May contain an indication for the dental overdose warning. The labeling symptomatic relief of hyperacidity as- for antacid drug products containing sociated with the diagnosis of peptic the active ingredients identified in ulcer, gastritis, peptic esophagitis, gas- § 331.11(a), (b), and (d) through (m); per- tric hyperacidity, and hiatal hernia. mitted combinations of these ingredi- (3) For products containing basic aluminum carbonate gel identified in ents provided for in § 331.10; and any of § 331.11(a)(1)—Indication. ‘‘For the these ingredients or combinations of treatment, control, or management of these ingredients in combination with hyperphosphatemia, or for use with a simethicone (identified in § 332.10 of low phosphate diet to prevent forma- this chapter and provided for in tion of phosphate urinary stones, § 331.15(c)), are exempt from the re- through the reduction of phosphates in quirement in § 330.1(g) of this chapter the serum and urine.’’ that the labeling bear the general (4) For products containing aluminum warning statement ‘‘In case of acci- identified in § 331.11(a)—Warnings. (i) dental overdose, seek professional as- Prolonged use of aluminum-containing sistance or contact a poison control antacids in patients with renal failure center immediately.’’ With the excep- may result in or worsen dialysis osteo- tion of sodium bicarbonate powder malacia. Elevated tissue aluminum products identified in § 331.11(k)(1), the levels contribute to the development of labeling must continue to bear the first the dialysis encephalopathy and osteo- part of the general warning in § 330.1(g) malacia syndromes. Small amounts of of this chapter, which states, ‘‘Keep aluminum are absorbed from the gas- this and all drugs out of the reach of trointestinal tract and renal excretion children.’’ of aluminum is impaired in renal fail- (g) [Reserved] ure. Aluminum is not well removed by (h) The word ‘‘doctor’’ may be sub- dialysis because it is bound to albumin and transferrin, which do not cross di- stituted for the word ‘‘physician’’ in alysis membranes. As a result, aluminum is deposited in bone, and dialysis osteomalacia may develop when large amounts of aluminum are ingested orally by patients with impaired 1 See § 201.66(b)(4) of this chapter. renal function.

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(ii) Aluminum forms insoluble com- flatulent. Neither term should be con- plexes with phosphate in the gastro- sidered as describing the mechanism of intestinal tract, thus decreasing phos- action of the active ingredient con- phate absorption. Prolonged use of alu- tained in the product. minum-containing antacids by normo- [61 FR 8838, Mar. 5, 1996] phosphatemic patients may result in hypophosphatemia if phosphate intake is not adequate. In its more severe Subpart B—Active Ingredients forms, hypophosphatemia can lead to § 332.10 Antiflatulent active ingredi- anorexia, malaise, muscle weakness, ents. and osteomalacia. (b) Professional labeling for an ant- Simethicone; maximum daily dose acid-antiflatulent combination may 500 mg. There is no dosage limitation contain the information allowed for at this time for professional labeling. health professionals for antacids and antiflatulents. § 332.15 Combination with non-antiflatulent active ingredients. [39 FR 19874, June 4, 1974. Redesignated and An antiflatulent may contain any amended at 55 FR 19859, May 11, 1990] generally recognized as safe and effective antacid ingredient(s) if it is indi- PART 332—ANTIFLATULENT PROD- cated for use solely for the concurrent UCTS FOR OVER-THE-COUNTER symptoms of gas associated with heart- HUMAN USE burn, sour stomach or acid indigestion.

Subpart A—General Provisions Subpart C—Labeling Sec. 332.1 Scope. § 332.30 Labeling of antiflatulent drug 332.3 Definitions. products. (a) Statement of identity. The labeling Subpart B—Active Ingredients of the product contains the established 332.10 Antiflatulent active ingredients. name of the drug, if any, and identifies 332.15 Combination with non-antiflatulent the product as an ‘‘antiflatulent,’’ active ingredients. ‘‘antigas,’’ or ‘‘antiflatulent (antigas).’’ (b) Indications. The labeling of the Subpart C—Labeling product states, under the heading ‘‘In- 332.30 Labeling of antiflatulent products. dications,’’ one or more of the phrases 332.31 Professional labeling. listed in this paragraph (b), as appropriate. Other truthful and nonmis- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, leading statements, describing only the 360, 371. indications for use that have been es- SOURCE: 39 FR 19877, June 4, 1974, unless tablished and listed in this paragraph otherwise noted. (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to Subpart A—General Provisions the provisions of section 502 of the Fed- eral Food, Drug, and Cosmetic Act (the § 332.1 Scope. act) relating to misbranding and the An over-the-counter antiflatulent prohibition in section 301(d) of the act product in a form suitable for oral ad- against the introduction or delivery for ministration is generally recognized as introduction into interstate commerce safe and effective and is not mis- of unapproved new drugs in violation of branded if it meets each of the fol- section 505(a) of the act. lowing conditions and each of the gen- (1) (Select one of the following: ‘‘Al- eral conditions established in § 330.1 of leviates or Relieves’’) ‘‘the symptoms this chapter. referred to as gas.’’ (2) (Select one of the following: ‘‘Al- § 332.3 Definitions. leviates’’ or ‘‘Relieves’’) (select one or As used in this part: more of the following: ‘‘bloating,’’ Antigas. A term that may be used ‘‘pressure,’’ ‘‘fullness,’’ or ‘‘stuffed feel- interchangeably with the term anti- ing’’) ‘‘commonly referred to as gas.’’

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(c) Exemption from the general acci- Subpart C—Topical Antifungal Drug dental overdose warning. The labeling Products for antiflatulent drug products containing simethicone identified in 333.201 Scope. 333.203 Definitions. § 332.10 and antacid/antiflatulent com- 333.210 Antifungal active ingredients. bination drug products provided for in 333.250 Labeling of antifungal drug prod- § 332.15, containing the active ingredi- ucts. ents identified in § 331.11(a), (b), and (d) 333.280 Professional labeling. through (m) of this chapter are exempt from the requirement in § 330.1(g) of Subpart D—Topical Acne Drug Products this chapter that the labeling bear the general warning statement ‘‘In case of 333.301 Scope. accidental overdose, seek professional 333.303 Definitions. 333.310 Acne active ingredients. assistance or contact a poison control 333.320 Permitted combinations of active in- center immediately.’’ The labeling gredients. must continue to bear the first part of 333.350 Labeling of acne drug products. the general warning in § 330.1(g) of this chapter, which states, ‘‘Keep this and AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. all drugs out of the reach of children.’’ SOURCE: 52 FR 47322, Dec. 11, 1987, unless [39 FR 19877, June 4, 1974, as amended at 40 otherwise noted. FR 11719, Mar. 13, 1975; 51 FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar. 13, 1987; 61 FR 8838, Mar. 5, 1996] Subpart A [Reserved] § 332.31 Professional labeling. Subpart B—First Aid Antibiotic (a) The labeling of the product pro- Drug Products vided to health professionals (but not to the general public) may contain as § 333.101 Scope. additional indications postoperative (a) An over-the-counter first aid antigas pain or for use in endoscopic exam- biotic drug product in a form suitable ination. for topical administration is generally (b) Professional labeling for an anti- recognized as safe and effective and is flatulent-antacid combination may not misbranded if it meets each of the contain information allowed for health conditions in this subpart and each of professionals for antacids and anti- the general conditions established in flatulents. § 330.1. (b) References in this subpart to reg- PART 333—TOPICAL ANTI- ulatory sections of the Code of Federal Regulations are to chapter I of title 21 MICROBIAL DRUG PRODUCTS unless otherwise noted. FOR OVER-THE-COUNTER HUMAN USE § 333.103 Definitions. As used in this subpart: Subpart A [Reserved] First aid antibiotic. An antibiotic-containing drug product applied topically Subpart B—First Aid Antibiotic Drug to the skin to help prevent infection in Products minor cuts, scrapes, and burns. Sec. [52 FR 47322, Dec. 11, 1987, as amended at 64 333.101 Scope. FR 403, Jan. 5, 1999] 333.103 Definitions. 333.110 First aid antibiotic active ingredi- § 333.110 First aid antibiotic active in- ents. gredients. 333.120 Permitted combinations of active ingredients. The product consists of any of the 333.150 Labeling of first aid antibiotic drug following active ingredients within the products. specified concentration established for 333.160 Labeling of permitted combinations each ingredient and in the specified of active ingredients. dosage form:

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(a) Bacitracin ointment containing, (5) Bacitracin zinc-neomycin sulfate- in each gram, 500 units of bacitracin in polymyxin B sulfate ointment con- a suitable ointment base. taining, in each gram, in a suitable (b) Bacitracin zinc ointment con- ointment base the following: taining, in each gram, 500 units of baci- (i) 400 units of bacitracin, 3 milli- tracin zinc in a suitable ointment base. grams of neomycin, and 8,000 units of (c) Chlortetracycline hydrochloride polymyxin B; or ointment containing, in each gram, 30 (ii) 400 units of bacitracin, 3.5 milli- milligrams of chlortetracycline hydro- grams of neomycin, and 5,000 units of chloride in a suitable ointment base. polymyxin B; or (d) Neomycin sulfate ointment con- (iii) 500 units of bacitracin, 3.5 milli- taining, in each gram, 3.5 milligrams of grams of neomycin, and 5,000 units of neomycin in a suitable water soluble or polymyxin B; or oleaginous ointment base. (iv) 500 units of bacitracin, 3.5 milli- (e) Neomycin sulfate cream con- grams of neomycin, and 10,000 units of taining, in each gram, 3.5 milligrams of polymyxin B; neomycin in a suitable cream base. (6) Bacitracin zinc-polymyxin B sul- (f) Tetracycline hydrochloride oint- fate ointment containing, in each ment containing, in each gram, 30 mil- gram, 500 units of bacitracin and 10,000 ligrams of tetracycline hydrochloride units of polymyxin B in a suitable oint- in a suitable ointment base. ment base. [52 FR 47322, Dec. 11, 1987, as amended at 53 (7) Bacitracin zinc-polymyxin B sul- FR 18838, May 25, 1988; 64 FR 403, Jan. 5, 1999] fate topical aerosol containing, in each gram, 120 units of bacitracin and 2,350 § 333.120 Permitted combinations of units of polymyxin B in a suitable ve- active ingredients. hicle, packaged in a pressurized con- The following combinations are per- tainer with suitable inert gases. mitted provided each active ingredient (8) Bacitracin zinc-polymyxin B sul- is present within the established con- fate topical powder containing, in each centration and in the specified dosage gram, 500 units of bacitracin and 10,000 form, and the product is labeled in ac- units of polymyxin B in a suitable cordance with § 333.160. base. (a) Combinations of antibiotic active in- (9) Neomycin sulfate-polymyxin B gredients. (1) Bacitracin-neomycin sul- sulfate ointment containing, in each fate ointment containing, in each gram, 3.5 milligrams of neomycin and gram, 500 units of bacitracin and 3.5 5,000 units of polymyxin B in a suitable milligrams of neomycin in a suitable water miscible base. ointment base. (10) Neomycin sulfate-polymyxin B (2) Bacitracin-neomycin sulfate-poly- sulfate cream containing, in each myxin B sulfate ointment containing, gram, 3.5 milligrams of neomycin and in each gram, in a suitable ointment 10,000 units of polymyxin B in a suit- base the following: able vehicle. (i) 500 units of bacitracin, 3.5 milli- (11) Oxytetracycline hydrochloride- grams of neomycin, and 5,000 units of polymyxin B sulfate ointment con- polymyxin B; or taining, in each gram, 30 milligrams of (ii) 400 units of bacitracin, 3.5 milli- oxytetracycline and 10,000 units of grams of neomycin, and 5,000 units of polymyxin B in a suitable ointment polymyxin B; base. (3) Bacitracin-polymyxin B sulfate (12) Oxytetracycline hydrochloride- topical aerosol containing, in each polymyxin B sulfate topical powder gram, 500 units of bacitracin and 5,000 containing, in each gram, 30 milli- units of polymyxin B in a suitable ve- grams of oxytetracycline and 10,000 hicle, packaged in a pressurized con- units of polymyxin B with a suitable tainer with suitable inert gases. filler. (4) Bacitracin zinc-neomycin sulfate (b) Combinations of first aid antibiotic ointment containing, in each gram, 500 active ingredients and local anesthetic ac- units of bacitracin and 3.5 milligrams tive ingredients. (1) Bacitracin ointment of neomycin in a suitable ointment containing, in each gram, 500 units of base. bacitracin and any single generally

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recognized as safe and effective amine units of polymyxin B, and any single or ‘‘caine’’-type local anesthetic active generally recognized as safe and effec- ingredient in a suitable ointment base. tive amine or ‘‘caine’’-type local anes- (2) Bacitracin-neomycin sulfate-poly- thetic active ingredient in a suitable myxin B sulfate ointment containing, ointment base. in each gram, in a suitable ointment (6) Neomycin sulfate-polymyxin B base the following: sulfate cream containing, in each (i) 500 units of bacitracin, 3.5 milligram, 3.5 milligrams of neomycin, grams of neomycin, 5,000 units of poly- 10,000 units of polymyxin B, and any myxin B, and any single generally rec- single generally recognized as safe and ognized as safe and effective amine or effective amine or ‘‘caine’’-type local ‘‘caine’’-type local anesthetic active anesthetic active ingredient in a suit- ingredient; or able vehicle. (ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of poly- [52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. myxin B, and any single generally rec- 24, 1987, as amended at 53 FR 18838, May 25, ognized as safe and effective amine or 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381, ‘‘caine’’-type local anesthetic active Oct. 3, 1990; 55 FR 50172, Dec. 5, 1990; 64 FR ingredient. 403, Jan. 5, 1999] (3) Bacitracin-polymyxin B sulfate topical aerosol containing, in each § 333.150 Labeling of first aid antibiotic drug products. gram, 500 units of bacitracin and 5,000 units of polymyxin B and any single (a) Statement of identity. The labeling generally recognized as safe and effec- of the product contains the established tive amine or ‘‘caine’’-type local anes- name of the drug, if any, and identifies thetic active ingredient in a suitable the product as a ‘‘first aid antibiotic.’’ vehicle, packaged in a pressurized con- (b) Indications. The labeling of the tainer with suitable inert gases. product states, under the heading ‘‘In- (4) Bacitracin zinc-neomycin sulfate- dications,’’ the following: ‘‘First aid to polymyxin B sulfate ointment con- help’’ [select one of the following: taining, in each gram, in a suitable ‘‘prevent,’’ (‘‘decrease’’ (‘‘the risk of’’ ointment base the following: or ‘‘the chance of’’)), (‘‘reduce’’ (‘‘the (i) 400 units of bacitracin, 3 milli- risk of’’ or ‘‘the chance of’’)), ‘‘guard grams of neomycin, 8,000 units of poly- against,’’ or ‘‘protect against’’] [select myxin B, and any single generally rec- one of the following: ‘‘infection,’’ ognized as safe and effective amine or ‘‘bacterial contamination,’’ or ‘‘skin ‘‘caine’’-type local anesthetic active infection’’] ‘‘in minor cuts, scrapes, ingredient; or and burns.’’ Other truthful and nonmis- (ii) 400 units of bacitracin, 3.5 milli- leading statements describing only the grams of neomycin, 5,000 units of poly- indications for use that have been es- myxin B, and any single generally rec- tablished and listed in this paragraph ognized as safe and effective amine or (b), may also be used, as provided in ‘‘caine’’-type local anesthetic active § 330.1(c)(2), subject to the provisions of ingredient; or (iii) 500 units of bacitracin, 3.5 milli- section 502 of the act relating to mis- grams of neomycin, 5,000 units of poly- branding and the prohibition in section myxin B, and any single generally rec- 301(d) of the act against the introduc- ognized as safe and effective amine or tion or delivery for introduction into ‘‘caine’’-type local anesthetic active interstate commerce of unapproved ingredient; or new drugs in violation of section 505(a) (iv) 500 units of bacitracin, 3.5 milli- of the act. grams of neomycin, 10,000 units of poly- (c) Warnings. The labeling of the myxin B, and any single generally rec- product contains the following warn- ognized as safe and effective amine or ings under the heading ‘‘Warnings’’: ‘‘caine’’-type local anesthetic active (1) ‘‘For external use only. Do not use ingredient; in the eyes or apply over large areas of (5) Bacitracin zinc-polymyxin B sul- the body. In case of deep or puncture fate ointment containing, in each wounds, animal bites, or serious burns, gram, 500 units of bacitracin, 10,000 consult a doctor.’’

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(2) For products containing chlortetra- tablished in the statement of identity cycline hydrochloride or tetracycline hy- sections of the applicable OTC drug drochloride.‘‘Stop use and consult a monographs. For a combination drug doctor if the condition persists or gets product that does not have an estab- worse. Do not use longer than 1 week lished name, the labeling of the prod- unless directed by doctor.’’ uct states the statement of identity for (3) For any product containing baci- each ingredient in the combination, as tracin, bacitracin zinc, neomycin, neomy- established in the statement of iden- cin sulfate, polymyxin B, and/or poly- tity sections of the applicable OTC myxin B sulfate. ‘‘Stop use and consult drug monographs. a doctor if the condition persists or (b) Indications. The labeling of the gets worse, or if a rash or other allergic product states, under the heading ‘‘In- reaction develops. Do not use if you are dications,’’ the indication(s) for each allergic to any of the ingredients. Do ingredient in the combination, as es- not use longer than 1 week unless di- tablished in the ‘‘Indications’’ sections rected by a doctor.’’ of the applicable OTC drug mono- (d) Directions. The labeling of the graphs, unless otherwise stated in this product contains the following state- paragraph. Other truthful and nonmis- ments under the heading ‘‘Directions’’: leading statements, describing only the (1) For ointment and cream products. indications for use that have been es- ‘‘Clean the affected area. Apply a small tablished and listed in this paragraph amount of this product (an amount (b), may also be used, as provided in equal to the surface area of the tip of § 330.1(c)(2), subject to the provisions of a finger) on the area 1 to 3 times daily. section 502 of the act relating to mis- May be covered with a sterile ban- branding and the prohibition in section dage.’’ 301(d) of the act against the introduc- (2) For powder products. ‘‘Clean the af- tion or delivery for introduction into fected area. Apply a light dusting of interstate commerce of unapproved the powder on the area 1 to 3 times new drugs in violation of section 505(a) daily. May be covered with a sterile of the act. bandage.’’ (1) For permitted combinations identi- (3) For aerosol products. ‘‘Clean the af- fied in § 333.120(a). The indications in fected area. Spray a small amount of § 333.150 should be used. this product on the area 1 to 3 times (2) For permitted combinations identi- daily. May be covered with a sterile fied in § 333.120(b). In addition to the re- bandage.’’ quired indication identified in § 333.150, (e) The word ‘‘doctor’’ may be sub- the labeling of the product may state, stituted for the word ‘‘physician’’ in under the heading ‘‘Indications,’’ the any of the labeling statements in this following additional indication: ‘‘First subpart. aid for the temporary relief of’’ (select [52 FR 47332, Dec. 11, 1987, as amended at 61 one of the following: ‘‘pain,’’ ‘‘discom- FR 58472, Nov. 15, 1996] fort,’’ ‘‘pain or discomfort’’ or ‘‘pain and itching’’) ‘‘in minor cuts, scrapes, § 333.160 Labeling of permitted com- and burns.’’ binations of active ingredients. (c) Warnings. The labeling of the Statements of identity, indications, product states, under the heading warnings, and directions for use, re- ‘‘Warnings,’’ the warning(s) for each in- spectively, applicable to each ingre- gredient in the combination, as estab- dient in the product may be combined lished in the warnings sections of the to eliminate duplicative words or applicable OTC drug monographs. phrases so that the resulting informa- (d) Directions. The labeling of the tion is clear and understandable. product states, under the heading ‘‘Di- (a) Statement of identity. For a com- rections,’’ directions that conform to bination drug product that has an es- the directions established for each in- tablished name, the labeling of the gredient in the directions sections of product states the established name of the applicable OTC drug monographs. the combination drug product, followed When the time intervals or age limita- by the statement of identity for each tions for administrations of the indi- ingredient in the combination, as es- vidual ingredients differ, the directions

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for the combination product may not (b) Haloprogin 1 percent. exceed any maximum dosage limits es- (c) Miconazole nitrate 2 percent. tablished for the individual ingredients (d) Povidone-iodine 10 percent. in the applicable OTC drug monograph. (e) Tolnaftate 1 percent. (f) Undecylenic acid, calcium Subpart C—Topical Antifungal undecylenate, copper undecylenate, Drug Products and zinc undecylenate may be used individually or in any ratio that provides SOURCE: 58 FR 49898, Sept. 23, 1993, unless a total undecylenate concentration of otherwise noted. 10 to 25 percent. (g) Clotrimazole 1 percent. § 333.201 Scope. [58 FR 49898, Sept. 23, 1993, as amended at 67 (a) An over-the-counter antifungal FR 5943, Feb. 8, 2002] drug product in a form suitable for topical administration is generally recog- § 333.250 Labeling of antifungal drug nized as safe and effective and is not products. misbranded if it meets each of the con- (a) Statement of identity. The labeling ditions in this subpart and each gen- of the product contains the established eral condition established in § 330.1 of name of the drug, if any, and identifies this chapter. the product as an ‘‘antifungal.’’ (b) Reference in this subpart to regu- (b) Indications. The labeling of the latory sections of the Code of Federal product states, under the heading ‘‘In- Regulations are to chapter I of title 21 dications,’’ the phrase listed in para- unless otherwise noted. graph (b)(1)(i) of this section and may § 333.203 Definitions. contain the additional phrase listed in paragraph (b)(1)(ii) of this section. As used in this subpart: Other truthful and nonmisleading (a) Antifungal. A drug which inhibits statements, describing only the indica- the growth and reproduction of fungal tions for use that have been established cells and decreases the number of fungi in paragraph (b) of this section, may present. (b) Athlete’s foot. An infection of the also be used, as provided in § 330.1(c)(2) feet caused by certain dermatophytic of this chapter, subject to the provi- fungi. sions of section 502 of the Federal (c) Dermatophyte. A fungus that in- Food, Drug, and Cosmetic Act (the act) vades and lives upon the skin or in the relating to misbranding and the prohi- hair or nails. bition in section 301(d) of the act (d) Fungus. Any of a large division of against the introduction or delivery for plants, including dermatophytes, introduction into interstate commerce yeasts, and molds, characterized by a of unapproved new drugs in violation of simple cell structure and the absence section 505(a) of the act. of chlorophyll. (1) For products containing any ingre- (e) Jock itch. A chronic and recurrent dient identified in § 333.210 labeled for the infection caused by certain treatment of athlete’s foot, jock itch, and dermatophytic fungi; affects the upper, ringworm. (i) (Select one of the fol- inner thighs and sometimes extends to lowing: ‘‘Treats,’’ ‘‘For the treatment the groin and the pubic area; the condi- of,’’ ‘‘For effective treatment of,’’ tion most frequently occurs in men, ‘‘Cures,’’ ‘‘For the cure of,’’ ‘‘Clears but may also occur in women. up,’’ or ‘‘Proven clinically effective in (f) Ringworm. A skin infection caused the treatment of’’) ‘‘most’’ (select one by certain dermatophytic fungi. condition from any one or more of the following groups of conditions: § 333.210 Antifungal active ingredi- (A) ‘‘Athlete’s foot,’’ athlete’s foot ents. (dermatophytosis),’’ ‘‘athlete’s foot The active ingredient of the product (tinea pedis),’’ or ‘‘tinea pedis (ath- consists of any one of the following lete’s foot)’’; within the specified concentration es- (B) ‘‘Jock itch,’’ ‘‘jock itch (tinea tablished for each ingredient: cruris),’’ or ‘‘tinea cruris (jock itch)’’; (a) Clioquinol 3 percent. or

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(C) ‘‘Ringworm,’’ ‘‘ringworm (tinea (4) For products labeled according to corporis),’’ or ‘‘tinea corporis paragraph (b)(2) of this section for the (ringworm).’’) prevention of athlete’s foot. ‘‘If irritation (ii) In addition to the information occurs, discontinue use and consult a identified in paragraph (b)(1)(i) of this doctor.’’ section, the labeling of the product (5) For products containing the ingre- may contain the following statement: dient identified in § 333.210(a) labeled ac- (Select one of the following: ‘‘Re- cording to paragraph (b)(1) of this sec- lieves,’’ ‘‘For relief of,’’ ‘‘For effective tion. The following statements must relief of,’’ or ‘‘Soothes,’’) (select one or appear in boldface type as the first more of the following: ‘‘Itching,’’ warnings under the ‘‘Warnings’’ head- ‘‘scaling,’’ ‘‘cracking,’’ ‘‘burning,’’ ing. (i) ‘‘Do not use on children under 2 ‘‘redness,’’ ‘‘soreness,’’ ‘‘irritation,’’ years of age.’’ (This warning is to be ‘‘discomfort,’’ ‘‘chafing associated with used in place of the warning in para- jock itch,’’ ‘‘itchy, scaly skin between graph (c)(1)(i) of this section.) the toes,’’ or ‘‘itching, burning feet’’). (2) For products containing the ingre- (ii) ‘‘Do not use for diaper rash.’’ dient identified in § 333.210(e) labeled for (d) Directions. The labeling of the the prevention of athlete’s foot. (i) (Se- product contains the following state- lect one of the following: ‘‘Clinically ments under the heading ‘‘Directions’’: proven to prevent,’’ ‘‘Prevents,’’ (1) For products labeled according to ‘‘Proven effective in the prevention paragraph (b)(1) of this section for the of,’’ ‘‘Helps prevent,’’ ‘‘For the preven- treatment of athlete’s foot, jock itch, and tion of,’’ ‘‘For the prophylaxis (preven- ringworm. [Select one of the following: tion) of,’’ ‘‘Guards against,’’ or ‘‘Pre- ‘‘Clean’’ or ‘‘Wash’’] ‘‘the affected area vents the recurrence of’’) ‘‘most’’ (se- and dry thoroughly. Apply’’ (the word lect one of the following: ‘‘Athlete’s ‘‘spray’’ may be used to replace the foot,’’ ‘‘athlete’s foot word ‘‘apply’’ for aerosol products) ‘‘a (dermatophytosis),’’ ‘‘athlete’s foot thin layer of the product over affected (tinea pedis),’’ or ‘‘tinea pedis (ath- area twice daily (morning and night) or lete’s foot)’’) ‘‘with daily use.’’ as directed by a doctor. Supervise chil- (ii) In addition to the information dren in the use of this product. For identified in paragraph (b)(2)(i) of this athlete’s foot: Pay special attention to section, the labeling of the product spaces between the toes; wear well-fit- may contain the following statement: ting, ventilated shoes, and change ‘‘Clears up most athlete’s foot infec- shoes and socks at least once daily. For tion and with daily use helps keep it athlete’s foot and ringworm, use daily from coming back.’’ for 4 weeks; for jock itch, use daily for (c) The labeling of the Warnings. 2 weeks. If condition persists longer, product contains the following warn- consult a doctor. This product is not ings under the heading ‘‘Warnings’’: effective on the scalp or nails.’’ (1) For products containing any ingredient identified in § 330.210. (i) ‘‘Do not (2) For products labeled according to use on children under 2 years of age un- paragraph (b)(2) of this section for the less directed by a doctor.’’ prevention of athlete’s foot. ‘‘To prevent (ii) ‘‘For external use only.’’ athlete’s foot,’’ (select one of the fol- (iii) ‘‘Avoid contact with the eyes.’’ lowing: ‘‘clean’’ or ‘‘wash’’) ‘‘the feet (2) For products labeled according to and dry thoroughly. Apply’’ (the word paragraph (b)(1) of this section for the ‘‘spray’’ may be used to replace the treatment of athlete’s foot and ringworm. word ‘‘apply’’ for aerosol products) ‘‘a ‘‘If irritation occurs or if there is no thin layer of the product to the feet improvement within 4 weeks, dis- once or twice daily (morning and/or continue use and consult a doctor.’’ night). Supervise children in the use of (3) For products labeled according to this product. Pay special attention to paragraph (b)(1) of this section for the spaces between the toes; wear well-fit- treatment of jock itch. ‘‘If irritation oc- ting, ventilated shoes, and change curs or if there is no improvement shoes and socks at least once daily.’’ within 2 weeks, discontinue use and (e) The word ‘‘physician’’ may be sub- consult a doctor.’’ stituted for the word ‘‘doctor’’ in any

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of the labeling statements in this sec- ized by a small, firm, whitish elevation tion. of the skin.

[58 FR 49898, Sept. 23, 1993, as amended at 65 § 333.310 Acne active ingredients. FR 52305, Aug. 29, 2000] The active ingredient of the product § 333.280 Professional labeling. consists of any of the following: The labeling provided to health pro- (a) Benzoyl peroxide, 2.5 to 10 per- fessionals (but not to the general pub- cent. lic) may contain the following addi- (b) Resorcinol, 2 percent, when com- tional indication: bined with sulfur in accordance with (a) For products containing haloprogin § 333.320(a). or miconazole nitrate identified in (c) Resorcinol monoacetate, 3 per- § 333.210 (a) and (c). ‘‘For the treatment cent, when combined with sulfur in ac- of superficial skin infections caused by cordance with § 333.320(b). yeast (Candida albicans).’’ (d) Salicylic acid, 0.5 to 2 percent. (b) [Reserved] (e) Sulfur, 3 to 10 percent. (f) Sulfur, 3 to 8 percent, when combined with resorcinol or resorcinol Subpart D—Topical Acne Drug monoacetate in accordance with Products § 333.320. [75 FR 9776, Mar. 4, 2010] SOURCE: 56 FR 41019, Aug. 16, 1991, unless otherwise noted. § 333.320 Permitted combinations of § 333.301 Scope. active ingredients. (a) An over-the-counter acne drug (a) Resorcinol identified in § 333.310(b) product in a form suitable for topical may be combined with sulfur identified application is generally recognized as in § 333.310(f). safe and effective and is not mis- (b) Resorcinol monoacetate identified branded if it meets each of the condi- in § 333.310(c) may be combined with tions in this subpart and each general sulfur identified in § 333.310(f). condition established in § 330.1 of this [75 FR 9776, Mar. 4, 2010] chapter. (b) References in this subpart to reg- § 333.350 Labeling of acne drug prod- ulatory sections of the Code of Federal ucts. Regulations are to chapter I of title 21 (a) Statement of identity. The labeling unless otherwise noted. of the product contains the established name of the drug, if any, and identifies § 333.303 Definitions. the product as an ‘‘acne medication,’’ As used in this subpart: ‘‘acne treatment,’’ ‘‘acne medication’’ (a) Acne. A disease involving the oil (insert dosage form, e.g., ‘‘cream,’’ glands and hair follicles of the skin ‘‘gel,’’ ‘‘lotion,’’ or ‘‘ointment’’), or which is manifested by blackheads, ‘‘acne treatment’’ (insert dosage form, whiteheads, acne pimples, and acne e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or blemishes. ‘‘ointment’’). (b) Acne blemish. A flaw in the skin (b) Indications. The labeling of the resulting from acne. product states, under the heading ‘‘In- (c) Acne drug product. A drug product dications,’’ the phrase listed in para- used to reduce the number of acne graph (b)(1) of this section and may blemishes, acne pimples, blackheads, contain any of the additional phrases and whiteheads. listed in paragraph (b)(2) of this sec- (d) Acne pimple. A small, prominent, tion. Other truthful and nonmisleading inflamed elevation of the skin result- statements, describing only the indica- ing from acne. tions for use that have been established (e) Blackhead. A condition of the skin and listed in paragraph (b) of this sec- that occurs in acne and is character- tion, may also be used, as provided in ized by a black tip. § 330.1(c)(2) of this chapter, subject to (f) Whitehead. A condition of the skin the provisions of section 502 of the Fed- that occurs in acne and is character- eral Food, Drug, and Cosmetic Act (the

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act) relating to misbranding and the (2) For products containing sulfur iden- prohibition in section 301(d) of the act tified in § 333.310(e) and (f). against the introduction or delivery for (i) The labeling states ‘‘Do not use on introduction into interstate commerce [bullet] broken skin [bullet] large areas of unapproved new drugs in violation of of the skin.’’ section 505(a) of the act. (ii) The labeling states ‘‘When using (1) ‘‘For the’’ (select one of the fol- this product [bullet] apply only to lowing: ‘‘management’’ or ‘‘treat- areas with acne.’’ ment’’) ‘‘of acne.’’ (3) For products containing any com- (2) In addition to the information bination identified in § 333.320. (i) The la- identified in paragraph (b)(1) of this beling states ‘‘When using this product section, the labeling of the product [bullet] rinse right away with water if may contain any one or more of the it gets in eyes.’’ following statements: (ii) The labeling states ‘‘Stop use and (i) (Select one of the following: ask a doctor [bullet] if skin irritation ‘‘Clears,’’ ‘‘Clears up,’’ ‘‘Clears up occurs or gets worse.’’ most,’’ ‘‘Dries,’’ ‘‘Dries up,’’ ‘‘Dries and (4) For products containing benzoyl per- clears,’’ ‘‘Helps clear,’’ ‘‘Helps clear oxide identified in § 333.310(a). up,’’ ‘‘Reduces the number of,’’ or ‘‘Re- (i) The labeling states ‘‘Do not use if duces the severity of’’) (select one or you [bullet] have very sensitive skin more of the following: ‘‘acne blem- [bullet] are sensitive to benzoyl per- ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ oxide.’’ or ‘‘whiteheads’’) which may be fol- (ii) The labeling states ‘‘When using lowed by ‘‘and allows skin to heal.’’ this product [bullet] avoid unnecessary (ii) ‘‘Penetrates pores to’’ (select one sun exposure and use a sunscreen [bul- of the following: ‘‘eliminate most,’’ let] avoid contact with the eyes, lips, ‘‘control,’’ ‘‘clear most,’’ or ‘‘reduce and mouth [bullet] avoid contact with the number of’’) (select one or more of hair and dyed fabrics, which may be the following: ‘‘acne blemishes,’’ ‘‘acne bleached by this product [bullet] skin pimples,’’ ‘‘blackheads,’’ or irritation may occur, characterized by ‘‘whiteheads’’). redness, burning, itching, peeling, or (iii) ‘‘Helps keep skin clear of new’’ possibly swelling. Irritation may be re- (select one or more of the following: duced by using the product less fre- ‘‘acne blemishes,’’ ‘‘acne pimples,’’ quently or in a lower concentration.’’ ‘‘blackheads,’’ or ‘‘whiteheads’’). (iii) The labeling states ‘‘Stop use (iv) ‘‘Helps prevent new’’ (select one and ask a doctor if [bullet] irritation or more of the following: ‘‘acne blem- becomes severe.’’ ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ (d) Directions. The labeling of the or ‘‘whiteheads’’) which may be fol- product contains the following infor- lowed by ‘‘from forming.’’ mation under the heading ‘‘Direc- (v) ‘‘Helps prevent the development tions’’: of new’’ (select one or more of the fol- (1) For products applied containing any lowing: ‘‘acne blemishes,’’ ‘‘acne pim- ingredient identified in § 333.310. The la- ples,’’ ‘‘blackheads,’’ or ‘‘whiteheads’’). beling states ‘‘[bullet] clean the skin (c) Warnings. The labeling of the thoroughly before applying this prod- product contains the following warn- uct [bullet] cover the entire affected ings under the heading ‘‘Warnings’’: area with a thin layer one to three (1) For products containing any ingredi- times daily [bullet] because excessive ents identified in § 330.310. drying of the skin may occur, start (i) The labeling states ‘‘For external with one application daily, then gradu- use only.’’ ally increase to two or three times (ii) The labeling states ‘‘When using daily if needed or as directed by a doc- this product [bullet] skin irritation and tor [bullet] if bothersome dryness or dryness is more likely to occur if you peeling occurs, reduce application to use another topical acne medication at once a day or every other day.’’ the same time. If irritation occurs, (2) For products applied and left on the only use one topical acne medication skin containing benzoyl peroxide identi- at a time.’’ fied in § 333.310(a).

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(i) The labeling states the directions branded if it meets each condition in in paragraph (d)(1) of this section. this part and each general condition es- (ii) The labeling states ‘‘[bullet] if tablished in § 330.1 of this chapter. going outside, apply sunscreen after (b) References in this part to regu- using this product. If irritation or sen- latory sections of the Code of Federal sitivity develops, stop use of both prod- Regulations are to chapter I of title 21 ucts and ask a doctor.’’ unless otherwise noted. (3) For products applied and removed from the skin containing any ingredient § 335.3 Definitions. identified in § 333.310. Products, such as As used in this part: soaps and masks, may be applied and (a) Antidiarrheal. A drug that can be removed and should include appro- shown by objective measurement to priate directions. All products con- treat or control (stop) the symptoms of taining benzoyl peroxide should in- diarrhea. clude the directions in paragraph (b) Diarrhea. A condition character- (d)(2)(ii) of this section. ized by increased frequency of loose, (4) Optional directions. In addition to watery stools (three or more daily) the required directions in paragraphs during a limited period (24 to 48 hours), (d)(1) and (d)(2) of this section, the usually with no identifiable cause. product may contain the following op- (c) Travelers’ diarrhea. A subset of ditional labeling: ‘‘Sensitivity Test for a arrhea occurring in travelers that is New User. Apply product sparingly to most commonly caused by an infec- one or two small affected areas during tious agent. the first 3 days. If no discomfort occurs, follow the directions stated (se- [68 FR 18881, Apr. 17, 2003, as amended at 69 lect one of the following: ‘elsewhere on FR 26302, May 12, 2004] this label,’ ‘above,’ or ‘below’).’’ Subpart B—Active Ingredients [56 FR 41019, Aug. 16, 1991, as amended at 75 FR 9776, Mar. 4, 2010] § 335.10 Antidiarrheal active ingredients. PART 335—ANTIDIARRHEAL DRUG The active ingredient of the product PRODUCTS FOR OVER-THE- consists of any one of the following COUNTER HUMAN USE when used within the dosage limits established for each ingredient in Subpart A—General Provisions § 335.50(d): Sec. (a) Bismuth subsalicylate. 335.1 Scope. (b) Kaolin. 335.3 Definitions. Subpart C—Labeling Subpart B—Active Ingredients 335.10 Antidiarrheal active ingredients. § 335.50 Labeling of antidiarrheal drug products. Subpart C—Labeling (a) Statement of identity. The labeling of the product contains the established 335.50 Labeling of antidiarrheal drug products. name of the drug, if any, and identifies the product either as an AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, ‘‘antidiarrheal’’ or ‘‘for diarrhea.’’ 360, 371. (b) Indications. The labeling of the SOURCE: 68 FR 18881, April 17, 2003, unless product states, under the heading otherwise noted. ‘‘Use,’’ one or more of the phrases listed in this paragraph (b), as appropriate. Subpart A—General Provisions Other truthful and nonmisleading statements, describing only the indica- § 335.1 Scope. tions for use that have been established (a) An over-the-counter antidiarrheal and listed in this paragraph (b) may drug product in a form suitable for oral also be used, as provided in § 330.1(c)(2) administration is generally recognized of this chapter, subject to the provi- as safe and effective and is not missions of section 502 of the Federal

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Food, Drug, and Cosmetic Act (the act) (iii) ‘‘Ask a doctor or pharmacist be- relating to misbranding and the prohi- fore use if you are taking any drug for bition in section 301(d) of the act [bullet] anticoagulation (thinning the against the introduction or delivery for blood) [bullet] diabetes [bullet] gout introduction into interstate commerce [bullet] arthritis’’. of unapproved new drugs in violation of (iv) ‘‘When using this product a tem- section 505(a) of the act. porary, but harmless, darkening of the (1) For products containing bismuth stool and/or tongue may occur’’. subsalicylate identified in § 335.10(a). The (v) ‘‘Stop use and ask a doctor if [bul- labeling states [select one of the fol- let] symptoms get worse [bullet] ring- lowing: ‘‘controls’’ or ‘‘relieves’’] [se- ing in the ears or loss of hearing occurs lect one or both of the following: ‘‘di- [bullet] diarrhea lasts more than 2 arrhea’’ or ‘‘travelers’ diarrhea’’]. If days’’. both ‘‘diarrhea’’ and ‘‘travelers’ diar- (3) For products containing kaolin iden- rhea’’ are selected, each shall be pre- tified in § 335.10(b). (i) ‘‘Ask a doctor or ceded by a bullet in accordance with pharmacist before use if you are taking § 201.66(b)(4) and (d)(4) of this chapter any other drugs. Try to use at least 3 and the heading ‘‘Uses’’ shall be used. hours before or after taking any other (2) For products containing kaolin iden- drugs.’’ tified in § 335.10(b). The labeling states (ii) ‘‘Stop use and ask a doctor if ‘‘helps firm stool within 24 to 48 [bullet] symptoms get worse [bullet] hours’’. diarrhea lasts more than 2 days’’. (3) Additional indications—(i) When (d) Directions. The labeling of the any additional indications are used, product contains the following infor- the heading ‘‘Uses’’ shall be used and mation under the heading ‘‘Direc- each listed use shall be preceded by a tions’’: bullet in accord with § 201.66(b)(4) of (1) For products containing any ingre- this chapter. dient identified in § 335.10. The labeling (ii) In addition to the indication in states ‘‘[bullet] drink plenty of clear paragraph (b)(1) of this section, one or fluids to help prevent dehydration both of the following may be used for caused by diarrhea’’. products containing bismuth subsalicy- (2) For products containing bismuth late in § 335.10(a): ‘‘[bullet] reduces subsalicylate identified in § 335.10(a). The number of bowel movements’’ ‘‘[bullet] labeling states ‘‘[bullet] adults and helps firm stool’’. children 12 years and over:’’ 525 milli- (c) Warnings. The labeling of the grams ‘‘every 1⁄2 to 1 hour, or’’ 1,050 product contains the following warn- milligrams ‘‘every hour as needed [bul- ings under the heading ‘‘Warnings’’: let] do not exceed’’ 4,200 milligrams ‘‘in (1) For products containing any ingre- 24 hours [bullet] use until diarrhea dient identified in § 335.10. (i) ‘‘Do not stops but not more than 2 days [bullet] use if you have [bullet] bloody or black children under 12 years: ask a doctor’’. stool’’. (3) For products containing kaolin iden- (ii) ‘‘Ask a doctor before use if you tified in § 335.10(b). The labeling states have [bullet] fever [bullet] mucus in ‘‘[bullet] adults and children 12 years the stool’’. and over:’’ 26.2 grams ‘‘after each loose (2) For products containing bismuth stool [bullet] continue to take every 6 subsalicylate identified in § 335.10(a). (i) hours until stool is firm but not more The following shall appear in accord- than 2 days [bullet] do not exceed’’ [262 ance with § 201.66(c)(5)(ii) of this chap- grams] ‘‘in 24 hours [bullet] children ter. under 12 years of age: ask a doctor’’. (A) The Reye’s syndrome warning in (e) Products that meet the criteria es- § 201.314(h) of this chapter. tablished in § 201.66(d)(10) of this chapter. (B) ‘‘Allergy alert: Contains salicy- The information described in § 201.66(c) late. Do not take if you are [bullet] al- of this chapter shall be printed in ac- lergic to salicylates (including aspirin), cordance with the following specifica- [bullet] taking other salicylate prod- tions. ucts’’. (1) The labeling shall meet the re- (ii) ‘‘Do not use if you have [bullet] quirements of § 201.66(c) of this chapter an ulcer [bullet] a bleeding problem’’. except that the information in

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§ 201.66(c)(3) of this chapter may be § 336.3 Definition. omitted, and the information in As used in this part: § 201.66(c)(5) and (c)(6) of this chapter may be presented as follows: Antiemetic. An agent that prevents or (i) The words ‘‘Contains salicylate.’’ treats nausea and vomiting. may be omitted from the warning in § 335.50(c)(2)(i)(B). Subpart B—Active Ingredients (ii) The subheading ‘‘When using this product’’ in § 335.50(c)(2)(iv) may be § 336.10 Antiemetic active ingredients. omitted. The active ingredient of the product (iii) The words ‘‘continue to’’ may be consists of any of the following when omitted from the directions in used within the dosage limits estab- § 335.50(d)(3). lished for each ingredient in § 336.50(d): (2) The labeling shall be printed in (a) Cyclizine hydrochloride. accordance with the requirements of (b) Dimenhydrinate. § 201.66(d) of this chapter except that (c) Diphenhydramine hydrochloride. any requirements related to (d) Meclizine hydrochloride. § 201.66(c)(3) of this chapter and the bullet in the warning in § 335.50(c)(1)(i) may be omitted. Subpart C—Labeling [68 FR 18881, Apr. 17, 2003, as amended at 69 § 336.50 Labeling of antiemetic drug FR 26302, May 12, 2004] products. (a) Statement of identity. The labeling PART 336—ANTIEMETIC DRUG of the product contains the established PRODUCTS FOR OVER-THE- name of the drug, if any, and identifies COUNTER HUMAN USE the product as an ‘‘antiemetic.’’ (b) Indications. The labeling of the Subpart A—General Provisions product states the following under the Sec. heading ‘‘Indications,’’ ‘‘For the pre- 336.1 Scope. vention and treatment of the nausea, 336.3 Definition. vomiting, or dizziness associated with motion sickness.’’ Other truthful and Subpart B—Active Ingredients nonmisleading statements, describing 336.10 Antiemetic active ingredients. only the indications for use that have been established and listed in this Subpart C—Labeling paragraph (b), may also be used, as provided in § 330.1(c)(2), subject to the pro- 336.50 Labeling of antiemetic drug products. visions of section 502 of the act relating 336.80 Professional labeling. to misbranding and the prohibition in AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, section 301(d) of the act against the in- 360, 371. troduction or delivery for introduction SOURCE: 52 FR 15892, Apr. 30, 1987, unless into interstate commerce of unap- otherwise noted. proved new drugs in violation of section 505(a) of the act. Subpart A—General Provisions (c) Warnings. The labeling of the product contains the following warn- § 336.1 Scope. ings under the heading ‘‘Warnings:’’ (a) An over-the-counter antiemetic (1) For products containing any ingre- drug product in a form suitable for oral dient identified in § 336.10—(i) When la- administration is generally recognized beled for use in adults and for those prod- as safe and effective and is not mis- ucts that can be and are labeled for use in branded if it meets each of the condi- children under 12 years of age. ‘‘Do not tions in this part and each of the gen- take this product, unless directed by a eral conditions established in § 330.1. doctor, if you have a breathing problem (b) References in this part to regu- such as emphysema or chronic bron- latory sections of the Code of Federal chitis, or if you have glaucoma or dif- Regulations are to chapter I of title 21 ficulty in urination due to enlargement unless otherwise noted. of the prostate gland.’’

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(ii) For those products that can be and (d) Directions. The labeling of the are labeled only for children under 12 product contains the following infor- years of age. ‘‘Do not give this product mation under the heading ‘‘Direc- to children who have a breathing prob- tions’’: lem such as chronic bronchitis or who (1) For products containing cyclizine have glaucoma, without first con- hydrochloride identified in § 336.10(a). sulting the child’s doctor.’’ Adults and children 12 years of age and (2) For products containing cyclizine over: Oral dosage is 50 milligrams hydrochloride identified in § 336.10(a). every 4 to 6 hours, not to exceed 200 ‘‘Do not give to children under 6 years milligrams in 24 hours, or as directed of age unless directed by a doctor.’’ by a doctor. Children 6 to under 12 (3) For products containing dimenhy- years of age: Oral dosage is 25 milli- drinate identified in § 336.10(b). ‘‘Do not grams every 6 to 8 hours, not to exceed give to children under 2 years of age 75 milligrams in 24 hours, or as di- unless directed by a doctor.’’ rected by a doctor. (4) For products containing (2) For products containing dimenhy- diphenhydramine hydrochloride identified drinate identified in § 336.10(b). Adults in § 336.10(c). ‘‘Do not give to children and children 12 years of age and over: under 6 years of age unless directed by Oral dosage is 50 to 100 milligrams a doctor.’’ every 4 to 6 hours, not to exceed 400 (5) For products containing meclizine milligrams in 24 hours, or as directed hydrochloride identified in § 336.10(d). by a doctor. Children 6 to under 12 ‘‘Do not give to children under 12 years years of age: Oral dosage is 25 to 50 mil- of age unless directed by a doctor.’’ ligrams every 6 to 8 hours, not to ex- (6) For products containing cyclizine ceed 150 milligrams in 24 hours, or as hydrochloride identified in § 336.10(a) or directed by a doctor. Children 2 to meclizine hydrochloride identified in under 6 years of age: Oral dosage is 12.5 § 330.10(d). ‘‘May cause drowsiness; al- to 25 milligrams every 6 to 8 hours, not cohol, sedatives, and tranquilizers may to exceed 75 milligrams in 24 hours, or increase the drowsiness effect. Avoid as directed by a doctor. alcoholic beverages while taking this (3) For products containing product. Do not take this product if diphenhydramine hydrochloride identified you are taking sedatives or tranquil- in § 336.10(c). Adults and children 12 izers, without first consulting your years of age and over: Oral dosage is 25 doctor. Use caution when driving a to 50 milligrams every 4 to 6 hours, not motor vehicle or operating machin- to exceed 300 milligrams in 24 hours, or ery.’’ as directed by a doctor. Children 6 to (7) For products containing dimenhy- under 12 years of age: Oral dosage is drinate identified in § 336.10(b) or 12.5 to 25 milligrams every 4 to 6 hours, diphenhydramine hydrochloride identified not to exceed 150 milligrams in 24 in § 336.10(c). ‘‘May cause marked hours, or as directed by a doctor. drowsiness; alcohol, sedatives, and (4) For products containing meclizine tranquilizers may increase the drowsi- hydrochloride identified in § 336.10(d). ness effect. Avoid alcoholic beverages Adults and children 12 years of age and while taking this product. Do not take over: Oral dosage is 25 to 50 milligrams this product if you are taking sedatives once daily, or as directed by a doctor. or tranquilizers, without first con- (e) The word ‘‘physician’’ may be sub- sulting your doctor. Use caution when stituted for the word ‘‘doctor’’ in any driving a motor vehicle or operating of the labeling statements in this sec- machinery.’’ tion. (8) For products containing [52 FR 15892, Apr. 30, 1987, as amended at 53 diphenhydramine hydrochloride identified FR 35809, Sept. 15, 1988; 59 FR 16982, Apr. 11, in § 336.10(c). ‘‘Do not use [bullet] 1 with 1994; 67 FR 72559, Dec. 6, 2003] any other product containing diphenhydramine, including one used § 336.80 Professional labeling. on skin’’. The labeling provided to health professionals (but not to the general pub- 1 See § 201.66(b)(4) of this chapter for defini- lic) may contain the following addition of bullet symbol. tional indications.

