CODE OF FEDERAL REGULATIONS
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The Code of Federal Regulations is a codification of the general and permanent rules published in the Federal Register by the Executive departments and agencies of the Federal Government. The Code is divided into 50 titles which represent broad areas subject to Federal regulation. Each title is divided into chapters which usually bear the name of the issuing agency. Each chapter is further subdivided into parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year and issued on a quarterly basis approximately as follows:
Title 1 through Title 16
Title 17 through Title 27
Title 28 through Title 41
Title 42 through Title 50
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Title 21—
(This book contains parts 300 to 499)
Food Safety and Inspection Service, Department of Agriculture: See 9 CFR chapter III.
Federal Trade Commission: See Commercial Practices, 16 CFR chapter I.
United States Customs Service, Department of the Treasury: See Customs Duties, 19 CFR chapter I.
Internal Revenue Service, Department of the Treasury: See Internal Revenue, 26 CFR chapter I.
Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury: See Alcohol, Tobacco Products and Firearms, 27 CFR chapter I.
(Parts 300 to 499)
For nomenclature changes to chapter I see 59 FR 14366, Mar. 28, 1994.
21 U.S.C. 331, 351, 352, 355, 360b, 361, 371.
The Food and Drug Administration's policy in administering the new-drug, antibiotic, and other regulatory provisions of the Federal Food, Drug, and Cosmetic Act regarding fixed combination dosage form prescription drugs for humans is as follows:
(a) Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug. Special cases of this general rule are where a component is added:
(1) To enhance the safety or effectiveness of the principal active component; and
(2) To minimize the potential for abuse of the principal active component.
(b) If a combination drug presently the subject of an approved new-drug application has not been recognized as effective by the Commissioner of Food and Drugs based on his evaluation of the appropriate National Academy of Sciences-National Research Council panel report, or if substantial evidence of effectiveness has not otherwise been presented for it, then formulation, labeling, or dosage changes may be proposed and any resulting formulation may meet the appropriate criteria listed in paragraph (a) of this section.
(c) A fixed-combination prescription drug for humans that has been determined to be effective for labeled indications by the Food and Drug Administration, based on evaluation of the NAS-NRC report on the combination, is considered to be in compliance with the requirements of this section.
The use of chlorofluorocarbons in human drugs as propellants in self-pressurized containers is generally prohibited except as provided by § 2.125 of this chapter.
21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 263b-263n.
As used in this part:
(a) The term
(b)
(c)
(d)
(e) The term
(f) The definitions and interpretations of terms contained in section 201 of the act shall be applicable to such terms when used in the regulations in this part.
(g)
(h) The newness of a drug may arise by reason (among other reasons) of:
(1) The newness for drug use of any substance which composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component.
(2) The newness for a drug use of a combination of two or more substances, none of which is a new drug.
(3) The newness for drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug.
(4) The newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body.
(5) The newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug.
(i) [Reserved]
(j) The term
(k) The phrase
(l)
(m) [Reserved]
(n) The term
(a) If a drug has an approved license under section 351 of the Public Health Service Act (42 U.S.C. 262
(b) To obtain marketing approval for radioactive biological products for human use, as defined in § 600.3(ee) of
(a) The Food and Drug Administration's conclusions on the effectiveness of drugs are currently being published in the
(b)(1) An identical, related, or similar drug includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety as well as of any drug moiety related in chemical structure or known pharmacological properties.
(2) Where experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs would conclude that the findings and conclusions, stated in a drug efficacy notice or notice of opportunity for hearing, that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective are applicable to an identical, related, or similar drug product, such product is affected by the notice. A combination drug product containing a drug that is identical, related, or similar to a drug named in a notice may also be subject to the findings and conclusions in a notice that a drug product is a “new drug” or that there is a lack of evidence to show that a drug product is safe or effective.
(3) Any person may request an opinion on the applicability of such a notice to a specific product by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section.
(c) Manufacturers and distributors of drugs should review their products as drug efficacy notices are published and assure that identical, related, or similar products comply with all applicable provisions of the notices.