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(a) For products containing cyclizine Subpart B—Active Ingredients hydrochloride, dimenhydrinate, and diphenhydramine hydrochloride identified § 338.10 Nighttime sleep-aid active in- in § 336.10 (a), (b), and (c). ‘‘For the gredients. treatment of vertigo of motion sick- The active ingredient of the product ness.’’ consists of any of the following when (b) For products containing meclizine used within the dosage limits estab- hydrochloride identified in § 336.10(d). lished for each ingredient in § 338.50(d): ‘‘For the treatment of vertigo.’’ (a) Diphenhydramine hydrochloride. (b) Diphenhydramine citrate. PART 338—NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE- Subpart C—Labeling COUNTER HUMAN USE § 338.50 Labeling of nighttime sleep- aid drug products. Subpart A—General Provisions (a) Statement of identity. The labeling Sec. of the product contains the established 338.1 Scope. name of the drug, if any, and identifies 338.3 Definition. the product as a ‘‘nighttime sleep-aid.’’ (b) Indications. The labeling of the Subpart B—Active Ingredients product states, under the heading ‘‘In- dications,’’ one or more of the phrases 338.10 Nighttime sleep-aid active ingredients. listed in this paragraph. Other truthful and nonmisleading statements, de- Subpart C—Labeling scribing only the indications for use that have been established and listed in 338.50 Labeling of nighttime sleep-aid drug this paragraph (b), may also be used, as products. provided in § 330.1(c)(2) of this chapter, AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, subject to the provisions of section 502 360, 371. of the act relating to misbranding and the prohibition in section 301(d) of the SOURCE: 54 FR 6826, Feb. 14, 1989, unless act against the introduction or deliv- otherwise noted. ery for introduction into interstate commerce of unapproved new drugs in Subpart A—General Provisions violation of section 505(a) of the act. (1) (‘‘Helps you’’ or ‘‘Reduces time § 338.1 Scope. to’’) ‘‘fall asleep if you have difficulty (a) An over-the-counter nighttime falling asleep.’’ sleep-aid drug product in a form suit- (2) ‘‘For relief of occasional sleepless- able for oral administration is gen- ness.’’ erally recognized as safe and effective (3) ‘‘Helps to reduce difficulty falling and is not misbranded if it meets each asleep.’’ condition in this part and each general (c) Warnings. The labeling of the condition established in § 330.1 of this product contains the following warn- chapter. ings under the heading ‘‘Warnings’’: (b) References in this part to regu- (1) ‘‘Do not give to children under 12 latory sections of the Code of Federal years of age.’’ Regulations are to chapter I of title 21 (2) ‘‘If sleeplessness persists continu- ously for more than 2 weeks, consult unless otherwise noted. your doctor. Insomnia may be a symp- § 338.3 Definition. tom of serious underlying medical illness.’’ As used in this part: (3) ‘‘Do not take this product, unless Nighttime sleep-aid. A drug that is use- directed by a doctor, if you have a ful for the relief of occasional sleep- breathing problem such as emphysema lessness by individuals who have dif- or chronic bronchitis, or if you have ficulty falling asleep. glaucoma or difficulty in urination due to enlargement of the prostate gland.’’

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(4) ‘‘Avoid alcoholic beverages while Subpart A—General Provisions taking this product. Do not take this product if you are taking sedatives or § 340.1 Scope. tranquilizers, without first consulting (a) An over-the-counter stimulant your doctor.’’ drug product in a form suitable for oral (5) ‘‘Do not use [bullet] 1 with any administration is generally recognized other product containing as safe and effective and is not mis- diphenhydramine, even one used on branded if it meets each of the condi- skin’’. tions in this part and each of the gen- (d) Directions. The labeling of the eral conditions established in § 330.1. product contains the following infor- (b) References in this part to regu- mation under the heading ‘‘Direc- latory sections of the Code of Federal tions’’: Regulations are to chapter I of title 21 (1) For products containing unless otherwise noted. diphenhydramine hydrochloride identified in § 338.10(a). Adults and children 12 § 340.3 Definition. years of age and over: Oral dosage is 50 As used in this part: milligrams at bedtime if needed, or as Stimulant. A drug which helps restore directed by a doctor. mental alertness or wakefulness during (2) For products containing fatigue or drowsiness. diphenhydramine citrate identified in § 338.10(b). Adults and children 12 years Subpart B—Active Ingredient of age and over: Oral dosage is 76 milligrams at bedtime if needed, or as di- § 340.10 Stimulant active ingredient. rected by a doctor. (e) The word ‘‘physician’’ may be sub- The active ingredient of the product consists of caffeine when used within stituted for the word ‘‘doctor’’ in any the dosage limits established in of the labeling statements in this sec- § 340.50(d). tion. [54 FR 6826, Feb. 14, 1989, as amended at 59 Subpart C—Labeling FR 16983, Apr. 11, 1994; 67 FR 72559, Dec. 6, 2002] § 340.50 Labeling of stimulant drug products. PART 340—STIMULANT DRUG (a) Statement of identity. The labeling PRODUCTS FOR OVER-THE- of the product contains the established COUNTER HUMAN USE name of the drug, if any, and identifies the product as an ‘‘altertness aid’’ or a Subpart A—General Provisions ‘‘stimulant.’’ (b) Indications. The labeling of the Sec. product states, under the heading ‘‘In- 340.1 Scope. 340.3 Definition. dications,’’ the following: ‘‘Helps restore mental alertness or wakefulness Subpart B—Active Ingredient when experiencing fatigue or drowsiness.’’ Other truthful and nonmis- 340.10 Stimulant active ingredient. leading statements, describing only the indications for use that have been es- Subpart C—Labeling tablished and listed in this paragraph 340.50 Labeling of stimulant drug products. (b), may also be used, as provided in § 330.1(c)(2), subject to the provisions of AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, section 502 of the Act relating to mis- 360, 371. branding and the prohibition in section SOURCE: 53 FR 6105, Feb. 29, 1988, unless 301(d) of the Act against the introduc- otherwise noted. tion or delivery for introduction into interstate commerce of unapproved 1 See § 201.66(b)(4) of this chapter for defini- new drugs in violation of section 505(a) tion of bullet symbol. of the Act.

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(c) Warnings. The labeling of the 341.76 Labeling of bronchodilator drug prod- product contains the following warn- ucts. ings under the heading ‘‘Warnings’’: 341.78 Labeling of expectorant drug prod- (1) ‘‘The recommended dose of this ucts. product contains about as much caf- 341.80 Labeling of nasal decongestant drug products. feine as a cup of coffee. Limit the use 341.85 Labeling of permitted combinations of caffeine-containing medications, of active ingredients. foods, or beverages while taking this 341.90 Professional labeling. product because too much caffeine may cause nervousness, irritability, sleep- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. lessness, and, occasionally, rapid heart beat.’’ EDITORIAL NOTE: Nomenclature changes to (2) ‘‘For occasional use only. Not in- part 341 appear at 69 FR 13717, Mar. 24, 2004. tended for use as a substitute for sleep. If fatigue or drowsiness persists or con- Subpart A—General Provisions tinues to recur, consult a’’ (select one of the following: ‘‘physician’’ or ‘‘doc- § 341.1 Scope. tor’’). (a) An over-the-counter cold, cough, (3) ‘‘Do not give to children under 12 allergy, bronchodilator, or anti- years of age.’’ asthmatic drug product in a form suit- (d) Directions. The labeling of the able for oral, inhalant, or topical ad- product contains the following infor- ministration is generally recognized as mation under the heading ‘‘Direc- safe and effective and is not mis- tions’’: Adults and children 12 years of branded if it meets each of the condi- age and over: Oral dosage is 100 to 200 tions in this part and each of the gen- milligrams not more often than every 3 eral conditions established in § 330.1. to 4 hours. (b) References in this part to regulatory sections of the Code of Federal PART 341—COLD, COUGH, AL- Regulations are to chapter I of title 21 LERGY, BRONCHODILATOR, AND unless otherwise noted. ANTIASTHMATIC DRUG PROD- [51 FR 35339, Oct. 2, 1986] UCTS FOR OVER-THE-COUNTER HUMAN USE § 341.3 Definitions. As used in this part: Subpart A—General Provisions (a) Bronchodilator drug. A drug used Sec. to overcome spasms that cause nar- 341.1 Scope. rowing of the bronchial air tubes, such 341.3 Definitions. as in the symptomatic treatment of the wheezing and shortness of breath of Subpart B—Active Ingredients asthma. (b) Oral antitussive drug. A drug that 341.12 Antihistamine active ingredients. 341.14 Antitussive active ingredients. either is taken by mouth or is dis- 341.16 Bronchodilator active ingredients. solved in the mouth in the form of a 341.18 Expectorant active ingredient. lozenge and acts systemically to re- 341.20 Nasal decongestant active ingredi- lieve cough. ents. (c) Topical antitussive drug. A drug 341.40 Permitted combinations of active in- that relieves cough when inhaled after gredients. being applied topically to the throat or Subpart C—Labeling chest in the form of an ointment or from a steam vaporizer, or when dis- 341.70 Labeling of OTC drug products con- solved in the mouth in the form of a taining ingredients that are used for lozenge for a local effect. treating concurrent symptoms (in either (d) Expectorant drug. A drug taken a single-ingredient or combination drug orally to promote or facilitate the re- product). 341.72 Labeling of antihistamine drug prod- moval of secretions from the res- ucts. piratory airways. 341.74 Labeling of antitussive drug prod- (e) Antihistamine drug. A drug used ucts. for the relief of the symptoms of hay

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fever and upper respiratory allergies the dosage forms established for each (allergic rhinitis). ingredient in § 341.74(d): (f) Oral nasal decongestant drug. A (a) Oral antitussives. (1) Chlophedianol drug that is taken by mouth and acts hydrochloride. systemically to reduce nasal conges- (2) Codeine ingredients. The following tion caused by acute or chronic rhi- ingredients may be used only in com- nitis. bination in accordance with § 290.2 and (g) Topical nasal decongestant drug. A 21 CFR 1308.15(c). drug that when applied topically inside (i) Codeine. the nose, in the form of drops, jellies, (ii) Codeine phosphate. or sprays, or when inhaled intranasally (iii) Codeine sulfate. reduces nasal congestion caused by (3) Dextromethorphan. acute or chronic rhinitis. (4) Dextromethorphan hydrobromide. (h) Calibrated dropper. A dropper cali- (5) Diphenhydramine citrate. brated such that the volume error in- (6) Diphenhydramine hydrochloride. curred in measuring any liquid does (b) Topical antitussives. (1) Camphor. not exceed 15 percent under normal use (2) Menthol. conditions. (i) Effervescent dosage form. A dosage [52 FR 30055, Aug. 12, 1987, as amended at 59 FR 29174, June 3, 1994; 67 FR 4907, Feb. 1, 2002] form intended to be dissolved in water before administration. It contains, in § 341.16 Bronchodilator active ingredi- addition to the active ingredient(s), ents. mixtures of acids (citric acid, tartaric The active ingredients of the product acid) and sodium bicarbonate, which consist of any of the following when release carbon dioxide when dissolved used within the dosage limits estab- in water. lished for each ingredient: [51 FR 35339, Oct. 2, 1986, as amended at 54 FR (a) Ephedrine. 8509, Feb. 28, 1989; 55 FR 40382, Oct. 3, 1990; 57 (b) Ephedrine hydrochloride. FR 58374, Dec. 9, 1992; 59 FR 43409, Aug. 23, (c) Ephedrine sulfate. 1994; 71 FR 43362, Aug. 1, 2006] (d) Epinephrine. (e) Epinephrine bitartrate. Subpart B—Active Ingredients (f) Racephedrine hydrochloride. (g) Racepinephrine hydrochloride. § 341.12 Antihistamine active ingredients. [51 FR 35339, Oct. 2, 1986] The active ingredient of the product § 341.18 Expectorant active ingredient. consists of any of the following when used within the dosage limits estab- The active ingredient of the product lished for each ingredient: is guaifenesin when used within the (a) Brompheniramine maleate. dosage limits established in § 341.78(d). (b) Chlorcyclizine hydrochloride. [54 FR 8509, Feb. 28, 1989] (c) Chlorpheniramine maleate. (d) Dexbrompheniramine maleate. § 341.20 Nasal decongestant active in- (e) Dexchlorpheniramine maleate. gredients. (f) Diphenhydramine citrate. The active ingredient of the product (g) Diphenhydramine hydrochloride. consists of any of the following when (h) Doxylamine succinate. used within the dosage limits and in (i) Phenindamine tartrate. the dosage forms established for each (j) Pheniramine maleate. ingredient: (k) Pyrilamine maleate. (a) Oral nasal decongestants. (1) Phen- (l) Thonzylamine hydrochloride. ylephrine hydrochloride. (m) Triprolidine hydrochloride. (2) Pseudoephedrine hydrochloride. [57 FR 58374, Dec. 9, 1992, as amended at 59 (3) Pseudoephedrine sulfate. FR 4218, Jan. 28, 1994] (4) Phenylephrine bitartrate in an effervescent dosage form. § 341.14 Antitussive active ingredients. (b) Topical nasal decongestants. (1) The active ingredients of the product Levmetamfetamine. consist of any of the following when (2) Ephedrine. used within the dosage limits and in (3) Ephedrine hydrochloride.

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(4) Ephedrine sulfate. active ingredient provided that the (5) [Reserved] product is labeled according to (6) Naphazoline hydrochloride. § 341.70(a). (7) Oxymetazoline hydrochloride. (e) Any single antihistamine active (8) Phenylephrine hydrochloride. ingredient identified in § 341.12(a) (9) Propylhexedrine. through (e) and (h) through (m) may be (10) Xylometazoline hydrochloride. combined with any single oral [59 FR 43409, Aug. 23, 1994, as amended at 63 antitussive active ingredient identified FR 40650, July 30, 1998; 71 FR 43362, Aug. 1, in § 341.14(a)(1) through (a)(4) and any 2006] single oral nasal decongestant active ingredient identified in § 341.20(a) pro- § 341.40 Permitted combinations of ac- vided that the product is labeled active ingredients. cording to § 341.85(c)(4). The following combinations are per- Diphenhydramine citrate in §§ 341.12(f) mitted provided each active ingredient and 341.14(a)(5) or diphenhydramine hy- is present within the dosage limits es- drochloride in §§ 341.12(g) and tablished in parts 341, 343, and 356 of 341.14(a)(6) may be both the antihis- this chapter and the product is labeled tamine and the antitussive active in- in accordance with §§ 341.70 or 341.85: gredient provided that the product is (a) Any single antihistamine active labeled according to § 341.70(a). ingredient identified in § 341.12 may be (f) Any single antihistamine active combined with any generally recog- ingredient identified in § 341.12(a) nized as safe and effective single an- through (e) and (h) through (m) may be algesic-antipyretic active ingredient, combined with any single oral or any combination of acetaminophen antitussive active ingredient identified with other analgesic-antipyretic active in § 341.14(a)(1) through (a)(4) and any ingredients, or any aspirin and antacid generally recognized as safe and effec- combination provided that the product is labeled according to § 341.85. tive single analgesic-antipyretic active (b) Any single antihistamine active ingredient, or any combination of acet- ingredient identified in § 341.12 may be aminophen with other analgesic-anti- combined with any single oral nasal de- pyretic active ingredients, or any aspi- congestant active ingredient identified rin and antacid combination provided in § 341.20(a) provided that the product that the product is labeled according to is labeled according to § 341.85. § 341.85(c)(4). Diphenhydramine citrate (c) Any single antihistamine active in §§ 341.12(f) and 341.14(a)(5) or ingredient identified in § 341.12 may be diphenhydramine hydrochloride in combined with any single oral nasal de- §§ 341.12(g) and 341.14(a)(6) may be both congestant active ingredient identified the antihistamine and the antitussive in § 341.20(a) and any generally recog- active ingredient provided that the nized as safe and effective single an- product is labeled according to algesic-antipyretic active ingredient, § 341.70(a). or any combination of acetaminophen (g) Any single antihistamine active with other analgesic-antipyretic active ingredient identified in § 341.12(a) ingredients, or any aspirin and antacid through (e) and (h) through (m) may be combination provided that the product combined with any single oral is labeled according to § 341.85. antitussive active ingredient identified (d) Any single antihistamine active in § 341.14(a)(1) through (a)(4) and any ingredient identified in § 341.12(a) single oral nasal decongestant active through (e) and (h) through (m) may be ingredient identified in § 341.20(a) and combined with any single oral any generally recognized as safe and ef- antitussive active ingredient identified fective single analgesic-antipyretic ac- in § 341.14(a)(1) through (a)(4) provided tive ingredient, or any combination of that the product is labeled according to acetaminophen with other analgesic- § 341.85(c)(4). Diphenhydramine citrate antipyretic active ingredients, or any in §§ 341.12(f) and 341.14(a)(5) or aspirin and antacid combination pro- diphenhydramine hydrochloride in vided that the product is labeled ac- §§ 341.12(g) and 341.14(a)(6) may be both cording to § 341.85(c)(4). the antihistamine and the antitussive Diphenhydramine citrate in §§ 341.12(f)

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and 341.14(a)(5) or diphenhydramine hy- (m) Any single oral antitussive ac- drochloride in §§ 341.12(g) and tive ingredient identified in § 341.14(a) 341.14(a)(6) may be both the antihis- may be combined with any single oral tamine and the antitussive active in- nasal decongestant active ingredient gredient provided that the product is identified in § 341.20(a) and any gen- labeled according to § 341.70(a). erally recognized as safe and effective (h) Any single oral antitussive active single analgesic-antipyretic active in- ingredient identified in § 341.14(a)(1) gredient, or any combination of acet- through (a)(4) may be combined with aminophen with other analgesic-anti- any single expectorant active ingre- pyretic active ingredients, or any aspi- dient identified in § 341.18 provided that rin and antacid combination provided the product is labeled according to that the product is labeled according to § 341.85. § 341.85. (i) Any single oral antitussive active (n) Any single oral antitussive active ingredient identified in § 341.14(a) may ingredient identified in § 341.14(a)(1) be combined with any single oral nasal through (a)(4) may be combined with decongestant active ingredient identi- any single oral nasal decongestant ac- fied in § 341.20(a) provided that the tive ingredient identified in § 341.20(a) product is labeled according to § 341.85. and any single expectorant active in- (j) Any single oral antitussive active gredient identified in § 341.18 and any ingredient identified in § 341.14(a)(1) generally recognized as safe and effec- through (a)(4) may be combined with tive single analgesic-antipyretic active any single oral nasal decongestant ac- ingredient, or any combination of acet- tive ingredient identified in § 341.20(a) aminophen with other analgesic-anti- and any single expectorant active in- pyretic active ingredients, or any aspi- gredient identified in § 341.18 provided rin and antacid combination provided that the product is labeled according to that the product is labeled according to § 341.85. § 341.85. (k) Any single antitussive active in- (o) Any single expectorant active ingredient identified in § 341.14(a) or (b)(2) gredient identified in § 341.18 may be may be combined with any generally combined with any generally recog- recognized as safe and effective single nized as safe and effective single an- oral anesthetic/analgesic active ingre- algesic-antipyretic active ingredient, dient, or any combination of anes- or any combination of acetaminophen thetic/analgesic active ingredients pro- with other analgesic-antipyretic active vided that the product is available in ingredients, or any aspirin and antacid either a liquid (to be swallowed) or a combination provided that the product solid dosage form (to be dissolved in is labeled according to § 341.85. the mouth and swallowed) and provided (p) Any single expectorant active in- that the product is labeled according to gredient identified in § 341.18 may be § 341.85. If the combination contains a combined with any single oral nasal de- topical antitussive, the product must congestant active ingredient identified be formulated in a solid dosage form to in § 341.20(a) provided that the product be dissolved in the mouth. Menthol in is labeled according to § 341.85. § 341.14(b)(2) and part 356 of this chapter (q) Any single expectorant active in- may be both the antitussive and the gredient identified in § 341.18 may be anesthetic/analgesic active ingredient combined with any single oral nasal de- provided that the product is labeled ac- congestant active ingredient identified cording to § 341.70(b). in § 341.20(a) and any generally recog- (l) Any single oral antitussive active nized as safe and effective single an- ingredient identified in § 341.14(a) may algesic-antipyretic active ingredient, be combined with any generally recog- or any combination of acetaminophen nized as safe and effective single an- with other analgesic-antipyretic active algesic-antipyretic active ingredient, ingredients, or any aspirin and antacid or any combination of acetaminophen combination provided that the product with other analgesic-antipyretic active is labeled according to § 341.85. ingredients, or any aspirin and antacid (r) Any single oral nasal deconges- combination provided that the product tant active ingredient identified in is labeled according to § 341.85. § 341.20(a) may be combined with any

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generally recognized as safe and effec- vided that the product is available in tive single analgesic-antipyretic active either a liquid (to be swallowed) or a ingredient, or any combination of acet- solid dosage form (to be dissolved in aminophen with other analgesic-anti- the mouth and swallowed) and provided pyretic active ingredients, or any aspi- that the product is labeled according to rin and antacid combination provided § 341.85. If the combination contains a that the product is labeled according to topical antitussive, the product must § 341.85. be formulated in a solid dosage form to (s) Any single oral nasal deconges- be dissolved in the mouth. tant active ingredient identified in (x) Any single oral nasal deconges- § 341.20(a) may be combined with any tant active ingredient identified in generally recognized as safe and effec- § 341.20(a) may be combined with any tive single oral anesthetic/analgesic ac- generally recognized as safe and effective ingredient identified, or any com- tive single oral demulcent active ingre- bination of anesthetic/analgesic active dient provided that the product is ingredients provided that the product available in either a liquid (to be swal- is available in either a liquid (to be lowed) or a solid dosage form (to be dis- swallowed) or a solid dosage form (to solved in the mouth and swallowed) be dissolved in the mouth and swal- and provided that the product is la- lowed) and provided that the product is beled according to § 341.85. labeled according to § 341.85. (y) Any single antitussive active in- (t) Any single oral nasal deconges- gredient identified in § 341.14(a) or (b)(2) tant active ingredient identified in may be combined with any single oral § 341.20(a) may be combined with any nasal decongestant active ingredient single antitussive active ingredient identified in § 341.20(a) and any gen- identified in § 341.14(a) or (b)(2) and any erally recognized as safe and effective generally recognized as safe and effec- single oral demulcent active ingredient tive single oral anesthetic/analgesic ac- provided that the product is available tive ingredient, or any combination of in either a liquid (to be swallowed) or a anesthetic/analgesic active ingredients solid dosage form (to be dissolved in provided that the product is available the mouth and swallowed) and provided in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in that the product is labeled according to the mouth and swallowed) and provided § 341.85. If the combination contains a that the product is labeled according to topical antitussive, the product must § 341.85. If the combination contains a be formulated in a solid dosage form to topical antitussive, the product must be dissolved in the mouth. be formulated in a solid dosage form to (z) Any single antitussive active in- be dissolved in the mouth. gredient identified in § 341.14(a) or (b)(2) (u) Camphor identified in § 341.14(b)(1) may be combined with any generally may be combined with menthol identi- recognized as safe and effective single fied in § 341.14(b)(2) and eucalyptus oil oral anesthetic/analgesic active ingre- (1.2 to 1.3 percent) provided that the dient or any combination of anesthetic/ product is available only in a suitable analgesic active ingredients and any ointment vehicle and provided that the generally recognized as safe and effec- product is labeled according to § 341.85. tive single oral demulcent active ingre- (v) Levmetamfetamine identified in dient provided that the product is § 341.20(b)(1) may be combined with aro- available in either a liquid (to be swal- matics (camphor (54 milligrams (mg)), lowed) or a solid dosage form (to be dis- menthol (80 mg), methyl salicylate (11 solved in the mouth and swallowed) mg), and lavender oil (4 mg)) provided and provided that the product is la- that the product is available only as a beled according to § 341.85. If the com- nasal inhaler and provided that the bination contains a topical antitussive, product is labeled according to § 341.85. the product must be formulated in a (w) Any single antitussive active in- solid dosage form to be dissolved in the gredient identified in § 341.14(a) or (b)(2) mouth. may be combined with any generally (aa) Any single oral nasal deconges- recognized as safe and effective single tant active ingredient identified in oral demulcent active ingredient pro- § 341.20(a) may be combined with any

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generally recognized as safe and effec- §§ 341.72(b) and 341.74(b). The warnings tive single oral anesthetic/analgesic ac- shall be combined from §§ 341.72(c)(1), tive ingredient or any combination of (c)(2), (c)(4), and (c)(6) and 341.74(c)(1), oral anesthetic/analgesic active ingre- (c)(2), (c)(3), and (c)(4). Alternatively, dients and any generally recognized as all of the warnings in § 341.74(c) shall be safe and effective single oral demulcent used. The directions for OTC labeling active ingredient provided that the shall follow §§ 341.74(d)(1)(iv) or product is available in either a liquid (d)(1)(v), as applicable. The directions (to be swallowed) or a solid dosage for professional labeling shall follow form (to be dissolved in the mouth and § 341.90(j) or (k), as applicable. swallowed) and provided that the prod- (b) For products containing menthol uct is labeled according to § 341.85. identified in §§ 341.14(b)(2) and 356.12(f) of (bb) Any single antitussive active in- this chapter. The product contains 5 to gredient identified in § 341.14(a) or (b)(2) 10 milligrams menthol. The labeling of may be combined with any single oral the product contains the established nasal decongestant active ingredient name of the drug, if any, and identifies identified in § 341.20(a) and any gen- the product as a ‘‘cough suppressant/ erally recognized as safe and effective oral anesthetic’’ or ‘‘antitussive (cough single oral anesthetic/analgesic active suppressant)/oral anesthetic.’’ The in- ingredient identified or any combina- dications shall be combined from tion of anesthetic/analgesic active in- § 341.74(b) and part 356 of this chapter. gredients and any generally recognized The warnings shall be combined from as safe and effective single oral demul- § 341.74(c)(1), (c)(2), and (c)(3) and part cent active ingredient provided that 356 of this chapter. The directions shall the product is available in either a liq- be: ‘‘Directions [in bold type] [bullet] 1 uid (to be swallowed) or a solid dosage adults and children 2 years and over: form (to be dissolved in the mouth and dissolve lozenge slowly in the mouth. swallowed) and provided that the prod- Repeat every 2 hours as needed or as uct is labeled according to § 341.85. If directed by a doctor. [bullet] children the combination contains a topical under 2 years of age: ask a doctor’’. antitussive, the product must be for- [61 FR 15703, Apr. 9, 1996, as amended at 67 mulated in a solid dosage form to be FR 78170, Dec. 23, 2002; 68 FR 17881, Apr. 14, dissolved in the mouth. 2003] [67 FR 78168, Dec. 23, 2002] § 341.72 Labeling of antihistamine drug products. Subpart C—Labeling (a) Statement of identity. The labeling § 341.70 Labeling of OTC drug prod- of the product contains the established ucts containing ingredients that are name of the drug, if any, and identifies used for treating concurrent symp- the product as an ‘‘antihistamine.’’ toms (in either a single-ingredient (b) Indications. The labeling of the or combination drug product). product states, under the heading ‘‘In- The statements of identity, indica- dications,’’ any of the phrases listed in tions, warnings, and directions for use, paragraph (b) of this section, as appro- respectively, applicable to each ingre- priate. Other truthful and nonmis- dient in the product may be combined leading statements, describing only the to eliminate duplicative words or indications for use that have been es- phrases so that the resulting informa- tablished and listed in this paragraph, tion is clear and understandable. may also be used, as provided in (a) For products containing § 330.1(c)(2) of this chapter, subject to diphenhydramine citrate and the provisions of section 502 of the Fed- diphenhydramine hydrochloride identified eral Food, Drug, and Cosmetic Act (the in § 341.14(a)(5) and (a)(6). The labeling act) relating to misbranding and the of the product contains the established prohibition in section 301(d) of the act name of the drug, if any, and identifies against the introduction or delivery for the product as an ‘‘antihistamine/ introduction into interstate commerce cough suppressant’’ or ‘‘antihistamine/ antitussive (cough suppressant).’’ The 1 See § 201.66(b)(4) of this chapter for defini- indications shall be combined from tion of bullet symbol.

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of unapproved new drugs in violation of erages while taking this product. Do section 505(a) of the act. not take this product if you are taking (1) ‘‘Temporarily’’ (select one of the sedatives or tranquilizers, without first following: ‘‘relieves,’’ ‘‘alleviates,’’ consulting your doctor. Use caution ‘‘decreases,’’ ‘‘reduces,’’ or ‘‘dries’’) when driving a motor vehicle or oper- ‘‘runny nose and’’ (select one of the fol- ating machinery.’’ lowing: ‘‘relieves,’’ ‘‘alleviates,’’ ‘‘de- (5) For products containing creases,’’ or ‘‘reduces’’) ‘‘sneezing, phenindamine tartrate identified in itching of the nose or throat, and § 341.12(i). ‘‘May cause nervousness and itchy, watery eyes due to hay fever’’ insomnia in some individuals.’’ (which may be followed by one or both (6) For products that are labeled only of the following: ‘‘or other upper res- for use by children under 12 years of age. piratory allergies’’ or ‘‘(allergic rhi- The labeling of the product contains nitis)’’). only the warnings identified in para- (2) ‘‘For the temporary relief of graphs (c)(1) and (c)(5) of this section as runny nose, sneezing, itching of the well as the following: nose or throat, and itchy, watery eyes (i) ‘‘Do not give this product to chil- due to hay fever’’ (which may be fol- dren who have a breathing problem lowed by one or both of the following: such as chronic bronchitis, or who have ‘‘or other upper respiratory allergies’’ glaucoma, without first consulting the or ‘‘(allergic rhinitis)’’). child’s doctor.’’ (c) Warnings. The labeling of the (ii) For products containing product contains the following warn- brompheniramine maleate, ings, under the heading ‘‘Warnings’’: chlorpheniramine maleate, (1) ‘‘May cause excitability especially dexbrompheniramine maleate, in children.’’ dexchlorpheniramine maleate, (2) ‘‘Do not take this product, unless phenindamine tartrate, pheniramine male- directed by a doctor, if you have a ate, pyrilamine maleate, thonzylamine hy- breathing problem such as emphysema drochloride, or triprolidine hydrochloride or chronic bronchitis, or if you have identified in § 341.12(a), (c), (d), (e), (i), glaucoma or difficulty in urination due (j), (k), (l), and (m). ‘‘May cause drowsi- to enlargement of the prostate gland.’’ ness. Sedatives and tranquilizers may (3) For products containing increase the drowsiness effect. Do not brompheniramine maleate, chlorcyclizine give this product to children who are hydrochloride, chlorpheniramine maleate, taking sedatives or tranquilizers, with- dexbrompheniramine maleate, out first consulting the child’s doctor.’’ dexchlorpheniramine maleate, (iii) For products containing phenindamine tartrate, pheniramine male- diphenhydramine citrate, ate, pyrilamine maleate, thonzylamine hy- diphenhydramine hydrochloride, or drochloride, or triprolidine hydrochloride doxylamine succinate identified in identified in § 341.12(a), (b), (c), (d), (e), § 341.12(f), (g), and (h). ‘‘May cause (i), (j), (k), (l), and (m). ‘‘May cause marked drowsiness. Sedatives and drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsi- tranquilizers may increase the drowsiness effect. Do not give this product to ness effect. Avoid alcoholic beverages children who are taking sedatives or while taking this product. Do not take tranquilizers, without first consulting this product if you are taking sedatives the child’s doctor.’’ or tranquilizers, without first con- (iv) For products containing sulting your doctor. Use caution when diphenhydramine citrate or driving a motor vehicle or operating diphenhydramine hydrochloride identified machinery.’’ in § 341.12(f) and (g). ‘‘Do not use [bul- (4) For products containing let] 1 with any other product con- diphenhydramine citrate, taining diphenhydramine, even one diphenhydramine hydrochloride, or used on skin’’. doxylamine succinate identified in (7) For products containing § 341.12(f), (g), and (h). ‘‘May cause diphenhydramine citrate or marked drowsiness; alcohol, sedatives, and tranquilizers may increase the 1 See § 201.66(b)(4) of this chapter for defini- drowsiness effect. Avoid alcoholic bev- tion of bullet symbol.

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diphenhydramine hydrochloride identified rected by a doctor. Children 6 to under in § 341.12(f) and (g). ‘‘Do not use [bul- 12 years of age: oral dosage is 1 milli- let] with any other product containing gram every 4 to 6 hours, not to exceed diphenhydramine, even one used on 6 milligrams in 24 hours, or as directed skin’’. by a doctor. Children under 6 years of (d) Directions. The labeling of the age: consult a doctor. product contains the following infor- (6) For products containing mation under the heading ‘‘Direc- diphenhydramine citrate identified in tions’’: § 341.12(f). Adults and children 12 years (1) For products containing of age and over: oral dosage is 38 to 76 brompheniramine maleate identified in milligrams every 4 to 6 hours, not to § 341.12(a). Adults and children 12 years exceed 456 milligrams in 24 hours, or as of age and over: oral dosage is 4 milli- directed by a doctor. Children 6 to grams every 4 to 6 hours, not to exceed under 12 years of age: oral dosage is 19 24 milligrams in 24 hours, or as di- to 38 milligrams every 4 to 6 hours, not rected by a doctor. Children 6 to under to exceed 228 milligrams in 24 hours, or 12 years of age: oral dosage is 2 milli- as directed by a doctor. Children under grams every 4 to 6 hours, not to exceed 6 years of age: consult a doctor. 12 milligrams in 24 hours, or as di- (7) For products containing rected by a doctor. Children under 6 diphenhydramine hydrochloride identified years of age: consult a doctor. in § 341.12(g). Adults and children 12 (2) For products containing years of age and over: oral dosage is 25 chlorcyclizine hydrochloride identified in to 50 milligrams every 4 to 6 hours, not § 341.12(b). Adults and children 12 years to exceed 300 milligrams in 24 hours, or of age and over: oral dosage is 25 milli- as directed by a doctor. Children 6 to grams every 6 to 8 hours, not to exceed under 12 years of age: oral dosage is 75 milligrams in 24 hours, or as di- 12.5 to 25 milligrams every 4 to 6 hours, rected by a doctor. Children under 12 not to exceed 150 milligrams in 24 years of age: consult a doctor. hours, or as directed by a doctor. Chil- (3) For products containing dren under 6 years of age: consult a chlorpheniramine maleate identified in doctor. § 341.12(c). Adults and children 12 years (8) For products containing doxylamine of age and over: oral dosage is 4 milli- succinate identified in § 341.12(h). Adults grams every 4 to 6 hours, not to exceed and children 12 years of age and over: 24 milligrams in 24 hours, or as di- oral dosage is 7.5 to 12.5 milligrams rected by a doctor. Children 6 to under every 4 to 6 hours, not to exceed 75 mil- 12 years of age: oral dosage is 2 milli- ligrams in 24 hours, or as directed by a grams every 4 to 6 hours, not to exceed doctor. Children 6 to under 12 years of 12 milligrams in 24 hours, or as di- age: oral dosage is 3.75 to 6.25 milli- rected by a doctor. Children under 6 grams every 4 to 6 hours, not to exceed years of age: consult a doctor. 37.5 milligrams in 24 hours, or as di- (4) For products containing rected by a doctor. Children under 6 dexbrompheniramine maleate identified in years of age: consult a doctor. § 341.12(d). Adults and children 12 years (9) For products containing of age and over: oral dosage is 2 milli- phenindamine tartrate identified in grams every 4 to 6 hours, not to exceed § 341.12(i). Adults and children 12 years 12 milligrams in 24 hours, or as di- of age and over: oral dosage is 25 milli- rected by a doctor. Children 6 to under grams every 4 to 6 hours, not to exceed 12 years of age: oral dosage is 1 milli- 150 milligrams in 24 hours, or as di- gram every 4 to 6 hours, not to exceed rected by a doctor. Children 6 to under 6 milligrams in 24 hours, or as directed 12 years of age: oral dosage is 12.5 milli- by a doctor. Children under 6 years of grams every 4 to 6 hours, not to exceed age: consult a doctor. 75 milligrams in 24 hours, or as di- (5) For products containing rected by a doctor. Children under 6 dexchlorpheniramine maleate identified in years of age: consult a doctor. § 341.12(e). Adults and children 12 years (10) For products containing of age and over: oral dosage is 2 milli- pheniramine maleate identified in grams every 4 to 6 hours, not to exceed § 341.12(j). Adults and children 12 years 12 milligrams in 24 hours, or as di- of age and over: oral dosage is 12.5 to 25

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milligrams every 4 to 6 hours, not to or an ‘‘antitussive (cough suppres- exceed 150 milligrams in 24 hours, or as sant).’’ directed by a doctor. Children 6 to (b) Indications. The labeling of the under 12 years of age: oral dosage is product states, under the heading ‘‘In- 6.25 to 12.5 milligrams every 4 to 6 dications,’’ any of the phrases listed in hours, not to exceed 75 milligrams in 24 this paragraph (b), as appropriate. hours, or as directed by a doctor. Chil- Other truthful and nonmisleading dren under 6 years of age: consult a statements, describing only the indica- doctor. tions for use that have been established (11) For products containing pyrilamine and listed in this paragraph, may also maleate identified in § 341.12(k). Adults be used, as provided in § 330.1(c)(2), sub- and children 12 years of age and over: ject to the provisions of section 502 of oral dosage is 25 to 50 milligrams every the act relating to misbranding and the 6 to 8 hours, not to exceed 200 milli- prohibition in section 301(d) of the act grams in 24 hours, or as directed by a against the introduction or delivery for doctor. Children 6 to under 12 years of introduction into interstate commerce age: oral dosage is 12.5 to 25 milligrams of unapproved new drugs in violation of every 6 to 8 hours, not to exceed 100 section 505(a) of the act. milligrams in 24 hours, or as directed (1) ‘‘Temporarily’’ (select one of the by a doctor. Children under 6 years of following: ‘‘alleviates,’’ ‘‘calms,’’ age: consult a doctor. ‘‘controls,’’ ‘‘decreases,’’ ‘‘quiets,’’ (12) For products containing thonzyl- ‘‘reduces,’’ ‘‘relieves,’’ or ‘‘suppresses’’) amine hydrochloride identified in ‘‘cough due to’’ (select one of the fol- § 341.12(l). Adults and children 12 years lowing: ‘‘minor bronchial irritation’’ or of age and over: oral dosage is 50 to 100 ‘‘minor throat and bronchial irrita- milligrams every 4 to 6 hours, not to tion’’) (select one of the following: ‘‘as exceed 600 milligrams in 24 hours, or as may occur with,’’ ‘‘associated with,’’ or directed by a doctor. Children 6 to ‘‘occurring with’’) (select one of the under 12 years of age: oral dosage is 25 following: ‘‘A cold’’ or ‘‘the common to 50 milligrams every 4 to 6 hours, not cold’’) ‘‘or inhaled irritants.’’ to exceed 300 milligrams in 24 hours, or (2) ‘‘Temporarily’’ (select one of the as directed by a doctor. Children under following: ‘‘alleviates,’’ ‘‘calms,’’ 6 years of age: consult a doctor. ‘‘controls,’’ ‘‘decreases,’’ ‘‘quiets,’’ (13) For products containing triprolidine ‘‘reduces,’’ ‘‘relieves,’’ or ‘‘suppresses’’) hydrochloride identified in § 341.12(m). ‘‘cough’’ (select one of the following: Adults and children 12 years of age and ‘‘as may occur with,’’ ‘‘associated over: oral dosage is 2.5 milligrams with,’’ or ‘‘occurring with’’) (select one every 4 to 6 hours, not to exceed 10 mil- of the following: ‘‘A cold,’’ ‘‘the com- ligrams in 24 hours, or as directed by a mon cold,’’ or ‘‘inhaled irritants’’). doctor. Children 6 to under 12 years of (3) In addition to the required infor- age: oral dosage is 1.25 milligrams mation identified in paragraphs (b) (1) every 4 to 6 hours, not to exceed 5 mil- and (2) of this section, the labeling of ligrams in 24 hours, or as directed by a the product may contain any (one or doctor. Children under 6 years of age: more) of the following statements: consult a doctor. (i) ‘‘Cough suppressant which tempo- (e) The word ‘‘physician’’ may be sub- rarily’’ (select one of the following: stituted for the word ‘‘doctor’’ in any ‘‘Alleviates,’’ ‘‘controls,’’ ‘‘decreases,’’ of the labeling statements in this sec- ‘‘reduces,’’ ‘‘relieves,’’ or ‘‘suppresses’’) tion. ‘‘the impulse to cough.’’ [57 FR 58374, Dec. 9, 1992, as amended at 59 (ii) ‘‘Temporarily helps you cough FR 4218, Jan. 28, 1994; 67 FR 72559, Dec. 6, less.’’ 2002] (iii) ‘‘Temporarily helps to’’ (select one of the following: ‘‘Alleviate,’’ § 341.74 Labeling of antitussive drug ‘‘control,’’ ‘‘decrease,’’ ‘‘reduce,’’ ‘‘re- products. lieve,’’ or ‘‘suppress’’) ‘‘the cough re- (a) Statement of identity. The labeling flex that causes coughing.’’ of the product contains the established (iv) ‘‘Temporarily’’ (select one of the name of the drug, if any, and identifies following: ‘‘Alleviates,’’ ‘‘controls,’’ the product as a ‘‘cough suppressant’’ ‘‘decreases,’’ ‘‘reduces,’’ ‘‘relieves,’’ or

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‘‘suppresses’’) ‘‘the intensity of in § 341.14(a)(2). ‘‘May cause or aggra- coughing.’’ vate constipation.’’ (v) (Select one of the following: ‘‘Al- (ii) For products containing codeine in- leviates,’’ ‘‘Controls,’’ ‘‘Decreases,’’ gredients identified in § 341.14(a)(2) when ‘‘Reduces,’’ ‘‘Relieves,’’ or ‘‘Sup- labeled only for adults. ‘‘Do not take presses’’) (select one of the following: this product if you have a chronic pul- ‘‘Cough,’’ ‘‘the impulse to cough,’’ or monary disease or shortness of breath ‘‘your cough’’) ‘‘to help you’’ (select unless directed by a doctor.’’ one of the following: ‘‘Get to sleep,’’ (iii) For products containing codeine in- ‘‘sleep,’’ or ‘‘rest’’). gredients identified in § 341.14(a)(2) when (vi) For products containing labeled only for children under 12 years of chlophedianol hydrochloride, codeine in- age. ‘‘Do not give this product to chil- gredients, dextromethorphan, or dren who have a chronic pulmonary dextromethorphan hydrobromide identi- disease, shortness of breath, or who are fied in § 341.14(a) (1), (2), (3), and (4). taking other drugs unless directed by a ‘‘Calms the cough control center and doctor.’’ relieves coughing.’’ (iv) For products containing codeine in- (vii) For products containing gredients identified in § 341.14(a)(2) when chlophedianol hydrochloride, labeled for use in adults and children dextromethorphan, dextromethorphan under 12 years of age. ‘‘Adults and chil- hydrobromide, camphor, or menthol iden- dren who have a chronic pulmonary tified in § 341.14(a) (1), (3), (4) and (b) (1) disease or shortness of breath, or chil- and (2). (a) ‘‘Nonnarcotic cough sup- dren who are taking other drugs, pressant for the temporary’’ (select one should not take this product unless di- of the following: ‘‘alleviation,’’ ‘‘con- rected by a doctor.’’ trol,’’ ‘‘decrease,’’ ‘‘reduction,’’ ‘‘re- (v) For products containing lief,’’ or ‘‘suppression’’) ‘‘of cough.’’ dextromethorphan or dextromethorphan (b) (Select one of the following: ‘‘Al- hydrobromide as identified in § 341.14 leviates,’’ ‘‘Controls,’’ ‘‘Decreases,’’ (a)(3) and (a)(4) when labeled for adults ‘‘Reduces,’’ ‘‘Relieves,’’ or ‘‘Sup- or for adults and children under 12 years presses’’) ‘‘cough impulses without nar- of age. Drug interaction precaution. ‘‘Do cotics.’’ not use if you are now taking a pre- (c) Warnings. The labeling of the scription monoamine oxidase inhibitor product contains the following warn- (MAOI) (certain drugs for depression, ings under the heading ‘‘Warnings’’: psychiatric, or emotional conditions, (1) For oral and topical antitussives. ‘‘A or Parkinson’s disease), or for 2 weeks persistent cough may be a sign of a se- after stopping the MAOI drug. If you do rious condition. If cough persists for not know if your prescription drug con- more than 1 week, tends to recur, or is tains an MAOI, ask a doctor or phar- accompanied by fever, rash, or per- macist before taking this product.’’ sistent headache, consult a doctor.’’ (vi) For products containing (2) For oral and topical antitussives la- dextromethorphan or dextromethorphan beled for adults or for adults and children hydrobromide as identified in § 341.14 under 12 years of age. ‘‘Do not take this (a)(3) and (a)(4) when labeled only for product for persistent or chronic cough children under 12 years of age. Drug such as occurs with smoking, asthma, interaction precaution. ‘‘Do not use in a or emphysema, or if cough is accom- child who is taking a prescription mon- panied by excessive phlegm (mucus) oamine oxidase inhibitor (MAOI) (cer- unless directed by a doctor.’’ tain drugs for depression, psychiatric, (3) For oral and topical antitussives la- or emotional conditions, or Parkin- beled only for children under 12 years of son’s disease), or for 2 weeks after stop- age. ‘‘Do not give this product for per- ping the MAOI drug. If you do not sistent or chronic cough such as occurs know if your child’s prescription drug with asthma or if cough is accom- contains an MAOI, ask a doctor or panied by excessive phlegm (mucus) pharmacist before giving this product.’’ unless directed by a doctor.’’ (vii) For products containing (4) Oral antitussives—(i) For products diphenhydramine citrate or containing codeine ingredients identified diphenhydramine hydrochloride identified

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in § 341.14 (a)(5) and (a)(6). ‘‘May cause for steam inhalation use. ‘‘For steam in- excitability especially in children.’’ halation only. Do not take by mouth.’’ (viii) For products containing (iii) For any product containing cam- diphenhydramine citrate or phor or menthol in a suitable ointment ve- diphenhydramine hydrochloride identified hicle or for steam inhalation use and in § 341.14 (a)(5) and (a)(6) when labeled meets the definition of one of the signal only for children under 12 years of age— words (‘‘extremely flammable,’’ ‘‘flam- (A) ‘‘Do not give this product to chil- mable,’’ ‘‘combustible’’) as described in 16 dren who have a breathing problem CFR 1500.3(b)(10). The labeling contains such as chronic bronchitis, or who have the appropriate flammability signal glaucoma, without first consulting the word(s) followed by a colon and the child’s doctor.’’ statement ‘‘Keep away from fire or (B) ‘‘May cause marked drowsiness. flame.’’ Sedatives and tranquilizers may in- (iv) For any product containing cam- crease the drowsiness effect. Do not phor or menthol in a suitable ointment ve- give this product to children who are hicle and that does not contain a flamma- taking sedatives or tranquilizers, with- bility signal word as described in 16 CFR out first consulting the child’s doctor.’’ 1500.3(b)(10). ‘‘When using this product, 1 (C) ‘‘Do not use [bullet] with any do not [bullet] 1 heat [bullet] micro- other product containing wave [bullet] add to hot water or any diphenhydramine, even one used on container where heating water. May skin’’. cause splattering and result in burns.’’ (ix) For products containing [Information highlighted in bold type.] diphenhydramine citrate or (v) For any product containing cam- diphenhydramine hydrochloride identified phor or menthol in a suitable ointment ve- in § 341.14 (a)(5) and (a)(6) when labeled hicle and that contains a flammability for use in adults and children under 12 signal word as described in 16 CFR years of age—(A) ‘‘Do not take this 1500.3(b)(10). ‘‘When using this product, product, unless directed by a doctor, if do not [bullet] heat [bullet] microwave you have a breathing problem such as [bullet] use near an open flame [bullet] emphysema or chronic bronchitis, or if add to hot water or any container you have glaucoma or difficulty in uri- where heating water. May cause splat- nation due to enlargement of the pros- tering and result in burns.’’ [Informa- tate gland.’’ tion highlighted in bold type.] (B) ‘‘May cause marked drowsiness; alcohol, sedatives, and tranquilizers (vi) For any product containing cam- may increase the drowsiness effect. phor or menthol for steam inhalation use. Avoid alcoholic beverages while taking ‘‘When using this product, do not [bul- this product. Do not take this product let] heat [bullet] microwave [bullet] if you are taking sedatives or tranquil- use near an open flame [bullet] add to izers, without first consulting your hot water or any container where heat- doctor. Use caution when driving a ing water except when adding to cold motor vehicle or operating machin- water only in a hot steam vaporizer. ery.’’ May cause splattering and result in (C) ‘‘Do not use [bullet] with any burns.’’ [Information highlighted in other product containing bold type.] diphenhydramine, even one used on (vii) For any product formulated in a skin’’. volatile vehicle. The labeling contains (5) Topical antitussives—(i) For prod- the following statement under the ucts containing camphor or menthol iden- heading ‘‘Other information’’: ‘‘Close tified in § 341.14 (b) (1) and (2) in a suit- container tightly and store at room able ointment vehicle. ‘‘For external use temperature away from heat.’’ only. Do not take by mouth or place in (d) Directions. The labeling of the nostrils.’’ product contains the following infor- (ii) For products containing camphor or mation under the heading ‘‘Direc- menthol identified in § 341.14(b) (1) and (2) tions’’:

1 See § 201.66(b)(4) of this chapter for defini- 1 For a definition of the term ‘‘bullet,’’ see tion of bullet symbol. § 201.66(b)(4) of this chapter.

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(1) Oral antitussives—(i) For products 12 years of age: oral dosage is 19 milli- containing chlophedianol hydrochloride grams every 4 hours, not to exceed 114 identified in § 341.14(a)(1). Adults and milligrams in 24 hours, or as directed children 12 years of age and over: Oral by a doctor. Children under 6 years of dosage is 25 milligrams every 6 to 8 age: consult a doctor. hours, not to exceed 100 milligrams in (v) For products containing 24 hours, or as directed by a doctor. diphenhydramine hydrochloride identified Children 6 to under 12 years of age: in § 341.14(a)(6). Adults and children 12 Oral dosage is 12.5 milligrams every 6 years of age and over: oral dosage is 25 to 8 hours, not to exceed 50 milligrams milligrams every 4 hours, not to exceed in 24 hours, or as directed by a doctor. 150 milligrams in 24 hours, or as di- Children under 6 years of age: Consult rected by a doctor. Children 6 to under a doctor. 12 years of age: oral dosage is 12.5 milli- (ii) For products containing codeine in- grams every 4 hours, not to exceed 75 gredients identified in § 341.14(a)(2). milligrams in 24 hours, or as directed Adults and children 12 years of age and by a doctor. Children under 6 years of over: Oral dosage is 10 to 20 milligrams age: consult a doctor. every 4 to 6 hours, not to exceed 120 (2) Topical antitussives—(i) For prod- milligrams in 24 hours, or as directed ucts containing camphor identified in by a doctor. Children 6 to under 12 § 341.14(b)(1) in a suitable ointment vehi- years of age: Oral dosage is 5 to 10 mil- cle. The product contains 4.7 to 5.3 per- ligrams every 4 to 6 hours, not to ex- cent camphor. ‘‘[bullet] see important ceed 60 milligrams in 24 hours, or as di- warnings under ‘When using this prod- rected by a doctor. Children under 6 uct’ [appears as the first statement years of age: Consult a doctor. A spe- under the heading ‘‘Directions’’ and is cial measuring device should be used to highlighted in bold type] [bullet] give an accurate dose of this product to adults and children 2 years and older: children under 6 years of age. Giving a [bullet] rub on the throat and chest in higher dose than recommended by a a thick layer [bullet] cover with a doctor could result in serious side ef- warm, dry cloth if desired [bullet] fects for your child. clothing should be loose about throat (iii) For products containing and chest to help vapors reach the nose dextromethorphan or dextromethorphan and mouth [bullet] use up to three hydrobromide identified in § 341.14(a) (3) times daily or as directed by a doctor and (4). The dosage is equivalent to [bullet] children under 2 years of age: dextromethorphan hydrobromide. Ask a doctor. Adults and children 12 years of age and (ii) For products containing menthol over: Oral dosage is 10 to 20 milligrams identified in § 341.14(b)(2) in a suitable every 4 hours or 30 milligrams every 6 ointment vehicle. The product contains to 8 hours, not to exceed 120 milligrams 2.6 to 2.8 percent menthol. ‘‘[bullet] see in 24 hours, or as directed by a doctor. important warnings under ’When using Children 6 to under 12 years of age: this product’ ’’ [appears as the first Oral dosage is 5 to 10 milligrams every statement under the heading ‘‘Direc- 4 hours or 15 milligrams every 6 to 8 tions’’ and is highlighted in bold type] hours, not to exceed 60 milligrams in 24 [bullet] adults and children 2 years and hours, or as directed by a doctor. Chil- older: [bullet] rub on the throat and dren 2 to under 6 years of age: Oral dos- chest in a thick layer [bullet] cover age is 2.5 to 5 milligrams every 4 hours with a warm, dry cloth if desired [bul- or 7.5 milligrams every 6 to 8 hours, not let] clothing should be loose about to exceed 30 milligrams in 24 hours, or throat and chest to help vapors reach as directed by a doctor. Children under the nose and mouth [bullet] use up to 2 years of age: Consult a doctor. three times daily or as directed by a (iv) For products containing doctor [bullet] children under 2 years diphenhydramine citrate identified in of age: Ask a doctor. § 341.14(a)(5). Adults and children 12 (iii) For products containing menthol years of age and over: oral dosage is 38 identified in § 341.14(b)(2) in a lozenge. milligrams every 4 hours, not to exceed The product contains 5 to 10 milli- 228 milligrams in 24 hours, or as di- grams menthol. Adults and children 2 rected by a doctor. Children 6 to under to under 12 years of age: Allow lozenge

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to dissolve slowly in the mouth. May chamber only) [bullet] breathe in the be repeated every hour as needed or as medicated vapors [bullet] use up to directed by a doctor. Children under 2 three times daily or as directed by a years of age: Consult a doctor. doctor [bullet] children under 2 years (iv) For products containing camphor of age: Ask a doctor. identified in § 341.14(b)(1) for steam inha- (e) The word ‘‘physician’’ may be sub- lation use. The product contains 6.2 per- stituted for the word ‘‘doctor’’ in any cent camphor. ‘‘[bullet] see important of the labeling statements in this sec- warnings under ‘When using this prod- tion. uct’ ’’ [appears as the first statement (f) Exemption from the general acci- under the heading ‘‘Directions’’ and is dental overdose warning. The labeling highlighted in bold type] [bullet] for antitussive drug products con- adults and children 2 years and older: taining the active ingredient identified (select one of the following, as appro- in § 341.14(b)(2) marketed in accordance priate: For products formulated to be with § 341.74(d)(2)(iii) is exempt from added directly to cold water inside a hot the requirement in § 330.1(g) of this steam vaporizer. [bullet] use 1 table- chapter that the labeling bear the gen- spoonful of solution for each quart of eral warning statement ‘‘In case of ac- water or 11⁄2 teaspoonsful of solution cidental overdose, seek professional as- for each pint of water [bullet] add solu- sistance or contact a poison control tion directly to cold water only in a center immediately.’’ The labeling hot steam vaporizer [bullet] follow must continue to bear the first part of manufacturer’s directions for using va- the general warning in § 330.1(g) of this porizer or For products formulated to be chapter, which states, ‘‘Keep this and placed in the medication chamber of a hot all drugs out of the reach of children.’’ steam vaporizer. [bullet] place water in [52 FR 30055, Aug. 12, 1987; 52 FR 35610, Sept. the vaporizer and follow manufactur- 22, 1987; 53 FR 35809, Sept. 15, 1988; 55 FR er’s directions for using vaporizer [bul- 27808, July 6, 1990; 55 FR 40383, Oct. 3, 1990; 58 let] place solution in the medication FR 54236, Oct. 20, 1993; 59 FR 29174, June 3, chamber only) [bullet] breathe in the 1994; 59 FR 36051, July 15, 1994; 64 FR 13295, medicated vapors [bullet] use up to Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 65 FR three times daily or as directed by a 46867, Aug. 1, 2000; 67 FR 72559, Dec. 6, 2002] doctor [bullet] children under 2 years of age: Ask a doctor. § 341.76 Labeling of bronchodilator drug products. (v) For products containing menthol identified in § 341.14(b)(2) for steam inha- (a) Statement of identity. The labeling lation use. The product contains 3.2 per- of the product contains the established cent menthol. ‘‘[bullet] see important name of the drug, if any, and identifies warnings under ‘When using this prod- the product as a ‘‘bronchodilator.’’ uct’ ’’[appears as the first statement (b) Indication. The labeling of the under the heading ‘‘Directions’’ and is product states the following under the highlighted in bold type] [bullet] heading ‘‘Use’’: ‘‘for temporary relief of adults and children 2 years and older: mild symptoms of intermittent asth- (select one of the following, as appro- ma: [bullet] 1 wheezing [bullet] tight- priate: For products formulated to be ness of chest [bullet] shortness of added directly to cold water inside a hot breath’’. Other truthful and nonmis- steam vaporizer. [bullet] use 1 table- leading statements, describing only the spoonful of solution for each quart of indication for use that has been estab- water or 11⁄2 teaspoonsful of solution lished and listed in this paragraph (b) for each pint of water [bullet] add solu- may also be used, as provided in tion directly to cold water only in a § 330.1(c)(2) of this chapter, subject to hot steam vaporizer [bullet] follow the provisions of section 502 of the Fed- manufacturer’s directions for using va- eral Food, Drug, and Cosmetic Act re- porizer or For products formulated to be lating to misbranding and the prohibi- placed in the medication chamber of a hot tion in section 301(d) of the Federal steam vaporizer. [bullet] place water in Food, Drug, and Cosmetic Act against the vaporizer and follow manufacturer’s directions for using vaporizer [bul- 1 See § 201.66(b)(4) of this chapter for the let] place solution in the medication definition of ‘‘bullet.’’

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the introduction or delivery for intro- more frequently or take more than the duction into interstate commerce of recommended dose’’. [in bold type] unapproved new drugs in violation of (iii) ‘‘[Bullet] avoid foods or bev- section 505(a) of the Federal Food, erages that contain caffeine’’. Drug, and Cosmetic Act. (iv) ‘‘[Bullet] avoid dietary supple- (c) Warnings. The labeling of the ments containing ingredients reported product contains the following warn- or claimed to have a stimulant effect’’. ings under the heading ‘‘Warnings’’: (5) For products containing ephedrine, (1) The following statements shall ap- ephedrine hydrochloride, ephedrine sul- pear after the subheading ‘‘Do not use’’ fate, or racephedrine hydrochloride iden- [in bold type]: tified in § 341.16(a), (b), (c), and (f). (i) (i) ‘‘[Bullet] unless a doctor said you The following information shall appear have asthma’’. after the subheading ‘‘Asthma alert: (ii) ‘‘[Bullet] if you are now taking a Because asthma may be life threat- prescription monoamine oxidase inhib- ening, see a doctor if you’’ [in bold itor (MAOI) (certain drugs taken for type]: depression, psychiatric or emotional (A) ‘‘[Bullet] are not better in 60 min- conditions, or Parkinson’s disease), or utes’’. for 2 weeks after stopping the MAOI (B) ‘‘[Bullet] get worse’’. drug. If you do not know if your pre- (C) ‘‘[Bullet] need more than [insert scription drug contains an MAOI, ask a total number of dosage units that doctor or pharmacist before taking this equals 150 milligrams] in 24 hours’’. product.’’ (D) ‘‘[Bullet] use more than [insert (2) The following information shall total number of dosage units that appear after the subheading ‘‘Ask a equals 100 milligrams] in 24 hours for 3 doctor before use if you have’’ [in bold or more days a week’’. type]: ‘‘[bullet] ever been hospitalized (E) ‘‘[Bullet] have more than 2 asth- for asthma [bullet] heart disease [bul- ma attacks in a week’’. let] high blood pressure [bullet] diabe- (F) ‘‘These may be signs that your tes [bullet] thyroid disease [bullet] sei- asthma is getting worse.’’ zures [bullet] narrow angle glaucoma (G) ‘‘[Bullet] This product will not [bullet] a psychiatric or emotional con- give you asthma relief as quickly as an dition [bullet] trouble urinating due to inhaled bronchodilator.’’ an enlarged prostate gland’’. (ii) This ‘‘Asthma alert’’ shall appear (3) The following information shall on any labeling that contains warnings appear after the subheading ‘‘Ask a and shall be the first warning state- doctor or pharmacist before use if you ment under the heading ‘‘Warnings’’. are’’ [in bold type]: (6) For products containing epineph- (i) ‘‘[Bullet] taking prescription rine, epinephrine bitartrate, or drugs for asthma, obesity, weight con- racepinephrine hydrochloride identified in trol, depression, or psychiatric or emo- § 341.16(d), (e), and (g). (i) The following tional conditions’’. information shall appear after the sub- (ii) ‘‘[Bullet] taking any drug that heading ‘‘Asthma alert: Because asth- contains phenylephrine, ma may be life threatening, see a doc- pseudoephedrine, ephedrine, or caffeine tor if you’’ [in bold type]: (such as for allergy, cough-cold, or (A) ‘‘[Bullet] are not better in 20 min- pain)’’. utes’’. (4) The following information shall (B) ‘‘[Bullet] get worse’’. appear after the subheading ‘‘When (C) ‘‘[Bullet] need more than 12 using this product’’ [in bold type]: inhalations in 24 hours’’. (i) ‘‘[Bullet] your blood pressure or (D) ‘‘[Bullet] use more than 9 heart rate may go up. This could in- inhalations in 24 hours for 3 or more crease your risk of heart attack or days a week’’. stroke, which may cause death.’’ [in (E) ‘‘[Bullet] have more than 2 asth- bold type] ma attacks in a week’’. (ii) ‘‘[Bullet] your risk of heart at- (F) ‘‘These may be signs that your tack or stroke increases if you: [Bullet] asthma is getting worse.’’ have a history of high blood pressure or (ii) This ‘‘Asthma alert’’ shall appear heart disease [Bullet] take this product on any labeling that contains warnings

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and shall be the first warning state- (iii) ‘‘[Bullet] children under 4 years ment under the heading ‘‘Warnings.’’ of age: ask a doctor’’. (iii) For products intended for use in a (Collection of information requirement ap- hand-held rubber bulb nebulizer. The fol- proved by the Office of Management and lowing statement shall also appear Budget under control number 0910–0237) after the subheading ‘‘Do not use’’ along with the other information in [51 FR 35339, Oct. 2, 1986, as amended at 52 FR paragraph (c)(1) of this section: ‘‘[bul- 7126, Mar. 9, 1987; 52 FR 7830, Mar. 13, 1987; 53 FR 35810, Sept. 15, 1988; 58 FR 54242, Oct. 20, let] if product is brown in color or 1993; 61 FR 25146, May 20, 1996; 62 FR 9684, cloudy’’. Mar. 4, 1997; 64 FR 13295, Mar. 17, 1999; 76 FR (7) The following information shall 44487, July 26, 2011] appear after the subheading ‘‘Stop use and ask a doctor if’’ [in bold type]: § 341.78 Labeling of expectorant drug (i) ‘‘[Bullet] your asthma is getting products. worse (see Asthma alert)’’. (a) Statement of identity. The labeling (ii) ‘‘[Bullet] you have difficulty of the product contains the established sleeping’’. name of the drug, if any, and identifies (iii) ‘‘[Bullet] you have a rapid heart the product as an ‘‘expectorant.’’ beat’’. (b) Indications. The labeling of the (iv) ‘‘[Bullet] you have tremors, nerv- product states, under the heading ‘‘In- ousness, or seizure’’. dications,’’ the following: ‘‘Helps loos- (d) Directions. The labeling of the en phlegm (mucus) and thin bronchial product contains the following infor- secretions to’’ (select one or more of mation under the heading ‘‘Direc- the following: ‘‘rid the bronchial pas- tions’’: sageways of bothersome mucus,’’ (1) For products containing ephedrine, ‘‘drain bronchial tubes,’’ and ‘‘make ephedrine hydrochloride, ephedrine sul- coughs more productive’’). Other truth- fate, or racephedrine hydrochloride iden- ful and nonmisleading statements, de- tified in § 341.16(a), (b), (c), and (f): (i) scribing only the indications for use ‘‘[Bullet] do not take more than di- that have been established and listed in rected’’ [sentence appears as first this paragraph (b), may also be used, as bulleted statement under ‘‘Directions’’ provided in § 330.1(c)(2) of this chapter, and in bold type] subject to the provisions of section 502 (ii) ‘‘[Bullet] adults and children 12 of the act relating to misbranding and years of age and over: oral dose is 12.5 the prohibition in section 301(d) of the to 25 milligrams every 4 hours as need- act against the introduction or deliv- ed. Do not take more than 150 milli- ery for introduction into interstate grams in 24 hours’’. commerce of unapproved new drugs in (iii) ‘‘[Bullet] children under 12 years violation of section 505(a) of the act. of age: ask a doctor’’. (c) Warnings. The labeling of the (2) For products containing epineph- product contains the following warn- rine, epinephrine bitartrate, and ings, under the heading ‘‘Warnings’’: racepinephrine hydrochloride identified in (1) ‘‘A persistent cough may be a sign § 341.16(d), (e), and (g) for use in a hand- of a serious condition. If cough persists held rubber bulb nebulizer. The ingre- for more than 1 week, tends to recur, dient is used in an aqueous solution at or is accompanied by a fever, rash, or a concentration equivalent to 1-percent persistent headache, consult a doctor.’’ epinephrine: (2) For expectorant drug products la- (i) ‘‘[Bullet] do not use more than di- beled for adults or for adults and children rected’’ [appears as first bulleted state- under 12 years of age. ‘‘Do not take this ment under ‘‘Directions’’ and in bold product for persistent or chronic cough type]. such as occurs with smoking, asthma, (ii) ‘‘[Bullet] adults and children 4 chronic bronchitis, or emphysema, or years of age and over: 1 to 3 inhalations where cough is accompanied by exces- not more often than every 3 hours. Do sive phlegm (mucus) unless directed by not use more than 12 inhalations in 24 a doctor.’’ hours. The use of this product by chil- (3) For expectorant drug products la- dren should be supervised by an adult.’’ beled only for children under 12 years of

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age. ‘‘Do not give this product for per- by any of the following in paragraphs sistent or chronic cough such as occurs (b)(1) (i), (ii), and (iii) of this section): with asthma or if cough is accom- (i) ‘‘due to’’ (select one of the fol- panied by excessive phlegm (mucus) lowing: ‘‘the common cold’’ or ‘‘a unless directed by a doctor.’’ cold’’). (d) Directions. The labeling of the (ii) ‘‘due to’’ (select one of the fol- product contains the following infor- lowing: ‘‘hay fever,’’ ‘‘hay fever (aller- mation under the heading ‘‘Directions’’ gic rhinitis),’’ ‘‘hay fever or other for products containing guaifenesin upper respiratory allergies,’’ or ‘‘hay identified in § 341.18: Adults and chil- fever or other upper respiratory aller- dren 12 years of age and over: oral dos- gies (allergic rhinitis)’’). age is 200 to 400 milligrams every 4 hours not to exceed 2,400 milligrams in (2) In addition to the information 24 hours. Children 6 to under 12 years of identified in paragraph (b)(1) of this age: oral dosage is 100 to 200 milligrams section, the labeling of the product every 4 hours not to exceed 1,200 milli- may contain any (one or more) of the grams in 24 hours. Children 2 to under following statements: 6 years of age: oral dosage is 50 to 100 (i) (Select one of the following: ‘‘For milligrams every 4 hours not to exceed the temporary relief of’’ or ‘‘Tempo- 600 milligrams in 24 hours. Children rarily relieves’’) (select one of the fol- under 2 years of age: consult a doctor. lowing: ‘‘stuffy nose,’’ ‘‘stopped up (e) The word ‘‘physician’’ may be sub- nose,’’ ‘‘nasal stuffiness,’’ or ‘‘clogged stituted for the word ‘‘doctor’’ in any up nose.’’) of the labeling statements in this sec- (ii) (Select one of the following: ‘‘Re- tion. duces swelling of,’’ ‘‘Decongests,’’ or [54 FR 8509, Feb. 28, 1989, as amended at 57 ‘‘Helps clear’’) ‘‘nasal passages; shrinks FR 29177, June 30, 1992] swollen membranes.’’ (iii) ‘‘Temporarily restores freer § 341.80 Labeling of nasal deconges- breathing through the nose.’’ tant drug products. (iv) ‘‘Helps decongest sinus openings (a) Statement of identity. The labeling and passages; temporarily relieves of the product contains the established sinus congestion and pressure.’’ name of the drug, if any, and identifies (v) ‘‘Promotes nasal and/or sinus the product as a ‘‘nasal decongestant.’’ drainage; temporarily relieves sinus (b) Indications. The labeling of the congestion and pressure.’’ product states, under the heading ‘‘In- (c) Warnings. The labeling of the dications,’’ the phrase listed in para- product contains the following warn- graph (b)(1) of this section, as appro- ings under the heading ‘‘Warnings’’: priate, and may contain any additional (1) Oral nasal decongestants—(i) For phrases listed in paragraph (b)(2) of products containing phenylephrine hydro- this section. Other truthful and non- chloride, pseudoephedrine hydrochloride, misleading statements, describing only pseudoephedrine sulfate, or phenyl- the indications for use that have been established and listed in paragraphs ephrine bitartrate identified in § 341.20 (b)(1) and (b)(2) of this section, may (a)(1) through (a)(4) when labeled for also be used, as provided in § 330.1(c)(2) adults. (A) ‘‘Do not exceed rec- of this chapter, subject to the provi- ommended dosage. [first sentence in sions of section 502 of the Federal boldface type] If nervousness, dizziness, Food, Drug, and Cosmetic Act (the act) or sleeplessness occur, discontinue use relating to misbranding and the prohi- and consult a doctor.’’ bition in section 301(d) of the act (B) ‘‘If symptoms do not improve against the introduction or delivery for within 7 days or are accompanied by introduction into interstate commerce fever, consult a doctor.’’ of unapproved new drugs in violation of (C) ‘‘Do not take this product if you section 505(a) of the act. have heart disease, high blood pressure, (1) (Select one of the following: ‘‘For thyroid disease, diabetes, or difficulty the temporary relief of nasal conges- in urination due to enlargement of the tion’’ or ‘‘Temporarily relieves nasal prostate gland unless directed by a doc- congestion’’) (which may be followed tor.’’

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(D) Drug interaction precaution. ‘‘Do § 341.20(b)(1) when used in an inhalant not use if you are now taking a pre- dosage form and when labeled for adults. scription monoamine oxidase inhibitor ‘‘Do not use this product for more than (MAOI) (certain drugs for depression, 7 days. Use only as directed. Frequent psychiatric, or emotional conditions, or prolonged use may cause nasal con- or Parkinson’s disease), or for 2 weeks gestion to recur or worsen. If symp- after stopping the MAOI drug. If you do toms persist, ask a doctor.’’ not know if your prescription drug con- (iii) For products containing ephedrine, tains an MAOI, ask a doctor or phar- ephedrine hydrochloride, ephedrine sul- macist before taking this product.’’ fate, naphazoline hydrochloride, (ii) For products containing phenyl- oxymetazoline hydrochloride, phenylephrine hydrochloride, pseudoephedrine ephrine hydrochloride, or xylometazoline hydrochloride, pseudoephedrine sulfate, hydrochloride identified in § 341.20 (b)(2), or phenylephrine bitartrate identified in (b)(3), (b)(4), (b)(6), (b)(7), (b)(8), and § 341.20 (a)(1) through (a)(4) when labeled (b)(10) when used as nasal sprays, drops, for children under 12 years of age. (A) or jellies and when labeled for adults. (A) ‘‘Do not exceed recommended dosage. ‘‘Do not use this product for more than [first sentence in boldface type] If 3 days. Use only as directed. Frequent nervousness, dizziness, or sleeplessness or prolonged use may cause nasal con- occur, discontinue use and consult a gestion to recur or worsen. If symp- doctor.’’ toms persist, consult a doctor.’’ (B) ‘‘If symptoms do not improve (B) ‘‘Do not use this product if you within 7 days or are accompanied by have heart disease, high blood pressure, fever, consult a doctor.’’ thyroid disease, diabetes, or difficulty (C) ‘‘Do not give this product to a in urination due to enlargement of the child who has heart disease, high blood prostate gland unless directed by a doc- pressure, thyroid disease, or diabetes tor.’’ unless directed by a doctor.’’ (iv) For products containing naphazo- (D) Drug interaction precaution. ‘‘Do line hydrochloride identified in not use in a child who is taking a prescription monoamine oxidase inhibitor § 341.20(b)(6) at a concentration of 0.05 (MAOI) (certain drugs for depression, percent. ‘‘Do not use this product in psychiatric, or emotional conditions, children under 12 years of age because or Parkinson’s disease), or for 2 weeks it may cause sedation if swallowed.’’ after stopping the MAOI drug. If you do (v) For products containing not know if your child’s prescription propylhexedrine identified in § 341.20(b)(9) drug contains an MAOI, ask a doctor or when used in an inhalant dosage form pharmacist before giving this product.’’ and when labeled for adults. ‘‘Do not use (iii) For oral nasal decongestant prod- this product for more than 3 days. Use ucts labeled for both adults and children only as directed. Frequent or prolonged under 12 years of age. The labeling of use may cause nasal congestion to the product contains the warnings recur or worsen. If symptoms persist, identified in paragraph (c)(1)(i) of this consult a doctor.’’ section. (vi) For products containing any topical (2) Topical nasal decongestants—(i) For nasal decongestant identified in § 341.20(b) products containing any topical nasal de- when labeled for children under 12 years congestant identified in § 341.20(b) when of age. The labeling of the product con- labeled for adults. (A) ‘‘Do not exceed tains the warnings identified in para- recommended dosage.’’ [sentence in graph (c)(2)(i) of this section. boldface type] (vii) For products containing (B) ‘‘This product may cause tem- levmetamfetamine identified in porary discomfort such as burning, § 341.20(b)(1) when used in an inhalant stinging, sneezing, or an increase in dosage form and when labeled for chil- nasal discharge.’’ dren under 12 years of age. ‘‘Do not use (C) ‘‘The use of this container by this product for more than 7 days. Use more than one person may spread in- only as directed. Frequent or prolonged fection.’’ use may cause nasal congestion to (ii) For products containing recur or worsen. If symptoms persist, levmetamfetamine identified in ask a doctor.’’

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(viii) For products containing ephed- 240 milligrams in 24 hours. Children 6 rine, ephedrine hydrochloride, ephedrine to under 12 years of age: 30 milligrams sulfate, naphazoline hydrochloride, every 4 to 6 hours not to exceed 120 oxymetazoline hydrochloride, phenyl- milligrams in 24 hours. Children 2 to ephrine hydrochloride, or xylometazoline under 6 years of age: 15 milligrams hydrochloride identified in § 341.20(b)(2), every 4 to 6 hours not to exceed 60 mil- (b)(3), (b)(4), (b)(6), (b)(7), (b)(8), and ligrams in 24 hours. Children under 2 (b)(10) when used as nasal sprays, drops, years of age: consult a doctor. or jellies and when labeled for children (iii) For products containing phenyl- under 12 years of age. (A) ‘‘Do not use ephrine bitartrate identified in this product for more than 3 days. Use § 341.20(a)(4). Include information on only as directed. Frequent or prolonged the number of dosage units and the use may cause nasal congestion to quantity of water the dosage units are recur or worsen. If symptoms persist, to be dissolved in prior to administra- consult a doctor.’’ tion as shown in the following table: (B) ‘‘Do not use this product in a child who has heart disease, high blood Age 1 Dose 1 pressure, thyroid disease, or diabetes Adults and children 15.6 milligrams every 4 hours not unless directed by a doctor.’’ 12 years of age to exceed 62.4 milligrams in 24 (ix) For products containing and over hours propylhexedrine identified in § 341.20(b)(9) Children 6 to under 7.8 milligrams every 4 hours not to when used in an inhalant dosage form 12 years of age exceed 31.2 milligrams in 24 and when labeled for children under 12 hours years of age. ‘‘Do not use this product Children under 6 Ask a doctor for more than 3 days. Use only as di- years of age rected. Frequent or prolonged use may 1Headings are not required to appear in the product’s cause nasal congestion to recur or labeling worsen. If symptoms persist, consult a doctor.’’ (2) Topical nasal decongestants—(i) For (x) For topical nasal decongestant prod- products containing levmetamfetamine ucts labeled for both adults and for chil- identified in § 341.20(b)(1) when used in an dren under 12 years of age. The labeling inhalant dosage form. The product deliv- of the product contains the applicable ers in each 800 milliliters of air 0.04 to warnings identified in paragraphs 0.150 milligrams of levmetamfetamine. (c)(2)(i), (c)(2)(ii), (c)(2)(iii), and (c)(2)(v) Adults: 2 inhalations in each nostril of this section. not more often than every 2 hours. (d) Directions. The labeling of the Children 6 to under 12 years of age product contains the following infor- (with adult supervision): 1 inhalation mation under the heading ‘‘Direc- in each nostril not more often than tions’’: every 2 hours. Children under 6 years of (1) Oral nasal decongestants—(i) For age: ask a doctor. products containing phenylephrine hydro- (ii) For products containing ephedrine, chloride identified in § 341.20(a)(1). ephedrine hydrochloride, or ephedrine Adults and children 12 years of age and sulfate identified in § 341.20(b) (2), (3), over: 10 milligrams every 4 hours not and (4)—(A) Nasal drops or sprays—For a to exceed 60 milligrams in 24 hours. 0.5-percent aqueous solution. Adults and Children 6 to under 12 years of age: 5 children 12 years of age and over: 2 or milligrams every 4 hours not to exceed 3 drops or sprays in each nostril not 30 milligrams in 24 hours. Children 2 to more often than every 4 hours. Chil- under 6 years of age: 2.5 milligrams dren 6 to under 12 years of age (with every 4 hours not to exceed 15 milli- adult supervision): 1 or 2 drops or grams in 24 hours. Children under 2 sprays in each nostril not more often years of age: consult a doctor. than every 4 hours. Children under 6 (ii) For products containing years of age: consult a doctor. pseudoephedrine hydrochloride or (B) Nasal jelly—For a 0.5-percent pseudoephedrine sulfate identified in water-based jelly. Adults and children 6 § 341.20 (a)(2) and (a)(3). Adults and chil- to under 12 years of age (with adult su- dren 12 years of age and over: 60 milli- pervision): place a small amount in grams every 4 to 6 hours not to exceed each nostril and inhale well back into

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the nasal passages. Use not more often (B) Nasal jelly—For a 0.05-percent than every 4 hours. water-based jelly. Adults and children 6 (iii) For products containing naphazo- to under 12 years of age (with adult su- line hydrochloride identified in pervision): place a small amount in § 341.20(b)(6)—(A) Nasal drops or sprays— each nostril and inhale well back into (1) For a 0.05-percent aqueous solution. the nasal passages. Use not more often Adults and children 12 years of age and than every 10 to 12 hours. Do not ex- over: 1 or 2 drops or sprays in each nos- ceed 2 doses in any 24-hour period. Chil- tril not more often than every 6 hours. dren under 6 years of age: consult a Do not give to children under 12 years doctor. of age unless directed by a doctor. (v) For products containing phenyl- (2) For a 0.025-percent aqueous solution. ephrine hydrochloride identified in Children 6 to under 12 years of age § 341.20(b)(8)—(A) Nasal drops or sprays— (with adult supervision): 1 or 2 drops or (1) For a 1-percent aqueous solution. sprays in each nostril not more often Adults and children 12 years of age and than every 6 hours. Children under 6 over: 2 or 3 drops or sprays in each nos- years of age: consult a doctor. tril not more often than every 4 hours. (B) Nasal jelly—(1) For a 0.05-percent Do not give to children under 12 years water-based jelly. Adults and children 12 of age unless directed by a doctor. years of age and over: place a small (2) For a 0.5-percent aqueous solution. amount in each nostril and inhale well Adults and children 12 years of age and back into the nasal passages. Use not over: 2 or 3 drops or sprays in each nos- more often than every 6 hours. Do not tril not more often than every 4 hours. give to children under 12 years of age Do not give to children under 12 years unless directed by a doctor. of age unless directed by a doctor. (2) For a 0.025-percent water-based (3) For a 0.25-percent aqueous solution. jelly. Children 6 to under 12 years of age Adults and children 6 to under 12 years (with adult supervision): place a small of age (with adult supervision): 2 or 3 amount in each nostril and inhale well drops or sprays in each nostril not back into the nasal passages. Use not more often than every 4 hours. Chil- more often than every 6 hours. Chil- dren under 6 years of age: consult a dren under 6 years of age: consult a doctor. doctor. (4) A 0.125-percent aqueous solution in (iv) For products containing a container having either a calibrated oxymetazoline hydrochloride identified in dropper or a metered-dose spray that de- § 341.20(b)(7)—(A) Nasal drops or sprays— livers no more than 0.135 milligrams of (1) For a 0.05-percent aqueous solution. phenylephrine per three drops or three Adults and children 6 to under 12 years sprays. Children 2 to under 6 years of of age (with adult supervision): 2 or 3 age (with adult supervision): 2 or 3 drops or sprays in each nostril not drops or sprays in each nostril not more often than every 10 to 12 hours. more often than every 4 hours. Use Do not exceed 2 doses in any 24-hour only recommended amount. [previous period. Children under 6 years of age: sentence in boldface type] Children consult a doctor. under 2 years of age: consult a doctor. (2) A 0.025-percent aqueous solution in (B) Nasal jelly—(1) For a 1-percent a container having either a calibrated water-based jelly. Adults and children 12 dropper or a metered-dose spray that de- years of age and over: place a small livers no more than 0.027 milligrams of amount in each nostril and inhale well oxymetazoline per three drops or three back into the nasal passages. Use not sprays. Children 2 to under 6 years of more often than every 4 hours. Do not age (with adult supervision): 2 or 3 give to children under 12 years of age drops or sprays in each nostril not unless directed by a doctor. more often than every 10 to 12 hours. (2) For a 0.5-percent water-based jelly. Use only recommended amount. Do not Adults and children 12 years of age and exceed 2 doses in any 24-hour period. over: place a small amount in each nos- [previous two sentences in boldface tril and inhale well back into the nasal type] Children under 2 years of age: passages. Use not more often than consult a doctor. every 4 hours. Do not give to children

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under 12 years of age unless directed by (with adult supervision): place a small a doctor. amount in each nostril and inhale well (3) For a 0.25-percent water-based jelly. back into the nasal passages. Use not Adults and children 6 to under 12 years more often than every 8 to 10 hours. of age (with adult supervision): place a Children under 6 years of age: consult a small amount in each nostril and in- doctor. hale well back into the nasal passages. (viii) Other required statements—For Use not more often than every 4 hours. products containing levmetamfetamine or Children under 6 years of age: consult a propylhexedrine identified in § 341.20(b)(1) doctor. or (b)(9) when used in an inhalant dosage (vi) For products containing form. (A) ‘‘This inhaler is effective for a propylhexedrine identified in § 341.20(b)(9) minimum of 3 months after first use.’’ when used in an inhalant dosage form. (B) ‘‘Keep inhaler tightly closed.’’ The product delivers in each 800 milliliters of air 0.40 to 0.50 milligrams of [59 FR 43409, Aug. 23, 1994, as amended at 63 propylhexedrine. Adults and children 6 FR 40650, July 30, 1998; 64 FR 13295, Mar. 17, to under 12 years of age (with adult su- 1999; 65 FR 8, Jan. 3, 2000; 70 FR 58977, Oct. 11, pervision): 2 inhalations in each nostril 2005; 71 FR 43362, Aug. 1, 2006] not more often than every 2 hours. § 341.85 Labeling of permitted com- Children under 6 years of age: consult a binations of active ingredients. doctor. (vii) For products containing The statements of identity, indica- xylometazoline hydrochloride identified in tions, warnings, and directions for use, § 341.20(b)(10)—(A) Nasal drops or respectively, applicable to each ingre- sprays—(1) For a 0.1-percent aqueous so- dient in the product may be combined lution. Adults and children 12 years of to eliminate duplicative words or age and over: 2 or 3 drops or sprays in phrases so that the resulting informa- each nostril not more often than every tion is clear and understandable. 8 to 10 hours. Do not give to children (a) Statement of identity. For a com- under 12 years of age unless directed by bination drug product that has an es- a doctor. tablished name, the labeling of the (2) A 0.05-percent aqueous solution in a product states the established name of container having either a calibrated drop- the combination drug product, followed per or a metered-dose spray that delivers by the statement of identity for each no more than 0.054 milligrams of ingredient in the combination, as es- xylometazoline per three drops or three tablished in the statement of identity sprays. Children 6 to under 12 years of sections of the applicable OTC drug age (with adult supervision): 2 or 3 monographs. If there is no established drops or sprays in each nostril not name, the labeling of the product more often than every 8 to 10 hours. states the statement of identity for Children 2 to under 6 years of age (with each ingredient in the combination, as adult supervision): 2 or 3 drops or established in the statement of iden- sprays in each nostril not more often tity sections of the applicable OTC than every 8 to 10 hours. Use only rec- drug monographs, unless otherwise ommended amount. Do not exceed 3 stated in this paragraph (a). doses in any 24-hour period. [previous (1) For permitted combinations identi- two sentences in boldface type] Chil- fied in § 341.40(a), (c), (f), (g), (l), (m), (n), dren under 2 years of age: consult a (o), (q), and (r) containing an analgesic- doctor. antipyretic active ingredient. The analge- (B) Nasal jelly—(1) For a 0.1-percent sic-antipyretic component of the prod- water-based jelly. Adults and children 12 uct shall be identified as a ‘‘pain re- years of age and over: place a small liever’’ or ‘‘analgesic (pain reliever).’’ amount in each nostril and inhale well If the product is also labeled to relieve back into the nasal passages. Use not fever, then the analgesic-antipyretic more often than every 8 to 10 hours. Do component is identified as a ‘‘pain re- not give to children under 12 years of liever-fever reducer’’ or ‘‘analgesic age unless directed by a doctor. (pain reliever)-antipyretic (fever re- (2) For a 0.05-percent water-based jelly. ducer).’’ Children 6 to under 12 years of age (2) [Reserved]

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(b) Indications. The labeling of the (3) For permitted combinations con- product states, under the heading taining an oral analgesic-antipyretic ac- ‘‘Uses,’’ the indication(s) for each in- tive ingredient identified in § 341.40(a), gredient in the combination, as estab- (c), (f), (g), (m), (q), and (r) when labeled lished in the indications sections of the for relief of general cough-cold symptoms applicable OTC drug monographs, un- and/or the common cold and for relief of less otherwise stated in this paragraph hay fever/allergic rhinitis and/or nasal (b). Other truthful and nonmisleading congestion symptoms. The labeling statements, describing only the indica- states both indications in paragraphs tions for use that have been established (b)(1) and (b)(2) of this section. and listed in the applicable OTC drug (4) For permitted combinations con- monographs or listed in this paragraph taining an oral anesthetic-analgesic ac- (b), may also be used, as provided in tive ingredient identified in § 341.40(k), (s), § 330.1(c)(2) of this chapter, subject to (t), (z), (aa), and (bb). The labeling for the provisions of section 502 of the Fed- the anesthetic-analgesic ingredients in eral Food, Drug, and Cosmetic Act (the part 356 of this chapter should be used. act) relating to misbranding and the (5) For permitted combinations con- prohibition in section 301(d) of the act taining camphor, menthol, and euca- against the introduction or delivery for lyptus oil identified in § 341.40(u). The la- introduction into interstate commerce beling for antitussive ingredients in of unapproved new drugs in violation of § 341.74(b) should be used. section 505(a) of the act. (6) For permitted combinations con- (1) For permitted combinations containing levmetamfetamine with aromatics taining an analgesic-antipyretic active in- identified in § 341.40(v). The labeling for gredient identified in § 341.40(a), (c), (f). nasal decongestant ingredients in (g), (l), (m), (n), (o), (q), and (r) when la- § 341.80(b) should be used. beled for relief of general cough-cold (7) Other allowable statements. In addi- symptoms and/or the common cold. (i) The tion to the required information identi- labeling for the analgesic-antipyretic fied in paragraph (b) of this section, the labeling of the combination drug ingredients states ‘‘[bullet] tempo- product may contain any of the ‘‘other rarily relieves [bullet] minor aches and allowable statements’’ (if any), that pains [bullet] headache’’ and ‘‘[bullet] are identified in the applicable OTC temporarily reduces fever’’. drug monographs, provided such state- (ii) The labeling for the cough-cold ments are neither placed in direct con- ingredient(s) may follow a separate junction with information required to bullet(s) or may be combined with the appear in the labeling nor occupy la- relieves part of the indication in para- beling space with greater prominence graph (b)(1)(i) of this section. or conspicuousness than the required (2) For permitted combinations con- information. taining an analgesic-antipyretic active in- (c) Warnings. The labeling of the gredient identified in § 341.40(a), (c), (f), product states, under the heading (g), (m), (q), and (r) when labeled for re- ‘‘Warnings,’’ the warning(s) for each in- lief of hay fever/allergic rhinitis and/or gredient in the combination, as estab- nasal congestion symptoms. (i) The label- lished in the warnings sections of the ing for the analgesic-antipyretic ingre- applicable OTC drug monographs, un- dients states ‘‘[bullet] temporarily re- less otherwise stated in paragraph (c) lieves [bullet] minor aches and pains of this section. [bullet] headache’’. (1) For permitted combinations con- (ii) The indication(s) for the cough- taining an antitussive and an analgesic- cold ingredient(s) consists of the label- antipyretic identified in § 341.40(f), (g), (l), ing for antihistamines in § 341.72(b)(1) and (m). The labeling states the fol- or (b)(2) and/or nasal decongestants in lowing warnings: § 341.80(b)(1)(ii), as appropriate, and the (i) For products labeled only for adults. labeling for any other cough-cold com- The following warning should be used bination. This labeling may follow a instead of the warnings in § 341.74(c)(1) separate bullet(s) or may be combined and part 343 of this chapter: ‘‘Stop use with the indication in paragraph and ask a doctor if [in bold type] [bul- (b)(2)(i) of this section. let] pain or cough gets worse or lasts

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more than 7 days [bullet] fever gets algesic-antipyretic identified in § 341.40(c), worse or lasts more than 3 days [bullet] (g), (m), (n), (q), and (r). The labeling redness or swelling is present [bullet] states the following warnings: new symptoms occur [bullet] cough (i) For products labeled only for adults. comes back or occurs with rash or The following warning should be used headache that lasts. These could be instead of the warnings in signs of a serious condition.’’ § 341.80(c)(1)(i)(B) and part 343 of this (ii) For products labeled only for chil- chapter: ‘‘Stop use and ask a doctor if dren under 12 years of age. The following [in bold type] [bullet] pain or nasal warning should be used instead of the congestion gets worse or lasts more warnings in § 341.74(c)(3) and part 343 of than 7 days [bullet] fever gets worse or this chapter: ‘‘Stop use and ask a doc- lasts more than 3 days [bullet] redness tor if [in bold type] [bullet] pain or or swelling is present [bullet] new cough gets worse or lasts more than 5 symptoms occur’’. days [bullet] fever gets worse or lasts (ii) For products labeled for only chil- more than 3 days [bullet] redness or dren under 12 years of age. The following swelling is present [bullet] new symp- warning should be used instead of the toms occur [bullet] cough comes back warnings in § 341.80(c)(1)(ii)(B) and part or occurs with rash or headache that 343 of this chapter: ‘‘Stop use and ask a lasts. These could be signs of a serious doctor if [in bold type] [bullet] pain or condition.’’ nasal congestion gets worse or lasts (iii) For products labeled for both more than 5 days [bullet] fever gets adults and for children under 12 years of worse or lasts more than 3 days [bullet] age. The following warning should be redness or swelling is present [bullet] used instead of the warnings in new symptoms occur’’. § 341.74(c)(2) and part 343 of this chapter: ‘‘Stop use and ask a doctor if [in (iii) For products labeled for both bold type] [bullet] pain or cough gets adults and children under 12 years of age. worse or lasts more than 5 days (chil- The following warning should be used dren) or 7 days (adults) [bullet] fever instead of the warnings in gets worse or lasts more than 3 days § 341.80(c)(1)(iii) and part 343 of this [bullet] redness or swelling is present chapter: ‘‘Stop use and ask a doctor if [bullet] new symptoms occur [bullet] [in bold type] [bullet] pain or nasal cough comes back or occurs with rash congestion gets worse or lasts more or headache that lasts. These could be than 5 days (children) or 7 days (adults) signs of a serious condition.’’ [bullet] fever gets worse or lasts more (2) For permitted combinations con- than 3 days [bullet] redness or swelling taining an expectorant and an analgesic- is present [bullet] new symptoms antipyretic identified in § 341.40(o). The occur’’. labeling states the following warnings: (4) For permitted combinations con- (i) For products labeled only for adults. taining an antihistamine combined with The warning in paragraph (c)(1)(i) of an oral antitussive. The labeling states this section should be used instead of the warning ‘‘When using this product the warnings in § 341.78(c)(3) and part [in bold type] [bullet] may cause 343 of this chapter. marked drowsiness.’’ The word (ii) For products labeled only for chil- ‘‘marked’’ may be deleted from the dren under 12 years of age. The warning warning upon petition under the provi- in paragraph (c)(1)(ii) of this section sions of § 10.30 of this chapter provided should be used instead of the warnings adequate data are submitted to dem- in § 341.78(c)(3) and part 343 of this onstrate that the combination product chapter. does not cause a significant increase in (iii) For products labeled for both drowsiness as compared with each ac- adults and for children under 12 years of tive ingredient when tested alone. The age. The warning in paragraph petition and the data it contains will (c)(1)(iii) of this section should be used be maintained in a permanent file for instead of the warnings in § 341.78(c)(3) public review in the Division of Dock- and part 343 of this chapter. ets Management (HFA–305), Food and (3) For permitted combinations con- Drug Administration, 5630 Fishers taining a nasal decongestant and an an- Lane, rm. 1061, Rockville, MD 20852.

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(5) For permitted combinations con- tified in § 341.16 (a), (b), (c), and (f). Chil- taining camphor, menthol, and euca- dren 6 to under 12 years of age: oral lyptus oil identified in § 341.40(u). The la- dosage is 6.25 to 12.5 milligrams every 4 beling states the warnings for topical hours, not to exceed 75 milligrams in 24 antitussive ingredients in § 341.74(c). hours. Children 2 to under 6 years of (6) For permitted combinations con- age: oral dosage is 0.3 to 0.5 milligram taining levmetamfetamine with aromatics per kilogram of body weight every 4 identified in § 341.40(v). The labeling hours, not to exceed 2 milligrams per states the warnings for topical nasal kilogram of body weight in 24 hours. decongestant ingredients in (b) For products containing § 341.80(c)(2). chlophedianol hydrochloride identified in (d) Directions. The labeling of the 341.14(a)(1). Children 2 to under 6 years product states, under the heading ‘‘Di- of age: oral dosage is 12.5 milligrams rections,’’ directions that conform to every 6 to 8 hours, not to exceed 50 mil- the directions established for each in- ligrams in 24 hours. gredient in the directions sections of (c) For products containing codeine in- the applicable OTC drug monographs, gredients identified in § 341.14(a)(2). (1) unless otherwise stated in paragraph Children 2 to under 6 years of age: Oral (d) of this section. When the time in- dosage is 1 milligram per kilogram tervals or age limitations for adminis- body weight per day administered in tration of the individual ingredients four equal divided doses. The average differ, the directions for the combina- body weight for each age may also be tion product may not exceed any max- used to determine dosage as follows: imum dosage limits established for the For children 2 years of age (average individual ingredients in the applicable body weight, 12 kilograms), the oral OTC drug monograph. dosage is 3 milligrams every 4 to 6 (1) For permitted combinations con- hours, not to exceed 12 milligrams in 24 taining an anesthetic/analgesic and/or a hours; for children 3 years of age (aver- demulcent in a liquid dosage form identi- age body weight, 14 kilograms), the fied in § 341.40(k), (s), (t), (w), (x), (y), (z), oral dosage is 3.5 milligrams every 4 to (aa), and (bb). The labeling states ‘‘[op- 6 hours, not to exceed 14 milligrams in tional, bullet] gargle, swish around, or 24 hours; for children 4 years of age (av- keep in the mouth for at least 1 minute erage body weight, 16 kilograms), the and then swallow. Do not spit out.’’ oral dosage is 4 milligrams every 4 to 6 (2) For permitted combinations con- hours, not to exceed 16 milligrams in 24 taining camphor, menthol, and euca- hours: for children 5 years of age (aver- lyptus oil identified in § 341.40(u). The la- age body weight, 18 kilograms), the beling states the directions for topical oral dosage is 4.5 milligrams every 4 to antitussive ingredients in § 341.74(d). 6 hours, not to exceed 18 milligrams in (3) For permitted combinations con- 24 hours. The manufacturer must retaining levmetamfetamine with aromatics late these dosages for its specific prod- identified in § 341.40(v). The labeling uct dosages for its specific product to states the directions for topical nasal the use of the calibrated measuring de- decongestant ingredients in vice discussed in paragraph (c)(3) of § 341.80(d)(2)(i) and (d)(2)(viii). this section. If age is used to determine [67 FR 78170, Dec. 23, 2002, as amended at 70 the dose, the directions must include FR 58977, Oct. 11, 2005; 71 FR 43362, Aug. 1, instructions to reduce the dose for low- 2006] weight children. (2) Parents should be instructed to § 341.90 Professional labeling. obtain and use a calibrated measuring The labeling of the product provided device for administering the drug to to health professionals (but not to the the child, to use extreme care in meas- general public) may contain the fol- uring the dosage, and not exceed the lowing additional dosage information recommended daily dosage. for products containing the active in- (3) A dispensing device (such as a gredients identified below: dropper calibrated for age or weight) (a) For products containing ephedrine, should be dispensed along with the ephedrine hydrochloride, ephedrine sul- product when it is intended for use in fate, or racephedrine hydrochloride iden- children 2 to under 6 years of age to

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prevent possible overdose due to im- every 4 to 6 hours, not to exceed 37.5 proper measuring of the dose. mg in 24 hours. (4) Codeine is not recommended for (l) For products containing doxylamine use in children under 2 years of age. succinate identified in § 341.12(h). Chil- Children under 2 years may be more dren 2 to under 6 years of age: oral dos- susceptible to the respiratory depres- age is 1.9 to 3.125 milligrams every 4 to sant effects of codeine, including res- 6 hours, not to exceed 18.75 milligrams piratory arrest, coma, and death. in 24 hours. (d) The following labeling indication (m) For products containing may be used for products containing phenindamine tartrate identified in guaifenesin identified in § 341.18 when § 341.12(i). Children 2 to under 6 years of used as a single ingredient product. age: oral dosage is 6.25 milligrams ‘‘Helps loosen phlegm and thin bron- every 4 to 6 hours, not to exceed 37.5 chial secretions in patients with stable milligrams in 24 hours. chronic bronchitis.’’ (n) For products containing (e) For products containing pheniramine maleate identified in brompheniramine maleate identified in § 341.12(j). Children 2 to under 6 years of § 341.12(a). Children 2 to under 6 years age: oral dosage is 3.125 to 6.25 milli- of age: oral dosage is 1 milligram every grams every 4 to 6 hours, not to exceed 4 to 6 hours, not to exceed 6 milligrams 37.5 milligrams in 24 hours. in 24 hours. (o) For products containing pyrilamine (f) For products containing maleate identified in § 341.12(k). Children chlorcyclizine hydrochloride identified in § 341.12(b). Children 6 to under 12 years 2 to under 6 years of age: oral dosage is of age: oral dosage is 12.5 milligrams 6.25 to 12.5 milligrams every 6 to 8 every 6 to 8 hours, not to exceed 37.5 hours, not to exceed 50 milligrams in 24 milligrams in 24 hours. Children 2 to hours. under 6 years of age: oral dosage is 6.25 (p) For products containing thonzyl- milligrams every 6 to 8 hours, not to amine hydrochloride identified in exceed 18.75 milligrams in 24 hours. § 341.12(l). Children 2 to under 6 years of (g) For products containing age: oral dosage is 12.5 to 25 milligrams chlorpheniramine maleate identified in every 4 to 6 hours, not to exceed 150 § 341.12(c). Children 2 to under 6 years of milligrams in 24 hours. age: oral dosage is 1 milligram every 4 (q) For products containing triprolidine to 6 hours, not to exceed 6 milligrams hydrochloride identified in § 341.12(m). in 24 hours. Children 4 to under 6 years of age: oral (h) For products containing dosage is 0.938 milligram every 4 to 6 dexbrompheniramine maleate identified in hours, not to exceed 3.744 milligrams in § 341.12(d). Children 2 to under 6 years 24 hours. Children 2 to under 4 years of of age: oral dosage is 0.5 milligram age: oral dosage is 0.625 milligram every 4 to 6 hours, not to exceed 3 mil- every 4 to 6 hours, not to exceed 2.5 ligrams in 24 hours. milligrams in 24 hours. Infants 4 (i) For products containing months to under 2 years of age: oral dexchlorpheniramine maleate identified in dosage is 0.313 milligram every 4 to 6 § 341.12(e). Children 2 to under 6 years: hours, not to exceed 1.252 milligrams in oral dosage is 0.5 milligram every 4 to 24 hours. 6 hours, not to exceed 3 milligrams in (r) For products containing 24 hours. diphenhydramine citrate identified in (j) For products containing § 341.14(a)(5). Children 2 to under 6 diphenhydramine citrate identified in years of age: oral dosage is 9.5 milli- § 341.12(f). Children 2 to under 6 years of age: oral dosage is 9.5 milligrams every grams every 4 hours, not to exceed 57 4 to 6 hours, not to exceed 57 milli- milligrams in 24 hours. grams in 24 hours. (s) For products containing (k) For products containing diphenhydramine hydrochloride identified diphenhydramine hydrochloride identified in § 341.14(a)(6). Children 2 to under 6 in § 341.12(g). Children 2 to under 6 years of age: oral dosage is 6.25 milligrams

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years of age: oral dosage is 6.25 milli- § 343.3 Definitions. grams every 4 hours, not to exceed 37.5 As used in this part: milligrams in 24 hours. Analgesic—antipyretic drug. An agent [51 FR 35339, Oct. 2, 1986, as amended at 52 FR used to alleviate pain and to reduce 30057, Aug. 12, 1987; 54 FR 8509, Feb. 28, 1989; fever. 57 FR 58376, Dec. 9, 1992; 59 FR 4218, Jan. 28, Cardiovascular drug. An agent used to 1994; 59 FR 29174, June 3, 1994; 59 FR 36051, prevent ischemic events. July 15, 1994] Rheumatologic drug. An agent used for the treatment of rheumatologic dis- PART 343—INTERNAL ANALGESIC, orders. ANTIPYRETIC, AND ANTIRHEUMATIC DRUG PROD- Subpart B—Active Ingredients UCTS FOR OVER-THE-COUNTER HUMAN USE § 343.10 [Reserved] § 343.12 Cardiovascular active ingredi- Subpart A—General Provisions ents. Sec. (a) Aspirin. 343.1 Scope. (b) Buffered aspirin. Aspirin identi- 343.3 Definitions. fied in paragraph (a) of this section may be buffered with any antacid in- Subpart B—Active Ingredients gredient(s) identified in § 331.11 of this chapter provided that the finished 343.10 [Reserved] product contains at least 1.9 milli- 343.12 Cardiovascular active ingredients. equivalents of acid-neutralizing capac- 343.13 Rheumatologic active ingredients. ity per 325 milligrams of aspirin as 343.20 [Reserved] measured by the procedure provided in 343.22 Permitted combinations of active in- the United States Pharmacopeia 23/Na- gredients for cardiovascular- rheumatologic use. tional Formulary 18. § 343.13 Rheumatologic active ingredi- Subpart C—Labeling ents. 343.50–343.60 [Reserved] (a) Aspirin. 343.80 Professional labeling. (b) Buffered aspirin. Aspirin identified in paragraph (a) of this section Subpart D—Testing Procedures may be buffered with any antacid in- 343.90 Dissolution and drug release testing. gredient(s) identified in § 331.11 of this chapter provided that the finished AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, product contains at least 1.9 milli- 360, 371. equivalents of acid-neutralizing capac- SOURCE: 63 FR 56814, Oct. 23, 1998, unless ity per 325 milligrams of aspirin as otherwise noted. measured by the procedure provided in the United States Pharmacopeia 23/Na- Subpart A—General Provisions tional Formulary 18.