(d) The published notices and summary lists of the conclusions are of particular interest to drug purchasing agents. These agents should take particular care to assure that the same purchasing policy applies to drug products that are identical, related, or similar to those named in the drug efficacy notices. The Food and Drug Administration applies the same regulatory policy to all such products. In many instances a determination can readily be made as to the applicability of a drug efficacy notice by an individual who is knowledgeable about drugs and their indications for use.
(e) Interested parties may submit to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Compliance, HFD-300, 5600 Fishers Lane, Rockville, MD 20857, the names of drug products, and of their manufacturers or distributors, that should be the subject of the same purchasing and regulatory policies as those reviewed by the Drug Efficacy Study Group. Appropriate action, including referral to purchasing officials of various government agencies, will be taken.
(f) This regulation does not apply to OTC drugs identical, similar, or related to a drug in the Drug Efficacy Study unless there has been or is notification in the
(a) Over the years since 1938 the Food and Drug Administration has given informal advice to inquirers as to the new drug status of preparations. These drugs have sometimes been identified only by general statements of composition. Generally, such informal opinions were incorporated in letters that did not explicitly relate all of the necessary conditions and qualifications such as the quantitative formula for the drug and the conditions under which it was prescribed, recommended, or suggested. This has contributed to misunderstanding and misinterpretation of such opinions.
(b) These informal opinions that an article is “not a new drug” or “no longer a new drug” require reexamination under the Kefauver-Harris Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval of a new drug application is withdrawn under provisions of section 505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally recognized as safe may become a “new drug” within the meaning of section 201(p) of said act as amended by the Kefauver-Harris Act on October 10, 1962. This is of special importance by reason of proposed actions to withdraw approval of new drug applications for lack of substantial evidence of effectiveness as a result of reports of the National Academy of Sciences—National Research Council on its review of drug effectiveness; for example, see the notice published in the
(c) Any marketed drug is a “new drug” if any labeling change made after October 9, 1962, recommends or suggests new conditions of use under which the drug is not generally recognized as safe and effective by qualified experts. Undisclosed or unreported side effects as well as the emergence of new knowledge presenting questions with respect to the safety or effectiveness of a drug may result in its becoming a “new drug” even though it was previously considered “not a new drug.” Any previously given informal advice that an article is “not a new drug” does not apply to such an article if it has been changed in formulation, manufacture control, or labeling in a way that may significantly affect the safety of the drug.
(d) For these reasons, all opinions previously given by the Food and Drug Administration to the effect that an article is “not a new drug” or is “no longer a new drug” are hereby revoked. This does not mean that all articles that were the subjects of such prior opinions will be regarded as new drugs. The prior opinions will be replaced by opinions of the Food and Drug Administration that are qualified and current on when an article is “not a new drug,” as set forth in this subchapter.
(a) The Food and Drug Administration is aware of the need in the practice of medicine for the ingredients of
(1) The shipment is made as a result of a specific request made to the manufacturer or distributor by a practitioner licensed by law to administer such drugs, and the use of such drugs for patch testing is not promoted by the manufacturer or distributor.
(2) The new drug substance requested is an ingredient in a marketed new drug and is not one that is an ingredient solely in a new drug that is legally available only under the investigational drug provisions of this part.
(3) The label bears the following prominently placed statements in lieu of adequate directions for use and in addition to complying with the other labeling provisions of the act:
(i) “Rx only”; and
(ii) “For use only in patch testing”.
(4) The quantity shipped is limited to an amount reasonable for the purpose of patch testing in the normal course of the practice of medicine and is used solely for such patch testing.
(5) The new drug substance is manufactured by the same procedures and meets the same specifications as the component used in the finished dosage form.
(6) The manufacturer or distributor maintains records of all shipments for this purpose for a period of 2 years after shipment and will make them available to the Food and Drug Administration on request.
(b) When the requested new drug substance is intended for investigational use in humans or the substance is legally available only under the investigational drug provisions of part 312 of this chapter, the submission of an “Investigational New Drug Application” (IND) is required. The Food and Drug Administration will offer assistance to any practitioner wishing to submit an Investigational New Drug Application.