§ 343.1 Scope. § 343.20 [Reserved] (a) An over-the-counter analgesic- § 343.22 Permitted combinations of ac- antipyretic drug product in a form tive ingredients for cardiovascular- suitable for oral administration is gen- rheumatologic use. erally recognized as safe and effective Combinations containing aspirin and is not misbranded if it meets each must meet the standards of an accept- of the conditions in this part in addi- able dissolution test, as set forth in tion to each of the general conditions § 343.90. The following combinations are established in § 330.1 of this chapter. permitted: Aspirin identified in §§ 343.12 (b) References in this part to regu- and 343.13 may be combined with any latory sections of the Code of Federal antacid ingredient identified in § 331.11 Regulations are to chapter I of title 21 of this chapter or any combination of unless otherwise noted. antacids permitted in accordance with

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§ 331.10(a) of this chapter provided that CLINICAL PHARMACOLOGY the finished product meets the require- Mechanism of Action: Aspirin is a more po- ments of § 331.10 of this chapter and is tent inhibitor of both prostaglandin syn- marketed in a form intended for inges- thesis and platelet aggregation than other tion as a solution. salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on Subpart C—Labeling the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo- §§ 343.50–343.60 [Reserved] oxygenase via acetylation.

§ 343.80 Professional labeling. PHARMACOKINETICS Absorption: In general, immediate release The labeling of an over-the-counter aspirin is well and completely absorbed from drug product written for health profes- the gastrointestinal (GI) tract. Following ab- sionals (but not for the general public) sorption, aspirin is hydrolyzed to salicylic shall consist of the following: acid with peak plasma levels of salicylic acid (a) For products containing aspirin occurring within 1–2 hours of dosing (see identified in §§ 343.12 and 343.13 or per- PHARMACOKINETICS—Metabolism). The rate of absorption from the GI tract is dependent mitted combinations identified in § 343.22. upon the dosage form, the presence or ab- (These products must meet United sence of food, gastric pH (the presence or ab- States Pharmacopeia (USP) standards sence of GI antacids or buffering agents), and for dissolution or drug release in other physiologic factors. Enteric coated as- § 343.90.) pirin products are erratically absorbed from (1) The labeling contains the fol- the GI tract. Distribution: Salicylic acid is widely dis- lowing prescribing information under tributed to all tissues and fluids in the body the heading ‘‘Comprehensive Pre- including the central nervous system (CNS), scribing Information’’ and the sub- breast milk, and fetal tissues. The highest headings ‘‘Description,’’ ‘‘Clinical concentrations are found in the plasma, Pharmacology,’’ ‘‘Clinical Studies,’’ liver, renal cortex, heart, and lungs. The pro- ‘‘Animal Toxicology,’’ ‘‘Indications and tein binding of salicylate is concentration- dependent, i.e., nonlinear. At low concentra- Usage,’’ ‘‘Contraindications,’’ ‘‘Warn- tions (<100 micrograms/milliliter (μg/mL)), ings,’’ ‘‘Precautions,’’ ‘‘Adverse Reac- approximately 90 percent of plasma salicy- tions,’’ ‘‘Drug Abuse and Dependence,’’ late is bound to albumin while at higher con- ‘‘Overdosage,’’ ‘‘Dosage and Adminis- centrations (>400 μg/mL), only about 75 per- tration,’’ and ‘‘How Supplied’’ in the cent is bound. The early signs of salicylic exact language and the exact order pro- overdose (salicylism), including tinnitus vided as follows: (ringing in the ears), occur at plasma concentrations approximating 200 μg/mL. Severe COMPREHENSIVE PRESCRIBING toxic effects are associated with levels >400 INFORMATION μg/mL. (See ADVERSE REACTIONS and OVER- DOSAGE.) DESCRIPTION Metabolism: Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that (Insert the proprietary name and the estab- plasma levels of aspirin are essentially lished name (if any) of the drug, type of dosage undetectable 1–2 hours after dosing. Salicylic form (followed by the phrase ‘‘for oral adminis- acid is primarily conjugated in the liver to tration’’), the established name(s) and quantity form salicyluric acid, a phenolic glu- of the active ingredient(s) per dosage unit, the curonide, an acyl glucuronide, and a number total sodium content in milligrams per dosage of minor metabolites. Salicylic acid has a unit if the sodium content of a single rec- plasma half-life of approximately 6 hours. ommended dose is 5 milligrams or more, the es- Salicylate metabolism is saturable and total tablished name(s) (in alphabetical order) of any body clearance decreases at higher serum inactive ingredient(s) which may cause an aller- concentrations due to the limited ability of gic hypersensitivity reaction, the pharma- the liver to form both salicyluric acid and cological or therapeutic class of the drug, and phenolic glucuronide. Following toxic doses the chemical name(s) and structural formula(s) (10–20 grams (g)), the plasma half-life may be of the drug.) Aspirin is an odorless white, increased to over 20 hours. needle-like crystalline or powdery substance. Elimination: The elimination of salicylic When exposed to moisture, aspirin acid follows zero order pharmacokinetics; hydrolyzes into salicylic and acetic acids, (i.e., the rate of drug elimination is constant and gives off a vinegary-odor. It is highly in relation to plasma concentration). Renal lipid soluble and slightly soluble in water. excretion of unchanged drug depends upon

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urine pH. As urinary pH rises above 6.5, the angina patients the event rate was reduced renal clearance of free salicylate increases to 5 percent from the 10 percent rate in the from <5 percent to >80 percent. placebo group. Alkalinization of the urine is a key concept Chronic Stable Angina Pectoris: In a random- in the management of salicylate overdose. ized, multi-center, double-blind trial de- (See OVERDOSAGE.) Following therapeutic signed to assess the role of aspirin for pre- doses, approximately 10 percent is found ex- vention of MI in patients with chronic stable creted in the urine as salicylic acid, 75 per- angina pectoris, aspirin significantly recent as salicyluric acid, and 10 percent phe- duced the primary combined endpoint of nolic and 5 percent acyl glucuronides of sali- nonfatal MI, fatal MI, and sudden death by 34 cylic acid. percent. The secondary endpoint for vascular Pharmacodynamics Aspirin affects platelet events (first occurrence of MI, stroke, or vas- aggregation by irreversibly inhibiting cular death) was also significantly reduced prostaglandin cyclo-oxygenase. This effect (32 percent). lasts for the life of the platelet and prevents Revascularization Procedures: Most patients the formation of the platelet aggregating who undergo coronary artery factor thromboxane A2. Nonacetylated revascularization procedures have already salicylates do not inhibit this enzyme and had symptomatic coronary artery disease for have no effect on platelet aggregation. At which aspirin is indicated. Similarly, pa- somewhat higher doses, aspirin reversibly in- tients with lesions of the carotid bifurcation hibits the formation of prostaglandin I 2 sufficient to require carotid endarterectomy (prostacyclin), which is an arterial vaso- dilator and inhibits platelet aggregation. are likely to have had a precedent event. As- At higher doses aspirin is an effective anti- pirin is recommended for patients who un- inflammatory agent, partially due to inhibi- dergo revascularization procedures if there is tion of inflammatory mediators via cyclo- a preexisting condition for which aspirin is oxygenase inhibition in peripheral tissues. In already indicated. vitro studies suggest that other mediators of Rheumatologic Diseases: In clinical studies inflammation may also be suppressed by as- in patients with rheumatoid arthritis, juve- pirin administration, although the precise nile rheumatoid arthritis, ankylosing spon- mechanism of action has not been eluci- dylitis and osteoarthritis, aspirin has been dated. It is this nonspecific suppression of shown to be effective in controlling various cyclo-oxygenase activity in peripheral tis- indices of clinical disease activity. sues following large doses that leads to its primary side effect of gastric irritation. (See ANIMAL TOXICOLOGY ADVERSE REACTIONS.) The acute oral 50 percent lethal dose in CLINICAL STUDIES rats is about 1.5 g/kilogram (kg) and in mice 1.1 g/kg. Renal papillary necrosis and de- Ischemic Stroke and Transient Ischemic At- creased urinary concentrating ability occur tack (TIA): In clinical trials of subjects with in rodents chronically administered high TIA’s due to fibrin platelet emboli or doses. Dose-dependent gastric mucosal in- ischemic stroke, aspirin has been shown to jury occurs in rats and humans. Mammals significantly reduce the risk of the combined may develop aspirin toxicosis associated endpoint of stroke or death and the com- with GI symptoms, circulatory effects, and bined endpoint of TIA, stroke, or death by central nervous system depression. (See about 13–18 percent. OVERDOSAGE.) Suspected Acute Myocardial Infarction (MI): In a large, multi-center study of aspirin, INDICATIONS AND USAGE streptokinase, and the combination of aspirin and streptokinase in 17,187 patients with Vascular Indications (Ischemic Stroke, TIA, suspected acute MI, aspirin treatment pro- Acute MI, Prevention of Recurrent MI, Unstable duced a 23-percent reduction in the risk of Angina Pectoris, and Chronic Stable Angina vascular mortality. Aspirin was also shown Pectoris): Aspirin is indicated to: (1) Reduce to have an additional benefit in patients the combined risk of death and nonfatal given a thrombolytic agent. stroke in patients who have had ischemic Prevention of Recurrent MI and Unstable An- stroke or transient ischemia of the brain due gina Pectoris: These indications are supported to fibrin platelet emboli, (2) reduce the risk by the results of six large, randomized, of vascular mortality in patients with a sus- multi-center, placebo-controlled trials of pected acute MI, (3) reduce the combined predominantly male post-MI subjects and risk of death and nonfatal MI in patients one randomized placebo-controlled study of with a previous MI or unstable angina pec- men with unstable angina pectoris. Aspirin toris, and (4) reduce the combined risk of MI therapy in MI subjects was associated with a and sudden death in patients with chronic significant reduction (about 20 percent) in stable angina pectoris. the risk of the combined endpoint of subse- Revascularization Procedures (Coronary Ar- quent death and/or nonfatal reinfarction in tery Bypass Graft (CABG), Percutaneous these patients. In aspirin-treated unstable Transluminal Coronary Angioplasty (PTCA),

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and Carotid Endarterectomy): Aspirin is indi- Hepatic Insufficiency: Avoid aspirin in pa- cated in patients who have undergone tients with severe hepatic insufficiency. revascularization procedures (i.e., CABG, Sodium Restricted Diets: Patients with so- PTCA, or carotid endarterectomy) when dium-retaining states, such as congestive there is a preexisting condition for which as- heart failure or renal failure, should avoid pirin is already indicated. sodium-containing buffered aspirin prepara- Rheumatologic Disease Indications (Rheu- tions because of their high sodium content. matoid Arthritis, Juvenile Rheumatoid Arthritis, Spondyloarthropathies, Osteoarthritis, and the Laboratory Tests Arthritis and Pleurisy of Systemic Lupus Aspirin has been associated with elevated Erythematosus (SLE)): Aspirin is indicated for hepatic enzymes, blood urea nitrogen and the relief of the signs and symptoms of rheu- serum creatinine, hyperkalemia, protein- matoid arthritis, juvenile rheumatoid arthri- uria, and prolonged bleeding time. tis, osteoarthritis, spondyloarthropathies, and arthritis and pleurisy associated with Drug Interactions SLE. Angiotensin Converting Enzyme (ACE) Inhibi- CONTRAINDICATIONS tors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by Allergy: Aspirin is contraindicated in pa- the concomitant administration of aspirin tients with known allergy to nonsteroidal due to its indirect effect on the renin- anti-inflammatory drug products and in pa- angiotensin conversion pathway. tients with the syndrome of asthma, rhinitis, Acetazolamide: Concurrent use of aspirin and nasal polyps. Aspirin may cause severe and acetazolamide can lead to high serum urticaria, angioedema, or bronchospasm concentrations of acetazolamide (and tox- (asthma). icity) due to competition at the renal tubule Reye’s Syndrome: Aspirin should not be used for secretion. in children or teenagers for viral infections, Anticoagulant Therapy (Heparin and War- with or without fever, because of the risk of farin): Patients on anticoagulation therapy Reye’s syndrome with concomitant use of as- are at increased risk for bleeding because of pirin in certain viral illnesses. drug-drug interactions and the effect on WARNINGS platelets. Aspirin can displace warfarin from protein binding sites, leading to prolonga- Alcohol Warning: Patients who consume tion of both the prothrombin time and the three or more alcoholic drinks every day bleeding time. Aspirin can increase the anti- should be counseled about the bleeding risks coagulant activity of heparin, increasing involved with chronic, heavy alcohol use bleeding risk. while taking aspirin. Anticonvulsants: Salicylate can displace Coagulation Abnormalities: Even low doses protein-bound phenytoin and valproic acid, of aspirin can inhibit platelet function lead- leading to a decrease in the total concentra- ing to an increase in bleeding time. This can tion of phenytoin and an increase in serum adversely affect patients with inherited (he- valproic acid levels. mophilia) or acquired (liver disease or vita- Beta Blockers: The hypotensive effects of min K deficiency) bleeding disorders. beta blockers may be diminished by the con- GI Side Effects: GI side effects include comitant administration of aspirin due to in- stomach pain, heartburn, nausea, vomiting, hibition of renal prostaglandins, leading to and gross GI bleeding. Although minor upper decreased renal blood flow, and salt and fluid GI symptoms, such as dyspepsia, are com- retention. mon and can occur anytime during therapy, Diuretics: The effectiveness of diuretics in physicians should remain alert for signs of patients with underlying renal or cardio- ulceration and bleeding, even in the absence vascular disease may be diminished by the of previous GI symptoms. Physicians should concomitant administration of aspirin due to inform patients about the signs and symp- inhibition of renal prostaglandins, leading to toms of GI side effects and what steps to decreased renal blood flow and salt and fluid take if they occur. retention. Peptic Ulcer Disease: Patients with a his- Methotrexate: Salicylate can inhibit renal tory of active peptic ulcer disease should clearance of methotrexate, leading to bone avoid using aspirin, which can cause gastric marrow toxicity, especially in the elderly or mucosal irritation and bleeding. renal impaired. Nonsteroidal Anti-inflammatory Drugs PRECAUTIONS (NSAID’s): The concurrent use of aspirin with other NSAID’s should be avoided because General this may increase bleeding or lead to de- Renal Failure: Avoid aspirin in patients creased renal function. with severe renal failure (glomerular filtra- Oral Hypoglycemics: Moderate doses of aspi- tion rate less than 10 mL/minute). rin may increase the effectiveness of oral

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hypoglycemic drugs, leading to hypo- coagulation, coagulopathy, glycemia. thrombocytopenia. Uricosuric Agents (Probenecid and Hypersensitivity: Acute anaphylaxis, Sulfinpyrazone): Salicylates antagonize the angioedema, asthma, bronchospasm, laryn- uricosuric action of uricosuric agents. geal edema, urticaria. Carcinogenesis, Mutagenesis, Impairment of Musculoskeletal: Rhabdomyolysis. Fertility: Administration of aspirin for 68 Metabolism: Hypoglycemia (in children), weeks at 0.5 percent in the feed of rats was hyperglycemia. not carcinogenic. In the Ames Salmonella Reproductive: Prolonged pregnancy and assay, aspirin was not mutagenic; however, labor, stillbirths, lower birth weight infants, aspirin did induce chromosome aberrations antepartum and postpartum bleeding. in cultured human fibroblasts. Aspirin inhib- Respiratory: Hyperpnea, pulmonary edema, its ovulation in rats. (See Pregnancy.) tachypnea. Pregnancy: Pregnant women should only Special Senses: Hearing loss, tinnitus. Pa- take aspirin if clearly needed. Because of the tients with high frequency hearing loss may known effects of NSAID’s on the fetal cardio- have difficulty perceiving tinnitus. In these vascular system (closure of the ductus patients, tinnitus cannot be used as a clin- arteriosus), use during the third trimester of ical indicator of salicylism. pregnancy should be avoided. Salicylate Urogenital: Interstitial nephritis, papillary products have also been associated with al- necrosis, proteinuria, renal insufficiency and terations in maternal and neonatal hemo- failure. stasis mechanisms, decreased birth weight, and with perinatal mortality. DRUG ABUSE AND DEPENDENCE Labor and Delivery: Aspirin should be Aspirin is nonnarcotic. There is no known avoided 1 week prior to and during labor and potential for addiction associated with the delivery because it can result in excessive use of aspirin. blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin in- OVERDOSAGE hibition have been reported. Nursing Mothers: Nursing mothers should Salicylate toxicity may result from acute avoid using aspirin because salicylate is ex- ingestion (overdose) or chronic intoxication. creted in breast milk. Use of high doses may The early signs of salicylic overdose lead to rashes, platelet abnormalities, and (salicylism), including tinnitus (ringing in bleeding in nursing infants. the ears), occur at plasma concentrations ap- Pediatric Use: Pediatric dosing rec- proaching 200 μg/mL. Plasma concentrations ommendations for juvenile rheumatoid ar- of aspirin above 300 μg/mL are clearly toxic. thritis are based on well-controlled clinical Severe toxic effects are associated with lev- studies. An initial dose of 90–130 mg/kg/day els above 400 μg/mL. (See CLINICAL PHARMA- in divided doses, with an increase as needed COLOGY.) A single lethal dose of aspirin in for anti-inflammatory efficacy (target plas- adults is not known with certainty but death ma salicylate levels of 150–300 μg/mL) are ef- may be expected at 30 g. For real or sus- fective. At high doses (i.e., plasma levels of pected overdose, a Poison Control Center greater than 200 μg/mL), the incidence of tox- should be contacted immediately. Careful icity increases. medical management is essential. Signs and Symptoms: In acute overdose, se- ADVERSE REACTIONS vere acid-base and electrolyte disturbances Many adverse reactions due to aspirin in- may occur and are complicated by gestion are dose-related. The following is a hyperthermia and dehydration. Respiratory list of adverse reactions that have been re- alkalosis occurs early while ported in the literature. (See WARNINGS.) hyperventilation is present, but is quickly Body as a Whole: Fever, hypothermia, followed by metabolic acidosis. thirst. Treatment: Treatment consists primarily of Cardiovascular: Dysrhythmias, hypo- supporting vital functions, increasing salicy- tension, tachycardia. late elimination, and correcting the acid- Central Nervous System: Agitation, cerebral base disturbance. Gastric emptying and/or edema, coma, confusion, dizziness, headache, lavage is recommended as soon as possible subdural or intracranial hemorrhage, leth- after ingestion, even if the patient has vom- argy, seizures. ited spontaneously. After lavage and/or Fluid and Electrolyte: Dehydration, hyper- emesis, administration of activated char- kalemia, metabolic acidosis, respiratory coal, as a slurry, is beneficial, if less than 3 alkalosis. hours have passed since ingestion. Charcoal Gastrointestinal: Dyspepsia, GI bleeding, ul- adsorption should not be employed prior to ceration and perforation, nausea, vomiting, emesis and lavage. transient elevations of hepatic enzymes, hep- Severity of aspirin intoxication is deter- atitis, Reye’s Syndrome, pancreatitis. mined by measuring the blood salicylate Hematologic: Prolongation of the pro- level. Acid-base status should be closely fol- thrombin time, disseminated intravascular lowed with serial blood gas and serum pH

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measurements. Fluid and electrolyte balance Carotid Endarterectomy: Doses of 80 mg once should also be maintained. daily to 650 mg twice daily, started In severe cases, hyperthermia and presurgery, are recommended. Continue hypovolemia are the major immediate therapy indefinitely. threats to life. Children should be sponged Rheumatoid Arthritis: The initial dose is 3 g with tepid water. Replacement fluid should a day in divided doses. Increase as needed for be administered intravenously and aug- anti-inflammatory efficacy with target plas- mented with correction of acidosis. Plasma ma salicylate levels of 150–300 μg/mL. At high electrolytes and pH should be monitored to doses (i.e., plasma levels of greater than 200 promote alkaline diuresis of salicylate if μg/mL), the incidence of toxicity increases. renal function is normal. Infusion of glucose Juvenile Rheumatoid Arthritis: Initial dose is may be required to control hypoglycemia. 90–130 mg/kg/day in divided doses. Increase as Hemodialysis and peritoneal dialysis can needed for anti-inflammatory efficacy with be performed to reduce the body drug con- target plasma salicylate levels of 150–300 μg/ tent. In patients with renal insufficiency or mL. At high doses (i.e., plasma levels of in cases of life-threatening intoxication, di- greater than 200 μg/mL), the incidence of tox- alysis is usually required. Exchange trans- icity increases. fusion may be indicated in infants and young Spondyloarthropathies: Up to 4 g per day in children. divided doses. DOSAGE AND ADMINISTRATION Osteoarthritis: Up to 3 g per day in divided doses. Each dose of aspirin should be taken with Arthritis and Pleurisy of SLE: The initial a full glass of water unless patient is fluid dose is 3 g a day in divided doses. Increase as restricted. Anti-inflammatory and analgesic needed for anti-inflammatory efficacy with dosages should be individualized. When aspi- target plasma salicylate levels of 150–300 μg/ rin is used in high doses, the development of mL. At high doses (i.e., plasma levels of tinnitus may be used as a clinical sign of ele- greater than 200 mμ/mL), the incidence of vated plasma salicylate levels except in pa- toxicity increases. tients with high frequency hearing loss. Ischemic Stroke and TIA: 50–325 mg once a HOW SUPPLIED day. Continue therapy indefinitely. Suspected Acute MI: The initial dose of 160– (Insert specific information regarding, 162.5 mg is administered as soon as an MI is strength of dosage form, units in which the dos- suspected. The maintenance dose of 160–162.5 age form is generally available, and information mg a day is continued for 30 days post-infarc- to facilitate identification of the dosage form as tion. After 30 days, consider further therapy required under § 201.57(k)(1), (k)(2), and (k)(3).) based on dosage and administration for pre- Store in a tight container at 25 °C (77 °F); ex- vention of recurrent MI. cursions permitted to 15–30 °C (59–86 °F). Prevention of Recurrent MI: 75–325 mg once a day. Continue therapy indefinitely. REV: October 23, 1998. Unstable Angina Pectoris: 75–325 mg once a (2) In addition to, and immediately day. Continue therapy indefinitely. preceding, the labeling required under Chronic Stable Angina Pectoris: 75–325 mg paragraph (a)(1) of this section, the once a day. Continue therapy indefinitely. professional labeling may contain the CABG: 325 mg daily starting 6 hours post- following highlights of prescribing in- procedure. Continue therapy for 1 year post- formation in the exact language and procedure. PTCA: The initial dose of 325 mg should be exact format provided, but only when given 2 hours pre-surgery. Maintenance dose accompanied by the comprehensive is 160–325 mg daily. Continue therapy indefi- prescribing information required in nitely. paragraph (a)(1) of this section.

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(b) [Reserved] [63 FR 56814, Oct. 23, 1998; 63 FR 66015, 66016, Dec. 1, 1998, as amended at 64 FR 49653, Sept. 14, 1999]

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Subpart D—Testing Procedures 344.3 Definitions. § 343.90 Dissolution and drug release Subpart B—Active Ingredients testing. 344.10 Earwax removal aid active ingre- (a) [Reserved] dient. (b) Aspirin capsules. Aspirin capsules 344.12 Ear drying aid active ingredient. must meet the dissolution standard for aspirin capsules as contained in the Subpart C—Labeling United States Pharmacopeia (USP) 23 at page 132. 344.50 Labeling of earwax removal aid drug (c) Aspirin delayed-release capsules and products. aspirin delayed-release tablets. Aspirin 344.52 Labeling of ear drying aid drug prod- delayed-release capsules and aspirin ucts. delayed-release tablets must meet the AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, drug release standard for aspirin de- 360, 371. layed-release capsules and aspirin de- SOURCE: 51 FR 28660, Aug. 8, 1986, unless layed-release tablets as contained in otherwise noted. USP 23 at pages 133 and 136 respectively. (d) Aspirin tablets. Aspirin tablets Subpart A—General Provisions must meet the dissolution standard for § 344.1 Scope. aspirin tablets as contained in USP 23 at page 134. (a) An over-the-counter topical otic (e) Aspirin, alumina, and magnesia tab- drug product in a form suitable for top- lets. Aspirin in combination with alu- ical administration is generally recog- mina and magnesia in a tablet dosage nized as safe and effective and is not form must meet the dissolution stand- misbranded if it meets each of the con- ard for aspirin, alumina, and magnesia ditions in this part in addition to each tablets as contained in USP 23 at page of the general conditions established in 138. § 330.1. (f) Aspirin, alumina, and magnesium (b) References in this part to regu- oxide tablets. Aspirin in combination latory sections of the Code of Federal with alumina, and magnesium oxide in Regulations are to chapter I of title 21 a tablet dosage form must meet the unless otherwise noted. dissolution standard for aspirin, alumina, and magnesium tablets as con- § 344.3 Definitions. tained in USP 23 at page 139. (g) Aspirin effervescent tablets for oral As used in this part: solution. Aspirin effervescent tablets (a) Anhydrous glycerin. An ingredient for oral solution must meet the dis- that may be prepared by heating glyc- solution standard for aspirin effer- erin U.S.P. at 150 °C for 2 hours to drive vescent tablets for oral solution as con- off the moisture content. tained in USP 23 at page 137. (b) Earwax removal aid. A drug used in (h) Buffered aspirin tablets. Buffered the external ear canal that aids in the aspirin tablets must meet the dissolu- removal of excessive earwax. tion standard for buffered aspirin tab- (c) Water-clogged ears. The retention lets as contained in USP 23 at page 135. of water in the external ear canal, thereby causing discomfort and a sen- PART 344—TOPICAL OTIC DRUG sation of fullness or hearing impair- PRODUCTS FOR OVER-THE- ment. COUNTER HUMAN USE (d) Ear drying aid. A drug used in the external ear canal to help dry water- Subpart A—General Provisions clogged ears. Sec. [51 FR 28660, Aug. 8, 1986, as amended at 65 344.1 Scope. FR 48905, Aug. 10, 2000]

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Subpart B—Active Ingredients (3) ‘‘Do not use for more than 4 days; if excessive earwax remains after use of § 344.10 Earwax removal aid active in- this product, consult a doctor.’’ gredient. (4) ‘‘Avoid contact with the eyes.’’ The active ingredient of the product (d) Directions. The labeling of the consists of carbamide peroxide 6.5 per- product contains the following state- cent formulated in an anhydrous glyc- ment under the heading ‘‘Directions’’: erin vehicle. FOR USE IN THE EAR ONLY. Adults and children over 12 years of age: tilt [51 FR 28660, Aug. 8, 1986, as amended at 65 head sideways and place 5 to 10 drops FR 48905, Aug. 10, 2000] into ear. Tip of applicator should not enter ear canal. Keep drops in ear for § 344.12 Ear drying aid active ingredient. several minutes by keeping head tilted or placing cotton in the ear. Use twice The active ingredient of the product daily for up to 4 days if needed, or as consists of isopropyl alcohol 95 percent directed by a doctor. Any wax remain- in an anhydrous glycerin 5 percent ing after treatment may be removed by base. gently flushing the ear with warm [65 FR 48905, Aug. 10, 2000] water, using a soft rubber bulb ear syringe. Children under 12 years of age: Subpart C—Labeling consult a doctor. [51 FR 28660, Aug. 8, 1986; 52 FR 7830, Mar. 13, § 344.50 Labeling of earwax removal 1987; 65 FR 48905, Aug. 10, 2000] aid drug products. (a) Statement of identity. The labeling § 344.52 Labeling of ear drying aid drug products. of the product contains the established name of the drug, if any, and identifies (a) Statement of identity. The labeling the product as an ‘‘earwax removal of the product contains the established aid.’’ name of the drug, if any, and identifies (b) Indication. The labeling of the the product as an ‘‘ear drying aid.’’ product states, under the heading ‘‘In- (b) Indications. The labeling of the dication,’’ the following: ‘‘For occa- product states, under the heading sional use as an aid to’’ (which may be ‘‘Use,’’ the following: ‘‘dries water in followed by: ‘‘soften, loosen, and’’) the ears’’ (optional, which may be fol- ‘‘remove excessive earwax.’’ Other lowed by: ‘‘and relieves water-clogged truthful and nonmisleading state- ears’’) (which may be followed by any ments, describing only the indications or all of the following: ‘‘after: [bullet] 1 for use that have been established and swimming [bullet] showering [bullet] listed in this paragraph (b), may also bathing [bullet] washing the hair’’). be used, as provided in § 330.1(c)(2), sub- Other truthful and nonmisleading ject to the provisions of section 502 of statements, describing only the indica- the act relating to misbranding and the tions for use that have been established prohibition in section 301(d) of the act and listed in paragraph (b) of this sec- against the introduction or delivery for tion, may also be used, as provided in introduction into interstate commerce § 330.1(c)(2) of this chapter, subject to of unapproved new drugs in violation of the provisions of section 502 of the Fed- section 505(a) of the act. eral Food, Drug, and Cosmetic Act (the (c) Warnings. The labeling of the act) relating to misbranding and the product contains the following warn- prohibition in section 301(d) of the act ings under the heading ‘‘Warnings’’: against the introduction or delivery for (1) ‘‘Do not use if you have ear drain- introduction into interstate commerce age or discharge, ear pain, irritation, of unapproved new drugs in violation of or rash in the ear or are dizzy; consult section 505(a) of the act. a doctor.’’ (c) Warnings. The labeling of the (2) ‘‘Do not use if you have an injury product contains the following warn- or perforation (hole) of the ear drum or ings under the heading ‘‘Warnings’’: after ear surgery unless directed by a doctor.’’ 1 See § 201.66(b)(4) of this chapter.

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(1) ‘‘Flammable [in bold type]: Keep this part and each general condition es- away from fire or flame.’’ tablished in § 330.1 of this chapter. (2) ‘‘Do not use [in bold type] in the (b) References in this part to regu- eyes.’’ latory sections of the Code of Federal (3) ‘‘Ask a doctor before use if you Regulations are to chapter I of title 212 have [in bold type] [bullet] ear drain- unless otherwise noted. age or discharge [bullet] pain, irritation, or rash in the ear [bullet] had ear § 346.3 Definitions. surgery [bullet] dizziness.’’ As used in this part: (4) ‘‘Stop use and ask a doctor if [in (a) Analgesic, anesthetic drug. A topi- bold type] irritation (too much burn- cally (externally) applied drug that re- ing) or pain occurs.’’ lieves pain by depressing cutaneous (d) Directions. The labeling of the sensory receptors. product contains the following state- (b) Anorectal drug. A drug that is used ment under the heading ‘‘Directions’’: to relieve symptoms caused by [optional, bullet] ‘‘apply 4 to 5 drops in anorectal disorders in the anal canal, each affected ear.’’ perianal area, and/or the lower rectal [65 FR 48905, Aug. 10, 2000] areas. (c) Antipruritic drug. A topically (ex- PART 346—ANORECTAL DRUG ternally) applied drug that relieves itching by depressing cutaneous sen- PRODUCTS FOR OVER-THE- sory receptors. COUNTER HUMAN USE (d) Astringent drug. A drug that is applied topically (externally) to the skin Subpart A—General Provisions or mucous membranes for a local and Sec. limited protein coagulant effect. 346.1 Scope. (e) External use. Topical application 346.3 Definitions. of an anorectal drug product to the skin of the perianal area and/or the Subpart B—Active Ingredients skin of the anal canal. 346.10 Local anesthetic active ingredients. (f) Intrarectal use. Topical application 346.12 Vasoconstrictor active ingredients. of an anorectal drug product to the 346.14 Protectant active ingredients. mucous membrane of the rectum. 346.16 Analgesic, anesthetic, and anti- (g) Keratolytic drug. A drug that pruritic active ingredients. causes desquamation (loosening) and 346.18 Astringent active ingredients. debridement or sloughing of the sur- 346.20 Keratolytic active ingredients. face cells of the epidermis. 346.22 Permitted combinations of anorectal (h) Local anesthetic drug. A drug that active ingredients. produces local disappearance of pain, Subpart C—Labeling burning, itching, irritation, and/or discomfort by reversibly blocking nerve 346.50 Labeling of anorectal drug products. conduction when applied to nerve tis- 346.52 Labeling of permitted combinations sue in appropriate concentrations. of anorectal active ingredients. (i) Protectant drug. A drug that pro- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, vides a physical barrier, forming a pro- 360, 371. tective coating over skin or mucous SOURCE: 55 FR 31779, Aug. 3, 1990, unless membranes. otherwise noted. (j) Vasoconstrictor. A drug that causes temporary constriction of blood ves- Subpart A—General Provisions sels. § 346.1 Scope. Subpart B—Active Ingredients (a) An over-the-counter anorectal drug product in a form suitable for ex- § 346.10 Local anesthetic active ingre- ternal (topical) or intrarectal (rectal) dients. administration is generally recognized The active ingredient of the product as safe and effective and is not mis- consists of any of the following when branded if it meets each condition in used in the concentration or within the

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concentration range established for (10) White petrolatum. each ingredient: (b) The following active ingredients (a) Benzocaine 5 to 20 percent. may not be used as a sole protectant (b) Benzyl alcohol 1 to 4 percent. ingredient but may be used in combina- (c) Dibucaine 0.25 to 1 percent. tion with one, two, or three other pro- (d) Dibucaine hydrochloride 0.25 to 1 tectant active ingredients in accord- percent. ance with § 346.22 (a), (b), (n), and (o) (e) Dyclonine hydrochloride 0.5 to 1 and with the following limitations: percent. (1) Calamine not to exceed 25 percent (f) Lidocaine 2 to 5 percent. by weight per dosage unit (based on the (g) Pramoxine hydrochloride 1 per- zinc oxide content of calamine). cent. (2) Cod liver oil, provided that the (h) Tetracaine 0.5 to 1 percent. product is labeled so that the amount (i) Tetracaine hydrochloride 0.5 to 1 of the product that is used in a 24-hour percent. period represents a quantity that provides 10,000 U.S.P. units of vitamin A § 346.12 Vasoconstrictor active ingre- and 400 U.S.P. units of cholecalciferol. dients. (3) Shark liver oil, provided that the The active ingredient of the product product is labeled so that the amount consists of any of the following when of the product that is used in a 24-hour used in the concentration or within the period represents a quantity that pro- concentration range established for vides 10,000 U.S.P. units of vitamin A each ingredient. and 400 U.S.P. units of cholecalciferol. (a) Ephedrine sulfate 0.1 to 1.25 per- (4) Zinc oxide not to exceed 25 percent. cent by weight per dosage unit. (b) Epinephrine 0.005 to 0.01 percent. (c) Epinephrine hydrochloride 0.005 to § 346.16 Analgesic, anesthetic, and 0.01 percent. antipruritic active ingredients. (d) Phenylephrine hydrochloride 0.25 The active ingredient of the product percent. consists of any of the following when used within the concentration range § 346.14 Protectant active ingredients. established for each ingredient: (a) The following active ingredients (a) Camphor 0.1 to 3 percent. may be used as the sole protectant ac- (b) Juniper tar 1 to 5 percent. tive ingredient in a product if the in- (c) Menthol 0.1 to 1 percent. gredient as identified constitutes 50 § 346.18 Astringent active ingredients. percent or more by weight of the final product. In addition, the following ac- The active ingredient of the product tive ingredients may be used in con- consists of any of the following when centrations of less than 50 percent by used within the concentration range weight only when used in combinations established for each ingredient: in accordance with § 346.22 (a), (b), or (a) Calamine, within a concentration (n). range of 5 to 25 percent by weight per (1) Aluminum hydroxide gel. dosage unit (based on the zinc oxide (2) Cocoa butter. content of calamine). (3) Glycerin in a 20- to 45-percent (b) Witch hazel, 10 to 50 percent. (weight/weight) aqueous solution so (c) Zinc oxide, within a concentration that the final product contains not less range of 5 to 25 percent by weight per than 10 and not more than 45 percent dosage unit. glycerin (weight/weight). Any combina- [55 FR 31779, Aug. 3, 1990, as amended at 59 tion product containing glycerin must FR 28767, June 3, 1994] contain at least this minimum amount of glycerin. § 346.20 Keratolytic active ingredients. (4) Hard fat. The active ingredient of the product (5) Kaolin. consists of any of the following when (6) Lanolin. used within the concentration range (7) Mineral oil. established for each ingredient: (8) Petrolatum. (a) Alcloxa 0.2 to 2 percent. (9) Topical starch. (b) Resorcinol 1 to 3 percent.

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§ 346.22 Permitted combinations of § 346.12 and with any single astringent anorectal active ingredients. identified in § 346.18. (a) Any two, three, or four (k) Any single local anesthetic iden- protectants identified in § 346.14(a) may tified in § 346.10 may be combined with be combined, except aluminum hydrox- any single astringent identified in ide gel in § 346.14(a)(1) and kaolin in § 346.18 and with any single keratolytic § 346.14(a)(5) may not be combined with identified in § 346.20. any ingredient in § 346.14(a) (2), (4), (6), (l) Any single vasoconstrictor identi- (7), (8) and (10), and (b) (2) and (3), pro- fied in § 346.12 may be combined with vided that the combined percentage by any single analgesic, anesthetic, and weight of all protectants in the com- antipruritic identified in § 346.16 and bination is at least 50 percent of the with any single astringent identified in final product (e.g., 1 gram of a 2-gram § 346.18. dosage unit). Any protectant ingre- (m) Any single analgesic, anesthetic, dient included in the combination must and antipruritic identified in § 346.16 be present at a level that contributes may be combined with any single as- at least 12.5 percent by weight (e.g., tringent identified in § 346.18 and with 0.25 gram of a 2-gram dosage unit), ex- any single keratolytic identified in cept cod liver oil and shark liver oil. If § 346.20. an ingredient in § 346.14(b) is included (n) Any combination of ingredients in the combination, it must not exceed listed in paragraphs (c) through (m) of the concentration limit specified in this section may be combined with up § 346.14(b). to four protectants in accordance with (b) Any single anorectal ingredient paragraph (a) of this section. identified in § 346.10, 346.12, 346.16, (o) Any product containing calamine 346.18, or 346.20 may be combined with for use as a protectant and/or as an as- up to four protectants in accordance tringent and/or containing zinc oxide with paragraph (a) of this section. for use as a protectant and/or as an as- (c) Any single local anesthetic identi- tringent may not have a total weight fied in § 346.10 may be combined with of zinc oxide exceeding 25 percent by any single vasoconstrictor identified in weight per dosage unit. § 346.12. (d) Any single local anesthetic iden- Subpart C—Labeling tified in § 346.10 may be combined with any single astringent identified in § 346.50 Labeling of anorectal drug § 346.18. products. (e) Any single local anesthetic identi- The labeling of the product contains fied in § 346.10 may be combined with the following information for anorectal any single keratolytic identified in ingredients identified in §§ 346.10, 346.12, § 346.20. 346.14, 346.16, 346.18, and 346.20, and for (f) Any single vasoconstrictor identi- combinations of anorectal ingredients fied in § 346.12 may be combined with identified in § 346.22. Unless otherwise any single astringent identified in specified, the labeling in this subpart is § 346.18. applicable to anorectal drug products (g) Any single analgesic, anesthetic, for both external and intrarectal use. and antipruritic identified in § 346.16 (a) Statement of identity. The labeling may be combined with any single as- of the product contains the established tringent identified in § 346.18. name of the drug, if any, and identifies (h) Any single analgesic, anesthetic, the product as ‘‘anorectal (hemor- and antipruritic identified in § 346.16 rhoidal),’’ ‘‘hemorrhoidal,’’ ‘‘hemor- may be combined with any single rhoidal (anorectal) (insert dosage form, keratolytic identified in § 346.20. e.g., cream, lotion, or ointment).’’ (i) Any single astringent identified in (b) Indications. The labeling of the § 346.18 may be combined with any sin- product states, under the heading ‘‘In- gle keratolytic identified in § 346.20. dications,’’ any of the phrases listed in (j) Any single local anesthetic identi- paragraph (b) of this section, as appro- fied in § 346.10 may be combined with priate. Other truthful and nonmis- any single vasoconstrictor identified in leading statements, describing only the

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indications for use that have been es- and/or intrarectal use containing any pro- tablished and listed in this paragraph, tectant identified in § 346.14(a) (2), (4), (6) may also be used, as provided in through (10), and (b) (1) through (4). § 330.1(c)(2) of this chapter, subject to (A) ‘‘Temporarily forms a protective the provisions of section 502 of the Fed- coating over inflamed tissues to help eral Food, Drug, and Cosmetic Act (the prevent drying of tissues.’’ act) relating to misbranding and the (B) ‘‘Temporarily protects irritated prohibition in section 301(d) of the act areas.’’ against the introduction or delivery for (C) ‘‘Temporarily relieves burning.’’ introduction into interstate commerce (D) ‘‘Provides temporary relief from of unapproved new drugs in violation of skin irritations.’’ section 505(a) of the act. (E) ‘‘Temporarily provides a coating (1) (‘‘For the temporary relief of,’’ for relief of anorectal discomforts.’’ ‘‘Gives temporary relief of,’’ or ‘‘Helps (F) ‘‘Temporarily protects the in- relieve the’’) (As an option, select one flamed, irritated anorectal surface’’ or both of the following: ‘‘local’’ or (select one of the following: ‘‘to help ‘‘anorectal’’) [select one or more of the make bowel movements less painful’’ following: ‘‘discomfort,’’ ‘‘itching,’’ or or ‘‘from irritation and abrasion during ‘‘itching and discomfort,’’ followed by: bowel movement’’). ‘‘in the perianal area’’ or ‘‘associated (G) ‘‘Temporarily protects inflamed with’’ (select one or more of the fol- perianal skin.’’ lowing: ‘‘hemorrhoids,’’ ‘‘anorectal dis- (H) ‘‘Temporarily relieves the symp- orders,’’ ‘‘inflamed hemorrhoidal tis- toms of perianal skin irritation.’’ sues,’’ ‘‘anorectal inflammation,’’ (iv) For products containing aluminum ‘‘hemorrhoidal tissues,’’ or ‘‘piles hydroxide gel identified in § 346.14(a)(1) (hemorrhoids).’’)] and for products containing kaolin identi- (2) Additional indications. Indications fied in § 346.14(a)(5). ‘‘For the temporary applicable to each active ingredient of relief of itching associated with moist the product may be combined to elimi- anorectal conditions.’’ nate duplicative words or phrases so (v) For products for external use only that the resulting indication is clear containing any analgesic, anesthetic, and and understandable. In addition to the antipruritic identified in § 346.16. (A) indication identified in paragraph (b)(1) ‘‘For the temporary relief of’’ (select of this section, the labeling of the prod- one or both of the following: ‘‘pain’’ or uct intended for external or intrarectal ‘‘burning’’). use may also contain the following in- (B) ‘‘Can help distract from pain.’’ dications, as appropriate. (C) ‘‘May provide a cooling sensa- (i) For products for external use only tion.’’ containing any ingredient identified in (vi) For products for external use only § 346.10. ‘‘For the temporary relief of’’ containing witch hazel identified in (select one or more of the following: § 346.18(b), and for products for external ‘‘pain,’’ ‘‘soreness,’’ or ‘‘burning’’). use and/or intrarectal use containing cal- (ii) For products containing epineph- amine or zinc oxide identified in § 346.18 rine or epinephrine hydrochloride identi- (a) and (c). fied in § 346.12 (b) and (c) for external use (A) ‘‘Aids in protecting irritated only, and for products containing ephed- anorectal areas.’’ rine sulfate or phenylephrine hydro- (B) ‘‘Temporary relief of’’ (select one chloride identified in § 346.12 (a) and (d). or both of the following: ‘‘irritation’’ (A) ‘‘Temporarily reduces the swell- or ‘‘burning’’). ing associated with’’ (select one of the (vii) For products for external use only following: ‘‘irritated hemorrhoidal tis- containing any ingredient identified in sue and other anorectal disorders’’ or § 346.20. The indication in paragraph ‘‘irritation in hemorrhoids and other (b)(1) of this section applies. anorectal disorders’’). (c) Warnings. Warnings applicable to (B) ‘‘Temporarily shrinks hemor- each active ingredient of the product rhoidal tissue.’’ may be combined to eliminate duplica- (iii) For products for external use only tive words or phrases so that the re- containing glycerin identified in sulting warning is clear and under- § 346.14(a)(3) and for products for external standable. The labeling of the product

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contains the following warnings under with the ability of this product to ad- the heading ‘‘Warnings’’: here properly to the skin area.’’ (1) ‘‘If condition worsens or does not (9) For products for external use only improve within 7 days, consult a doc- containing resorcinol identified in tor.’’ § 346.20(b). ‘‘Do not use on open wounds (2) ‘‘Do not exceed the recommended near the anus.’’ daily dosage unless directed by a doc- (d) Directions. Directions applicable tor.’’ to each active ingredient of the prod- (3) ‘‘In case of bleeding, consult a uct may be combined to eliminate du- doctor promptly.’’ plicative words or phrases so that the (4) For products for external use only. resulting information is clear and un- ‘‘Do not put this product into the rec- derstandable. The labeling of the prod- tum by using fingers or any mechan- uct contains the following information ical device or applicator.’’ under the heading ‘‘Directions’’: (5) For products for intrarectal use to be (1) ‘‘Adults: When practical, cleanse used with a special applicator such as a the affected area’’ (select one or both pile pipe or other mechanical device. ‘‘Do of the following: ‘‘with mild soap and not use this product with an applicator warm water and rinse thoroughly’’ or if the introduction of the applicator ‘‘by patting or blotting with an appro- into the rectum causes additional pain. priate cleansing pad’’). ‘‘Gently dry by Consult a doctor promptly.’’ patting or blotting with toilet tissue or (6) For products for external use only a soft cloth before application of this containing any local anesthetic identified product.’’ [Other appropriate directions in § 346.10, menthol identified in in this section may be inserted here.] § 346.16(c), or resorcinol identified in ‘‘Children under 12 years of age: con- § 346.20(b). ‘‘Certain persons can develop sult a doctor.’’ allergic reactions to ingredients in this (2) For products for external use only. product. If the symptom being treated ‘‘Apply externally to the affected area’’ does not subside or if redness, irrita- (insert appropriate time interval of ad- tion, swelling, pain, or other symptoms ministration as identified in para- develop or increase, discontinue use graphs (d)(6), (7), (8), or (9) of this sec- and consult a doctor.’’ tion). (3) For products for external use that (7) For products containing any vaso- are pads containing anorectal ingredients. constrictor identified in § 346.12. (i) ‘‘Do ‘‘Gently apply to the affected area by not use this product if you have heart patting and then discard.’’ disease, high blood pressure, thyroid (4) For products for intrarectal use that disease, diabetes, or difficulty in urina- are wrapped suppositories. ‘‘Remove tion due to enlargement of the prostate wrapper before inserting into the rec- gland unless directed by a doctor.’’ tum.’’ (ii) ‘‘Ask a doctor or pharmacist be- (5) For products for intrarectal use that fore use if you are [bullet] 1 presently are to be used with a special applicator taking a prescription drug for high such as a pile pipe or other mechanical blood pressure or depression.’’ device. ‘‘FOR INTRARECTAL USE: At- (iii) For products containing ephedrine tach applicator to tube. Lubricate ap- sulfate identified in § 346.12(a). ‘‘Some plicator well, then gently insert appli- users of this product may experience cator into the rectum.’’ nervousness, tremor, sleeplessness, (6) For products for external use only nausea, and loss of appetite. If these containing any of the local anesthetics symptoms persist or become worse, identified in § 346.10; analgesics, anes- consult your doctor.’’ thetics, and antipruritics identified in (8) For products containing aluminum § 346.16; or alcloxa or resorcinol identified hydroxide gel identified in § 346.14(a)(1) in § 346.20. Apply to the affected area up and for products containing kaolin identi- to 6 times daily. fied in § 346.14(a)(5). ‘‘Remove petro- (i) For products for external use only latum or greasy ointment before using containing dibucaine or dibucaine hydro- this product because they interfere chloride identified in § 346.10 (c) and (d). Apply to the affected area up to 3 or 4 1 See § 201.66(b)(4) of this chapter. times daily.

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(ii) For products for external use only gredient in the combination, as estab- containing pramoxine hydrochloride iden- lished in the warnings sections of this tified in § 346.10(g). Apply to the affected subpart. area up to 5 times daily. (d) Directions. The labeling of the (7) For products containing vaso- product states, under the heading ‘‘Di- constrictors identified in § 346.12. Apply rections,’’ directions that conform to to the affected area up to 4 times daily. the directions established for each in- (8) For products for external use only gredient in the directions sections of containing glycerin identified in this subpart. When the time intervals § 346.14(a)(3) or witch hazel identified in or age limitations for administration § 346.18(b), and for products for external of the individual ingredients differ, the and/or intrarectal use containing any pro- directions for the combination product tectant identified in § 346.14(a)(1), (2), (4), may not exceed any maximum dosage (5), (6), (7), and (9), and (b)(1), (2), (3), limits established for the individual in- and (4), or any astringent identified in gredients in the applicable OTC drug § 346.18(a) and (c). Apply to the affected monograph. area up to 6 times daily or after each bowel movement. PART 347—SKIN PROTECTANT (9) For products containing petrolatum DRUG PRODUCTS FOR OVER-THE- or white petrolatum identified in § 346.14(a)(8) and (10). Apply liberally to COUNTER HUMAN USE the affected area as often as necessary. (e) The word ‘‘physician’’ may be sub- Subpart A—General Provisions stituted for the word ‘‘doctor’’ in any Sec. of the labeling statements in this sec- 347.1 Scope. tion. 347.3 Definitions.

[55 FR 31779, Aug. 3, 1990, as amended at 59 Subpart B—Active Ingredients FR 28767, June 3, 1994; 64 FR 13295, Mar. 17, 1999] 347.10 Skin protectant active ingredients. 347.12 Astringent active ingredients. § 346.52 Labeling of permitted com- 347.20 Permitted combinations of active in- binations of anorectal active ingre- gredients. dients. Indications, warnings, and directions Subpart C—Labeling for use, respectively, applicable to each 347.50 Labeling of skin protectant drug ingredient in the product may be com- products. bined to eliminate duplicative words or 347.52 Labeling of astringent drug products. phrases so that the resulting informa- 347.60 Labeling of permitted combinations tion is clear and understandable. of active ingredients. (a) Statement of identity. For a com- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, bination drug product that has an es- 360, 371. tablished name, the labeling of the product states the established name of SOURCE: 58 FR 54462, Oct. 21, 1993, unless the combination drug product, followed otherwise noted. by the statement of identity established in § 346.50(a). For a combination Subpart A—General Provisions drug product that does not have an established name, the labeling of the § 347.1 Scope. product states the statement of iden- (a) An over-the-counter skin protect- tity established in § 346.50(a). ant drug product in a form suitable for (b) Indications. The labeling of the topical administration is generally rec- product states, under the heading ‘‘In- ognized as safe and effective and is not dications,’’ the indication(s) for each misbranded if it meets each condition ingredient in the combination, as es- in this part and each general condition tablished in the indications sections of established in § 330.1 of this chapter. this subpart. (b) References in this part to regu- (c) Warnings. The labeling of the latory sections of the Code of Federal product states, under the heading Regulations are to chapter I of title 21 ‘‘Warnings,’’ the warning(s) for each in- unless otherwise noted.

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§ 347.3 Definitions. (l) Mineral oil, 50 to 100 percent; 30 to 35 percent in combination with col- As used in this part: loidal oatmeal in accordance with Astringent drug product. A drug prod- § 347.20(a)(4). uct applied to the skin or mucous (m) Petrolatum, 30 to 100 percent. membranes for a local and limited pro- (n) [Reserved] tein coagulant effect. (o) Sodium bicarbonate. Lip protectant drug product. A drug (p) [Reserved] product that temporarily prevents dry- (q) Topical starch, 10 to 98 percent. ness and helps relieve chapping of the (r) White petrolatum, 30 to 100 per- exposed surfaces of the lips; tradition- cent. ally called ‘‘lip balm.’’ (s) Zinc acetate, 0.1 to 2 percent. Poison ivy, oak, sumac dermatitis. An (t) Zinc carbonate, 0.2 to 2 percent. allergic contact dermatitis due to ex- (u) Zinc oxide, 1 to 25 percent. posure to plants of the genus Rhus (poison ivy, poison oak, poison sumac), § 347.12 Astringent active ingredients. which contain urushiol, a potent skin- The active ingredient of the product sensitizer. consists of any one of the following Skin protectant drug product. A drug within the specified concentration es- product that temporarily protects in- tablished for each ingredient: jured or exposed skin or mucous mem- (a) Aluminum acetate, 0.13 to 0.5 per- brane surfaces from harmful or annoy- cent (depending on the formulation and ing stimuli, and may help provide re- concentration of the marketed product, lief to such surfaces. the manufacturer must provide ade- [68 FR 33376, June 4, 2003] quate directions so that the resulting solution to be used by the consumer Subpart B—Active Ingredients contains 0.13 to 0.5 percent aluminum acetate). (b) Aluminum sulfate, 46 to 63 per- SOURCE: 68 FR 33377, June 4, 2003, unless cent (the concentration is based on the otherwise noted. anhydrous equivalent). § 347.10 Skin protectant active ingredi- (c) Witch hazel. ents. § 347.20 Permitted combinations of ac- The active ingredients of the product tive ingredients. consist of any of the following, within (a) Combinations of skin protectant ac- the concentration specified for each in- tive ingredients. (1) Any two or more of gredient: the ingredients identified in § 347.10(a), (a) Allantoin, 0.5 to 2 percent. (d), (e), (i), (k), (l), (m), and (r) may be (b) Aluminum hydroxide gel, 0.15 to 5 combined provided the combination is percent. labeled according to § 347.50(b)(1) and (c) Calamine, 1 to 25 percent. provided each ingredient in the com- (d) Cocoa butter, 50 to 100 percent. bination is within the concentration (e) Cod liver oil, 5 to 13.56 percent, in specified in § 347.10. accordance with § 347.20(a)(1) or (a)(2), (2) Any two or more of the ingredi- provided the product is labeled so that ents identified in § 347.10(a), (d), (e), (g), the quantity used in a 24-hour period (h), (i), (k), (l), (m), and (r) may be does not exceed 10,000 U.S.P. Units vi- combined provided the combination is tamin A and 400 U.S.P. Units cholecal- labeled according to § 347.50(b)(2) and ciferol. provided each ingredient in the com- (f) Colloidal oatmeal, 0.007 percent bination is within the concentration minimum; 0.003 percent minimum in specified in § 347.10. combination with mineral oil in ac- (3) Any two or more of the ingredi- cordance with § 347.20(a)(4). ents identified in § 347.10(b), (c), (j), (s), (g) Dimethicone, 1 to 30 percent. (t), and (u) may be combined provided (h) Glycerin, 20 to 45 percent. the combination is labeled according to (i) Hard fat, 50 to 100 percent. § 347.50(b)(3) and provided each ingre- (j) Kaolin, 4 to 20 percent. dient in the combination is within the (k) Lanolin, 12.5 to 50 percent. concentration specified in § 347.10.

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(4) The ingredients identified in §§ 347.60(b)(3) and 352.60(b) of this chap- § 347.10(f) and (l) may be combined pro- ter. vided the combination is labeled ac- [68 FR 33377, June 4, 2003, as amended at 74 cording to § 347.50(b)(7) and provided FR 9765, Mar. 6, 2009] each ingredient in the combination is EFFECTIVE DATE NOTE: At 68 FR 33377, June within the concentration specified in 4, 2003, in § 347.20 paragraph (d) was stayed § 347.10. until further notice, effective June 4, 2004. At (b) Combination of ingredients to pre- 74 FR 9765, Mar. 6, 2009, in § 347.20, paragraph pare an aluminum acetate solution. Alu- (d) was redesignated as paragraph (e). minum sulfate tetradecahydrate may be combined with calcium acetate Subpart C—Labeling monohydrate in powder or tablet form to provide a 0.13 to 0.5 percent alu- SOURCE: 68 FR 33377, June 4, 2003, unless minum acetate solution when the pow- otherwise noted. der or tablet is dissolved in the volume § 347.50 Labeling of skin protectant of water specified in ‘‘Directions.’’ drug products. (c) Combinations of skin protectant and A skin protectant drug product may external analgesic active ingredients. Any have more than one labeled use and la- one (two when required to be in com- beling appropriate to different uses bination) or more of the active ingredi- may be combined to eliminate duplica- ents identified in § 347.10(a), (d), (e), (i), tive words or phrases as long as the la- (k), (l), (m), and (r) may be combined beling is clear and understandable. with any of the following generally rec- When the labeling of the product con- ognized as safe and effective external tains more than one labeled use, the analgesic active ingredients: Single appropriate statement(s) of identity, amine and ‘‘caine’’-type local anes- indications, warnings, and directions thetics, alcohols and ketones, antihis- must be stated in the labeling. tamines, or any permitted combination (a) Statement of identity. The labeling of these ingredients, but not with hy- of the product contains the established drocortisone, provided the product is name of the drug, if any, and identifies labeled according to § 347.60(b)(l). the product with one or more of the (d) Combinations of skin protectant and following: first aid antiseptic active ingredients. Any (1) For any product. ‘‘Skin protectant’’ (optional, may add dosage form, one (two when required to be in com- e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or bination) or more of the active ingredi- ‘‘ointment’’). ents identified in § 347.10(a), (d), (e), (i), (2) For any product formulated as a lip (k), (l), (m), and (r) may be combined protectant. ‘‘Skin protectant,’’ ‘‘lip pro- with any generally recognized as safe tectant,’’ or ‘‘lip balm’’ (optional, may and effective single first aid antiseptic add dosage form, e.g., ‘‘cream,’’ ‘‘gel,’’ active ingredient, or any permitted ‘‘lotion,’’ or ‘‘ointment’’). combination of these ingredients, pro- (3) For products containing any ingre- vided the product is labeled according dient in § 347.10(b), (c), (j), (s), (t), and to § 347.60(b)(2). (u). ‘‘Poison ivy, oak, sumac drying’’ (e) Combinations of skin protectant and (optional, may add dosage form, e.g., sunscreen active ingredients. Any one ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or ‘‘oint- (two when required to be in combina- ment’’). tion) or more of the skin protectant ac- (4) For products containing any ingre- tive ingredients identified in § 347.10(a), dient in § 347.10(b), (c), (f), (j), (o), (s), (t), (d), (e), (g), (h), (i), (k), (l), (m), and (r) and (u). ‘‘Poison ivy, oak, sumac pro- may be combined with any generally tectant.’’ recognized as safe and effective single (b) Indications. The labeling of the sunscreen active ingredient, or any product states, under the heading ‘‘Uses,’’ one or more of the phrases list- permitted combination of these ingre- ed in this paragraph (b), as appropriate. dients, provided the product meets the Other truthful and nonmisleading conditions in § 352.20(b) of this chapter statements, describing only the uses and is labeled according to that have been established and listed in

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this paragraph (b), may also be used, as (5) For products containing sodium bi- provided in § 330.1(c)(2) of this chapter, carbonate identified in § 347.10(o). The la- subject to the provisions of section 502 beling states ‘‘temporarily protects of the Federal Food, Drug, and Cos- and helps relieve minor skin irritation metic Act (the act) relating to mis- and itching due to: [bullet] poison ivy, branding and the prohibition in section oak, or sumac [bullet] insect bites’’. 301(d) of the act against the introduc- (6) For products containing topical tion or delivery for introduction into starch identified in § 347.10(q). The label- interstate commerce of unapproved ing states ‘‘temporarily protects and new drugs in violation of section 505(a) helps relieve minor skin irritation’’. of the act. (7) For products containing the com- (1) For products containing any ingre- bination of ingredients in § 347.20(a)(4). dient in § 347.10(a), (d), (e), (i), (k), (l), The labeling states ‘‘temporarily pro- (m), and (r). The labeling states ‘‘tem- tects and helps relieve minor skin irri- porarily protects minor: [bullet] 1 cuts tation and itching due to: [select one [bullet] scrapes [bullet] burns’’. or more of the following: ‘rashes’ or (2) For products containing any ingre- ‘eczema’].’’ [If both conditions are dient in § 347.10(a), (d), (e), (g), (h), (i), used, each is preceded by a bullet.] (k), (l), (m), and (r)—(i) The labeling (c) Warnings. The labeling of the states (optional: ‘‘helps prevent and’’) product contains the following warn- ‘‘temporarily protects’’ (optional: ‘‘and ings under the heading ‘‘Warnings’’: helps relieve’’) (optional: ‘‘chafed,’’) (1) ‘‘For external use only’’ in accord ‘‘chapped or cracked skin’’ (optional: with § 201.66(c)(5)(i) of this chapter. For ‘‘and lips’’). This statement may be fol- products containing only mineral oil in lowed by the optional statement: § 347.10(l) or sodium bicarbonate in ‘‘helps’’ (optional: ‘‘prevent and’’) § 347.10(o), this warning may be omitted ‘‘protect from the drying effects of if labeling for oral use of the product is also provided. wind and cold weather’’. [If both state- (2) ‘‘When using this product [bullet] ments are used, each is preceded by a do not get into eyes’’. bullet.] (3) ‘‘Stop use and ask a doctor if [bul- (ii) For products formulated as a lip let] condition worsens [bullet] symp- protectant. The labeling states (op- toms last more than 7 days or clear up tional: ‘‘helps prevent and’’) ‘‘tempo- and occur again within a few days’’. rarily protects’’ (optional: ‘‘and helps (4) For products labeled according to relieve’’) (optional: ‘‘chafed,’’) § 347.50(b)(1) or (b)(2): ‘‘Do not use on ‘‘chapped or cracked lips’’. This state- [bullet] deep or puncture wounds [bul- ment may be followed by the optional let] animal bites [bullet] serious statement: ‘‘helps’’ (optional: ‘‘prevent burns’’. and’’) ‘‘protect from the drying effects (5) For products containing colloidal of wind and cold weather’’. [If both oatmeal identified in § 347.10(f) when la- statements are used, each is preceded beled for use as a soak in a tub. ‘‘When by a bullet.] using this product [bullet] to avoid (3) For products containing any ingre- slipping, use mat in tub or shower’’. dient in § 347.10(b), (c), (j), (s), (t), and (6) For powder products containing (u). The labeling states ‘‘dries the ooz- kaolin identified in § 347.10(j) or topical ing and weeping of poison: [bullet] ivy starch identified in § 347.10(q)—(i) ‘‘Do [bullet] oak [bullet] sumac’’. not use on [bullet] broken skin’’. (4) For products containing colloidal (ii) ‘‘When using this product [bullet] oatmeal identified in § 347.10(f). The la- keep away from face and mouth to beling states ‘‘temporarily protects avoid breathing it’’. and helps relieve minor skin irritation (7) For products containing colloidal and itching due to: [select one or more oatmeal identified in § 347.10(f) or so- of the following: ‘[bullet] rashes’ ‘[bul- dium bicarbonate identified in let] eczema’ ‘[bullet] poison ivy, oak, § 347.10(o) when labeled for use as a or sumac’ ‘[bullet] insect bites’].’’ soak, compress, or wet dressing. ‘‘When using this product [bullet] in some skin 1 See § 201.66(b)(4) of this chapter for defini- conditions, soaking too long may tion of bullet symbol. overdry’’.

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(d) Directions. The labeling of the (ii) The labeling states ‘‘For use as a product contains the following state- soak in a bath: [bullet] dissolve 1 to 2 ments, as appropriate, under the head- cupfuls in a tub of warm water [bullet] ing ‘‘Directions’’: soak for 10 to 30 minutes as needed, or (1) For products labeled according to as directed by a doctor [bullet] pat dry § 347.50(b)(1), (b)(2), (b)(3), (b)(5), or (do not rub) to keep a thin layer on the (b)(6). The labeling states ‘‘apply as skin’’. needed’’. (iii) The labeling states ‘‘For use as a (2) For products containing colloidal compress or wet dressing: [bullet] add oatmeal identified in § 347.10(f)—(i) For sodium bicarbonate to water to make a products requiring dispersal in water. The mixture in a container [bullet] soak a labeling states ‘‘[bullet] turn warm clean, soft cloth in the mixture [bullet] water faucet on to full force [bullet] apply cloth loosely to affected area for slowly sprinkle’’ (manufacturer to in- 15 to 30 minutes [bullet] repeat as need- sert quantity to be used) ‘‘of colloidal ed or as directed by a doctor [bullet] oatmeal directly under the faucet into discard mixture after each use’’. the tub or container [bullet] stir any (iv) Any of the directions in para- colloidal oatmeal settled on the bot- graphs (d)(3)(i), (d)(3)(ii), or (d)(3)(iii) of tom’’. this section shall be followed by the statement: ‘‘[bullet] children under 2 (A) For products used as a soak in a years: ask a doctor’’. bath. The manufacturer must provide (4) For products containing aluminum adequate directions to obtain a solu- hydroxide gel identified in § 347.10(b). The tion containing a minimum of 0.007 labeling states ‘‘[bullet] children under percent colloidal oatmeal or 0.003 per- 6 months: ask a doctor’’. cent colloidal oatmeal in the oilated (5) For products containing glycerin form for a tub bath, sitz bath, or infant identified in § 347.10(h). The labeling bath, or a minimum of 0.25 percent col- states ‘‘[bullet] children under 6 loidal oatmeal for a foot bath. ‘‘For use months: ask a doctor’’. as a soak in a bath: [bullet] soak af- (6) For products containing zinc acetate fected area for 15 to 30 minutes as need- identified in § 347.10(s). The labeling ed, or as directed by a doctor [bullet] states ‘‘[bullet] children under 2 years: pat dry (do not rub) to keep a thin ask a doctor’’. layer on the skin’’. (e) Products formulated and labeled as (B) For products used as a compress or a lip protectant and that meet the criteria wet dressing. The manufacturer must established in § 201.66(d)(10) of this chap- provide adequate directions to obtain a ter. The title, headings, subheadings, solution containing a minimum of 0.25 and information described in § 201.66(c) percent colloidal oatmeal. ‘‘For use as of this chapter shall be printed in ac- a compress or wet dressing: [bullet] cordance with the following specifica- soak a clean, soft cloth in the mixture tions: [bullet] apply cloth loosely to affected (1) The labeling shall meet the re- area for 15 to 30 minutes [bullet] repeat quirements of § 201.66(c) of this chapter as needed or as directed by a doctor except that the title, headings, and in- [bullet] discard mixture after each formation described in § 201.66(c)(1), use’’. (c)(3), (c)(6), and (c)(7) may be omitted, (ii) For topical products intended for di- and the headings, subheadings, and in- rect application. The labeling states formation described in § 201.66(c)(2), ‘‘apply as needed’’. (c)(4), and (c)(5) may be presented as (3) For products containing sodium bi- follows: carbonate identified in § 347.10(o). The la- (i) The active ingredients beling states ‘‘[bullet] adults and chil- (§ 201.66(c)(2) of this chapter) shall be dren 2 years of age and over:’’ listed in alphabetical order. (i) The labeling states ‘‘For use as a (ii) The heading and the indication paste: [bullet] add enough water to the required by § 201.66(c)(4) of this chapter sodium bicarbonate to form a paste may be limited to: ‘‘Use [in bold type] [bullet] apply to the affected area of helps’’ (optional: ‘‘prevent and’’) ‘‘pro- the skin as needed, or as directed by a tect’’ (optional: ‘‘and relieve’’) doctor’’. ‘‘chapped lips’’. If both optional terms

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are used, the indication may be limited (2) The labeling shall be printed in to: ‘‘Use [in bold type] helps prevent, accordance with the requirements of protect, and relieve chapped lips’’. § 201.66(d) of this chapter except that (iii) The ‘‘external use only’’ warning any requirements related to in § 347.50(c)(1) and in § 201.66(c)(5)(i) of § 201.66(c)(3) and (c)(7) may be omitted. this chapter may be omitted. The [68 FR 33377, June 4, 2003, as amended at 68 warnings in § 347.50(c)(2), (c)(3), and FR 68511, Dec. 9, 2003; 73 FR 6017, Feb. 1, 2008] (c)(4) are not required. (iv) The subheadings in § 347.52 Labeling of astringent drug § 201.66(c)(5)(iii) through (c)(5)(vi) of products. this chapter may be omitted, provided (a) Statement of identity. The labeling the information after the heading of the product contains the established ‘‘Warning’’ contains the warning in name of the drug, if any, and identifies § 347.50(e)(1)(iii). the product as an ‘‘astringent.’’ For (v) The warnings in § 201.66(c)(5)(x) of products containing the combination of this chapter may be omitted. aluminum sulfate tetradecahydrate and (2) The labeling shall be printed in calcium acetate monohydrate identified in accordance with the requirements of § 347.20(b), under the ‘‘Purpose’’ heading § 201.66(d) of this chapter except that identified in § 201.66(c)(3) of this chap- any requirements related to ter, the labeling of each active ingre- § 201.66(c)(1), (c)(3), (c)(6), and (c)(7), and dient in the product states the horizontal barlines and hairlines ‘‘Astringent*’’, which is followed by described in § 201.66(d)(8), may be omit- the statements ‘‘* When combined to- ted. gether in water, these ingredients form (f) Products containing only cocoa but- the active ingredient aluminum ace- ter, petrolatum, or white petrolatum iden- tate. See [the following in bold italic tified in § 347.10(d), (m), and (r), singly or type] Directions.’’ in combination with each other, and mar- (b) Indications. The labeling of the keted other than as a lip protectant. (1) product states, under the heading The labeling shall meet the require- ‘‘Uses’’ any of the phrases listed in this ments of § 201.66(c) of this chapter ex- paragraph (b), as appropriate. Other cept that the headings and information truthful and nonmisleading statements described in § 201.66(c)(3) and (c)(7) may describing only the indications for use be omitted, and the headings, sub- that have been established and listed in headings, and information described in this paragraph (b) may also be used, as § 201.66(c)(2), (c)(4), and (c)(5) may be provided in § 330.1(c)(2) of this chapter, presented as follows: subject to the provisions of section 502 (i) The active ingredients of the Federal Food, Drug, and Cos- (§ 201.66(c)(2) of this chapter) shall be metic Act (the act) relating to mis- listed in alphabetical order. branding and the prohibition of section (ii) The heading and the indication 301(d) of the act against the introduc- required by § 201.66(c)(4) of this chapter tion or delivery for introduction into may be limited to ‘‘Use [in bold type] interstate commerce of unapproved helps protect minor cuts and burns’’ or new drugs in violation of section 505(a) ‘‘Use [in bold type] helps’’ (optional: of the act. ‘‘prevent and’’) ‘‘protect chapped skin’’ (1) For products containing aluminum or ‘‘Use [in bold type] helps protect acetate identified in § 347.12(a) or the com- minor cuts and burns and’’ (optional: bination of aluminum sulfate ‘‘prevent and protect’’) ‘‘chapped tetradecahydrate and calcium acetate skin’’. monohydrate identified in § 347.20(b). (iii) The warning in § 347.50(c)(3) may ‘‘For temporary relief of minor skin ir- be revised to read ‘‘See a doctor if con- ritations due to: [select one or more of dition lasts more than 7 days.’’ the following: ‘poison ivy,’ ‘poison (iv) The subheadings in oak,’ ‘poison sumac,’ ‘insect bites,’ § 201.66(c)(5)(iv) through (c)(5)(vii) of ‘athlete’s foot,’ or ‘rashes caused by this chapter may be omitted, provided soaps, detergents, cosmetics, or jew- the information after the heading elry’].’’ ‘‘Warnings’’ contains the warnings in (2) For products containing aluminum § 347.50(c)(2), (c)(4), and (f)(1)(iii). sulfate identified in § 347.12(b) for use as a

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styptic pencil. ‘‘Stops bleeding caused [bullet] soak affected area for 15 to 30 by minor surface cuts and abrasions as minutes as needed, or as directed by a may occur during shaving.’’ doctor [bullet] repeat 3 times a day or (3) For products containing witch hazel as directed by a doctor [bullet] discard identified in § 347.12(c). ‘‘Relieves minor solution after each use’’ . skin irritations due to: [select one or (ii) For products used as a compress or more of the following: ’insect bites,’ wet dressing. ‘‘For use as a compress or ’minor cuts,’ or ’minor scrapes’].’’ [If wet dressing: [preceding words in bold more than one condition is used, each type] [bullet] soak a clean, soft cloth in is preceded by a bullet.] the solution [bullet] apply cloth loose- (c) Warnings. The labeling of the ly to affected area for 15 to 30 minutes product contains the following warn- [bullet] repeat as needed or as directed ings under the heading ‘‘Warnings’’: by a doctor [bullet] discard solution (1) For all products—(i) The labeling after each use’’. states ‘‘For external use only’’. (2) For products containing aluminum (ii) The labeling states ‘‘When using sulfate identified in § 347.12(b) for use as a this product [bullet] avoid contact with styptic pencil. ‘‘Moisten tip of pencil eyes. If contact occurs, rinse thor- with water and apply to the affected oughly with water.’’ area. Dry pencil after use.’’ (2) For products containing aluminum (3) For products containing witch hazel acetate identified in § 347.12(a), witch identified in § 347.12(c). ‘‘Apply as often hazel identified in § 347.12(c), or the com- as needed’’. bination of aluminum sulfate (4) tetradecahydrate and calcium acetate For products containing the com- monohydrate identified in § 347.20(b). The bination of aluminum sulfate labeling states ‘‘Stop use and ask a tetradecahydrate and calcium acetate doctor if [bullet] condition worsens or monohydrate identified in § 347.20(b)—(i) symptoms last more than 7 days’’. For powder dosage form. The labeling (3) For products containing aluminum states ‘‘[bullet] dissolve 1 to 3 packets acetate identified in § 347.12(a) or the com- in [insert volume] of cool or warm bination of aluminum sulfate water [bullet] stir until fully dissolved; tetradecahydrate and calcium acetate do not strain or filter. The resulting monohydrate identified in § 347.20(b) mixture contains [insert percent] (1 when labeled for use as a compress or wet packet), [insert percent] (2 packets), or dressing. The labeling states ‘‘When [insert percent] (3 packets) aluminum using this product [bullet] do not cover acetate and is ready for use.’’ These compress or wet dressing with plastic statements shall be the first state- to prevent evaporation’’. ments under the heading ‘‘Directions’’. (4) For products containing aluminum (ii) For tablet dosage form. The label- acetate identified in § 347.12(a) or the coming states ‘‘[bullet] dissolve 1 to 3 tab- bination of aluminum sulfate lets in [insert volume] of cool or warm tetradecahydrate and calcium acetate water [bullet] stir until fully dissolved; monohydrate identified in § 347.20(b) do not strain or filter. The resulting when labeled for use as a soak, compress, mixture contains [insert percent] (1 or wet dressing. The labeling states tablet), [insert percent] (2 tablets), or ‘‘When using this product [bullet] in [insert percent] (3 tablets) aluminum some skin conditions, soaking too long acetate and is ready for use.’’ These may overdry’’. statements shall be the first state- (d) Directions. The labeling of the ments under the heading ‘‘Directions’’. product contains the following infor- (e) Products formulated and labeled as mation under the heading ‘‘Direc- a styptic pencil and that meet the criteria tions’’: established in § 201.66(d)(10) of this chap- (1) For products containing aluminum ter. The title, headings, subheadings, acetate identified in § 347.12(a) or the com- and information described in § 201.66(c) bination of aluminum sulfate of this chapter shall be printed in ac- tetradecahydrate and calcium acetate cordance with the following specifica- monohydrate identified in § 347.20(b)—(i) tions: For products used as a soak. ‘‘For use as (1) The labeling shall meet the re- a soak: [preceding words in bold type] quirements of § 201.66(c) of this chapter

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except that the headings and informa- tity sections of the applicable OTC tion described in § 201.66(c)(3) and (c)(7) drug monographs. may be omitted, and the headings, sub- (b) Indications. The labeling of the headings, and information described in product states, under the heading § 201.66(c)(4) and (c)(5) may be presented ‘‘Uses,’’ the indication(s) for each in- as follows: gredient in the combination as estab- (i) The heading and indication re- lished in the indications sections of the quired by § 201.66(c)(4) of this chapter applicable OTC drug monographs, un- may be limited to: ‘‘Use [in bold type] less otherwise stated in this paragraph stops bleeding of minor cuts from shav- (b). Other truthful and nonmisleading ing’’. statements, describing only the indica- (ii) The ‘‘external use only’’ warning tions for use that have been established in § 347.52(c)(1) and in § 201.66(c)(5)(i) of in the applicable OTC drug monographs this chapter may be omitted. The sec- or listed in this paragraph (b) may also ond warning in § 347.52(c)(1) may state: be used, as provided in § 330.1(c)(2) of ‘‘avoid contact with eyes’’. The warn- this chapter, subject to the provisions ing in § 201.66(c)(5)(x) may be limited to of section 502 of the Federal Food, the following: ‘‘Keep out of reach of Drug, and Cosmetic Act (the act) relat- children.’’ The subheadings in ing to misbranding and the prohibition § 201.66(c)(5)(iii) through (c)(5)(vii) may in section 301(d) of the act against the be omitted, provided the information introduction or delivery for introduc- after the heading ‘‘Warning’’ contains tion into interstate commerce of unap- the warnings in this paragraph. proved new drugs in violation of sec- (2) The labeling shall be printed in tion 505(a) of the act. In addition to the accordance with the requirements of required information identified in this § 201.66(d) of this chapter except that paragraph (b), the labeling of the prod- any requirements related to uct may contain any of the ‘‘other al- § 201.66(c)(3) and (c)(7), and the hori- lowable statements’’ that are identified zontal barlines and hairlines described in § 201.66(d)(8), may be omitted. in the applicable monographs, provided such statements are neither placed in [68 FR 33377, June 4, 2003, as amended at 68 direct conjunction with information re- FR 35293, June 13, 2003; 69 FR 3005, Jan. 22, quired to appear in the labeling nor oc- 2004; 74 FR 9765, Mar. 6, 2009] cupy labeling space with greater prominence or conspicuousness than the re- § 347.60 Labeling of permitted combinations of active ingredients. quired information. (1) Combinations of skin protectant and The statement of identity, indica- external analgesic active ingredients in tions, warnings, and directions for use, § 347.20(b). In addition to any or all of respectively, applicable to each ingre- the indications for skin protectant dient in the product may be combined drug products in § 347.50(b)(1), any or all to eliminate duplicative words or of the allowable indications for exter- phrases so that the resulting information is clear and understandable. nal analgesic drug products may be used if the product is labeled for con- (a) Statement of identity. For a com- current symptoms. bination drug product that has an established name, the labeling of the (2) Combinations of skin protectant and product states the established name of first aid antiseptic active ingredients in the combination drug product, followed § 347.20(c). In addition to any or all of by the statement of identity for each the indications for skin protectant ingredient in the combination, as es- drug products in § 347.50(b)(1), the re- tablished in the statement of identity quired indications for first aid anti- sections of the applicable OTC drug septic drug products should be used. monographs. For a combination drug (3) Combinations of skin protectant and product that does not have an estab- sunscreen active ingredients in § 347.20(d). lished name, the labeling of the prod- In addition to any or all of the indica- uct states the statement of identity for tions for skin protectant drug products each ingredient in the combination, as in § 347.50(b)(2)(i), the required indica- established in the statement of iden- tions for sunscreen drug products

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should be used and any or all of the ad- Subpart C—Labeling ditional indications for sunscreen drug 348.50 Labeling of external analgesic drug products may be used. products. (c) Warnings. The labeling of the AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, product states, under the heading 360, 371. ‘‘Warnings,’’ the warning(s) for each ingredient in the combination, as estab- SOURCE: 57 FR 27656, June 19, 1992, unless otherwise noted. lished in the warnings section of the applicable OTC drug monographs unless otherwise stated in this paragraph Subpart A—General Provisions (c). § 348.1 Scope. (1) For combinations containing a skin (a) An over-the-counter external an- protectant and a sunscreen identified in algesic drug product in a form suitable §§ 347.20(d) and 352.20(b). The warnings for topical administration is generally for sunscreen drug products in recognized as safe and effective and is § 352.60(c) of this chapter are used. not misbranded if it meets each condi- (2) [Reserved] tion in this part and each general con- (d) Directions. The labeling of the dition established in § 330.1 of this product states, under the heading ‘‘Di- chapter. rections,’’ directions that conform to (b) References in this part to regu- the directions established for each in- latory sections of the Code of Federal gredient in the directions sections of Regulations are to chapter I of title 21 the applicable OTC drug monographs, unless otherwise noted. unless otherwise stated in this para- § 348.3 Definitions. graph (d). When the time intervals or age limitations for administration of As used in this part: the individual ingredients differ, the (a) Male genital desensitizing drug directions for the combination product product. A drug product applied to the penis to help in temporarily slowing may not contain any dosage that ex- the onset of ejaculation. ceeds those established for any indi- (b) [Reserved] vidual ingredient in the applicable OTC drug monograph(s), and may not provide for use by any age group lower Subpart B—Active Ingredients than the highest minimum age limit § 348.10 Analgesic, anesthetic, and established for any individual ingre- antipruritic active ingredients. dient. The active ingredient of the product (1) For combinations containing a skin consists of any of the following within protectant and a sunscreen identified in the specified concentration established §§ 347.20(d) and 352.20(b). The directions for each ingredient: for sunscreen drug products in (a) Male genital desensitizers. (1) Ben- § 352.60(d) of this chapter are used. zocaine, 3 to 7.5 percent in a water- (2) [Reserved] soluble base. (2) Lidocaine in a metered spray with PART 348—EXTERNAL ANALGESIC approximately 10 milligrams per spray. (b) [Reserved] DRUG PRODUCTS FOR OVER-THE- COUNTER HUMAN USE Subpart C—Labeling Subpart A—General Provisions § 348.50 Labeling of external analgesic drug products. Sec. 348.1 Scope. (a) Statement of identity. The labeling 348.3 Definitions. of the product contains the established name of the drug, if any, and identifies Subpart B—Active Ingredients the product as follows: (1) For products containing any ingre- 348.10 Analgesic, anesthetic, and anti- dient identified in § 348.10(a). ‘‘Male gen- pruritic active ingredients. ital desensitizer.’’

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(2) [Reserved] course, or use as directed by a doctor. (b) Indications. The labeling of the Wash product off after intercourse.’’ product states, under the heading ‘‘In- (ii) For products containing lidocaine dications,’’ any of the phrases listed in identified in § 348.10(a)(2). ‘‘Apply 3 or paragraph (b) of this section. Other more sprays, not to exceed 10, to head truthful and nonmisleading state- and shaft of penis before intercourse, ments, describing only the indications or use as directed by a doctor. Wash for use that have been established and product off after intercourse.’’ listed in paragraph (b) of this section, may also be used, as provided in (2) [Reserved] § 330.1(c)(2) of this chapter, subject to (e) The word ‘‘physician’’ may be sub- the provisions of section 502 of the Fed- stituted for the word ‘‘doctor’’ in any eral Food, Drug, and Cosmetic Act (the of the labeling statements in this sec- act) relating to misbranding and the tion. prohibition in section 301(d) of the act against the introduction or delivery for PART 349—OPHTHALMIC DRUG introduction into interstate commerce PRODUCTS FOR OVER-THE- of unapproved new drugs in violation of section 505(a) of the act. COUNTER HUMAN USE (1) For products containing any ingredient identified in § 348.10(a). (i) ‘‘Helps Subpart A—General Provisions in the prevention of premature ejacula- Sec. tion.’’ 349.1 Scope. (ii) ‘‘For temporary male genital de- 349.3 Definitions. sensitization, helping to slow the onset of ejaculation.’’ Subpart B—Active Ingredients (iii) ‘‘Helps in temporarily’’ (select one of the following: ‘‘retarding the 349.10 Ophthalmic astringent. onset of,’’ ‘‘slowing the onset of,’’ or 349.12 Ophthalmic demulcents. ‘‘prolonging the time until’’) followed 349.14 Ophthalmic emollients. by ‘‘ejaculation.’’ 349.16 Ophthalmic hypertonicity agent. (iv) ‘‘For reducing oversensitivity in 349.18 Ophthalmic vasoconstrictors. the male in advance of intercourse.’’ 349.20 Eyewashes. (2) [Reserved] 349.30 Permitted combinations of active in- (c) Warnings. The labeling of the gredients. product contains the following warnings under the heading ‘‘Warnings’’: Subpart C—Labeling (1) For products containing any ingre- 349.50 Labeling of ophthalmic drug prod- dient identified in § 348.10(a). (i) ‘‘Pre- ucts. mature ejaculation may be due to a 349.55 Labeling of ophthalmic astringent condition requiring medical super- drug products. vision. If this product, used as directed, 349.60 Labeling of ophthalmic demulcent does not provide relief, discontinue use drug products. and consult a doctor.’’ 349.65 Labeling of ophthalmic emollient (ii) ‘‘Avoid contact with the eyes.’’ drug products. (iii) ‘‘If you or your partner develop a 349.70 Labeling of ophthalmic hypertonicity rash or irritation, such as burning or drug products. itching, discontinue use. If symptoms 349.75 Labeling of ophthalmic vasocon- persist, consult a doctor.’’ strictor drug products. (2) [Reserved] 349.78 Labeling of eyewash drug products. (d) Directions. The labeling of the 349.79 Labeling of permitted combinations product contains the following infor- of active ingredients. mation under the heading ‘‘Direc- 349.80 Professional labeling. tions’’: AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (1) For products containing any ingre- 360, 371. dient identified in § 348.10(a)—(i) For products containing benzocaine identified SOURCE: 53 FR 7090, Mar. 4, 1988, unless oth- in § 348.10(a)(1). ‘‘Apply a small amount erwise noted. to head and shaft of penis before inter-

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Subpart A—General Provisions causes transient constriction of con- junctival blood vessels. § 349.1 Scope. (a) An over-the-counter ophthalmic Subpart B—Active Ingredients drug product in a form suitable for topical administration is generally recog- § 349.10 Ophthalmic astringent. nized as safe and effective and is not The active ingredient and its con- misbranded if it meets each of the concentration in the product is as follows: ditions in this part and each of the gen- Zinc sulfate, 0.25 percent. eral conditions established in § 330.1. (b) References in this part to regu- § 349.12 Ophthalmic demulcents. latory sections of the Code of Federal The active ingredients of the product Regulations are to chapter I of title 21 consist of any of the following, within unless otherwise noted. the established concentrations for each ingredient: § 349.3 Definitions. (a) Cellulose derivatives: As used in this part: (1) Carboxymethylcellulose sodium, (a) Ophthalmic drug product. A drug 0.2 to 2.5 percent. product, which should be sterile in ac- (2) Hydroxyethyl cellulose, 0.2 to 2.5 cordance with § 200.50, to be applied to percent. the eyelid or instilled in the eye. (3) Hypromellose, 0.2 to 2.5 percent. (b) Astringent. A locally acting phar- (4) Methylcellulose, 0.2 to 2.5 percent. macologic agent which, by precipi- (b) Dextran 70, 0.1 percent when used tating protein, helps to clear mucus with another polymeric demulcent from the outer surface of the eye. agent in this section. (c) Buffering agent. A substance which (c) Gelatin, 0.01 percent. stabilizes the pH of solutions against (d) Polyols, liquid: changes produced by introduction of (1) Glycerin, 0.2 to 1 percent. acids or bases from such sources as (2) Polyethylene glycol 300, 0.2 to 1 drugs, body fluids, tears, etc. percent. (d) An agent, usually a Demulcent. (3) Polyethylene glycol 400, 0.2 to 1 water-soluble polymer, which is ap- percent. plied topically to the eye to protect (4) Polysorbate 80, 0.2 to 1 percent. and lubricate mucous membrane sur- (5) Propylene glycol, 0.2 to 1 percent. faces and relieve dryness and irrita- (e) Polyvinyl alcohol, 0.1 to 4 percent. tion. (f) Povidone, 0.1 to 2 percent. (e) Emollient. An agent, usually a fat or oil, which is applied locally to eye- [53 FR 7090, Mar. 4, 1988, as amended at 68 FR lids to protect or soften tissues and to 32982, June 3, 2003] prevent drying and cracking. (f) Eyewash, eye lotion, irrigating solu- § 349.14 Ophthalmic emollients. tion. A sterile aqueous solution in- The active ingredients of the product tended for washing, bathing, or flush- consist of any of the following: ing the eye. (a) Lanolin preparations: (g) Hypertonicity agent. An agent (1) Anhydrous lanolin, 1 to 10 percent which exerts an osmotic gradient in combination with one or more ole- greater than that present in body tis- aginous emollient agents included in sues and fluids, so that water is drawn the monograph. from the body tissues and fluids across (2) Lanolin, 1 to 10 percent in com- semipermeable membranes. Applied bination with one or more oleaginous topically to the eye, a hypertonicity emollient agents included in the mono- agent creates an osmotic gradient graph. which draws water out of the cornea. (b) Oleaginous ingredients: (h) Isotonicity. A state or quality in (1) Light mineral oil, up to 50 percent which the osmotic pressure in two in combination with one or more other fluids is equal. emollient agents included in the mono- (i) Vasoconstrictor. A pharmacologic graph. agent which, when applied topically to (2) Mineral oil, up to 50 percent in the mucous membranes of the eye, combination with one or more other

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emollient agents included in the mono- may be combined with any single oph- graph. thalmic vasoconstrictor active ingre- (3) Paraffin, up to 5 percent in com- dient identified in § 349.18. bination with one or more other emol- (b) Any two or three ophthalmic de- lient agents included in the mono- mulcent active ingredients identified graph. in § 349.12 may be combined. (4) Petrolatum, up to 100 percent. (c) Any single ophthalmic demulcent (5) White ointment, up to 100 percent. active ingredient identified in § 349.12 (6) White petrolatum, up to 100 per- or any ophthalmic demulcent combina- cent. tion identified in paragraph (b) of this (7) White wax, up to 5 percent in com- section may be combined with any sin- bination with one or more other emol- gle ophthalmic vasoconstrictor identi- lient agents included in the mono- fied in § 349.18. graph. (d) Any single ophthalmic astringent (8) Yellow wax, up to 5 percent in active ingredient identified in § 349.10 combination with one or more other may be combined with any single oph- emollient agents included in the mono- thalmic vasoconstrictor active ingre- graph. dient identified in § 349.18 and any single ophthalmic demulcent identified in § 349.16 Ophthalmic hypertonicity § 349.12 or ophthalmic demulcent com- agent. bination identified in paragraph (b) of The active ingredient and its con- this section. centration in the product is as follows: (e) Any two or more emollient active Sodium chloride, 2 to 5 percent. ingredients identified in § 349.14 may be combined as necessary to give the § 349.18 Ophthalmic vasoconstrictors. product proper consistency for applica- The active ingredient of the product tion to the eye. consists of one of the following, within the established concentration for each Subpart C—Labeling ingredient: (a) Ephedrine hydrochloride, 0.123 § 349.50 Labeling of ophthalmic drug percent. products. (b) Naphazoline hydrochloride, 0.01 to (a) The word ‘‘physician’’ may be 0.03 percent. substituted for the word ‘‘doctor’’ in (c) Phenylephrine hydrochloride, 0.08 any of the labeling statements in this to 0.2 percent. part. (d) Tetrahydrozoline hydrochloride, (b) Where applicable, indications in 0.01 to 0.05 percent. this part applicable to each ingredient § 349.20 Eyewashes. in the product may be combined to eliminate duplicative words or phrases The active ingredient of the product so that the resulting information is is purified water. The product also con- clear and understandable. Other truth- tains suitable tonicity agents to estab- ful and nonmisleading statements, de- lish isotonicity with tears, suitable scribing only the indications for use agents for establishing pH and that have been established and listed in buffering to achieve the same pH as this part, may also be used, as provided tears, and a suitable preservative in § 330.1(c)(2), subject to the provisions agent. of section 502 of the act relating to [68 FR 7921, Feb. 19, 2003] misbranding and the prohibition in section 301(d) of the act against the intro- § 349.30 Permitted combinations of ac- duction or delivery for introduction tive ingredients. into interstate commerce of unap- The following combinations are per- proved new drugs in violation of sec- mitted provided each active ingredient tion 505(a) of the act. is present within the established con- (c) The labeling of the product concentration, and the product is labeled tains the following warnings, under the in accordance with § 349.79. heading ‘‘Warnings’’: (a) Any single ophthalmic astringent (1) For ophthalmic drug products pack- active ingredient identified in § 349.10 aged in multi-use containers. ‘‘To avoid

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contamination, do not touch tip of con- ‘‘demulcent (lubricant)’’ (select one of tainer to any surface. Replace cap after the following: ‘‘eye’’ or ‘‘ophthalmic’’) using.’’ ‘‘(insert dosage form, e.g., drops).’’ (2) For ophthalmic drug products pack- (b) Indications. The labeling of the aged in single-use containers. ‘‘To avoid product states, under the heading ‘‘In- contamination, do not touch tip of con- dications,’’ one or more of the fol- tainer to any surface. Do not reuse. lowing phrases: Once opened, discard.’’ (1) ‘‘For the temporary relief of burn- (3) For ophthalmic drug products con- ing and irritation due to dryness of the taining mercury compounds used as a pre- eye.’’ servative. ‘‘This product contains (name (2) ‘‘For the temporary relief of dis- and quantity of mercury-containing in- comfort due to minor irritations of the gredient) as a preservative. Do not use eye or to exposure to wind or sun.’’ this product if you are sensitive to’’ (3) ‘‘For use as a protectant against (select one of the following: ‘‘mercury’’ further irritation or to relieve dryness or ‘‘(insert name of mercury-con- of the eye.’’ taining ingredient) or any other ingre- (4) ‘‘For use as a lubricant to prevent dient containing mercury).’’ further irritation or to relieve dryness § 349.55 Labeling of ophthalmic astrin- of the eye.’’ gent drug products. (c) Warnings. In addition to the warnings in § 349.50, the labeling of the prod- (a) Statement of identity. The labeling uct contains the following warnings of the product contains the established under the heading ‘‘Warnings’’ for name of the drug, if any, and identifies products containing any ingredient the product as an ‘‘astringent’’ (select identified in § 349.12: one of the following: ‘‘eye’’ or ‘‘oph- (1) ‘‘If you experience eye pain, thalmic’’) ‘‘(insert dosage form, e.g., changes in vision, continued redness or drops).’’ irritation of the eye, or if the condition (b) Indications. The labeling of the worsens or persists for more than 72 product states, under the heading ‘‘In- hours, discontinue use and consult a dications,’’ the following phrase: ‘‘For doctor.’’ the temporary relief of discomfort from minor eye irritations.’’ (2) ‘‘If solution changes color or be- (c) Warnings. In addition to the warn- comes cloudy, do not use.’’ ings in § 349.50, the labeling of the prod- (d) Directions. The labeling of the uct contains the following warnings product contains the following infor- under the heading ‘‘Warnings’’ for mation under the heading ‘‘Direc- products containing any ingredient tions’’: Instill 1 or 2 drops in the af- identified in § 349.10: fected eye(s) as needed. (1) ‘‘If you experience eye pain, changes in vision, continued redness or § 349.65 Labeling of ophthalmic emollient drug products. irritation of the eye, or if the condition worsens or persists for more than 72 (a) Statement of identity. The labeling hours, discontinue use and consult a of the product contains the established doctor.’’ name of the drug(s), if any, and identi- (2) ‘‘If solution changes color or be- fies the product as a ‘‘lubricant’’ or comes cloudy, do not use.’’ ‘‘emollient (lubricant)’’ (select one of (d) Directions. The labeling of the the following: ‘‘eye’’ or ‘‘ophthalmic’’) product contains the following infor- ‘‘(insert dosage form, e.g., ointment).’’ mation under the heading ‘‘Direc- (b) Indications. The labeling of the tions’’: Instill 1 to 2 drops in the af- product states, under the heading ‘‘In- fected eye(s) up to four times daily. dications,’’ one or more of the following phrases: § 349.60 Labeling of ophthalmic demul- (1) ‘‘For the temporary relief of burn- cent drug products. ing and irritation due to dryness of the (a) Statement of identity. The labeling eye.’’ of the product contains the established (2) ‘‘For the temporary relief of dis- name of the drug(s), if any, and identi- comfort due to minor irritations of the fies the product as a ‘‘lubricant’’ or eye or to exposure to wind or sun.’’

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(3) ‘‘For use as a protectant against tions’’: Instill 1 or 2 drops in the af- further irritation or to relieve dryness fected eye(s) every 3 or 4 hours, or as of the eye.’’ directed by a doctor. (4) ‘‘For use as a lubricant to prevent further irritation or to relieve dryness § 349.75 Labeling of ophthalmic vaso- of the eye.’’ constrictor drug products. (c) Warnings. In addition to the warn- (a) Statement of identity. The labeling ings in § 349.50, the labeling of the prod- of the product contains the established uct contains the following warnings name of the drug(s), if any, and identi- under the heading ‘‘Warnings’’ for fies the product as a ‘‘redness reliever’’ products containing any ingredient or ‘‘vasoconstrictor (redness reliever)’’ identified in § 349.14: ‘‘If you experience (select one of the following: ‘‘eye’’ or eye pain, changes in vision, continued redness or irritation of the eye, or if ‘‘ophthalmic’’) ‘‘(insert dosage form, the condition worsens or persists for e.g., drops).’’ more than 72 hours, discontinue use (b) Indications. The labeling of the and consult a doctor.’’ product states, under the heading ‘‘In- (d) Directions. The labeling of the dications,’’ the following phrase: ‘‘Re- product contains the following infor- lieves redness of the eye due to minor mation under the heading ‘‘Direc- eye irritations.’’ tions’’: Pull down the lower lid of the (c) Warnings. In addition to the warn- affected eye and apply a small amount ings in § 349.50, the labeling of the prod- (one-fourth inch) of ointment to the in- uct contains the following warnings side of the eyelid. under the heading ‘‘Warnings’’ for products containing any ingredient § 349.70 Labeling of ophthalmic identified in § 349.18: hypertonicity drug products. (1) ‘‘If you experience eye pain, (a) Statement of identity. The labeling changes in vision, continued redness or of the product contains the established irritation of the eye, or if the condition name of the drug, if any, and identifies worsens or persists for more than 72 the product as a ‘‘hypertonicity’’ (se- hours, discontinue use and consult a lect one of the following: ‘‘eye’’ or doctor.’’ ‘‘ophthalmic’’) ‘‘(insert dosage form, (2) ‘‘Ask a doctor before use if you e.g., drops).’’ have [in bold type] narrow angle glau- (b) Indications. The labeling of the product states, under the heading ‘‘In- coma.’’ dications,’’ the following phrase: ‘‘For (3) ‘‘Overuse of this product may the temporary relief of corneal produce increased redness of the eye.’’ edema.’’ (4) ‘‘If solution changes color or be- (c) Warnings. In addition to the warn- comes cloudy, do not use.’’ ings in § 349.50, the labeling of the prod- (5) ‘‘When using this product [in bold uct contains the following warnings type] pupils may become enlarged tem- under the heading ‘‘Warnings’’ for porarily.’’ products containing any ingredient (d) Directions. The labeling of the identified in § 349.16: product contains the following infor- (1) ‘‘Do not use this product except mation under the heading ‘‘Direc- under the advice and supervision of a tions’’: Instill 1 to 2 drops in the af- doctor. If you experience eye pain, fected eye(s) up to four times daily. changes in vision, continued redness or irritation of the eye, or if the condition [53 FR 7090, Mar. 4, 1988, as amended at 65 FR worsens or persists, consult a doctor.’’ 38428, June 21, 2000] (2) ‘‘This product may cause temporary burning and irritation on being § 349.78 Labeling of eyewash drug products. instilled into the eye.’’ (3) ‘‘If solution changes color or be- (a) Statement of identity. The labeling comes cloudy, do not use.’’ of the product identifies the product (d) Directions. The labeling of the with one or more of the following product contains the following infor- terms: ‘‘eyewash,’’ ‘‘eye irrigation,’’ or mation under the heading ‘‘Direc- ‘‘eye irrigating solution.’’

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(b) Indications. The labeling of the § 349.79 Labeling of permitted com- product states, under the heading ‘‘In- binations of active ingredients. dications,’’ one of the following Statements of identity, indications, phrases: warnings, and directions for use, re- (1) ‘‘For’’ (select one of the following: spectively, applicable to each ingre- ‘‘flushing,’’ ‘‘irrigating,’’ ‘‘cleansing,’’ dient in the product may be combined ‘‘washing,’’ or ‘‘bathing’’) ‘‘the eye to to eliminate duplicative words or remove’’ (select one or more of the fol- phrases so that the resulting informa- lowing: ‘‘loose foreign material,’’ ‘‘air tion is clear and understandable. pollutants (smog or pollen),’’ or (a) Statement of identity. For a com- ‘‘chlorinated water’’). bination drug product that has an es- (2) ‘‘For’’ (select one of the following: tablished name, the labeling of the ‘‘flushing,’’ ‘‘irrigating,’’ ‘‘cleansing,’’ product states the established name of ‘‘washing,’’ or ‘‘bathing’’) ‘‘the eye to the combination drug product, followed help relieve’’ (select one or more of the by the statement of identity for each following: ‘‘irritation,’’ ‘‘discomfort,’’ ingredient in the combination, as es- ‘‘burning,’’ ‘‘stinging,’’ ‘‘smarting,’’ or tablished in the statement of identity ‘‘itching’’) ‘‘by removing’’ (select one sections of this part. For a combina- or more of the following: ‘‘loose foreign tion drug product that does not have material,’’ ‘‘air pollutants (smog or an established name, the labeling of pollen),’’ or ‘‘chlorinated water’’). the product states the statement of (c) Warnings. In addition to the warn- identity for each ingredient in the ings in § 349.50, the labeling of the prod- combination, as established in the uct contains the following warnings statement of identity sections of this under the heading ‘‘Warnings’’ for all part. eyewash products: (b) Indications. The labeling of the (1) ‘‘If you experience eye pain, product states, under the heading ‘‘In- changes in vision, continued redness or dications,’’ the indication(s) for each irritation of the eye, or if the condition ingredient in the combination, as es- worsens or persists, consult a doctor.’’ tablished in the indications sections of (2) ‘‘Obtain immediate medical treat- this part. ment for all open wounds in or near the (c) Warnings. The labeling of the eyes.’’ product states, under the heading ‘‘Warnings,’’ the warning(s) for each in- (3) ‘‘If solution changes color or be- gredient in the combination, as estab- comes cloudy, do not use.’’ lished in the warnings sections of this (d) Directions. The labeling of the part. product contains the following infor- (d) Directions. The labeling of the mation under the heading ‘‘Direc- product states, under the heading ‘‘Di- tions’’: rections,’’ directions that conform to (1) For eyewash products intended for the directions established for each in- use with an eyecup. Rinse cup with gredient in the directions sections of clean water immediately before each this part. When the time intervals or use. Avoid contamination of rim and age limitations for administration of inside surfaces of cup. Fill cup half full the individual ingredients differ, the and apply the cup to the affected eye, directions for the combination product pressing tightly to prevent the escape may not exceed any maximum dosage of the liquid, and tilt the head back- limits established for the individual in- ward. Open eyelids wide and rotate eye- gredients in the applicable OTC drug ball to ensure thorough bathing with monograph. the wash or lotion. Rinse cup with clean water after each use. § 349.80 Professional labeling. (2) For eyewash products intended for The labeling of any OTC ophthalmic use with a nozzle applicator. Flush the demulcent drug product provided to affected eye as needed, controlling the health professionals (but not to the rate of flow of solution by pressure on general public) may contain instruc- the bottle. tions for the use of these products in [53 FR 7090, Mar. 4, 1988, as amended at 68 FR professional eye examinations (i.e., 7921, Feb. 19, 2003] gonioscopy, electroretinography).

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PART 350—ANTIPERSPIRANT DRUG chloride, aluminum to zirconium, and PRODUCTS FOR OVER-THE- aluminum plus zirconium to chloride COUNTER HUMAN USE atomic ratios described in the U.S. Pharmacopeia-National Formulary. Subpart A—General Provisions The concentration of ingredients in paragraphs (b) through (j) of this sec- Sec. tion is calculated on an anhydrous 350.1 Scope. basis, omitting from the calculation 350.3 Definition. any buffer component present in the compound, in an aerosol or nonaerosol Subpart B—Active Ingredients dosage form. The concentration of in- 350.10 Antiperspirant active ingredients. gredients in paragraphs (k) through (r) of this section is calculated on an an- Subpart C—Labeling hydrous basis, omitting from the cal- 350.50 Labeling of antiperspirant drug prod- culation any buffer component present ucts. in the compound, in a nonaerosol dosage form. The labeled declaration of Subpart D—Guidelines for Effectiveness the percentage of the active ingredient Testing should exclude any water, buffer components, or propellant. 350.60 Guidelines for effectiveness testing of antiperspirant drug products. (a) Aluminum chloride up to 15 percent, calculated on the hexahydrate AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, form, in an aqueous solution nonaer- 360, 371. osol dosage form. SOURCE: 68 FR 34291, June 9, 2003, unless (b) Aluminum chlorohydrate up to 25 otherwise noted. percent. (c) Aluminum chlorohydrex poly- Subpart A—General Provisions ethylene glycol up to 25 percent. (d) Aluminum chlorohydrex pro- § 350.1 Scope. pylene glycol up to 25 percent. (a) An over-the-counter anti- (e) Aluminum dichlorohydrate up to perspirant drug product in a form suit- 25 percent. able for topical administration is gen- (f) Aluminum dichlorohydrex poly- erally recognized as safe and effective ethylene glycol up to 25 percent. and is not misbranded if it meets each (g) Aluminum dichlorohydrex pro- condition in this part and each general pylene glycol up to 25 percent. condition established in § 330.1 of this chapter. (h) Aluminum sesquichlorohydrate (b) References in this part to regu- up to 25 percent. latory sections of the Code of Federal (i) Aluminum sesquichlorohydrex Regulations are to chapter I of title 21 polyethylene glycol up to 25 percent. unless otherwise noted. (j) Aluminum sesquichlorohydrex propylene glycol up to 25 percent. § 350.3 Definition. (k) Aluminum zirconium As used in this part: octachlorohydrate up to 20 percent. Antiperspirant. A drug product ap- (l) Aluminum zirconium plied topically that reduces the produc- octachlorohydrex gly up to 20 percent. tion of perspiration (sweat) at that (m) Aluminum zirconium site. pentachlorohydrate up to 20 percent. (n) Aluminum zirconium Subpart B—Active Ingredients pentachlorohydrex gly up to 20 percent. (o) Aluminum zirconium § 350.10 Antiperspirant active ingredi- tetrachlorohydrate up to 20 percent. ents. (p) Aluminum zirconium The active ingredient of the product tetrachlorohydrex gly up to 20 percent. consists of any of the following within (q) Aluminum zirconium the established concentration and dos- trichlorohydrate up to 20 percent. age formulation. Where applicable, the (r) Aluminum zirconium ingredient must meet the aluminum to trichlorohydrex gly up to 20 percent.

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Subpart C—Labeling extra effective protection,’’ ‘‘extra effective protection lasts 24 hours,’’ or § 350.50 Labeling of antiperspirant ‘‘extra effective protection lasts all drug products. day’’. (a) Statement of identity. The labeling (c) Warnings. The labeling of the of the product contains the established product contains the following state- name of the drug, if any, and identifies ments under the heading ‘‘Warnings’’: the product as an ‘‘antiperspirant.’’ (1) ‘‘Do not use on broken skin’’. (b) Indications. The labeling of the (2) ‘‘Stop use if rash or irritation oc- product states, under the heading curs’’. ‘‘Uses,’’ the phrase listed in paragraph (3) ‘‘Ask a doctor before use if you (b)(1) of this section and may contain have kidney disease’’. any additional phrases listed in paragraphs (b)(2) through (b)(5) of this sec- (4) For products in an aerosolized dos- tion, as appropriate. Other truthful and age form. (i) ‘‘When using this product nonmisleading statements, describing [bullet] 1 keep away from face and only the uses that have been estab- mouth to avoid breathing it’’. lished and listed in paragraphs (b)(1) (ii) The warning required by § 369.21 through (b)(5) of this section, may also of this chapter for drugs in dispensers be used, as provided in § 330.1(c)(2) of pressurized by gaseous propellants. this chapter, subject to the provisions (d) Directions. The labeling of the of section 502 of the Federal Food, product contains the following state- Drug, and Cosmetic Act (the act) relat- ment under the heading ‘‘Directions’’: ing to misbranding and the prohibition ‘‘apply to underarms only’’. in section 301(d) of the act against the introduction or delivery for introduc- EFFECTIVE DATE NOTE: At 69 FR 61149, Oct. tion into interstate commerce of unap- 15, 2004, the limitation of the enhanced dura- proved new drugs in violation of section claim to 24 hours (21 CFR 350.50 (b)(3) and (b) (5)) was stayed until further notice. tion 505(a) of the act. (1) For any product, the labeling states [select one of the following: Subpart D—Guidelines for ‘‘decreases,’’ ‘‘lessens,’’ or ‘‘reduces’’] Effectiveness Testing ‘‘underarm’’ [select one of the following: ‘‘dampness,’’ ‘‘perspiration,’’ § 350.60 Guidelines for effectiveness ‘‘sweat,’’ ‘‘sweating,’’ or ‘‘wetness’’]. testing of antiperspirant drug prod- (2) The labeling may state ‘‘also [se- ucts. lect one of the following: ‘decreases,’ An antiperspirant in finished dosage ‘lessens,’ or ‘reduces’] underarm [select form may vary in degree of effective- one of the following: ‘dampness,’ ‘per- ness because of minor variations in for- spiration,’ ‘sweat,’ ‘sweating,’ or ‘wet- mulation. To assure the effectiveness ness’] due to stress’’. of an antiperspirant, the Food and (3) For products that demonstrate Drug Administration is providing standard effectiveness (20 percent guidelines that manufacturers may use sweat reduction) over a 24-hour period, in testing for effectiveness. These the labeling may state [select one of guidelines are on file in the Dockets the following: ‘‘all day protection,’’ Management Branch (HFA–305), Food ‘‘lasts all day,’’ ‘‘lasts 24 hours,’’ or ‘‘24 and Drug Administration, 5630 Fishers hour protection’’]. Lane, rm. 1061, Rockville, MD 20852. (4) For products that demonstrate extra effectiveness (30 percent sweat These guidelines are available on the reduction), the labeling may state FDA’s web site at http://www.fda.gov/ ‘‘extra effective’’. cder/otc/index.htm or on request for a (5) Products that demonstrate extra nominal charge by submitting a Free- effectiveness (30 percent sweat reduc- dom of Information (FOI) request in tion) sustained over a 24-hour period writing to FDA’s Division of Freedom may state the claims in paragraphs of Information (address is located on (b)(3) and (b)(4) of this section either individually or combined, e.g., ‘‘24 hour 1 See § 201.66(b)(4) of this chapter for defini- extra effective protection’’, ‘‘all day tion of bullet.

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the agency’s web site at http:// § 352.3 Definitions. www.fda.gov. As used in this part: [68 FR 34291, June 9, 2003, as amended at 76 (a) Minimal erythema dose (MED). The FR 31470, June 1, 2011; 79 FR 68115, Nov. 14, quantity of erythema-effective energy 2014] (expressed as Joules per square meter) required to produce the first percep- PART 352—SUNSCREEN DRUG tible, redness reaction with clearly de- PRODUCTS FOR OVER-THE- fined borders. COUNTER HUMAN USE [STAYED (b) Product category designation (PCD). INDEFINITELY] A labeling designation for sunscreen drug products to aid in selecting the Subpart A—General Provisions type of product best suited to an individual’s complexion (pigmentation) Sec. and desired response to ultraviolet 352.1 Scope. 352.3 Definitions. (UV) radiation. (1) Minimal sun protection product. A Subpart B—Active Ingredients sunscreen product that provides a sun protection factor (SPF) value of 2 to 352.10 Sunscreen active ingredients. under 12. 352.20 Permitted combinations of active ingredients. (2) Moderate sun protection product. A sunscreen product that provides an Subpart C—Labeling SPF value of 12 to under 30. (3) High sun protection product. A sun- 352.50 Principal display panel of all sunscreen product that provides an SPF screen drug products. value of 30 or above. 352.52 Labeling of sunscreen drug products. 352.60 Labeling of permitted combinations (c) Sunscreen active ingredient. An ac- of active ingredients. tive ingredient listed in § 352.10 that ab- sorbs, reflects, or scatters radiation in Subpart D—Testing Procedures the UV range at wavelengths from 290 to 400 nanometers. 352.70 Standard sunscreen. 352.71 Light source (solar simulator). (d) Sun protection factor (SPF) value. 352.72 General testing procedures. The UV energy required to produce an 352.73 Determination of SPF value. MED on protected skin divided by the 352.76 Determination if a product is water UV energy required to produce an MED resistant or very water resistant. on unprotected skin, which may also be 352.77 Test modifications. defined by the following ratio: SPF AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, value = MED (protected skin (PS))/ 360, 371. MED (unprotected skin (US)), where SOURCE: 64 FR 27687, May 21, 1999, unless MED (PS) is the minimal erythema otherwise noted. dose for protected skin after application of 2 milligrams per square centi- EFFECTIVE DATE NOTE: At 68 FR 33381, June 4, 2003, part 352 was stayed until further no- meter of the final formulation of the tice, effective June 4, 2004. sunscreen product, and MED (US) is the minimal erythema dose for unpro- Subpart A—General Provisions tected skin, i.e., skin to which no sunscreen product has been applied. In ef- § 352.1 Scope. fect, the SPF value is the reciprocal of (a) An over-the-counter sunscreen the effective transmission of the prod- drug product in a form suitable for top- uct viewed as a UV radiation filter. ical administration is generally recognized as safe and effective and is not Subpart B—Active Ingredients misbranded if it meets each condition in this part and each general condition § 352.10 Sunscreen active ingredients. established in § 330.1 of this chapter. The active ingredient of the product (b) References in this part to regu- consists of any of the following, within latory sections of the Code of Federal the concentration specified for each in- Regulations are to Chapter I of Title 21 gredient, and the finished product pro- unless otherwise noted. vides a minimum SPF value of not less

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than 2 as measured by the testing pro- combined with each other in a single cedures established in subpart D of this product when used in the concentra- part: tions established for each ingredient in (a) Aminobenzoic acid (PABA) up to § 352.10. The concentration of each ac- 15 percent. tive ingredient must be sufficient to (b) Avobenzone up to 3 percent. contribute a minimum SPF of not less (c) Cinoxate up to 3 percent. than 2 to the finished product. The fin- (d) [Reserved] ished product must have a minimum (e) Dioxybenzone up to 3 percent. SPF of not less than the number of (f) Homosalate up to 15 percent. sunscreen active ingredients used in (g) [Reserved] (h) Menthyl anthranilate up to 5 per- the combination multiplied by 2. cent. (2) Two or more sunscreen active in- (i) Octocrylene up to 10 percent. gredients identified in § 352.10(b), (c), (j) Octyl methoxycinnamate up to 7.5 (e), (f), (i) through (l), (o), and (q) may percent. be combined with each other in a single (k) Octyl salicylate up to 5 percent. product when used in the concentra- (l) Oxybenzone up to 6 percent. tions established for each ingredient in (m) Padimate O up to 8 percent. § 352.10. The concentration of each ac- (n) Phenylbenzimidazole sulfonic tive ingredient must be sufficient to acid up to 4 percent. contribute a minimum SPF of not less (o) Sulisobenzone up to 10 percent. than 2 to the finished product. The fin- (p) Titanium dioxide up to 25 percent. ished product must have a minimum (q) Trolamine salicylate up to 12 per- SPF of not less than the number of cent. sunscreen active ingredients used in (r) Zinc oxide up to 25 percent. the combination multiplied by 2. [64 FR 27687, May 21, 1999] (b) Combinations of sunscreen and skin EFFECTIVE DATE NOTE: At 67 FR 41823, June protectant active ingredients. Any single 20, 2002, § 352.10 was amended by revising sunscreen active ingredient or any per- paragraphs (f) through (n), effective Sept. 1, mitted combination of sunscreen ac- 2002. This amendment could not be incor- tive ingredients when used in the con- porated because at 66 FR 67485, Dec. 31, 2001, centrations established for each ingre- the effective date was stayed until further notice. For the convenience of the user, the dient in § 352.10 may be combined with revised text is set forth as follows: one or more skin protectant active ingredients identified in § 347.10(a), (d), § 352.10 Sunscreen active ingredients. (e), (g), (h), (i), (k), (l), (m), and (r) of this chapter. The concentration of each * * * * * sunscreen active ingredient must be (f) Ensulizole up to 4 percent. sufficient to contribute a minimum (g) Homosalate up to 15 percent. SPF of not less that 2 to the finished (h) [Reserved] product. The finished product must (i) Meradimate up to 5 percent. have a minimum SPF of not less than (j) Octinoxate up to 7.5 percent. (k) Octisalate up to 5 percent. the number of sunscreen active ingredi- (l) Octocrylene up to 10 percent. ents used in the combination multi- (m) Oxybenzone up to 6 percent. plied by 2, and the product must be la- (n) Padimate O up to 8 percent. beled according to § 352.60. (c) [Reserved] * * * * * [64 FR 27687, May 21, 1999, as amended at 68 § 352.20 Permitted combinations of ac- FR 33380, June 4, 2003] tive ingredients. EFFECTIVE DATE NOTE: At 67 FR 41823, June The SPF of any combination product 20, 2002, § 352.20 was amended by revising is measured by the testing procedures paragraphs (a)(1) through (a)(2), effective established in subpart D of this part. Sept. 1, 2002. This amendment could not be (a) Combinations of sunscreen active in- incorporated because at 66 FR 67485, Dec. 31, gredients. (1) Two or more sunscreen ac- 2001 the effective date was stayed until fur- tive ingredients identified in § 352.10(a), ther notice. For the convenience of the user, (c), (e), (f), and (h) through (r) may be the text is set forth as follows:

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§ 352.20 Permitted combinations of active (b) For products that satisfy the water ingredients. resistant sunscreen product testing procedures in § 352.76. (1) (Select one of the * * * * * following: ‘‘Water,’’ ‘‘Water/Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Resistant.’’ (a) Combinations of sunscreen active ingredients. (1) Two or more sunscreen active ingre- (2) ‘‘SPF (insert SPF value of the dients identified in § 352.10(a), (c), (e), (f), (g), product, as stated in paragraph (a)(1) and (i) through (r) may be combined with or (a)(2) of this section, after it has each other in a single product when used in been tested using the water resistant the concentrations established for each in- sunscreen product testing procedures gredient in § 352.10. The concentration of in § 352.76).’’ each active ingredient must be sufficient to (c) For products that satisfy the very contribute a minimum SPF of not less than water resistant sunscreen product testing 2 to the finished product. The finished prod- procedures in § 352.76. (1) ‘‘Very’’ (select uct must have a minimum SPF of not less than the number of sunscreen active ingredi- one of the following: ‘‘Water,’’ ‘‘Water/ ents used in the combination multiplied by 2. Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Re- (2) Two or more sunscreen active ingredi- sistant.’’ ents identified in § 352.10(b), (c), (e), (g), (j) (2) ‘‘SPF (insert SPF value of the through (m), (o), and (q) may be combined product, as stated in paragraph (a)(1) with each other in a single product when or (a)(2) of this section, after it has used in the concentrations established for been tested using the very water resist- each ingredient in § 352.10. The concentration ant sunscreen product testing proce- of each active ingredient must be sufficient dures in § 352.76).’’ to contribute a minimum SPF of not less than 2 to the finished product. The finished § 352.52 Labeling of sunscreen drug product must have a minimum SPF of not products. less than the number of sunscreen active ingredients used in the combination multiplied (a) Statement of identity. The labeling by 2. of the product contains the established name of the drug, if any, and identifies * * * * * the product as a ‘‘sunscreen.’’ (b) Indications. The labeling of the product states, under the heading Subpart C—Labeling ‘‘Uses,’’ all of the phrases listed in paragraph (b)(1) of this section that are § 352.50 Principal display panel of all applicable to the product and may con- sunscreen drug products. tain any of the additional phrases list- In addition to the statement of iden- ed in paragraph (b)(2) of this section, as tity required in § 352.52, the following appropriate. Other truthful and non- labeling statements shall be promi- misleading statements, describing only nently placed on the principal display the uses that have been established and panel: listed in this paragraph (b), may also (a) For products that do not satisfy the be used, as provided in § 330.1(c)(2) of water resistant or very water resistant this chapter, subject to the provisions sunscreen product testing procedures in of section 502 of the act relating to § 352.76—(1) For products with SPF values misbranding and the prohibition in sec- up to 30. ‘‘SPF (insert tested SPF value tion 301(d) of the act against the intro- of the product up to 30).’’ duction or delivery for introduction (2) For products with SPF values over into interstate commerce of unap- 30. ‘‘SPF 30’’ (select one of the fol- proved new drugs in violation of sec- lowing: ‘‘plus’’ or ‘‘ + ’’). Any state- tion 505(a) of the act. ment accompanying the marketed (1) For products containing any ingre- product that states a specific SPF dient in § 352.10. (i) ‘‘[bullet] 1 helps pre- value above 30 or similar language in- vent sunburn [bullet] higher SPF gives dicating a person can stay in the sun more sunburn protection’’. more than 30 times longer than with- (ii) For products that satisfy the water out sunscreen will cause the product to resistant testing procedures identified in be misbranded under section 502 of the § 352.76. ‘‘[bullet] retains SPF after 40 Federal Food, Drug, and Cosmetic Act (the act). 1 See § 201.66(b)(4) of this chapter.

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minutes of’’ (select one or more of the ing ‘‘Directions.’’ More detailed direc- following: ‘‘activity in the water,’’ tions applicable to a particular product ‘‘sweating,’’ or ‘‘perspiring’’). formulation (e.g., cream, gel, lotion, (iii) For products that satisfy the very oil, spray, etc.) may also be included. water resistant testing procedures identi- (1) For products containing any ingre- fied in § 352.76. ‘‘[bullet] retains SPF dient in § 352.10. (i) ‘‘[bullet] apply’’ (se- after 80 minutes of’’ (select one or more lect one or more of the following, as of the following: ‘‘activity in the applicable: ‘‘liberally,’’ ‘‘generously,’’ water,’’ ‘‘sweating,’’ or ‘‘perspiring’’). ‘‘smoothly,’’ or ‘‘evenly’’) ‘‘(insert ap- (2) Additional indications. In addition propriate time interval, if a waiting pe- to the indications provided in para- riod is needed) before sun exposure and graph (b)(1) of this section, the fol- as needed’’. lowing may be used for products con- (ii) ‘‘[bullet] children under 6 months taining any ingredient in § 352.10: of age: ask a doctor’’. (i) For products that provide an SPF of (2) In addition to the directions pro- 2 to under 12. Select one or both of the vided in § 352.52(d)(1), the following may following: [‘‘[bullet]’’ (select one of the be used for products containing any in- following: ‘‘provides minimal,’’ ‘‘pro- gredient in § 352.10. ‘‘[bullet] reapply as vides minimum,’’ ‘‘minimal,’’ or ‘‘min- needed or after towel drying, swim- imum’’) ‘‘protection against’’ (select ming, or’’ (select one of the following: one of the following: ‘‘sunburn’’ or ‘‘sweating’’ or ‘‘perspiring’’). ‘‘sunburn and tanning’’)], or ‘‘[bullet] (3) If the additional directions provided for skin that sunburns minimally’’. in § 352.52(d)(2) are used, the phrase ‘‘and (ii) For products that provide an SPF of as needed’’ in § 352.52(d)(1) is not re- 12 to under 30. Select one or both of the quired. following: [‘‘[bullet]’’ (select one of the (4) For products marketed as a lip pro- following: ‘‘provides moderate’’ or tectant or lipstick. The directions in ‘‘moderate’’) ‘‘protection against’’ (se- paragraphs (d)(1) and (d)(2) of this sec- lect one of the following: ‘‘sunburn’’ or tion are not required. ‘‘sunburn and tanning’’)], or ‘‘[bullet] (e) Statement on product performance— for skin that sunburns easily’’. (1) For products containing any ingre- (iii) For products that provide an SPF dient identified in § 352.10, the following of 30 or above. Select one or both of the PCD labeling claims may be used under following: [‘‘[bullet]’’ (select one of the the heading ‘‘Other information’’ or any- following: ‘‘provides high’’ or ‘‘high’’) where outside of the ‘‘Drug Facts’’ box or ‘‘protection against’’ (select one of the enclosure. following: ‘‘sunburn’’ or ‘‘sunburn and (i) For products containing active ingre- tanning’’)], or ‘‘[bullet] for skin highly dient(s) that provide an SPF value of 2 to sensitive to sunburn’’. under 12. (Select one of the following: (c) Warnings. The labeling of the ‘‘minimal’’ or ‘‘minimum’’) ‘‘sun pro- product contains the following warn- tection product.’’ ings under the heading ‘‘Warnings:’’ (ii) For products containing active in- (1) For products containing any ingre- gredient(s) that provide an SPF value of dient in § 352.10. (i) ‘‘When using this 12 to under 30. ‘‘moderate sun protec- product [bullet] keep out of eyes. Rinse tion product.’’ with water to remove.’’ (iii) For products containing active in- (ii) ‘‘Stop use and ask a doctor if gredient(s) that provide an SPF value of [bullet] rash or irritation develops and 30 or above. ‘‘high sun protection prod- lasts’’. uct.’’ (2) For products containing any ingre- (2) For products containing any ingredient identified in § 352.10 marketed as a dient identified in § 352.10, the following lip protectant or lipstick. The external labeling statement may be used under the use only warning in § 201.66(c)(5)(i) of heading ‘‘Other information’’ or any- this chapter and the warning in para- where outside of the ‘‘Drug Facts’’ box or graph (c)(1)(i) of this section are not re- enclosure. ‘‘Sun alert: Limiting sun ex- quired. posure, wearing protective clothing, (d) Directions. The labeling of the and using sunscreens may reduce the product contains the following state- risks of skin aging, skin cancer, and ments, as appropriate, under the head- other harmful effects of the sun.’’ Any

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variation of this statement will cause horizontal barlines and hairlines de- the product to be misbranded under scribed in § 201.66(d)(8), may be omitted. section 502 of the act. [64 FR 27687, May 21, 1999, as amended at 68 (f) Products labeled for use only on spe- FR 33380, June 4, 2003] cific small areas of the face (e.g., lips, nose, ears, and/or around eyes) and that § 352.60 Labeling of permitted com- meet the criteria established in binations of active ingredients. § 201.66(d)(10) of this chapter. The title, Statements of identity, indications, headings, subheadings, and information warnings, and directions for use, re- described in § 201.66(c) of this chapter spectively, applicable to each ingre- shall be printed in accordance with the dient in the product may be combined following specifications: to eliminate duplicative words or (1) The labeling shall meet the re- phrases so that the resulting informa- quirements of § 201.66(c) of this chapter tion is clear and understandable. except that the title, headings, and in- (a) Statement of identity. For a com- formation described in § 201.66(c)(1), bination drug product that has an es- (c)(3), and (c)(7) may be omitted, and tablished name, the labeling of the the headings, subheadings, and infor- product states the established name of mation described in § 201.66(c)(2), (c)(4), the combination drug product, followed (c)(5), and (c)(6) may be presented as by the statement of identity for each follows: ingredient in the combination, as es- (i) The active ingredients tablished in the statement of identity (§ 201.66(c)(2) of this chapter) shall be sections of the applicable OTC drug listed in alphabetical order. monographs. For a combination drug (ii) The heading and the indication product that does not have an estab- required by § 201.66(c)(4) of this chapter lished name, the labeling of the prod- may be limited to: ‘‘Use [in bold type] uct states the statement of identity for helps protect against sunburn.’’ For a each ingredient in the combination, as lip protectant product, the heading and established in the statement of iden- the indication required by § 201.66(c)(4) tity sections of the applicable OTC may be limited to: ‘‘Use [in bold type] drug monographs. helps protect against sunburn and (b) Indications. The labeling of the chapped lips.’’ product states, under the heading (iii) The ‘‘external use only’’ warning ‘‘Uses,’’ the indication(s) for each in- in § 201.66(c)(5)(i) of this chapter may be gredient in the combination as estab- omitted. lished in the indications sections of the (iv) The subheadings in applicable OTC drug monographs, un- § 201.66(c)(5)(iii) through (c)(5)(vii) of less otherwise stated in this paragraph. this chapter may be omitted, provided Other truthful and nonmisleading the information after the heading statements, describing only the indica- ‘‘Warnings’’ states: ‘‘Keep out of eyes.’’ tions for use that have been established and ‘‘Stop use if skin rash occurs.’’ in the applicable OTC drug monographs (v) The warning in § 201.66(c)(5)(x) of or listed in this paragraph (b), may this chapter may be limited to the fol- also be used, as provided by § 330.1(c)(2) lowing: ‘‘Keep out of reach of chil- of this chapter, subject to the provi- dren.’’ sions of section 502 of the Federal (vi) For a lip protectant product or Food, Drug, and Cosmetic Act (the act) lipstick, the warnings ‘‘Keep out of relating to misbranding and the prohi- eyes’’ in § 352.52(f)(1)(iv) and ‘‘Keep out bition in section 301(d) of the act of reach of children’’ in § 352.52(f)(1)(v) against the introduction or delivery for and the directions in § 352.52(d) may be introduction into interstate commerce omitted. of unapproved new drugs in violation of (2) The labeling shall be printed in section 505(a) of the act. accordance with the requirements of (1) In addition, the labeling of the § 201.66(d) of this chapter except that product may contain any of the ‘‘other any requirements related to allowable statements’’ that are identi- § 201.66(c)(1), (c)(3), and (c)(7), and the fied in the applicable monographs.

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(2) For permitted combinations con- mining the SPF value of a sunscreen taining a sunscreen and a skin protect- drug product to ensure the uniform ant identified in § 352.20(b), any or all of evaluation of sunscreen drug products. the applicable indications for sun- The standard sunscreen shall be an 8- screens in § 352.52(b) and the indication percent homosalate preparation with a for skin protectants in § 347.50(b)(2)(i) of mean SPF value of 4.47 (standard devi- this chapter should be used. For prod- ation = 1.279). In order for the SPF de- ucts marketed as a lip protectant, the termination of a test product to be indication in § 352.52(f)(1)(ii) should be considered valid, the SPF of the stand- used. ard sunscreen must fall within the (c) Warnings. The labeling of the standard deviation range of the ex- product states, under the heading pected SPF (i.e., 4.47 ±1.279) and the 95- ‘‘Warnings,’’ the warning(s) for each in- percent confidence interval for the gredient in the combination, as estab- mean SPF must contain the value 4. lished in the warnings section of the (b) Preparation of the standard applicable OTC drug monographs, ex- homosalate sunscreen. (1) The standard cept that the warning for skin homosalate sunscreen is prepared from protectants in § 347.50(c)(3) of this chap- two different preparations (preparation ter is not required for permitted com- A and preparation B) with the fol- binations containing a sunscreen and a lowing compositions: skin protectant identified in § 352.20(b). For products marketed as a lip protect- COMPOSITION OF PREPARATION A AND ant or lipstick, § 352.52(f)(1)(iii), PREPARATION B OF THE STANDARD SUNSCREEN (f)(1)(iv) (except ‘‘Keep out of eyes,’’ which may be omitted), and (f)(1)(vi) Ingredients Percent by weight apply. Preparation A (d) Directions. The labeling of the Lanolin ...... 5.00 Homosalate ...... 8.00 product states, under the heading ‘‘di- White petrolatum ...... 2.50 rections,’’ directions that conform to Stearic acid ...... 4.00 the directions established for each in- Propylparaben ...... 0.05 gredient in the directions sections of Preparation B Methylparaben ...... 0.10 the applicable OTC drug monographs, Edetate disodium ...... 0.05 unless otherwise stated in this para- Propylene glycol ...... 5.00 graph. When the time intervals or age Triethanolamine ...... 1.00 limitations for administration of the Purified water U.S.P ...... 74.30 individual ingredients differ, the direc- (2) Preparation A and preparation B tions for the combination product may are heated separately to 77 to 82 °C, not contain any dosage that exceeds with constant stirring, until the con- those established for any individual in- tents of each part are solubilized. Add gredient in the applicable OTC drug preparation A slowly to preparation B monograph(s), and may not provide for while stirring. Continue stirring until use by any age group lower than the the emulsion formed is cooled to room highest minimum age limit established temperature (15 to 30 °C). Add suffi- for any individual ingredient. For per- cient purified water to obtain 100 mitted combinations containing a sun- grams of standard sunscreen prepara- screen and a skin protectant identified tion. in § 352.20(b), the directions for sun- (c) Assay of the standard homosalate screens in § 352.52(d) should be used. For sunscreen. Assay the standard products marketed as a lip protectant or lipstick, § 352.52(d)(4) applies. homosalate sunscreen preparation by the following method to ensure proper [64 FR 27687, May 21, 1999, as amended at 68 concentration: FR 33380, June 4, 2003] (1) Preparation of the assay solvent. The solvent consists of 1 percent gla- Subpart D—Testing Procedures cial acetic acid (V/V) in denatured ethanol. The denatured ethanol should not § 352.70 Standard sunscreen. contain a UV radiation absorbing dena- (a) Laboratory validation. A standard turant. sunscreen shall be used concomitantly (2) Preparation of a 1-percent solution in the testing procedures for deter- of the standard homosalate sunscreen

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preparation. Accurately weigh 1 gram of its total energy output contributed by the standard homosalate sunscreen wavelengths longer than 400 nano- preparation into a 100-milliliter volu- meters. In addition, a solar simulator metric flask. Add 50 milliliters of the should have no significant time-related assay solvent. Heat on a steam bath fluctuations in radiation emissions and mix well. Cool the solution to after an appropriate warmup time, and room temperature (15 to 30 °C). Then it should have good beam uniformity dilute the solution to volume with the (within 10 percent) in the exposure assay solvent and mix well to make a plane. To ensure that the solar simu- 1-percent solution. lator delivers the appropriate spectrum (3) Preparation of the test solution (1:50 of UV radiation, it must be measured dilution of the 1-percent solution). Filter periodically with an accurately-cali- a portion of the 1-percent solution brated spectroradiometer system or through number 1 filter paper. Discard equivalent instrument. the first 10 to 15 milliliters of the filtrate. Collect the next 20 milliliters of § 352.72 General testing procedures. the filtrate (second collection). Add 1 (a) Selection of test subjects (male and milliliter of the second collection of female). (1) Only fair-skin subjects with the filtrate to a 50-milliliter volu- skin types I, II, and III using the fol- metric flask. Dilute this solution to lowing guidelines shall be selected: volume with assay solvent and mix well. This is the test solution (1:50 dilu- Selection of Fair-skin Subjects tion of the 1-percent solution). Skin Type and Sunburn and Tanning History (4) Spectrophotometric determination. (Based on first 30 to 45 minutes sun exposure The absorbance of the test solution is after a winter season of no sun exposure.) measured in a suitable double beam I—Always burns easily; never tans (sen- spectrophotometer with the assay sol- sitive). vent and reference beam at a wave- II—Always burns easily; tans minimally (sensitive). length near 306 nanometers. III—Burns moderately; tans gradually (light (5) Calculation of the concentration of brown) (normal). homosalate. The concentration of IV—Burns minimally; always tans well homosalate is determined by the fol- (moderate brown) (normal). lowing formula which takes into con- V—Rarely burns; tans profusely (dark sideration the absorbance of the sam- brown) (insensitive). ple of the test solution, the dilution of VI—Never burns; deeply pigmented (insensi- the 1-percent solution (1:50), the weight tive). of the sample of the standard (2) A medical history shall be ob- homosalate sunscreen preparation (1 tained from all subjects with emphasis gram), and the standard absorbance on the effects of sunlight on their skin. value (172) of homosalate as deter- Ascertain the general health of the in- mined by averaging the absorbance of a dividual, the individual’s skin type (I, large number of batches of raw II, or III), whether the individual is homosalate: taking medication (topical or sys- Concentration of homosalate = absorb- temic) that is known to produce abnor- ance × 50 × 100 × 172 = percent con- mal sunlight responses, and whether centration by weight. the individual is subject to any abnor- mal responses to sunlight, such as a § 352.71 Light source (solar simulator). phototoxic or photoallergic response. A solar simulator used for deter- (b) Test site inspection. The physical mining the SPF of a sunscreen drug examination shall determine the pres- product should be filtered so that it ence of sunburn, suntan, scars, active provides a continuous emission spec- dermal lesions, and uneven skin tones trum from 290 to 400 nanometers simi- on the areas of the back to be tested. lar to sunlight at sea level from the The presence of nevi, blemishes, or sun at a zenith angle of 10° it has less moles will be acceptable if in the phy- than 1 percent of its total energy out- sician’s judgment they will not inter- put contributed by nonsolar wave- fere with the study results. Excess hair lengths shorter than 290 nanometers; on the back is acceptable if the hair is and it has not more than 5 percent of clipped or shaved.

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(c) Informed consent. Legally effective being evaluated at the same time, the written informed consent must be ob- test products and the standard sun- tained from all individuals. screen, as specified in § 352.70, should be (d) Test site delineation—(1) Test site applied in a blinded, randomized man- area. A test site area serves as an area ner. If only one sunscreen drug product for determining the subject’s MED is being tested, the testing subsites after application of either the sun- should be exposed to the varying doses screen standard or the test sunscreen of UV radiation in a randomized man- product, or for determining the sub- ner. ject’s MED when the skin is unpro- (f) Waiting period. Before exposing the tected (control site). The area to be test site areas after applying a product, tested shall be the back between the a waiting period of at least 15 minutes beltline and the shoulder blade is required. (scapulae) and lateral to the midline. (g) Number of subjects. A test panel Each test site area for applying a prod- shall consist of not more than 25 sub- uct or the standard sunscreen shall be jects with the number fixed in advance a minimum of 50-square centimeters, by the investigator. From this panel, e.g., 5 × 10 centimeters. The test site at least 20 subjects must produce valid areas are outlined with ink. If the per- data for analysis. son is to be tested in an upright position, the lines shall be drawn on the (h) Response criteria. In order that the skin with the subject upright. If the person who evaluates the MED re- subject is to be tested while prone, the sponses does not know which sunscreen markings shall be made with the sub- formulation was applied to which site ject prone. or what doses of UV radiation were ad- (2) Test subsite area. Each test site ministered, he/she must not be the area shall be divided into at least three same person who applied the sunscreen test subsite areas that are at least 1 drug product to the test site or admin- square centimeter. Usually four or five istered the doses of UV radiation. After subsites are employed. Each test UV radiation exposure from the solar subsite within a test site area is sub- simulator is completed, all immediate jected to a specified dosage of UV radi- responses shall be recorded. These ination, in a series of UV radiation expo- clude several types of typical responses sures, in which the test site area is ex- such as the following: An immediate posed for the determination of the darkening or tanning, typically greyish MED. or purplish in color, fading in 30 to 60 (e) Application of test materials. To en- minutes, and attributed to photo-oxi- sure standardized reporting and to de- dation of existing melanin granules; fine a product’s SPF value, the applica- immediate reddening, fading rapidly, tion of the product shall be expressed and viewed as a normal response of on a weight basis per unit area which capillaries and venules to heat, visible establishes a standard film. Both the and infrared radiation; and an imme- test sunscreen product and the stand- diate generalized heat response, resem- ard sunscreen application shall be 2 bling prickly heat rash, fading in 30 to milligrams per square centimeter. For 60 minutes, and apparently caused by oils and most lotions, the viscosity is heat and moisture generally irritating such that the material can be applied to the skin’s surface. After the imme- with a volumetric syringe. For creams, diate responses are noted, each subject heavy gels, and butters, the product shall shield the exposed area from fur- shall be warmed slightly so that it can ther UV radiation for the remainder of be applied volumetrically. On heating, the test day. The MED is determined 22 care shall be taken not to alter the to 24 hours after exposure. The ery- product’s physical characteristics, es- thema responses of the test subject pecially separation of the formula- should be evaluated under the fol- tions. Pastes and ointments shall be lowing conditions: The source of illu- weighed, then applied by spreading on mination should be either a tungsten the test site area. A product shall be light bulb or a warm white fluorescent spread by using a finger cot. If two or light bulb that provides a level of illu- more sunscreen drug products are mination at the test site within the

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range of 450 to 550 lux, and the test sub- ly), or if the subject was noncompliant ject should be in the same position (e.g., subject withdraws from the test used when the test site was irradiated. due to illness or work conflicts, subject Testing depends upon determining the does not shield the exposed testing smallest dose of energy that produces sites from further UV radiation until redness reaching the borders of the ex- the MED is read, etc.). posure site at 22 to 24 hours postexposure for each series of expo- § 352.73 Determination of SPF value. sures. To determine the MED, some- (a)(1) The following erythema action what more intense erythemas must spectrum shall be used to calculate the also be produced. The goal is to have some exposures that produce abso- erythema effective exposure of a solar lutely no effect, and of those exposures simulator:

that produce an effect, the maximal ex- Vi (λ) = 1.0 (250 <λ <298 nm) posure should be no more than twice 0.094 (298 - λ) Vi (λ) = 1.0 (298 <λ <328 nano- the total energy of the minimal expo- meters) sure. 0.015 (139 - λ) Vi (λ) = 1.0 (328 <λ <400 nano- (i) Rejection of test data. Test data meters) shall be rejected if the exposure series fails to elicit an MED response on ei- (2) The data contained in this action ther the treated or unprotected skin spectrum are to be used as spectral sites, or if the responses on the treated weighting factors to calculate the ery- sites are randomly absent (which indi- thema effective exposure of a solar cates the product was not spread even- simulator as follows:

(b) Determination of MED of the unprotected skin to determine the subject’s tected skin. A series of UV radiation ex- inherent MED. The doses selected shall posures expressed as Joules per square be a geometric series represented by meter (adjusted to the erythema action (1.25n), wherein each exposure time in- spectrum calculated according to terval is 25 percent greater than the § 352.73(a)) is administered to the previous time to maintain the same subsite areas on each subject with an relative uncertainty (expressed as a accurately calibrated solar simulator. constant percentage), independent of A series of five exposures shall be ad- the subject’s sensitivity to UV radi- ministered to the untreated, unpro- ation, regardless of whether the subject

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has a high or low MED. Usually, the quired to produce the MED of the un- MED of a person’s unprotected skin is protected skin (control site) as follows: determined the day prior to testing a SPF value = the ratio of erythema ef- product. This MED(US) shall be used in fective exposure (Joules per square the determination of the series of UV meter) (MED(PS)) to the erythema ef- radiation exposures to be administered fective exposure (Joules per square to the protected site in subsequent meter) (MED(US)). testing. The MED(US) should be deter- (d) Determination of the test product’s mined again on the same day as the SPF value and PCD. Use data from at standard and test sunscreens and this least 20 test subjects with n rep- MED(US) should be used in calculating resenting the number of subjects used. the SPF. First, for each subject, compute the (c) Determination of individual SPF SPF value as stated in § 352.73(b) and values. A series of UV radiation expo- (c). Second, compute the mean SPF sures expressed as Joules per square value, x¯ , and the standard deviation, s, meter (adjusted to the erythema action for these subjects. Third, obtain the spectrum calculated according to upper 5-percent point from the t dis- § 352.73(a)) is administered to the tribution table with n-1 degrees of free- subsite areas on each subject with an dom. Denote this value by t. Fourth, accurately-calibrated solar simulator. compute ts/ √n. Denote this quantity A series of seven exposures shall be ad- by A (i.e., A = ts/ √n). Fifth, calculate ministered to the protected test sites the SPF value to be used in labeling as to determine the MED of the protected follows: the label SPF equals the larg- skin (MED(PS)). The doses selected est whole number less than x¯ . - A. shall consist of a geometric series of Sixth and last, the drug product is five exposures, where the middle expo- classified into a PCD as follows: if 30 + sure is placed to yield the expected A

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(2) 20 minutes moderate activity in be subject to the disclosure rules in water. part 20 of this chapter. (3) 20-minute rest period (do not towel test sites). PART 355—ANTICARIES DRUG (4) 20 minutes moderate activity in water. PRODUCTS FOR OVER-THE- (5) Conclude water test (air dry test COUNTER HUMAN USE sites without toweling). (6) Begin solar simulator exposure to Subpart A—General Provisions test site areas as described in § 352.73. Sec. (b) Procedure for testing a very water 355.1 Scope. resistant sunscreen product. For sun- 355.3 Definitions. screen products making the claim of ‘‘very water resistant,’’ the label SPF Subpart B—Active Ingredients shall be the label SPF value determined after 80 minutes of water immer- 355.10 Anticaries active ingredients. sion using the following procedure for 355.20 Packaging conditions. the very water resistant test: (1) Apply sunscreen product (followed Subpart C—Labeling by the waiting period after application 355.50 Labeling of anticaries drug products. of the sunscreen product indicated on 355.55 Principal display panel of all fluoride the product labeling). rinse drug products. (2) 20 minutes moderate activity in 335.60 Professional labeling. water. (3) 20-minute rest period (do not Subpart D—Testing Procedures towel test sites). (4) 20 minutes moderate activity in 355.70 Testing procedures for fluoride den- water. tifrice drug products. (5) 20-minute rest period (do not AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, towel test sites). 360, 371. (6) 20 minutes moderate activity in SOURCE: 60 FR 52507, Oct. 6, 1995, unless water. otherwise noted. (7) 20-minute rest period (do not towel test sites). EDITORIAL NOTE: Nomenclature changes to (8) 20 minutes moderate activity in part 355 appear at 69 FR 13717, Mar. 24, 2004. water. (9) Conclude water test (air dry test Subpart A—General Provisions sites without toweling). (10) Begin solar simulator exposure § 355.1 Scope. to test site areas as described in (a) An over-the-counter anticaries § 352.73. drug product in a form suitable for top- § 352.77 Test modifications. ical administration to the teeth is generally recognized as safe and effective The formulation or mode of adminis- and is not misbranded if it meets each tration of certain products may require condition in this part and each general modification of the testing procedures condition established in § 330.1 of this in this subpart. In addition, alternative chapter. methods (including automated or in (b) References in this part to regu- vitro procedures) employing the same latory sections of the Code of Federal basic procedures as those described in Regulations are to chapter I of title 21 this subpart may be used. Any proposed modification or alternative procedure unless otherwise noted. shall be submitted as a petition in ac- § 355.3 Definitions. cord with § 10.30 of this chapter. The petition should contain data to support As used in this part: the modification or data dem- (a) Abrasive. Solid materials that are onstrating that an alternative proce- added to dentifrices to facilitate me- dure provides results of equivalent ac- chanical removal of dental plaque, de- curacy. All information submitted will bris, and stain from tooth surfaces.

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(b) Anhydrous glycerin. An ingredient the appropriate fluoride concentration that may be prepared by heating glyc- specified in the monograph. ° erin U.S.P. at 150 C for 2 hours to drive [60 FR 52507, Oct. 6, 1995, as amended at 61 FR off the moisture content. 52286, Oct. 7, 1996] (c) Anticaries drug. A drug that aids in the prevention and prophylactic Subpart B—Active Ingredients treatment of dental cavities (decay, caries). § 355.10 Anticaries active ingredients. (d) Dental caries. A disease of calcified The active ingredient of the product tissues of teeth characterized by consists of any of the following when demineralization of the inorganic por- used in the concentration and dosage tion and destruction of the organic ma- form established for each ingredient: trix. (a) Sodium fluoride—(1) Dentifrices con- (e) Dentifrice. An abrasive-containing taining 850 to 1,150 ppm theoretical total dosage form (gel, paste, or powder) for fluorine in a gel or paste dosage form. So- delivering an anticaries drug to the dium fluoride 0.188 to 0.254 percent with teeth. an available fluoride ion concentration (f) Fluoride. The inorganic form of the ≥650 parts per million (ppm). chemical element fluorine in combina- (2) Dentifrices containing 850 to 1,150 tion with other elements. ppm theoretical total fluorine in a pow- (g) Fluoride ion. The negatively dered dosage form. Sodium fluoride 0.188 charged atom of the chemical element to 0.254 percent with an available fluo- fluorine. ride ion concentration of ≥850 ppm for (h) Fluoride supplement. A special products containing the abrasive so- treatment rinse dosage form that is indium bicarbonate and a poured-bulk tended to be swallowed, and is pro- density of 1.0 to 1.2 grams per milli- moted to health professionals for use in liter. areas where the water supply contains (3) Treatment rinses. (i) An aqueous so- 0 to 0.7 parts per million (ppm) fluoride lution of acidulated phosphate fluoride ion. derived from sodium fluoride (i) Preventive treatment gel. A dosage acidulated with a mixture of sodium form for delivering an anticaries drug phosphate, monobasic, and phosphoric to the teeth. Preventive treatment gels acid to a level of 0.1 molar phosphate are formulated in an anhydrous glyc- ion and a pH of 3.0 to 4.5 and which erin base with suitable thickening yields an effective fluoride ion con- agents included to adjust viscosity. centration of 0.02 percent. (ii) An aqueous solution of acidulated Preventive treatment gels do not con- phosphate fluoride derived from so- tain abrasives. dium fluoride acidulated with a mix- (j) Treatment rinse. A liquid dosage ture of sodium phosphate, dibasic, and form for delivering an anticaries drug phosphoric acid to a pH of 3.5 and to the teeth. which yields an effective fluoride ion (k) Treatment rinse concentrated solu- concentration of 0.01 percent. tion. A fluoride treatment rinse in a (iii) Sodium fluoride 0.02 percent concentrated form to be mixed with aqueous solution with a pH of approxi- water before using to result in the ap- mately 7. propriate fluoride concentration speci- (iv) Sodium fluoride 0.05 percent fied in the monograph. aqueous solution with a pH of approxi- (l) Treatment rinse effervescent tablets. mately 7. A fluoride treatment rinse prepared by (v) Sodium fluoride concentrate con- adding an effervescent tablet (a containing adequate directions for mixing centrated solid dosage form) to water with water before using to result in a before using to result in the appro- 0.02-percent or 0.05-percent aqueous so- priate fluoride concentration specified lution with a pH of approximately 7. in the monograph. (b) Sodium monofluorophosphate—(1) (m) Treatment rinse powder. A fluoride Dentifrices containing 850 to 1,150 ppm treatment rinse prepared by adding the theoretical total fluorine in a gel or paste powder (a concentrated solid dosage dosage form. Sodium monofluoro- form) to water before using to result in phosphate 0.654 to 0.884 percent with an

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available fluoride ion concentration ride powdered dentifrices shall be pack- = ¥ (consisting of PO3 F and F combined) aged in a tight container as defined as ≥800 ppm. a container that protects the contents (2) Dentifrices containing 1,500 ppm the- from contamination by extraneous liq- oretical total fluorine in a gel or paste uids, solids, or vapors, from loss of the dosage form. Sodium monofluoro- article, and from efflorescence, deli- phosphate 1.153 percent with an avail- quescence, or evaporation under the or- able fluoride ion concentration (con- dinary or customary conditions of han- = ¥ sisting of PO3 F and F combined) dling, shipment, storage, and distribu- ≥1,275 ppm. tion, and is capable of tight reclosure. (c) Stannous fluoride—(1) Dentifrices containing 850 to 1,150 ppm theoretical total fluorine in a gel or paste dosage Subpart C—Labeling form. (i) Stannous fluoride 0.351 to 0.474 § 355.50 Labeling of anticaries drug percent with an available fluoride ion products. concentration ≥700 ppm for products containing abrasives other than cal- (a) Statement of identity. The labeling cium pyrophosphate. of the product contains the established (ii) Stannous fluoride 0.351 to 0.474 name of the drug, if any, and identifies percent with an available fluoride ion the product as: (select one or both of concentration ≥290 ppm for products the following: ‘anticavity’ or ‘fluoride’) containing the abrasive calcium (select one of the following as appro- pyrophosphate. priate: ‘‘dentifrice,’’ ‘‘toothpaste,’’ (2) Preventive treatment gel. Stannous ‘‘tooth polish,’’ ‘‘tooth powder;’’ (op- fluoride 0.4 percent in an anhydrous tional: ‘‘dental’’) ‘‘preventive treat- glycerin gel, made from anhydrous ment gel;’’ or (optional: ‘‘treatment’’ glycerin and the addition of suitable or ‘‘dental’’)) (select one of the fol- thickening agents to adjust viscosity. lowing: ‘‘rinse,’’ ‘‘concentrated solu- (3) Treatment rinse. Stannous fluoride tion,’’ ‘‘rinse powder,’’ or ‘‘rinse effer- concentrate marketed in a stable form vescent tablets’’). The word ‘‘mouth- and containing adequate directions for wash’’ may be substituted for the word mixing with water immediately before ‘‘rinse’’ in this statement of identity if using to result in a 0.1-percent aqueous the product also has a cosmetic use, as solution. defined in section 201(i) of the Federal [60 FR 52507, Oct. 6, 1995, as amended at 61 FR Food, Drug, and Cosmetic Act (the act) 52286, Oct. 7, 1996] (21 U.S.C. 321(i)). (b) Indication. The labeling of the § 355.20 Packaging conditions. product states, under the heading ‘‘In- (a) Package size limitation. Due to the dication,’’ the following: ‘‘Aids in the toxicity associated with fluoride active prevention of dental (select one of the ingredients, the following package size following: ‘‘cavities,’’ ‘‘decay,’’ ‘‘caries limitations are required for anticaries (decay),’’ or ‘‘caries (cavities)’’). Other drug products: truthful and nonmisleading state- (1) Dentifrices. Dentifrice (toothpastes ments, describing only the indication and tooth powders) packages shall not for use that has been established and contain more than 276 milligrams (mg) listed in this paragraph (b), may also total fluorine per package. be used, as provided in § 330.1(c)(2) of (2) Preventive treatment gels and treat- this chapter, subject to the provisions ment rinses. Preventive treatment gel of section 502 of the Federal Food, and treatment rinse packages shall not Drug, and Cosmetic Act (the act) relat- contain more than 120 mg total fluo- ing to misbranding and the prohibition rine per package. in section 301(d) of the act against the (3) Exception. Package size limita- introduction or delivery for introduc- tions do not apply to anticaries drug tion into interstate commerce of unap- products marketed for professional of- proved new drugs in violation of sec- fice use only and labeled in accord with tion 505(a) of the act. § 355.60. (c) Warning. The labeling of the prod- (b) Tight container packaging. To min- uct contains the following warning imize moisture contamination, all fluo- under the heading ‘‘Warning’’:

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(1) For all fluoride dentifrice (gel, paste, older: Apply powder to a wet tooth- and powder) products. ‘‘Keep out of brush; completely cover all bristles. reach of children under 6 years of age. Brush for at least 30 seconds. Reapply [highlighted in bold type] If more than powder as before and brush again. used for brushing is accidentally swal- Rinse and spit out thoroughly. Brush lowed, get medical help or contact a teeth, preferably after each meal or at Poison Control Center right away.’’ least twice a day, or as directed by a These warnings shall be used in place dentist or doctor. Instruct children of the general warning statements re- under 12 years of age in good brushing quired by § 330.1(g) of this chapter. and rinsing habits (to minimize swal- (2) For all fluoride rinse and preventive lowing). Supervise children as nec- treatment gel products. ‘‘Keep out of essary until capable of using without reach of children. [highlighted in bold supervision. Children under 6 years of type] If more than used for’’ (select ap- age: Do not use unless directed by a propriate word: ‘‘brushing’’ or ‘‘rins- dentist or doctor. ing’’) ‘‘is accidentally swallowed, get (2) For anticaries treatment rinse prod- medical help or contact a Poison Con- ucts—(i) For acidulated phosphate fluo- trol Center right away.’’ These warn- ride solution containing 0.02 percent fluo- ings shall be used in place of the gen- ride ion, sodium fluoride 0.05 percent, so- eral warning statements required by dium fluoride concentrate, and stannous § 330.1(g) of this chapter. fluoride concentrate identified in (d) Directions. The labeling of the § 355.10(a)(3)(i), (a)(3)(iv), (a)(3)(v), and product contains the following state- (c)(3). Adults and children 6 years of ments under the heading ‘‘Directions’’: age and older: Use once a day after (1) For anticaries dentifrice products— brushing your teeth with a toothpaste. (i) Gel or paste dosage form with a theo- Vigorously swish 10 milliliters of rinse retical total fluorine concentration of 850 between your teeth for 1 minute and to 1,150 ppm identified in § 355.10(a)(1), then spit out. Do not swallow the rinse. (b)(1), and (c)(1). Adults and children 2 Do not eat or drink for 30 minutes after years of age and older: Brush teeth rinsing. Instruct children under 12 thoroughly, preferably after each meal years of age in good rinsing habits (to or at least twice a day, or as directed minimize swallowing). Supervise chil- by a dentist or doctor. Instruct children as necessary until capable of dren under 6 years of age in good using without supervision. Children brushing and rinsing habits (to mini- under 6 years of age: Consult a dentist mize swallowing). Supervise children or doctor. as necessary until capable of using (ii) For acidulated phosphate fluoride without supervision. Children under 2 solution containing 0.01 percent fluoride years of age: Consult a dentist or doc- ion and sodium fluoride 0.02 percent aque- tor. ous solution identified in § 355.10(a)(3)(ii) (ii) Gel or paste dosage form with a the- and (a)(3)(iii). Adults and children 6 oretical total fluorine concentration of years of age and older: Use twice a day 1,500 ppm identified in § 355.10(b)(2). after brushing your teeth with a tooth- Adults and children 6 years of age and paste. Vigorously swish 10 milliliters of older: Brush teeth thoroughly, pref- rinse between your teeth for 1 minute erably after each meal or at least twice and then spit out. Do not swallow the a day, or as directed by a dentist or rinse. Do not eat or drink for 30 min- doctor. Instruct children under 12 years utes after rinsing. Instruct children of age in good brushing and rinsing under 12 years of age in good rinsing habits (to minimize swallowing). Su- habits (to minimize swallowing). Su- pervise children as necessary until ca- pervise children as necessary until capable of using without supervision. pable of using without supervision. Children under 6 years of age: Do not Children under 6 years of age: consult a use unless directed by a dentist or doc- dentist or doctor. tor. (3) For stannous fluoride treatment (iii) Powdered dosage form with a theo- rinse products. (i) ‘‘Use immediately retical total fluorine concentration of 850 after preparing the rinse.’’ to 1,150 ppm identified in § 355.10(a)(2). (ii) For powder or effervescent tablets Adults and children 6 years of age and used to prepare treatment rinses. ‘‘Do not

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use as a rinse until all the’’ (select one age may wish to use this extra- of the following: ‘‘powder’’ or ‘‘tablet’’) strength fluoride dentifrice if they re- ‘‘has dissolved.’’ side in a nonfluoridated area or if they (4) For anticaries preventive treatment have a greater tendency to develop cav- gel products. Adults and children 6 ities.’’ years of age and older: Use once a day [60 FR 52507, Oct. 6, 1995; 60 FR 57927, Nov. 24, after brushing your teeth with a tooth- 1995; 61 FR 51187, Oct. 7, 1996; 64 FR 13296, paste. Apply the gel to your teeth and Mar. 17, 1999] brush thoroughly. Allow the gel to remain on your teeth for 1 minute and § 355.55 Principal display panel of all then spit out. Do not swallow the gel. fluoride rinse drug products. Do not eat or drink for 30 minutes after In addition to the statement of iden- brushing. Instruct children under 12 tity required in § 355.50, the following years of age in the use of this product statement shall be prominently placed (to minimize swallowing). Supervise on the principal display panel: ‘‘IM- children as necessary until capable of PORTANT: Read directions for proper using without supervision. Children use.’’ under 6 years of age: consult a dentist or doctor. § 355.60 Professional labeling. (5) For all concentrated treatment rinse (a) The labeling for anticaries fluo- solutions, powders, and effervescent tab- ride treatment rinses identified in lets. The following statement shall ap- § 355.10(a)(3) and (c)(3) that are spe- pear as the first statement under direc- cially formulated so they may be swal- tions: ‘‘Do not use before mixing with lowed (fluoride supplements) and are water.’’ provided to health professionals (but (e) Additional labeling statements for not to the general public) may contain anticaries drug products. The following the following additional dosage infor- statements need not appear under mation: Children 3 to under 14 years of warnings, but are required to appear on age: As a supplement in areas where the label of anticaries drugs products the water supply is nonfluoridated (less as applicable. than 0.3 parts per million (ppm)), clean (1) For all preventive treatment gels. the teeth with a toothpaste and rinse ‘‘This is a(n)’’ (select one or both of the with 5 milliliters (mL) of 0.02 percent following: ‘‘anticavity’’ or ‘‘fluoride’’) or 10 mL of 0.01 percent fluoride ion ‘‘preventive treatment gel, not a tooth- rinse daily, then swallow. When the paste. Read directions carefully before water supply contains 0.3 to 0.7 ppm using.’’ fluoride ion, reduce the dose to 2.5 mL (2) For all stannous fluoride treatment of 0.02 percent or 5 mL of 0.01 percent rinse, preventive treatment gel, and den- fluoride ion rinse daily. tifrice products. ‘‘This product may (b) The labeling for products mar- produce surface staining of the teeth. keted to health to health professionals Adequate toothbrushing may prevent in package sizes larger than those spec- these stains which are not harmful or ified in § 355.20 shall include the state- permanent and may be removed by ments: ‘‘For Professional Office Use your dentist.’’ Only’’ and ‘‘This product is not in- (f) Optional additional labeling state- tended for home or unsupervised con- ments—(1) For fluoride treatment rinses sumer use.’’ and preventive treatment gels. The following labeling statement may appear Subpart D—Testing Procedures in the required boxed area designated ‘‘APPROVED USES’’: ‘‘The combined § 355.70 Testing procedures for fluo- daily use of a fluoride preventive treat- ride dentifrice drug products. ment’’ (select one of the following: (a) A fluoride dentifrice drug product ‘‘rinse’’ or ‘‘gel’’) ‘‘and a fluoride tooth- shall meet the biological test require- paste can help reduce the incidence of ments for animal caries reduction and dental cavities.’’ one of the following tests: Enamel solu- (2) For dentifrice products containing bility reduction or fluoride enamel up- 1,500 ppm theoretical total fluorine. take. The testing procedures for these ‘‘Adults and children over 6 years of biological tests are labeled Biological

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Testing Procedures for Fluoride 357.250 Labeling of cholecystokinetic drug Dentifrices; these testing procedures are products. on file under Docket No. 80N–0042 in 357.280 Professional labeling. the Division of Dockets Management Subparts D–H [Reserved] (HFA–305), Food and Drug Administra- tion, 5630 Fishers Lane, rm. 1061, Rock- Subpart I—Deodorant Drug Products for ville, MD 20852, and are available on re- Internal Use quest to that office. (b) The United States Pharmacopeia 357.801 Scope. 357.803 Definitions. fluoride dentifrice reference standards 357.810 Active ingredients for deodorant along with reference standard stability drug products for internal use. profiles (total fluoride, available fluo- 357.850 Labeling of deodorant drug products ride ion, pH, and specific gravity) re- for internal use. quired to be used in the biological tests AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, are available to any purchaser upon 360, 371. written request to the United States Pharmacopeial Convention, Inc., 1260 Subpart A [Reserved] Twinbrook Parkway, Rockville, MD 20852. (c) Alternative testing procedures Subpart B—Anthelmintic Drug may be used. Any proposed modifica- Products tion or alternative testing procedures shall be submitted as a petition in ac- SOURCE: 51 FR 27759, Aug. 1, 1986, unless cord with § 10.30 of this chapter. The pe- otherwise noted. tition should contain data to support the modification or data dem- § 357.101 Scope. onstrating that an alternative testing (a) An over-the-counter anthelmintic procedure provides results of equiva- drug product in a form suitable for oral lent accuracy. All information sub- administration is generally recognized mitted will be subjected to the disclo- as safe and effective and is not mis- sure rules in part 20 of this chapter. branded if it meets each condition in this subpart and each general condition [60 FR 52507, Oct. 6, 1995, as amended at 68 FR established in § 330.1. 24879, May 9, 2003] (b) References in this subpart to regulatory sections of the Code of Federal PART 357—MISCELLANEOUS INTER- Regulations are to chapter I of title 21 NAL DRUG PRODUCTS FOR unless otherwise noted. OVER-THE-COUNTER HUMAN USE § 357.103 Definition. As used in this subpart: Subpart A [Reserved] Anthelmintic. An agent that is destructive to worms. Subpart B—Anthelmintic Drug Products § 357.110 Anthelmintic active ingre- Sec. dient. 357.101 Scope. 357.103 Definition. The active ingredient of the product 357.110 Anthelmintic active ingredient. is pyrantel pamoate when used within 357.150 Labeling of anthelmintic drug prod- the dosage limits established in ucts. § 357.150(d)(1). 357.152 Package inserts for anthelmintic drug products. § 357.150 Labeling of anthelmintic 357.180 Professional labeling. drug products. (a) Statement of identity. The labeling Subpart C—Cholecystokinetic Drug of the product contains the established Products name of the drug, if any, and identifies 357.201 Scope. the product as a ‘‘pinworm treatment.’’ 357.203 Definition. (b) Indication. The labeling of the 357.210 Cholecystokinetic active ingredi- product states, under the heading ‘‘In- ents. dication,’’ the following: ‘‘For the

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treatment of pinworms.’’ Other truth- directed by a doctor. Medication should ful and nonmisleading statements, de- only be taken on time as a single dose; scribing only the indications for use do not repeat treatment unless di- that have been established and listed in rected by a doctor. When one indi- this paragraph (b), may also be used, as vidual in a household has pinworms, provided in § 330.1(c)(2), subject to the the entire household should be treated provisions of section 502 of the act re- unless otherwise advised. See Warn- lating to misbranding and the prohibi- ings. If any worms other than tion in section 301(d) of the act against pinworms are present before or after the introduction or delivery for intro- treatment, consult a doctor. If any duction into interstate commerce of symptoms or pinworms are still unapproved new drugs in violation of present after treatment, consult a doc- section 505(a) of the act. tor. (c) Warnings. The labeling of the (3) ‘‘This product can be taken any product contains the following warn- time of day, with or without meals. It ings under the heading ‘‘Warnings’’: may be taken alone or with milk or (1) ‘‘Abdominal cramps, nausea, vom- fruit juice. Use of a laxative is not nec- iting, diarrhea, headache, or dizziness essary prior to, during, or after medi- sometimes occur after taking this cation.’’ drug. If any of these conditions persist (e) Optional wording. The word ‘‘phy- consult a doctor.’’ sician’’ may be substituted for the (2) ‘‘If you are pregnant or have liver word ‘‘doctor’’ in any of the labeling disease, do not take this product unless statements in this section. directed by a doctor.’’ [51 FR 27759, Aug. 1, 1986; 52 FR 7831, Mar. 13, (d) Directions. The labeling of the 1987, as amended at 53 FR 35810, Sept. 15, product contains the following infor- 1988] mation under the heading ‘‘Direc- tions’’: § 357.152 Package inserts for anthel- (1) Adults, children 12 years of age mintic drug products. and over, and children 2 years to under The labeling of the product contains 12 years of age: Oral dosage is a single a consumer package insert which in- dose of 5 milligrams of pyrantel base cludes the following information: per pound, or 11 milligrams per kilo- (a) A discussion of the symptoms sug- gram, of body weight not to exceed 1 gestive of pinworm infestation, includ- gram. Dosing information should be ing a statement that pinworms must be converted to easily understood direc- visually identified before taking this tions for the consumer using the fol- medication. lowing dosage schedule: (b) A detailed description of how to find and identify the pinworm. Weight Dosage (taken as a single dose) 1 (c) A commentary on the life cycle of the pinworm. Less than 25 pounds or Do not use unless directed under 2 years old. by a doctor. (d) A commentary on the ways in 25 to 37 pounds ...... 125 milligrams. which pinworms may be spread from 38 to 62 pounds ...... 250 milligrams. person to person and hygienic proce- 63 to 87 pounds ...... 375 milligrams. dures to follow to avoid such spreading. 88 to 112 pounds ...... 500 milligrams. 113 to 137 pounds ...... 625 milligrams. (e) The appropriate labeling informa- 138 to 162 pounds ...... 750 milligrams. tion contained in § 357.150 163 to 187 pounds ...... 875 milligrams. 188 pounds and over ...... 1,000 milligrams. (Collection of information requirement approved by the Office of Management and 1 Depending on the product, the label should state the quantity of drug as a liquid measurement (e.g., teaspoonsful) Budget under control number 0910–0232) or as the number of dosage units (e.g., tablets) to be taken for the varying body weights. (If appropriate, it is rec- [51 FR 27759, Aug. 1, 1986, as amended at 52 ommended that a measuring cup graduated by body weight FR 2515, Jan. 23, 1987] and/or liquid measurement be provided with the product.) Manufacturers should present this information as appropriate for their product and may vary the format of this chart as § 357.180 Professional labeling. necessary. The labeling provided to health pro- (2) ‘‘Read package insert carefully fessionals (but not to the general pub- before taking this medication. Take lic) may contain an additional indica- only according to directions and do not tion: ‘‘For the treatment of common exceed the recommended dosage unless roundworm infestation.’’

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Subpart C—Cholecystokinetic § 357.250 Labeling of cholecystokinetic Drug Products drug products. (a) Statement of identity. The labeling § 357.201 Scope. of the product contains the established (a) An over-the-counter name of the drug, if any, and identifies cholecystokinetic drug product in a the product as a ‘‘gallbladder diag- form suitable for oral administration is nostic agent.’’ generally recognized as safe and effec- (b) Indications. The labeling of the tive and is not misbranded if it meets product states, under the heading ‘‘In- each of the conditions in this subpart dications,’’ the following: ‘‘For the in addition to each of the general con- contraction of the gallbladder during ditions established in § 330.1. diagnostic gallbladder studies.’’ Other (b) References in this subpart to reg- truthful and nonmisleading state- ulatory sections of the Code of Federal ments, describing only the indications Regulations are to chapter I of title 21 for use that have been established and unless otherwise noted. listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2), sub- [48 FR 27005, June 10, 1983] ject to the provisions of section 502 of the act relating to misbranding and the § 357.203 Definition. prohibition in section 301(d) of the act As used in this subpart: against the introduction or delivery for Cholecystokinetic drug product. A drug introduction into interstate commerce product that causes contraction of the of unapproved new drugs in violation of gallbladder and is used during the section 505(a) of the act. course of diagnostic gallbladder studies (c) Warnings. [Reserved] (cholecystography). (d) Directions. The labeling of the product contains the following state- [48 FR 27005, June 10, 1983] ments under the heading ‘‘Directions’’: (1) ‘‘Take only when instructed by a § 357.210 Cholecystokinetic active ingredients. doctor:’’ (2) For products containing 50-percent The active ingredient of the product aqueous emulsion of corn oil. consists of any of the following when (i) ‘‘Shake well before using.’’ used within the specified concentration (ii) Oral dosage is 60 milliliters 20 and dosage form established for each minutes before diagnostic gallbladder ingredient: x-ray or as directed by a doctor. (a) 50-percent aqueous emulsion of (3) For products containing corn oil. hydrogeneated soybean oil. Oral dosage (b) Hydrogenated soybean oil in a is 12.4 grams in a suitable, water-dis- suitable, water-dispersible powder. The persible powder in 2 to 3 ounces of hydrogenated soybean oil is food-grade, water. Stir briskly to prepare a suspen- partially hydrogenated with a melting sion before using. Drink 20 minutes be- point of 41 to 43.5 °C, an iodine value of fore diagnostic gallbladder x-ray or as 65 to 69, and a fatty acid composition directed by a doctor. as follows: (e) The word ‘‘physician’’ may be substituted for the word ‘‘doctor’’ in any Percent Fatty acid com- of the labeling statements in this sec- position tion. Myristic acid ...... 0.1 [48 FR 27005, June 10, 1983, as amended at 51 Palmitic acid ...... 10.0 FR 16267, May 1, 1986; 52 FR 7830, Mar. 13, Palmitoleic acid ...... 0.1 1987; 54 FR 8321, Feb. 28, 1989] Stearic acid ...... 13.5 Oleic acid ...... 72.0 § 357.280 Professional labeling. Linoleic acid ...... 3.8 Linolenic acid ...... 0.1 The labeling provided to health pro- Arachidic acid ...... 0.5 fessionals (but not to the general pub- Behenic acid ...... 0.2 lic) may contain the following information for ingredients identified in [54 FR 8321, Feb. 28, 1989] § 357.210: Indication. ‘‘For visualization

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of biliary ducts during cholecys- (b) Indications. The labeling of the tography.’’ product states, under the heading ‘‘In- dications,’’ any of the phrases listed in [54 FR 8321, Feb. 28, 1989] paragraph (b) of this section as appropriate. Other truthful and nonmis- Subparts D–H [Reserved] leading statements, describing only the indications for use that have been es- Subpart I—Deodorant Drug tablished and listed in paragraph (b) of Products for Internal Use this section may also be used, as provided in § 330.1(c)(2) of this chapter, SOURCE: 55 FR 19865, May 11, 1990, unless subject to the provisions of section 502 otherwise noted. of the Federal Food, Drug, and Cos- metic Act (the act) relating to mis- § 357.801 Scope. branding and the prohibition in section (a) An over-the-counter deodorant 301(d) of the act against the introduc- drug product for internal use in a form tion or delivery for introduction into suitable for oral administration is gen- interstate commerce of unapproved erally recognized as safe and effective new drugs in violation of section 505(a) and is not misbranded if it meets each of the act. condition in this subpart and each gen- (1) For products containing bismuth eral condition established in § 330.1 of subgallate identified in § 357.810(a). ‘‘An this chapter. aid to reduce odor from a colostomy or (b) References in this subpart to reg- ileostomy.’’ ulatory sections of the Code of Federal (2) For products containing Regulations are to chapter I of title 21 chlorophyllin copper complex identified in unless otherwise noted. § 357.810(b). (i) ‘‘An aid to reduce odor from a colostomy or ileostomy.’’ § 357.803 Definitions. (ii) ‘‘An aid to reduce fecal odor due As used in this subpart: to incontinence.’’ (a) Colostomy. An external operative (c) Warnings. The labeling of the opening of the colon. product contains the following warn- (b) Deodorant for internal use. An in- ings under the heading ‘‘Warnings’’: (1) gredient taken internally to reduce For products containing chlorophyllin odors arising from conditions such as copper complex identified in § 357.810(b). colostomies, ileostomies, or fecal in- (i) ‘‘If cramps or diarrhea occurs, re- continence. duce the dosage. If symptoms persist, (c) Ileostomy. An external operative consult your doctor.’’ opening from the ileum. (ii) The warning required by § 330.1(g) (d) Incontinence. An inability to re- of this chapter concerning overdose is tain urine or feces. not required on products containing chlorophyllin copper complex identi- § 357.810 Active ingredients for deo- fied in § 357.810(b). dorant drug products for internal (2) [Reserved] use. (d) Directions. The labeling of the The active ingredient of the product product contains the following infor- consists of either of the following when mation under the heading ‘‘Direc- used within the dosage limits estab- tions.’’ lished for each ingredient in § 357.850(d): (1) For products containing bismuth (a) Bismuth subgallate. subgallate identified in § 357.810(a). (b) Chlorophyllin copper complex. Adults and children 12 years of age and over: Oral dosage is 200 to 400 milli- § 357.850 Labeling of deodorant drug grams up to 4 times daily. Children products for internal use. under 12 years of age: consult a doctor. (a) Statement of identity. The labeling (2) For products containing of the product contains the established chlorophyllin copper complex identified in name of the drug, if any, and identifies § 357.810(b). Adults and children 12 years the product as a ‘‘deodorant for inter- of age and over: Oral dosage is 100 to nal use’’ or as a ‘‘colostomy or ileos- 200 milligrams daily in divided doses as tomy deodorant.’’ required. If odor is not controlled, take

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up to an additional 100 milligrams 358.720 Permitted combinations of active in- daily in divided doses as required. The gredients. smallest effective dose should be used. 358.750 Labeling of drug products for the Do not exceed 300 milligrams daily. control of dandruff, seborrheic dermatitis, or psoriasis. Children under 12 years of age: consult 358.760 Labeling of permitted combinations a doctor. of active ingredients for the control of dandruff.

PART 358—MISCELLANEOUS EXTER- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, NAL DRUG PRODUCTS FOR 360, 371.

OVER-THE-COUNTER HUMAN SOURCE: 55 FR 33255, Aug. 14, 1990, unless USE otherwise noted.

Subpart A [Reserved] Subpart A [Reserved] Subpart B—Wart Remover Drug Products Subpart B—Wart Remover Drug Sec. Products 358.101 Scope. 358.103 Definitions. § 358.101 Scope. 358.110 Wart remover active ingredients. 358.150 Labeling of wart remover drug prod- (a) An over-the-counter wart remover ucts. drug product in a form suitable for topical application is generally recognized Subpart C [Reserved] as safe and effective and is not misbranded if it meets each of the condi- Subpart D—Ingrown Toenail Relief Drug tions in this subpart and each of the Products general conditions established in § 330.1 358.301 Scope. of this chapter. 358.303 Definitions. (b) References in this subpart to reg- 358.310 Ingrown toenail relief active ingre- ulatory sections of the Code of Federal dient. Regulations are to chapter I of title 21 358.350 Labeling of ingrown toenail relief unless otherwise noted. drug products. § 358.103 Definitions. Subpart E [Reserved] As used in this subpart: Subpart F—Corn and Callus Remover Drug (a) Wart remover drug product. A top- Products ical agent used for the removal of common or plantar warts. 358.501 Scope. (b) Collodion-like vehicle. A solution 358.503 Definitions. containing pyroxylin (nitrocellulose) 358.510 Corn and callus remover active ingredients. in an appropriate nonaqueous solvent 358.550 Labeling of corn and callus remover that leaves a transparent cohesive film drug products. when applied to the skin in a thin layer. Subpart G—Pediculicide Drug Products (c) Plaster vehicle. A fabric, plastic, or other suitable backing material in 358.601 Scope. which medication is usually incor- 358.603 Definition. 358.610 Pediculicide active ingredients. porated for topical application to the 358.650 Labeling of pediculicide drug prod- skin. ucts. § 358.110 Wart remover active ingredi- Subpart H—Drug Products for the Control ents. of Dandruff, Seborrheic Dermatitis, and The product consists of any of the Psoriasis following active ingredients within the specified concentration and in the dos- 358.701 Scope. 358.703 Definitions. age form established for each ingre- 358.710 Active ingredients for the control of dient. dandruff, seborrheic dermatitis, or psori- (a) Salicylic acid 12 to 40 percent in a asis. plaster vehicle.

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(b) Salicylic acid 5 to 17 percent in a flammable,’’ ‘‘flammable,’’ ‘‘combus- collodion-like vehicle. tible,’’ consistent with 16 CFR (c) Salicylic acid 15 percent in a 1500.3(b)(10). karaya gum, glycol plaster vehicle. (ii) ‘‘Keep away from fire or flame.’’ (3) For any product formulated in a § 358.150 Labeling of wart remover volatile vehicle. ‘‘Cap bottle tightly and drug products. store at room temperature away from (a) Statement of identity. The labeling heat.’’ of the product contains the established (4) For any product formulated in a col- name of the drug, if any, and identifies lodion-like vehicle. (i) ‘‘If product gets the product as a ‘‘wart remover.’’ into the eye, flush with water for 15 (b) Indications. The labeling of the minutes.’’ product states, under the heading ‘‘In- (ii) ‘‘Avoid inhaling vapors.’’ dications,’’ any of the phrases listed in (d) Directions. The labeling of the paragraph (b) of this section. Other product contains the following infor- truthful and nonmisleading statements, describing only the indications mation under the heading ‘‘Direc- for use that have been established in tions’’: paragraph (b) of this section, may also (1) For products containing salicylic be used, as provided in § 330.1(c)(2) of acid identified in § 358.110(a). ‘‘Wash af- this chapter, subject to the provisions fected area.’’ (Optional: ‘‘May soak of section 502 of the Federal Food, wart in warm water for 5 minutes.’’) Drug, and Cosmetic Act (the act) relat- ‘‘Dry area thoroughly.’’ (If appropriate: ing to misbranding and the prohibition ‘‘Cut plaster to fit wart.’’) ‘‘Apply in section 301(d) of the act against the medicated plaster. Repeat procedure introduction or delivery for introduc- every 48 hours as needed (until wart is tion into interstate commerce of unap- removed) for up to 12 weeks.’’ proved new drugs in violation of sec- (2) For products containing salicylic tion 505(a) of the act. acid identified in § 358.110(b). ‘‘Wash af- (1) ‘‘For the removal of common fected area.’’ (Optional: ‘‘May soak warts. The common wart is easily rec- wart in warm water for 5 minutes.’’) ognized by the rough ‘cauliflower-like’ ‘‘Dry area thoroughly. Apply’’ (select appearance of the surface.’’ one of the following, as appropriate: (2) ‘‘For the removal of plantar warts ‘‘one drop’’ or ‘‘small amount’’) ‘‘at a on the bottom of the foot. The plantar time with’’ (select one of the following, wart is recognized by its location only as appropriate: ‘‘applicator’’ or on the bottom of the foot, its tender- ‘‘brush’’) ‘‘to sufficiently cover each ness, and the interruption of the foot- wart. Let dry. Repeat this procedure print pattern.’’ once or twice daily as needed (until (c) Warnings. The labeling of the wart is removed) for up to 12 weeks.’’ product contains the following warn- (3) For products containing salicylic ings under the heading ‘‘Warnings’’: acid identified in § 358.110(c). ‘‘Wash af- (1) For products containing any ingre- fected area.’’ (Optional: ‘‘May soak dient identified in § 358.110. (i) ‘‘For ex- wart in warm water for 5 minutes.’’) ternal use only.’’ ‘‘Dry area thoroughly. Gently smooth (ii) ‘‘Do not use this product on irri- wart surface with emery file supplied.’’ tated skin, on any area that is infected (If appropriate: ‘‘Cut plaster to fit or reddened, if you are a diabetic, or if wart.’’) ‘‘Apply a drop of warm water to you have poor blood circulation.’’ the wart, keeping the surrounding skin (iii) ‘‘If discomfort persists, see your dry. Apply medicated plaster at bed- doctor.’’ time and leave in place for at least 8 (iv) ‘‘Do not use on moles, birth- hours. In the morning, remove plaster marks, warts with hair growing from and discard. Repeat procedure every 24 them, genital warts, or warts on the hours as needed (until wart is removed) face or mucous membranes.’’ for up to 12 weeks.’’ (2) For any product formulated in a (e) The word ‘‘physician’’ may be sub- flammable vehicle. (i) The labeling stituted for the word ‘‘doctor’’ in any should contain an appropriate flamma- of the labeling statements in this sec- bility signal word, e.g. ‘‘extremely tion.

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(f) The phrase ‘‘or podiatrist’’ may be molecules interpenetrated with a liq- used in addition to the word ‘‘doctor’’ uid. in any of the labeling statements in this section when a product is labeled § 358.350 Labeling of ingrown toenail with the indication identified in relief drug products. § 358.150(b)(2). (a) Statement of identity. The labeling of the product contains the established [55 FR 33255, Aug. 14, 1990; 55 FR 37403, Sept. 11, 1990, as amended at 57 FR 44495, Sept. 28, name of the product, if any, and identi- 1992; 59 FR 60317, Nov. 23, 1994] fies the product as an ‘‘ingrown toenail relief product’’ or as an ‘‘ingrown toe- Subpart C [Reserved] nail discomfort reliever.’’ (b) Indications. The labeling of the product states, under the heading Subpart D—Ingrown Toenail Relief ‘‘Use,’’ the following: ‘‘for temporary Drug Products relief of’’ [select one or both of the following: ‘pain’ or ‘discomfort’] ‘‘from in- SOURCE: 68 FR 24348, May 7, 2003, unless grown toenails’’. Other truthful and otherwise noted. nonmisleading statements, describing only the use that has been established § 358.301 Scope. and listed in this paragraph (b), may (a) An over-the-counter ingrown toe- also be used, as provided in § 330.1(c)(2) nail relief drug product in a form suit- of this chapter, subject to the provi- able for topical administration is gen- sions of section 502 of the Federal erally recognized as safe and effective Food, Drug, and Cosmetic Act (the act) and is not misbranded if it meets each relating to misbranding and the prohi- condition in this subpart and each gen- bition in section 301(d) of the act eral condition established in § 330.1 of against the introduction or delivery for this chapter. introduction into interstate commerce (b) References in this subpart to reg- of unapproved new drugs in violation of ulatory sections of the Code of Federal section 505(a) of the act. Regulations are to chapter 1 of title 21 (c) Warnings. The labeling of the unless otherwise noted. product contains the following warnings under the heading ‘‘Warnings’’: § 358.303 Definitions. (1) ‘‘For external use only’’ in accord As used in this subpart: with § 201.66(c)(5)(i) of this chapter. (a) Ingrown toenail relief drug product. (2) ‘‘Do not use [bullet] 1 on open A drug product applied to an ingrown sores’’. toenail that relieves pain or discomfort (3) ‘‘Ask a doctor before use if you either by softening the nail or by hard- have [bullet] diabetes [bullet] poor cir- ening the nail bed. culation [bullet] gout’’. (b) Retainer ring. A die cut poly- (4) ‘‘When using this product [bullet] ethylene foam pad coated on one side use with a retainer ring’’. with medical grade acrylic pressure- (5) ‘‘Stop use and ask a doctor if [bul- sensitive adhesive. The retainer ring let] redness or swelling of your toe in- has slots, center-cut completely creases [bullet] discharge is present through the foam with the cut of suffi- around the nail [bullet] symptoms last cient size to allow for localization of an more than 7 days or clear up and occur active ingredient in a gel vehicle to a again within a few days’’. specific target area. The retainer ring (d) Directions. The labeling of the is used with adhesive bandage strips to product contains the following state- place over the retainer ring to hold it ments under the heading ‘‘Directions’’: in place. (1) ‘‘[Bullet] adults and children 12 years and over:’’ § 358.310 Ingrown toenail relief active (i) ‘‘[Bullet] wash the affected area ingredient. and dry thoroughly [bullet] place re- The active ingredient of the product tainer ring on toe with slot over the is sodium sulfide 1 percent in a gel vehicle. The gel vehicle is an aqueous, 1 See § 201.66(b)(4) of this chapter for defini- semisolid system with large organic tion of bullet.

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area where the ingrown nail and the § 358.510 Corn and callus remover ac- skin meet. Smooth ring down firmly. tive ingredients. [bullet] apply enough gel product to fill The product consists of any of the the slot in the ring [bullet] place round following active ingredients within the center section of bandage strip directly specified concentrations and in the dos- over the gel-filled ring to seal the gel age form established for each ingre- in place. Smooth ends of bandage strip dient. around toes.’’ (a) Salicylic acid 12 to 40 percent in a (ii) ‘‘[Bullet] repeat twice daily plaster vehicle. (morning and night) for up to 7 days (b) Salicylic acid 12 to 17.6 percent in until discomfort is relieved or until the a collodion-like vehicle. nail can be lifted out of the nail groove § 358.550 Labeling of corn and callus and easily trimmed’’. remover drug products. (2) ‘‘[Bullet] children under 12 years: (a) Statement of identity. The labeling ask a doctor’’. of the product contains the established name of the drug, if any, and identifies Subpart E [Reserved] the product as a ‘‘corn and callus remover.’’ Subpart F—Corn and Callus (b) Indications. The labeling of the Remover Drug Products product states, under the heading ‘‘In- dications,’’ the phrase listed in paragraph (b)(1) of this section and may SOURCE: 55 FR 33261, Aug. 14, 1990, unless contain the additional phrase listed in otherwise noted. paragraph (b)(2) of this section. Other truthful and nonmisleading state- § 358.501 Scope. ments, describing only the indications (a) An over-the-counter corn and cal- for use that have been established in lus remover drug product in a form paragraph (b) of this section, may also suitable for topical application is gen- be used, as provided in § 330.1(c)(2) of erally recognized as safe and effective this chapter, subject to the provisions and is not misbranded if it meets each of section 502 of the Federal Food, of the conditions in this subpart and Drug, and Cosmetic Act (the act) relat- each of the general conditions estab- ing to misbranding and the prohibition lished in § 330.1 of this chapter. in section 301(d) of the act against the (b) References in this subpart to reg- introduction or delivery for introduc- ulatory sections of the Code of Federal tion into interstate commerce of unap- Regulations are to chapter I of title 21 proved new drugs in violation of sec- unless otherwise noted. tion 505(a) of the act. (1) ‘‘For the removal of corns and cal- § 358.503 Definitions. luses.’’ (2) In addition to the information As used in this subpart: identified in paragraph (b)(1) of this (a) Corn and callus remover drug prod- section, the labeling of the product uct. A topical agent used for the re- may contain the following statement: moval of corns and calluses. ‘‘Relieves pain by removing corns and (b) Collodion-like vehicle. A solution calluses.’’ containing pyroxylin (nitrocellulose) (c) Warnings. The labeling of the in an appropriate nonaqueous solvent product contains the following warn- that leaves a transparent cohesive film ings under the heading ‘‘Warnings’’: when applied to the skin in a thin (1) For products containing any ingre- layer. dient identified in § 358.510. (i) ‘‘For ex- (c) Plaster vehicle. A fabric, plastic, or ternal use only.’’ other suitable backing material in (ii) ‘‘Do not use this product on irritated skin, on any area that is infected which medication is usually incor- or reddened, if you are a diabetic, or if porated for topical application to the you have poor blood circulation.’’ skin. (iii) ‘‘If discomfort persists, see your doctor or podiatrist.’’

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(2) For any product formulated in a § 358.601 Scope. flammable vehicle. (i) The labeling (a) An over-the-counter pediculicide should contain an appropriate flamma- drug product in a form suitable for top- bility signal word, e.g., ‘‘extremely ical application is generally recognized flammable,’’ ‘‘flammable,’’ ‘‘combus- as safe and effective and is not mis- tible,’’ consistent with 16 CFR branded if it meets each condition in 1500.3(b)(10). this subpart and each general condition (ii) ‘‘Keep away from fire or flame.’’ established in § 330.1 of this chapter. (3) For any product formulated in a volatile vehicle. ‘‘Cap bottle tightly and (b) References in this subpart to reg- store at room temperature away from ulatory sections of the Code of Federal heat.’’ Regulations are to chapter I of title 21 unless otherwise noted. (4) For any product formulated in a collodion-like vehicle. (i) ‘‘If product gets § 358.603 Definition. into the eye, flush with water for 15 minutes.’’ As used in this subpart: (ii) ‘‘Avoid inhaling vapors.’’ Pediculicide drug product. A drug (d) Directions. The labeling of the product for the treatment of head, product contains the following infor- pubic (crab), and body lice. mation under the heading ‘‘Direc- tions’’: § 358.610 Pediculicide active ingredi- (1) For products containing salicylic ents. acid identified in § 358.510(a). ‘‘Wash af- The active ingredients of the product fected area and dry thoroughly.’’ (If ap- consist of the combination of pyre- propriate: ‘‘Cut plaster to fit corn/cal- thrum extract (providing a concentra- lus.’’) ‘‘Apply medicated plaster. After tion of pyrethrins of 0.17 to 0.33 per- 48 hours remove the medicated plaster. cent) with piperonyl butoxide (2 to 4 Repeat this procedure every 48 hours as percent) in a nonaerosol dosage formu- needed for up to 14 days (until corn/cal- lation. lus is removed).’’ (Optional: ‘‘May soak corn/callus in warm water for 5 min- [63 FR 43303, Aug. 13, 1998] utes to assist in removal.’’) § 358.650 Labeling of pediculicide drug (2) For products containing salicylic products. acid identified in § 358.510(b). ‘‘Wash affected area and dry thoroughly. Apply’’ (a) Statement of identity. The labeling (select one of the following, as appro- of the product contains the established priate: ‘‘one drop’’ or ‘‘small amount’’) name of the drug, if any, and identifies ‘‘at a time with’’ (select one of the fol- the product as a ‘‘lice treatment.’’ lowing, as appropriate: ‘‘applicator’’ or (b) Indications. The labeling of the ‘‘brush’’) ‘‘to sufficiently cover each product states, under the heading corn/callus. Let dry. Repeat this proce- ‘‘Uses,’’ the following: ‘‘treats head, dure once or twice daily as needed for pubic (crab), and body lice.’’ Other up to 14 days (until corn/callus is re- truthful and nonmisleading state- moved).’’ (Optional: ‘‘May soak corn/ ments, describing only the uses that callus in warm water for 5 minutes to have been established and listed in this assist in removal.’’) paragraph (b), may also be used, as pro- (e) The word ‘‘physician’’ may be sub- vided in § 330.1(c)(2) of this chapter, stituted for the word ‘‘doctor’’ in any subject to the provisions of section 502 of the labeling statements in this sec- of the Federal Food, Drug, and Cos- tion. metic Act (the act) relating to misbranding and the prohibition in section [55 FR 33261, Aug. 14, 1990, as amended at 57 301(d) of the act against the introduc- FR 44494, Sept. 28, 1992] tion or delivery for introduction into interstate commerce of unapproved Subpart G—Pediculicide Drug new drugs in violation of section 505(a) Products of the act. (c) Warnings. The labeling of the SOURCE: 58 FR 65455, Dec. 14, 1993, unless product contains the following warn- otherwise noted. ings under the heading ‘‘Warnings’’:

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(1) ‘‘For external use only’’ in accord (ii) For nonshampoo products ‘‘Treat with § 201.66(c)(5)(i) of this chapter. [in bold type] [bullet] apply thoroughly (2) ‘‘Do not use [bullet] 1 near eyes to (optional, may add ‘‘dry’’) hair or [bullet] inside nose, mouth, or vagina other affected area. For head lice, first [bullet] on lice in eyebrows or eye- apply behind ears and to back of neck. lashes. See a doctor if lice are present [bullet] allow product to remain for 10 in these areas.’’ minutes, but no longer [bullet] wash (3) ‘‘Ask a doctor before use if you area thoroughly with warm water and are [bullet] allergic to ragweed. May soap or shampoo [bullet] for head lice, cause breathing difficulty or an asth- towel dry hair and comb out tangles’’. matic attack.’’ (5) ‘‘Remove lice and their eggs (nits) (4) ‘‘When using this product [bullet] [in bold type] [bullet] use a fine-tooth keep eyes tightly closed and protect or special lice/nit comb. Remove any eyes with a washcloth or towel [bullet] remaining nits by hand (using a throw- if product gets in eyes, flush with away glove). [bullet] hair should re- water right away [bullet] scalp itching main slightly damp while removing or redness may occur’’. nits [bullet] if hair dries during comb- (5) ‘‘Stop use and ask a doctor if [bul- ing, dampen slightly with water [bullet] breathing difficulty occurs [bullet] let] for head lice, part hair into sec- eye irritation occurs [bullet] skin or tions. Do one section at a time starting scalp irritation continues or infection on top of head. Longer hair may take 1 occurs’’. to 2 hours. [bullet] lift a 1- to 2-inch (d) Directions. The labeling of the wide strand of hair. Place comb as product contains the following infor- close to scalp as possible and comb mation under the heading ‘‘Direc- with a firm, even motion away from tions’’: scalp. [bullet] pin back each strand of (1) The labeling states ‘‘[bullet] Im- hair after combing [bullet] clean comb portant: Read warnings before use’’ often. Wipe nits away with tissue and [statement shall appear first and in discard in a plastic bag. Seal bag and bold type]. discard to prevent lice from coming (2) The labeling states ‘‘adults and back. [bullet] after combing, thor- children 2 years and over:’’ [in bold oughly recheck for lice/nits. Repeat type]. combing if necessary. [bullet] check (3) For head lice treatment products daily for any lice/nits that you ‘‘Inspect [in bold type] [bullet] check missed’’. each household member with a magni- (6) The labeling states ‘‘[bullet] a sec- fying glass in bright light for lice/nits ond treatment must be done in 7 to 10 (eggs) [bullet] look for tiny nits near days to kill any newly hatched lice’’. scalp, beginning at back of neck and (7) The labeling states ‘‘[bullet] if in- behind ears [bullet] examine small sec- festation continues, see a doctor for tions of hair at a time [bullet] unlike other treatments’’. dandruff which moves when touched, (8) The labeling states ‘‘children nits stick to the hair [bullet] if either under 2 years:’’ [in bold type] ‘‘ask a lice or nits are found, treat with this doctor’’. product’’. (e) Other information. The labeling of (4) Select one of the following: the product contains the following (i) For shampoo products ‘‘Treat [in statements, as appropriate, under the bold type] [bullet] apply thoroughly to heading ‘‘Other information.’’ This in- (optional, may add ‘‘dry’’) hair or other formation may appear in a package in- affected area. For head lice, first apply sert. If a package insert is used, the behind ears and to back of neck. [bul- ‘‘Other information’’ section on the let] allow product to remain for 10 min- outer carton or container label shall utes, but no longer [bullet] use warm include a statement referring to the water to form a lather, shampoo, then package insert for additional informa- thoroughly rinse [bullet] for head lice, tion. towel dry hair and comb out tangles’’. (1) ‘‘Head lice [highlighted in bold type] [bullet] lay small white eggs 1 See § 201.66(b)(4) of this chapter for defini- (nits) on hair shaft close to scalp [bul- tion of bullet symbol. let] nits are most easily found on back

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of neck or behind ears [bullet] disinfect Subpart H—Drug Products for the hats, hair ribbons, scarves, coats, tow- Control of Dandruff, els, and bed linens by machine washing Seborrheic Dermatitis, and in hot water (above 54 °C (130 °F)), then Psoriasis using hottest dryer cycle for at least 20 minutes [bullet] items that cannot be washed (bedspreads, blankets, pillows, SOURCE: 56 FR 63568, Dec. 4, 1991, unless otherwise noted. stuffed toys, etc.) should be dry- cleaned or sealed in a plastic bag for 4 § 358.701 Scope. weeks, then removed outdoors and (a) An over-the-counter dandruff, shaken out very hard before using seborrheic dermatitis, or psoriasis drug again [bullet] items that cannot be product in a form suitable for topical washed, dry-cleaned, or stored may be application is generally recognized as sprayed with a product designed for safe and effective and is not mis- this purpose [bullet] soak all combs branded if it meets each of the condi- ° and brushes in hot water (above 54 C tions in this subpart and each general (130 °F)) for at least 10 minutes [bullet] condition established in § 330.1 of this vacuum all carpets, mattresses, uphol- chapter. stered furniture, and car seats that (b) References in this subpart to reg- may have been used by affected peo- ulatory sections of the Code of Federal ple’’. Regulations are to chapter I of title 21 (2) ‘‘Pubic (crab) lice [highlighted in unless otherwise noted. bold type] [bullet] may be transmitted by sexual contact. Sexual partners § 358.703 Definitions. should be treated simultaneously to As used in this subpart: avoid reinfestation [bullet] lice are (a) Coal tar. The tar used for medic- very small and look like brown or grey inal purposes that is obtained as a by- dots on skin [bullet] usually cause in- product during the destructive distilla- tense itching and lay small white eggs tion of bituminous coal at tempera- (nits) on the hair shaft generally close tures in the range of 900 °C to 1,100 °C. to the skin surface [bullet] may be It may be further processed using ei- present on the short hairs of groin, ther extraction with alcohol and suit- thighs, trunk, and underarms, and oc- able dispersing agents and maceration casionally on the beard and mustache times or fractional distillation with or [bullet] disinfect underwear by ma- without the use of suitable organic sol- chine washing in hot water (above 54 °C vents. (130 °F)), then using hottest dryer cycle (b) Dandruff. A condition involving for at least 20 minutes’’. an increased rate of shedding of dead (3) ‘‘Body lice [highlighted in bold epidermal cells of the scalp. type] [bullet] body lice and their eggs (c) Psoriasis. A condition of the scalp (nits) are generally found in the seams or body characterized by irritation, of clothing particularly in waistline itching, redness, and extreme excess shedding of dead epidermal cells. and armpit area [bullet] body lice feed on skin then return to clothing to lay (d) Seborrheic dermatitis. A condition of the scalp or body characterized by their eggs [bullet] disinfect clothing by irritation, itching, redness, and excess machine washing in hot water (above shedding of dead epidermal cells. 54 °C (130 °F)), then using hottest dryer (e) Selenium sulfide, micronized. Se- cycle for at least 20 minutes [bullet] do lenium sulfide that has been finely not seal clothing in a plastic bag be- ground and that has a median particle cause nits can remain dormant for up size of approximately 5 micrometers to 30 days’’. (μm), with not more than 0.1 percent of [68 FR 75417, Dec. 31, 2003] the particles greater than 15 μm and not more than 0.1 percent of the particles less than 0.5 μm. [56 FR 63568, Dec. 4, 1991, as amended at 59 FR 4001, Jan. 28, 1994]

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§ 358.710 Active ingredients for the § 358.720 Permitted combinations of control of dandruff, seborrheic der- active ingredients. matitis, or psoriasis. (a) Combination of active ingredients The active ingredient of the product for the control of dandruff. Salicylic consists of any of the following within acid identified in § 358.710(a)(4) may be the specified concentration established combined with sulfur identified in for each ingredient: § 358.710(a)(7) provided each ingredient (a) Active ingredients for the control of is present within the established con- dandruff. (1) Coal tar, 0.5 to 5 percent. centration and the product is labeled When a coal tar solution, derivative, or according to § 358.750. fraction is used as the source of the (b) Combination of control of dandruff coal tar, the labeling shall specify the and external analgesic active ingredients. identity and concentration of the coal Coal tar identified in § 358.710(a)(1) may tar source used and the concentration be used at a concentration of 1.8 per- of the coal tar present in the final cent coal tar solution, on a weight to product. volume basis, in combination with (2) Pyrithione zinc, 0.3 to 2 percent menthol, 1.5 percent, in a shampoo for- when formulated to be applied and then mulation provided the product is la- washed off after brief exposure. beled according to § 358.760. (3) Pyrithione zinc, 0.1 to 0.25 percent [72 FR 9852, Mar. 6, 2007] when formulated to be applied and left on the skin or scalp. § 358.750 Labeling of drug products for (4) Salicylic acid, 1.8 to 3 percent. the control of dandruff, seborrheic (5) Selenium sulfide, 1 percent. dermatitis, or psoriasis. (6) Selenium sulfide, micronized, 0.6 (a) Statement of identity. The labeling percent. of the product contains the established (7) Sulfur, 2 to 5 percent. name of the drug, if any, and identifies (b) Active ingredients for the control of the product with one or more of the seborrheic dermatitis. (1) Coal tar, 0.5 to following, as appropriate: 5 percent. When a coal tar solution, de- (1) ‘‘Dandruff (insert product form)’’ rivative, or fraction is used as the or ‘‘antidandruff (insert product source of the coal tar, the labeling form)’’. shall specify the identity and con- (2) ‘‘Seborrheic dermatitis (insert centration of the coal tar source used product form)’’. and the concentration of the coal tar (3) ‘‘Psoriasis (insert product form)’’. present in the final product. (b) Indications. The labeling of the (2) Pyrithione zinc, 0.95 to 2 percent product states, under the heading ‘‘In- when formulated to be applied and then dications,’’ the phrase listed in para- washed off after brief exposure. graph (b)(1) of this section and may (3) Pyrithione zinc, 0.1 to 0.25 percent contain any of the terms listed in para- when formulated to be applied and left graph (b)(2) or (b)(3) of this section. on the skin or scalp. Other truthful and nonmisleading (4) Salicylic acid, 1.8 to 3 percent. statements, describing only the indica- (5) Selenium sulfide, 1 percent. tions for use that have been established and listed in paragraph (b) of this sec- (c) Active ingredients for the control of tion, may also be used, as provided in psoriasis. (1) Coal tar, 0.5 to 5 percent. § 330.1(c)(2) of this chapter, subject to When a coal tar solution, derivative, or the provisions of section 502 of the Fed- fraction is used as the source of the eral Food, Drug, and Cosmetic Act (the coal tar, the labeling shall specify the act) relating to misbranding and the identity and concentration of the coal prohibition in section 301(d) of the act tar source used and the concentration against the introduction or delivery for of the coal tar present in the final introduction into interstate commerce product. of unapproved new drugs in violation of (2) Salicylic acid, 1.8 to 3 percent. section 505(a) of the act. [56 FR 63568, Dec. 4, 1991, as amended at 59 (1) (‘‘For relief of’’ or ‘‘Controls’’) FR 4001, Jan. 28, 1994] ‘‘the symptoms of’’ (select one or more

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of the following, as appropriate: ‘‘dan- of the body, consult your doctor before druff,’’ ‘‘seborrheic dermatitis,’’ and/or using this product.’’ ‘‘psoriasis.’’) (d) Directions. The labeling of the (2) The following terms or phrases product contains the following infor- may be used in place of or in addition mation under the heading ‘‘Direc- to the words ‘‘For the relief of’’ or tions.’’ More detailed directions appli- ‘‘Controls’’ in the indications in para- cable to a particular product formula- graph (b)(1) of this section: ‘‘fights,’’ tion may also be included. ‘‘reduces,’’ ‘‘helps eliminate,’’ ‘‘helps (1) For products containing active in- stop,’’ ‘‘controls recurrence of,’’ ‘‘fights gredients for the control of dandruff, recurrence of,’’ ‘‘helps prevent recur- seborrheic dermatitis, or psoriasis when rence of,’’ ‘‘reduces recurrence of,’’ formulated to be applied and then washed ‘‘helps eliminate recurrence of,’’ ‘‘helps off after brief (a few minutes) exposure stop recurrence of.’’ (e.g, shampoos, preshampoo rinses, (3) The following terms may be used in place of the words ‘‘the symptoms postshampoo rinses). ‘‘For best results of’’ in the indications in paragraph use at least twice a week or as directed (b)(1) of this section: (‘‘skin’’ and/or by a doctor.’’ ‘‘scalp,’’ as appropriate) (select one or (2) For products containing active in- more of the following: ‘‘itching,’’ ‘‘irri- gredients for the control of dandruff, tation,’’ ‘‘redness,’’ ‘‘flaking,’’ ‘‘scal- seborrheic dermatitis, or psoriasis when ing,’’) ‘‘associated with.’’ formulated so as to be applied and left on (c) Warnings. The labeling of the the skin or scalp (e.g., creams, ointments, product contains the following warn- lotions, hairgrooms). ‘‘Apply to affected ings under the heading ‘‘Warnings’’: areas one to four times daily or as di- (1) For products containing any ingre- rected by a doctor.’’ dient identified in § 358.710. (i) ‘‘For ex- (3) For products containing active internal use only.’’ gredients for the control of seborrheic der- (ii) ‘‘Avoid contact with the eyes. If matitis or psoriasis of the skin when for- contact occurs, rinse eyes thoroughly mulated as soaps. ‘‘Use on affected areas with water.’’ in place of your regular soap.’’ (iii) ‘‘If condition worsens or does not (e) The word ‘‘physician’’ may be sub- improve after regular use of this prod- stituted for the word ‘‘doctor’’ in any uct as directed, consult a doctor.’’ of the labeling statements in this sec- (2) For any product containing coal tar tion. identified in § 358.710(a), (b), or (c). (i) ‘‘Use caution in exposing skin to sun- § 358.760 Labeling of permitted com- light after applying this product. It binations of active ingredients for may increase your tendency to sunburn the control of dandruff. for up to 24 hours after application.’’ The statement of identity, indica- (ii) ‘‘Do not use for prolonged periods tions, warnings, and directions for use, without consulting a doctor.’’ respectively, applicable to each ingre- (3) For products containing coal tar dient in the product may be combined when formulated to be applied and left on to eliminate duplicative words or the skin (e.g., creams, ointments, lotions). ‘‘Do not use this product in or around phrases so that the resulting informa- the rectum or in the genital area or tion is clear and understandable. groin except on the advice of a doctor.’’ (a) Statement of identity. For a com- (4) For products containing coal tar bination drug product that has an es- identified in § 358.710(c) for the control of tablished name, the labeling of the psoriasis. ‘‘Do not use this product with product states the established name of other forms of psoriasis therapy such the combination drug product, followed as ultraviolet radiation or prescription by the statement of identity for each drugs unless directed to do so by a doc- ingredient in the combination, as es- tor.’’ tablished in the statement of identity (5) For products containing any ingre- sections of the applicable OTC drug dient identified in § 358.710(b) or (c) for monographs. the control of seborrheic dermatitis or pso- (1) Combinations of control of dandruff riasis. ‘‘If condition covers a large area and external analgesic active ingredients

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in § 358.720(b). The label states ‘‘dan- graph (d). When the time intervals or druff/anti-itch shampoo’’ or ‘‘anti- age limitations for administration of dandruff/anti-itch shampoo’’. the individual ingredients differ, the (2) [Reserved] directions for the combination product (b) Indications. The labeling of the may not contain any dosage that ex- product states, under the heading ceeds those established for any indi- ‘‘Uses,’’ one or more of the phrases list- vidual ingredient in the applicable OTC ed in this paragraph (b), as appropriate. drug monograph(s), and may not pro- Other truthful and nonmisleading vide for use by any age group lower statements, describing only the uses than the highest minimum age limit that have been established and listed in established for any individual ingre- this paragraph (b), may also be used, as dient. provided in § 330.1(c)(2) of this chapter, (1) Combinations of control of dandruff subject to the provisions of section 502 and external analgesic active ingredients of the Federal Food, Drug, and Cos- in § 358.720(b). The labeling states metic Act (the act) relating to mis- ‘‘[bullet] wet hair [bullet] apply sham- branding and the prohibition in section poo and work into a lather [bullet] 301(d) of the act against the introduc- rinse thoroughly [bullet] for best re- tion or delivery for introduction into sults, use at least twice a week or as interstate commerce of unapproved directed by a doctor’’. new drugs in violation of section 505(a) (2) [Reserved] of the act. [72 FR 9852, Mar. 6, 2007] (1) Combinations of control of dandruff and external analgesic active ingredients PART 361—PRESCRIPTION DRUGS in § 358.720(b). The labeling states FOR HUMAN USE GENERALLY ‘‘[bullet] [select one of the following: ‘for relief of’ or ‘controls’] the symp- RECOGNIZED AS SAFE AND EF- toms of dandruff [bullet] [select one of FECTIVE AND NOT MISBRANDED: the following: ‘additional’ or ‘extra’] DRUGS USED IN RESEARCH relief of itching due to dandruff’’. (2) The following terms or phrases AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, may be used in place of or in addition 371; 42 U.S.C. 262. to the words ‘‘for the relief of’’ or ‘‘controls’’ in the indications in para- § 361.1 Radioactive drugs for certain graph (b)(1) of this section: ‘‘fights,’’ research uses. ‘‘reduces,’’ ‘‘helps eliminate,’’ ‘‘helps (a) Radioactive drugs (as defined in stop,’’ ‘‘controls recurrence of,’’ ‘‘fights § 310.3(n) of this chapter) are generally recurrence of,’’ ‘‘helps prevent recur- recognized as safe and effective when rence of,’’ ‘‘reduces recurrence of,’’ administered, under the conditions set ‘‘helps eliminate recurrence of,’’ ‘‘helps forth in paragraph (b) of this section, stop recurrence of.’’ to human research subjects during the (3) The following terms may be used course of a research project intended to in place of the words ‘‘the symptoms obtain basic information regarding the of’’ in the indication in paragraph (b)(1) metabolism (including kinetics, dis- of this section: ‘‘scalp’’ (select one or tribution, and localization) of a radio- more of the following: ‘‘itching,’’ ‘‘irri- actively labeled drug or regarding tation,’’ ‘‘redness,’’ ‘‘flaking,’’ ‘‘scal- human physiology, pathophysiology, or ing’’) ‘‘associated with’’. biochemistry, but not intended for im- (c) Warnings. The labeling of the mediate therapeutic, diagnostic, or product states, under the heading similar purposes or to determine the ‘‘Warnings,’’ the warning(s) listed in safety and effectiveness of the drug in § 358.750(c)(1) and (c)(2). humans for such purposes (i.e., to carry (d) Directions. The labeling of the out a clinical trial). Certain basic re- product states, under the heading ‘‘Di- search studies, e.g., studies to deter- rections,’’ directions that conform to mine whether a drug localizes in a par- the directions established for each in- ticular organ or fluid space and to de- gredient in the directions sections of scribe the kinetics of that localization, the applicable OTC drug monographs, may have eventual therapeutic or diag- unless otherwise stated in this para- nostic implications, but the initial

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studies are considered to be basic re- (3) Limit on radiation dose. The search within the meaning of this sec- amount of radioactive material to be tion. administered shall be such that the (b) The conditions under which use of subject receives the smallest radiation radioactive drugs for research are con- dose with which it is practical to per- sidered safe and effective are: form the study without jeopardizing (1) Approval by Radioactive Drug Re- the benefits to be obtained from the search Committee. A Radioactive Drug study. Research Committee, composed and ap- (i) Under no circumstances may the proved by the Food and Drug Adminis- radiation dose to an adult research tration in accordance with paragraph subject from a single study or cumula- (c) of this section, has determined, in tively from a number of studies con- accordance with the standards set ducted within 1 year be generally rec- forth in paragraph (d) of this section, ognized as safe if such dose exceeds the that: following: (i) The pharmacological dose is with- Whole body, active blood-forming or- in the limits set forth in paragraph gans, lens of the eye, and gonads: (b)(2) of this section; Rems (ii) The radiation dose is within the limits set forth in paragraph (b)(3) of Single dose ...... 3 Annual and total dose commitment ...... 5 this section; Other organs: (iii) The radiation exposure is justi- Single dose ...... 5 fied by the quality of the study being Annual and total dose commitment ...... 15 undertaken and the importance of the (ii) For a research subject under 18 information it seeks to obtain; years of age at his last birthday, the (iv) The study meets the other re- radiation dose shall not exceed 10 per- quirements set forth in paragraph (d) cent of that set forth in paragraph of this section regarding qualifications (b)(3)(i) of this section. of the investigator, proper licensure for (iii) All radioactive material included handling radioactive materials, selec- in the drug either as essential material tion and consent of research subjects, or as a significant contaminant or im- quality of radioactive drugs used, re- purity shall be included when deter- search protocol design, reporting of ad- mining the total radiation doses and verse reactions, and approval by an ap- dose commitments. Radiation doses propriate Institutional Review Com- from x-ray procedures that are part of mittee; and the research study (i.e., would not have (v) The use of the radioactive drug in occurred but for the study) shall also human subjects has the approval of the be included. The possibility of followup Radioactive Drug Research Committee. studies shall be considered for inclu- (2) Limit on pharmacological dose. The sion in the dose calculations. amount of active ingredient or com- (iv) Numerical definitions of dose bination of active ingredients to be ad- shall be based on an absorbed fraction ministered shall be known not to cause method of radiation absorbed dose cal- any clinically detectable pharma- culation, such as the system set forth cological effect in human beings. If the by the Medical Internal Radiation Dose same active ingredients (exclusive of Committee of the Society of Nuclear the radionuclide) are to be adminis- Medicine, or the system set forth by tered simultaneously, e.g., under a the International Commission on Radi- ‘‘Investigational New Drug Applica- ological Protection. tion’’ or for a therapeutic use in ac- (c) A Radioactive Drug Research cordance with labeling for a drug ap- Committee, in order to comply with proved under part 314 of this chapter, paragraph (b)(1) of this section, shall be the total amount of active ingredients composed, shall function, and shall ob- including the radionuclide shall be tain and maintain approval of the Food known not to exceed the dose limita- and Drug Administration in con- tions applicable to the separate admin- formity with the following: istration of the active ingredients ex- (1) Membership. A Radioactive Drug cluding the radionuclide. Research Committee shall consist of at

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least five individuals. Each committee (3) Reports. Each Radioactive Drug shall include the following three indi- Research Committee shall submit an viduals: (i) A physician recognized as a annual report on or before January 31 specialist in nuclear medicine, (ii) a of each year to the Food and Drug Ad- person qualified by training and experi- ministration, Center for Drug Evalua- ence to formulate radioactive drugs, tion and Research, HFD–160, 5600 Fish- and (iii) a person with special com- ers Lane, Rockville, MD 20857. The an- petence in radiation safety and radi- nual report shall include the names ation dosimetry. The remainder of the and qualifications of the members of, committee shall consist of individuals and of any consultants used by, the Ra- qualified in various disciplines perti- dioactive Drug Research Committee, nent to the field of nuclear medicine and, for each study conducted during (e.g., radiology, internal medicine, the preceding year, a summary of in- clinical pathology, hematology, endo- formation presented in the following crinology, radiation therapy, radiation format: physics, radiation biophysics, health physics, and radiopharmacy). Member- REPORT ON RESEARCH USE OF RADIOACTIVE ship shall be sufficiently diverse to per- DRUG mit expert review of the technical and 1. Title of the research project. scientific aspects of proposals sub- 2. Brief description of the purpose of the mitted to the committee. The addition research project. of consultants in other pertinent med- 3. Name of the investigator responsible. ical disciplines is encouraged. A Radio- 4. Pharmacological dose: a. Active ingredients. active Drug Research Committee shall b. Maximum amount administered per sub- be either associated with a medical in- ject. stitution operated for care of patients 5. Name of the radionuclide(s) used, includ- and with sufficient scientific expertise ing any present, as significant contaminants to allow for selection of committee or impurities. members from its faculty, or with a 6. Radiation absorbed dose. Provide the committee established by a State au- maximum dose commitement to the whole thority to provide advice on radiation body and each organ specified in 21 CFR 361.1(b)(3)(i) that was received by a rep- health matters. Joint committees in- resentative subject and the calculations or volving more than one medical institu- references that were used to estimate these tion which have been established in maximum dose commitments. The report order to achieve a high level and diver- shall include the dose contribution of both sity of experience will be acceptable. the administered radionuclide(s) and any X- The Director of the Center for Drug ray procedures associated with the study. If Evaluation and Research may modify the study elicits data on the uptake or excre- any of the foregoing requirements in a tion of the radioactive drug pertinent to the estimation of dose commitment, report the particular situation where alternative mean value and range of values. For each factors provide substantially the same subject provide: composition and association. (a) Age, sex, and approximate weight. (2) Function. Each Radioactive Drug (b) Total activity of each radionuclide ad- Research Committee shall select a ministered for each radioactive drug used in chairman, who shall sign all applica- the study. Report each X-ray procedure used tions, minutes, and reports of the com- in conjunction with the study. mittee. Each committee shall meet at (c) If the subject has participated in other radioactive drug research studies, report the least once each quarter in which re- name of the radioactive drug used in these search activity has been authorized or other studies, the date of administration, conducted. A quorum consisting of and the total activity of each radionuclide more than 50 percent of the member- administered. If any X-ray procedures were ship must be present with appropriate used, identify the X-ray procedure(s) and in- representation of the required fields of clude an estimate of the absorbed radiation specialization. Minutes shall be kept doses. and shall include the numerical results (d) If more than one administration of a radioactive drug per subject, cumulative radi- of votes on protocols involving use in ation dose and dose commitment, expressed human subjects. No member shall vote as whole body, active blood-forming organs, on a protocol in which he is an investi- lens of the eye, gonads, and other organ gator. doses from the administered radionuclides.

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7. A claim of confidentiality, if any. (5) Monitoring. The Food and Drug NOTE: Contents of this report are available Administration shall conduct periodic for public disclosure unless confidentiality is reviews of approved committees. Moni- requested by the investigator and it is ade- toring of the activities of the com- quately shown by the investigator that the mittee shall be conducted through re- report constitutes a trade secret or confiden- view of its annual report, through re- tial commercial information as defined in 21 view of minutes and full protocols for CFR 20.61. certain studies, and through on-site in- llllllllllll spections. Investigator (d) In making the determination re- llllllllllll quired in paragraph (b)(1) of this sec- Chairman, Radioactive Drug tion, a Radioactive Drug Research Research Committee Committee shall consider the following At any time a proposal is approved requirements and assure that each is which involves exposure either of more met: than 30 research subjects, or of any re- (1) Radiation dose to subjects. To as- search subject under 18 years of age, sure that the radiation dose to re- the committee shall immediately sub- search subjects is as low as practicable mit to the Food and Drug Administra- to perform the study and meet the cri- tion a special summary of information teria of § 361.1(b)(3), the Radioactive in the format shown in this paragraph. Drug Research Committee shall require Contents of these reports are available that: for public disclosure, unless confiden- (i) The investigator provide absorbed tiality is requested by the investigator dose calculations based on biologic dis- and it is adequately shown by the in- tribution data available from published vestigator that the report constitutes a literature or from other valid studies. trade secret or confidential commer- (ii) The investigator provide for an cial information as defined in § 20.61 of acceptable method of radioassay of the this chapter. radioactive drug prior to its use to as- (4) Approval. Each Radioactive Drug sure that the dose calculations actu- Research Committee shall be specifi- ally reflect the administered dose. cally approved by the Center for Drug (iii) The radioactive drug chosen for Evaluation and Research of the Food the study has that combination of half- and Drug Administration. Applications life, types of radiations, radiation en- shall be submitted to the Food and ergy, metabolism, chemical properties, Drug Administration, Center for Drug etc., which results in the lowest dose to Evaluation and Research, HFD–160, 5600 the whole body or specific organs with Fishers Lane, Rockville, MD 20857, and which it is possible to obtain the nec- shall contain the names and qualifica- essary information. tions of the members of the committee, (iv) The investigator utilize adequate and a statement that the committee and appropriate instrumentation for agrees to comply with the require- the detection and measurement of the ments set forth in this section. Ap- specific radionuclide. proval shall be based upon an assess- (2) Pharmacological dosage. To deter- ment of the qualifications of the mem- mine that the amount of active ingre- bers of the committee, and the assur- dients to be administered does not ex- ance that all necessary fields of exper- ceed the limitations set forth in para- tise are covered. Approval of a com- graph (b)(2) of this section, the committee may be withdrawn at any time mittee shall require that the investi- for failure of the committee to comply gator provide pharmacological dose with any of the requirements of this calculations based on data available section. Approval of a committee shall from published literature or from other remain effective unless and until the valid human studies. FDA withdraws such approval. Changes (3) Qualifications of investigators. Each in membership and applications for investigator shall be qualified by train- new members shall be submitted to the ing and experience to conduct the pro- Food and Drug Administration as soon posed research studies. as, or before, vacancies occur on the (4) License to handle radioactive mate- committee. rials. The responsible investigator or

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institutions shall, in the case of reac- this chapter, to research subjects under tor-produced isotopes, be licensed by this section, shall be permitted unless the Nuclear Regulatory Commission or the Radioactive Drug Research Com- Agreement State to possess and use the mittee concludes, in its judgment, that specific radionuclides for research use scientific knowledge and benefit is or be a listed investigator under a likely to result from that study. There- broad license, or in the case of non-re- fore, the protocol shall be based upon a actor-produced isotopes, be licensed by sound rationale derived from appro- other appropriate State or local au- priate animal studies or published lit- thorities, when required by State or erature and shall be of sound design local law, to possess and use the spe- such that information of scientific cific radionuclides for research use. value may result. The radiation dose (5) Human research subjects. Each in- shall be both sufficient and no greater vestigator shall select appropriate than necessary to obtain valid meas- human subjects and shall obtain the re- urement. The projected number of sub- view and approval of an institutional jects shall be sufficient but no greater review committee that conforms to the than necessary for the purpose of the requirements of part 56 of this chapter, study. The number of subjects shall and shall obtain the consent of the sub- also reflect the fact that the study is jects or their legal representatives in intended to obtain basic research infor- accordance with part 50 of this chapter. mation referred to in paragraph (a) of The research subjects shall be at least this section and not intended for imme- 18 years of age and legally competent. diate therapeutic, diagnostic or similar Exceptions are permitted only in those purposes or to determine the safety special situations when it can be dem- and effectiveness of the drug in humans onstrated to the committee that the for such purposes (i.e., to carry out a study presents a unique opportunity to clinical trial). gain information not currently avail- (8) Adverse reactions. The investigator able, requires the use of research sub- shall immediately report to the Radio- jects less than 18 years of age, and is active Drug Research Committee all without significant risk to the subject. adverse effects associated with the use Studies involving minors shall be sup- of the radioactive drug in the research ported with review by qualified pedi- study. All adverse reactions probably atric consultants to the Radioactive attributable to the use of the radio- Drug Research Committee. Each fe- active drug in the research study shall male research subject of childbearing be immediately reported by the Radio- potential shall state in writing that active Drug Research Committee to she is not pregnant, or, on the basis of the Food and Drug Administration, a pregnancy test be confirmed as not Center for Drug Evaluation and Re- pregnant, before she may participate in search, HFD–160, 5600 Fishers Lane, any study. Rockville, MD 20857. (6) Quality of radioactive drug. The ra- (9) Approval by an institutional review dioactive drug used in the research board. The investigator shall obtain the study shall meet appropriate chemical, review and approval of an institutional pharmaceutical, radiochemical, and review board that conforms to the re- radionuclidic standards of identity, quirements of part 56 of this chapter. strength, quality, and purity as needed (e) The results of any research con- for safety and be of such uniform and ducted pursuant to this section as part reproducible quality as to give signifi- of the evaluation of a drug pursuant to cance to the research study conducted. part 312 of this chapter shall be in- The Radioactive Drug Research Com- cluded in the submissions required mittee shall determine that radio- under part 312 of this chapter. active materials for parenteral use are (f) A radioactive drug prepared, pack- prepared in sterile and pyrogen-free aged, distributed, and primarily inform. tended for use in accordance with the (7) Research protocol. No matter how requirements of this section shall be small the amount of radioactivity, no exempt from section 502(f)(1) of the act study involving administration of a ra- and §§ 201.5 and 201.100 of this chapter if dioactive drug, as defined in § 310.3(n) of the packaging, label, and labeling are

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in compliance with Federal, State, and (1) and (12) of this section may be local law regarding radioactive mate- placed on the shielded container only. rials and if the label of the immediate container and shielded container, if [40 FR 31308, July 25, 1975, as amended at 40 FR 44543, Sept. 29, 1975; 42 FR 15674, Mar. 22, any, either separate from or as part of 1977; 43 FR 14646, Apr. 7, 1978; 46 FR 8955, Jan. any label and labeling required for ra- 27, 1981; 49 FR 44460, Nov. 7, 1984; 50 FR 8996, dioactive materials by the Nuclear Mar. 6, 1985; 55 FR 11582, Mar. 29, 1990; 56 FR Regulatory Commission or by State or 10806, Mar. 14, 1991; 67 FR 4907, Feb. 1, 2002] local radiological health authorities bear the following: PART 369—INTERPRETATIVE STATE- (1) The statement ‘‘Rx only’’; MENTS RE WARNINGS ON DRUGS (2) The statement ‘‘To be administered in compliance with the require- AND DEVICES FOR OVER-THE- ments of Federal regulations regarding COUNTER SALE radioactive drugs for research use (21 CFR 361.1)’’; Subpart A—Definitions and Interpretations (3) The established name of the drug, Sec. if any; 369.1 Purpose of issuance. (4) The established name and quan- 369.2 Definitions. tity of each active ingredient; 369.3 Warnings required on drugs exempted (5) The name and half-life of the from prescription-dispensing require- radionuclide, total quantity of radioac- ments of section 503(b)(1)(C). tivity in the drug product’s immediate 369.4 Warnings suggested for drugs by for- container, and amount of radioactivity mal or informal statements of policy. per unit volume or unit mass at a des- 369.6 [Reserved] ignated referenced time; 369.7 Warnings required by official com- (6) The route of administration, if it pendia. is for the other than oral use; 369.8 Warning statements in relation to (7) The net quantity of contents; conditions for use. 369.9 General warnings re accidental inges- (8) An identifying lot or control num- tion by children. ber from which it is possible to deter- 369.10 Conspicuousness of warning state- mine the complete manufacturing his- ments. tory of the package of the drug; (9) The name and address of the man- Subpart B—Warning and Caution ufacturer, packer, or distributor; Statements for Drugs (10) The expiration date, if any; (11) If the drug is intended for paren- 369.20 Drugs; recommended warning and teral use, a statement as to whether caution statements. the contents are sterile; 369.21 Drugs; warning and caution statements required by regulations. (12) If the drug is for other than oral use, the names of all inactive ingredi- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, ents, except that: 355, 371. (i) Trace amounts of harmless sub- SOURCE: 39 FR 11745, Mar. 29, 1974, unless stances added solely for individual otherwise noted. product identification need not be EDITORIAL NOTE: Nomenclature changes to named. part 369 appear at 69 FR 13717, Mar. 24, 2004. (ii) If the drug is intended for parenteral use, the quantity or proportion of all inactive ingredients, except that in- Subpart A—Definitions and gredients added to adjust pH or to Interpretations make the drug isotonic may be de- clared by name and a statement of § 369.1 Purpose of issuance. their effect; if the vehicle is water for The warning and caution statements injection, it need not be named. Pro- suggested in subparts B and C of this vided, however, That in the case of con- part, for inclusion in the label or label- tainers too small or otherwise unable ing of drugs and devices subject to sec- to accommodate a label with sufficient tion 502(d) and (f)(2) and other relevant space to bear all such information, the provisions of the Federal Food, Drug, information required by paragraphs (f) and Cosmetic Act are issued for the

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purpose of assisting industry in pre- § 369.4 Warnings suggested for drugs paring proper labeling for these arti- by formal or informal statements of cles for over-the-counter sale and in policy. meeting the legal requirements of the The warning and caution statements act that the label or labeling of drugs included in subpart B of this part in no and devices bear adequate warnings, in way affect any warning statement sug- such manner and form as are necessary gested for such drugs or devices by any for the protection of users. Only sec- statement of policy or interpretation tion 502(d) of the act requires use of the in subchapter C of this chapter. specific language included in these suggested warning and caution state- [39 FR 11745, Mar. 29, 1974, as amended at 40 ments. These suggested warning or FR 13496, Mar. 27, 1975] caution statements are illustrative of § 369.6 [Reserved] those that may be necessary or desirable. It is the responsibility of the § 369.7 Warnings required by official manufacturer, packer, shipper, or dis- compendia. tributor in interstate commerce to see Any drug included in the official that such statements are adequate for compendia defined by the act shall compliance with the provisions of the bear such warning or caution state- law. Omission of any article from this ment as may be required by such com- suggested list does not relieve drugs pendia, and no statement in subpart B and devices subject to provisions of the or subpart C of this part is intended to act from bearing adequate warning or alter, modify, or permit the omission caution statements where such state- of any such statement required by such ments are necessary or desirable for compendia. the protection of the user. § 369.8 Warning statements in relation § 369.2 Definitions. to conditions for use. (a) As used in this part, the term act The mention in any warning or cau- means the Federal Food, Drug, and tion statement included in subparts A, Cosmetic Act. B, and C of this part, of a disease condi- (b) The terms drugs and devices are tion does not imply a finding on the defined in section 201(g) and (k) of the part of the Food and Drug Administra- act. tion that any drug or device is effica- (c) Official compendia are defined in cious in such condition; nor is any drug section 201(j) of the act. or device bearing labeling referring to such disease condition precluded from § 369.3 Warnings required on drugs ex- regulatory action under the applicable empted from prescription-dispensing requirements of section provisions of the act if such claim is 503(b)(1)(C). considered to be misbranding. Drugs exempted from prescription- § 369.9 General warnings re accidental dispensing requirements under section ingestion by children. 503(b)(1)(C) of the act are subject to the Section 369.20 includes under certain labeling requirements prescribed in items, but not all medicines, the state- § 310.201(a) of this chapter. Although, ment: ‘‘Keep this and all medicines out for convenience, warning and caution of children’s reach. In case of overdose, statements for a number of the drugs get medical help or contact a Poison named in § 310.201 of this chapter Control Center right away,’’ or ‘‘Keep (cross-referenced in the text of this out of reach of children.’’ However, in part) are included in subpart B of this view of the possibility of accidental in- part, the inclusion of such drugs in gestion of drugs, it is not only sug- §§ 369.20, 369.21, 369.22 in no way affects gested but is recommended that one of the requirements for compliance with these statements be used on the label § 310.201(a) of this chapter, or the provi- of all drug products. sions of an effective application pursuant to section 505(b) of the act. [64 FR 13296, Mar. 17, 1999]

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§ 369.10 Conspicuousness of warning ANTIHISTAMINICS, ORAL. (See also statements. § 310.201(a)(4) and (a)(24) of this chapter.) Necessary warning statements should appear in the labeling prominently and Caution—This preparation may cause conspicuously as compared to other drowsiness. Do not drive or operate words, statements, designs, and de- machinery while taking this medica- vices, and in bold type on clearly con- tion. Do not give to children under 6 trasting background, in order to com- years of age or exceed the rec- ply with the provisions of section 502(c) ommended dosage unless directed by and (f)(2) of the act. The warning state- physician. ments should be placed in the labeling The reference to drowsiness is not required on preparations for the pro- in juxtaposition with the directions for motion of sleep or on preparations that use and, in any case, should appear on are shown not to produce drowsiness. the label when there is sufficient label space in addition to mandatory label ANTIPYRINE. information. Warning—Do not exceed recommended dosage. If skin rash appears, Subpart B—Warning and Caution discontinue use and consult physician. Statements for Drugs ANTISEPTICS FOR EXTERNAL USE. Caution—In case of deep or puncture § 369.20 Drugs; recommended warning wounds or serious burns, consult physi- and caution statements. cian. If redness, irritation, swelling, or ACETANILID. pain persists or increases or if infection occurs discontinue use and consult Warning—Do not exceed rec- physician. ommended dosage. Overdosage or con- The reference to wounds and burns is tinued use may result in serious blood not required on preparations intended disturbances. solely for diaper rash. ACETOPHENETIDIN CONTAINING ARSENIC PREPARATIONS. PREPARATIONS. (See § 201.309 of this Warning—Frequent or prolonged use chapter.) may cause serious injury. Do not ex- Warning—This medication may dam- ceed recommended dosage. Keep out of age the kidneys when used in large the reach of children. amounts or for a long period of time. BELLADONNA PREPARATIONS AND Do not take more than the rec- PREPARATIONS OF ITS ALKALOIDS ommended dosage, nor take regularly (ATROPINE, HYOSCYAMINE, AND for longer than 10 days without con- SCOPOLAMINE (HYOSCINE); sulting your physician. HYOSCYAMUS, STRAMONIUM, THEIR DERIVATIVES, AND RE- ANESTHETICS FOR EXTERNAL USE LATED DRUG PREPARATIONS. (LOCAL ANESTHETICS). (See also § 310.201(a)(19) and (23) of this chapter.) Warning—Not to be used by persons having glaucoma or excessive pressure Caution—Do not use in the eyes. Not within the eye, by elderly persons for prolonged use. If the condition for (where undiagnosed glaucoma or exces- which this preparation is used persists sive pressure within the eye occurs or if a rash or irritation develops, dis- most frequently), or by children under continue use and consult physician. 6 years of age, unless directed by a phy- ANTIHISTAMINICS FOR EXTERNAL sician. Discontinue use if blurring of USE (EXCEPT PREPARATIONS FOR vision, rapid pulse, or dizziness occurs. OPHTHALMIC USE). Do not exceed recommended dosage. Not for frequent or prolonged use. If Caution—Do not use in the eyes. If dryness of the mouth occurs, decrease the condition for which this prepara- dosage. If eye pain occurs, discontinue tion is used persists or if a rash or irri- use and see your physician imme- tation develops, discontinue use and diately as this may indicate consult physician. undiagnosed glaucoma.

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In the case of scopolamine or scopol- more than 2 months unless directed by amine aminoxide preparations indi- physician. cated for insomnia, the portion of the This warning is not required on arti- above warning that reads ‘‘children cles containing not more than 0.5 milli- under 6 years of age’’ should read in- gram of cobalt as a cobalt salt per dos- stead ‘‘children under 12 years of age’’. age unit and which recommend admin- BORIC ACID (POWDERED, CRYS- istration of not more than 0.5 milli- TALLINE, OR GRANULAR). gram per dose and not more than 2 milligrams per 24-hour period. Warning—Do not use as a dusting ‘‘COUGH-DUE-TO-COLD’’ PREPARA- powder, especially on infants, or take TIONS. (See also § 310.201(a)(20) of this internally. Use only as a solution. Do chapter.) not apply to badly broken or raw skin, or to large areas of the body. Warning—Persons with a high fever BROMIDES. or persistent cough should not use this preparation unless directed by physi- Caution—Use only as directed. Do not cian. give to children or use in the presence COUNTERIRRITANTS AND of kidney disease. If skin rash appears RUBEFACIENTS. or if nervous symptoms persist, recur frequently, or are unusual, discontinue Caution—Do not apply to irritated use and consult physician. skin or if excessive irritation develops. CARBOLIC ACID (PHENOL) PREP- Avoid getting into the eyes or on mu- ARATIONS (MORE THAN 0.5 PER- cous membranes. CENT) FOR EXTERNAL USE. If offered for use in arthritis or rheumatism, in juxtaposition therewith, Warning—Use according to direc- the statement: tions. Do not apply to large areas of Caution—If pain persists for more the body. If applied to fingers or toes, than 10 days, or redness is present, or do not bandage. in conditions affecting children under CATHARTICS AND LAXATIVES—IR- 12 years of age consult a physician im- RITANTS AND OTHER PERISTALTIC mediately. STIMULANTS. See also ‘‘Salicylates’’ in this section for additional warnings for prepara- Warning—Do not use when abdominal tions containing methyl salicylate. pain, nausea, or vomiting are present. Frequent or prolonged use of this prep- CREOSOTE, CRESOLS, GUAIACOL, aration may result in dependence on AND SIMILAR SUBSTANCES IN laxatives. PREPARATIONS FOR EXTERNAL Mercury preparations should have USE. added to the ‘‘frequent use’’ statement, Caution—Do not apply to large areas the words ‘‘and serious mercury poi- of the body. soning’’. CREOSOTE, CRESOLS, GUAIACOL, Phenolphthalein preparations should AND SIMILAR SUBSTANCES IN bear, in addition to the general warn- DOUCHE PREPARATIONS. ing, the following statement: Caution—If skin rash appears, do not Warning—The use of solutions use this or any other preparation con- stronger than those recommended may taining phenolphthalein. result in severe local irritation, burns, See also Mineral Oil Laxatives. or serious poisoning. Mix as directed before pouring into douche bag. Do not CHLORATES: MOUTH WASH OR GAR- use more often than twice weekly un- GLE. less directed by physician. Avoid swallowing. DENTURE RELINERS, PADS, AND COBALT PREPARATIONS (See also CUSHIONS. § 250.106 of this chapter.) Warning—For temporary use only. Warning—Do not exceed the rec- Long-term use of this product may lead ommended dosage. Do not administer to faster bone loss, continuing irrita- to children under 12 years of age unless tion, sores, and tumors. For Use Only directed by physician. Do not use for Until a Dentist Can Be Seen.

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DENTURE REPAIR KITS. children. In case of overdose, get med- Warning—For emergency repairs only. ical help or contact a Poison Control Long-term use of home-repaired den- Center right away.’’ tures may cause faster bone loss, con- OPHTHALMIC PREPARATIONS. (See tinuing irritation, sores, and tumors. also § 200.50 of this chapter.) This kit for emergency use only. See Boric acid offered for use in the prep- Dentist Without Delay. aration of ophthalmic solutions should DOUCHE PREPARATIONS. bear the statement: Prepare solution Warning—Do not use more often than by boiling in water. Store in a sterile twice weekly unless directed by physi- container. Prepare sufficient for one cian. day’s use and discard unused portion. See also Creosote * * * Douche for PHENACETIN-CONTAINING PREPA- additional warning. RATION. (See acetophenetidin.) DRESSINGS, PROTECTIVE SPRAY- PHENYLPROPANOLAMINE HY- ON TYPE. (See also § 310.201(a) (11) and DROCHLORIDE PREPARATIONS, (18) of this chapter.) ORAL. Warning—In case of deep or puncture Caution—Individuals with high blood wounds or serious burns consult physi- pressure, heart disease, diabetes, or cian. If redness, irritation, swelling or thyroid disease should use only as di- pain persists or increases or if infection rected by physician. occurs consult physician. Keep away POTASSIUM PERMANGANATE from eyes or other mucous membranes. AQUEOUS SOLUTIONS (CONTAINING Avoid inhaling. NOT MORE THAN 0.04 PERCENT PO- See also Dispensers Pressurized by TASSIUM PERMANGANATE). (See Gaseous Propellants * * * for addi- § 250.108 of this chapter.) tional warnings to be included for products under pressure. Warning—For external use on the IODINE AND IODIDES (ORAL). skin only. Severe injury may result from use internally or as a douche. Caution—If a skin rash appears, dis- Avoid contact with mucous mem- continue use and consult physician. branes. MERCURY PREPARATIONS FOR EX- QUININE AND OTHER CINCHONA DE- TERNAL USE. RIVATIVES (EXCEPT FOR USE IN Warning—Discontinue use if rash or MALARIA). irritation develops or if condition for Caution—Discontinue use if ringing which used persists. Frequent or pro- in the ears, deafness, skin rash, or vis- longed use, or application to large ual disturbances occur. areas may cause serious mercury poi- RESINS, OLEORESINS, AND VOLA- soning. TILE OILS. MINERAL OIL LAXATIVES. (See also § 201.302 of this chapter.) Caution—If nausea, vomiting, abdominal discomfort, diarrhea, or skin rash Caution—Take only at bedtime. occurs, discontinue use and consult Avoid prolonged use. Do not administer physician. to infants or young children, in pregnancy, or to bedridden or aged patients RESORCINOL (NOT THE unless directed by physician. MONOACETATE) HAIR PREPARA- TIONS. NASAL PREPARATIONS: VASO- CONSTRICTORS (PHENYL- Caution—Excessive use of this prepa- PROPANOLAMINE). ration may temporarily discolor blond, white, or red hair. Caution—Do not exceed recommended dosage. SALICYLATES, INCLUDING ASPIRIN AND SALICYLAMIDE (EXCEPT NUX VOMICA AND STRYCHNINE METHYL SALICYLATE, EFFER- PREPARATIONS. VESCENT SALICYLATE PREPARA- ‘‘Do not use more than the rec- TIONS, AND PREPARATIONS OF ommended dosage. Keep out of reach of AMINOSALICYLIC ACID AND ITS

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SALTS). (See also § 201.314 of this chap- SODIUM PERBORATE MOUTHWASH ter.) AND GARGLE AND TOOTHPASTE. ‘‘Keep out of reach of children. In Caution—Discontinue use if irritation case of overdose, get medical help or or inflammation develops, or increases. contact a Poison Control Center right Avoid swallowing. away;’’ or ‘‘Keep out of reach of children.’’ SULFONAMIDE NOSE DROPS. If the article is an aspirin prepara- Caution—Do not use if a known al- tion, it should bear the first of the lergy to sulfonamide drugs exists. above two warning statements. In either case, the above information SULFUR PREPARATION FOR EX- should appear on the label. TERNAL USE. Caution—For children under 3 years Caution—If undue skin irritation de- of age, consult your physician; or velops or increases, discontinue use Caution—For younger children, con- and consult physician. sult your physician. THROAT PREPARATIONS FOR TEM- One of the two immediately pre- PORARY RELIEF OF MINOR SORE ceding caution statements is required THROAT: LOZENGES, TROCHES, on the label of all aspirin tablets, but WASHES, GARGLES, ETC. (See also such a statement is not required on the § 201.315 of this chapter.) labels of other salicylates clearly offered for administration to adults only. Warning—Severe or persistent sore If offered for use in arthritis or rheu- throat or sore throat accompanied by matism, in juxtaposition therewith, high fever, headache, nausea, and vom- the statement: iting may be serious. Consult physician Caution—If pain persists for more promptly. Do not use more than 2 days than 10 days, or redness is present, or or administer to children under 3 years in conditions affecting children under of age unless directed by physician. 12 years of age, consult a physician im- TOOTHACHE PREPARATIONS. mediately. For temporary use only until a den- SALICYLATES: METHYL SALICY- tist can be consulted. LATE (WINTERGREEN OIL). (See also §§ 201.303 and 201.314 of this chapter.) ZINC STEARATE DUSTING POW- DERS. ‘‘Do not use otherwise than as directed. Keep out of reach of children to ‘‘Keep out of reach of children; avoid avoid accidental poisoning. If swal- inhaling. If swallowed, get medical lowed, get medical help or contact a help or contact a Poison Control Cen- Poison Control Center right away.’’ ter right away.’’ If the preparation is a counter-irri- [39 FR 11745, Mar. 29, 1974, as amended at 40 tant or rubefacient the statement: FR 8917, Mar. 3, 1975; 40 FR 13496, Mar. 27, Caution—Discontinue use if excessive 1975; 41 FR 10885, Mar. 15, 1976; 51 FR 27760, irritation of the skin develops. Avoid Aug. 1, 1986; 51 FR 35340, Oct. 2, 1986; 52 FR getting into the eyes or on mucous 15893, Apr. 30, 1987; 52 FR 30057, Aug. 12, 1987; membranes. 52 FR 47324, Dec. 11, 1987; 53 FR 7093, Mar. 4, 1988; 55 FR 31783, Aug. 3, 1990; 57 FR 58376, If offered for use in arthritis or rheu- Dec. 9, 1992; 59 FR 43412, Aug. 23, 1994; 64 FR matism, in juxtaposition therewith, 13296, Mar. 17, 1999; 68 FR 18882, Apr. 17, 2003; the statement: 68 FR 34293, June 9, 2003] Caution—If pain persists for more than 10 days, or redness is present, or § 369.21 Drugs; warning and caution in conditions affecting children under statements required by regulations. 12 years of age consult a physician im- ACETAMINOPHEN (N-ACETYL-p- mediately. AMINOPHENOL) (See § 310.201(a)(1) of SILVER. this chapter.) Caution—Frequent or prolonged use Warning—Do not give to children of this preparation may result in per- under 3 years of age or use for more manent discoloration of skin and mu- than 10 days unless directed by a physi- cous membranes. cian.

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If offered for use in arthritis, or rheu- If the label of any package is too matism, in juxtaposition therewith, small to accommodate the warnings, the statement: the Commissioner may establish by Caution—If pain persists for more regulation an acceptable alternative than 10 days, or redness is present, or method, e.g., a type size smaller than in conditions affecting children under 1⁄16 inch in height. A petition request- 12 years of age consult a physician im- ing such a regulation, as an amend- mediately. ment to this paragraph, shall be sub- ALCOHOL RUBBING COMPOUND. mitted to the Division of Dockets Man- (See 26 CFR 182.855(a)(5); The National agement in the form established in Formulary, Tenth Edition 1955, pp. 27– part 10 of this chapter. 28; and section 502(g) of the act). Warning—Avoid spraying in eyes. Contents under pressure. Do not punc- Warning—For external use only. If ture or incinerate. Do not store at tem- taken internally serious gastric perature above 120 °F. Keep out of distrubances will result. reach of children. ANTIHISTAMINICS, ORAL (PHENYL- In the case of products packaged in TOLOXAMINE DIHYDROGEN CIT- glass containers, the word ‘‘break’’ RATE AND CHLOROTHEN CITRATE may be substituted for the word PREPARATIONS). (See § 310.201(a)(4) ‘‘puncture.’’ and (a)(24) of this chapter.) The words ‘‘Avoid spraying in eyes’’ may be deleted from the warning in the Caution—This preparation may cause case of a product not expelled as a drowsiness. Do not drive or operate spray, or that is intended to be used in machinery while taking this medica- the eyes. tion. Do not give to children under 6 In addition to the above warning, the years of age or exceed the rec- label of a drug packaged in a self-pres- ommended dosage unless directed by surized container in which the propel- physician. lant consists in whole or in part of a If offered for symptoms of colds, the halocarbon or hydrocarbon shall bear statement: the following warning: Caution—If relief does not occur Warning—Use only as directed. Inten- within 3 days, discontinue use and con- tional misuse by deliberately concen- sult physician. trating and inhaling the contents can DICYCLOMINE HYDROCHLORIDE be harmful or fatal. WITH AN ANTACID. (See § 310.201(a)(8) The warning is not required for the of this chapter.) following products: Warning—Do not exceed the rec- (a) Products expelled in the form of a ommended dosage. Do not administer foam or cream, which contain less than to children under 12 years of age or use ten percent propellant in the con- for a prolonged period unless directed tainer; by physician, since persistent or recur- (b) Products in a container with a ring symptoms may indicate a serious physical barrier that prevents escape of disease requiring medical attention. the propellant at the time of use; (c) Products of a net quantity of con- DIPHEMANIL METHYLSULFATE tents of less than 2 ozs. that are de- FOR EXTERNAL USE. (See signed to release a measured amount of § 310.201(a)(22) of this chapter.) product with each valve actuation; Caution—If redness, irritation, swell- (d) Products of a net quantity of con- ing, or pain persists or increases, dis- tents of less than 1⁄2 oz. continue use and consult physician. DYCLONINE HYDROCHLORIDE. (See DRUGS IN DISPENSERS PRESSUR- § 310.201(a)(23) of this chapter.) IZED BY GASEOUS PROPELLANTS. Caution—Do not use in the eyes. Not (See also § 310.201(a) (11) and (18) of this for prolonged use. Do not apply to chapter.) large areas of the body. If redness, irri- The warnings herein shall appear tation, swelling, or pain persists or in- prominently and conspicuously, but in creases, discontinue use unless directed no case may the letters be less than 1⁄16 by physician. Do not use, but consult inch in height. physician for deep or puncture wounds

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or serious burns. Do not use in case of apply to large areas of the body. If red- rectal bleeding, as this may indicate ness, irritation, swelling, or pain per- serious disease. sists or increases, discontinue use un- HEXADENOL. (See § 310.201(a)(11) of less directed by a physician. this chapter.) SODIUM GENTISATE. (See §§ 201.314 Caution—Do not use for treatment of and 310.301(a)(2) of this chapter.) serious burns or skin conditions or for Warning—Do not use in children conditions which persist for prolonged under 6 years of age or use for pro- periods. In such cases, consult your longed period unless directed by physi- physician. Do not spray in vicinity of cian. eyes, mouth, nose, or ears. Do not store ‘‘Keep out of reach of children. In above 120 °F. case of overdose, get medical help or IPECAC SYRUP IN ONE-FLUID contact a Poison Control Center right OUNCE CONTAINERS FOR EMER- away.’’ GENCY TREATMENT OF POISONING, If offered for use in arthritis or rheu- TO INDUCE VOMITING. (See § 201.308 matism, in juxtaposition therewith, of this chapter.) the statement: Ipecac syrup packaged for over-the- Caution—If pain persists for more counter sale must bear statements to than 10 days, or redness is present, or the following effect, in a prominent in conditions affecting children under and conspicuous manner: 12 years of age, consult a physician im- The following statement (boxed and mediately. in red letters): TUAMINOHEPTANE SULFATE ‘‘For emergency use to cause vom- NASAL PREPARATIONS. (See iting in poisoning. Before using, call § 310.201(a)(16) of this chapter.) physician, the Poison Control Center, or hospital emergency room imme- Caution—Do not exceed recommended diately for advice.’’ dosage. Overdosage may cause nervous- The following warning: Warning— ness, restlessness, or sleeplessness. In- Keep out of reach of children. Do not dividuals with high blood pressure, use in unconscious persons. Ordinarily, heart disease, diabetes, or thyroid dis- this drug should not be used if strych- ease should use only as directed by nine, corrosives such as alkalies (lye) physician. Do not use for more than 3 and strong acids, or petroleum dis- or 4 consecutive days unless directed tillates such as kerosene, gasoline, coal by physician. oil, fuel oil, paint thinner, or cleaning VIBESATE PREPARATIONS. (See fluid have been ingested. § 310.201(a)(18) of this chapter.) ISOAMYLHYRDOCUPREINE AND ZO- LAMINE HYDROCHLORIDE RECTAL Caution—Do not use but consult phy- PREPARATIONS FOR EXTERNAL sician for deep or puncture wounds or USE (See § 310.201(a)(3) of this chapter.) serious burns. If redness, irritation, swelling, or pain persists or increases, Warning—Do not use this preparation discontinue use and consult physician. in case of rectal bleeding, as this may Warning—Contents under pressure. indicate serious disease. Do not puncture. Do not use or store NEOMYCIN SULFATE WITH A VASO- near heat or open flame. Exposure to CONSTRICTOR, IN NASAL PREPARA- temperatures above 130 °Fahrenheit TIONS (SPRAY OR DROPS). may cause bursting. Never throw con- Caution—Do not exceed recommended tainer into fire or incinerator. dosage. Do not administer to children [39 FR 11745, Mar. 29, 1974] under 3 years of age unless directed by physician. EDITORIAL NOTE: For FEDERAL REGISTER citations affecting § 369.21, see the List of CFR PRAMOXINE HYDROCHLORIDE FOR Sections Affected, which appears in the EXTERNAL USE. (See § 310.201(a)(19) of Finding Aids section of the printed volume this chapter.) and at www.govinfo.gov. Caution—Do not use in the eyes or nose. Not for prolonged use. Do not PARTS 370–499 [RESERVED] 357

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