(c) This section does not apply to drugs or their components that are subject to the licensing requirements of the Public Health Service Act of 1944, as amended. (See subchapter F—Biologics, of this chapter.)
(a)
(b)
(c)
(d)
(e)
(a) The prescription-dispensing requirements of section 503(b)(1)(C) of the Federal Food, Drug, and Cosmetic Act are not necessary for the protection of the public health with respect to the following drugs subject to new drug applications:
(1)
(i) The
(ii) The
(iii) If the preparation is a new drug, an application pursuant to section 505 (b) of the act is approved for it.
(iv) The preparation contains not more than 0.325 gram (5 grains) of
(v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.
(vi) The dosages of
(vii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 3 years of age and against use of the drug for more than 10 days, unless such uses are directed by a physician.
(viii) If the article is offered for use in arthritis or rheumatism, the labeling prominently bears a statement that the beneficial effects claimed are limited to the temporary relief of minor aches and pains of arthritis and rheumatism and, in juxtaposition with directions for use in such conditions, a conspicuous warning statement, such as “Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately”.
(2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations meeting all the following conditions:
(i) The sodium gentisate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The sodium gentisate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhydrous sodium gentisate per dosage unit.
(v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.
(vi) The dosages of sodium gentisate recommended or suggested in the labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of 2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage recommendations,
(3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-N′-2-thiazolyl-N′-
(i) The isoamylhydrocupreine and zolamine hydrochloride are prepared in dosage form suitable for self-medication as rectal suppositories or as an ointment and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 0.25 percent of isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.
(v) If the preparation is in suppository form, it contains not more than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0 milligrams of zolamine hydrochloride per suppository.
(vi) The preparation is labeled with adequate directions for use in the temporary relief of local pain and itching associated with hemorrhoids.
(vii) The directions provide for the use of not more than two suppositories or two applications of ointment in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against use of the preparation in case of rectal bleeding, as this may indicate serious disease.
(4) Phenyltoloxamine dihydrogen citrate (
(i) The phenyltoloxamine dihydrogen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The phenyltoloxamine dihydrogen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dosage unit.
(v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dose or 264 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150 milligrams of phenyltoloxamine) per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage recommendations:
(
(
(5)-(7) [Reserved]
(8) Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid. β-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-bicyclohexyl hydrochloride) preparations meeting all the following conditions:
(i) The dicyclomine hydrochloride is prepared with suitable antacid and other components, in tablet or other
(ii) The dicyclomine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 milligrams of dicyclomine hydrochloride per dosage unit, or if it is in liquid form not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use only by adults and children over 12 years of age, in the temporary relief of gastric hyperacidity.
(vi) The dosages recommended or suggested in the directions for use do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30 milligrams in a 24-hour period.
(vii) The labeling bears, in juxtaposition with the dosage recommendations, clear warning statements against:
(
(
(
(9)-(10) [Reserved]
(11) Hexadenol (a mixture of tetracosanes and their oxidation products) preparations meeting all the following conditions:
(i) The hexadenol is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The hexadenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 percent by weight of hexadenol.
(v) The preparation is labeled with adequate directions for use by external application in the treatment of minor burns and minor skin irritations.
(vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:
(
(
(12) Sulfur dioxide preparations meeting all the following conditions:
(i) The sulfur dioxide is prepared with or without other drugs, in an aqueous solution packaged in a hermetic container suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The sulfur dioxide and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 5 grams of sulfur dioxide per 100 milliliters of solution.
(v) The preparation is labeled with adequate directions for use by external application to the smooth skin in the prevention or treatment of minor conditions in which it is indicated.
(vi) The directions for use recommend or suggest not more than two applications a day for not more than 1 week, except as directed by a physician.
(13)-(15) [Reserved]
(16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations meeting all the following conditions:
(i) The tuaminoheptane sulfate is prepared, with or without other drugs, in an aqueous vehicle suitable for administration in self-medication as nose drops, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The preparation is packaged with a style of container or assembly suited to self-medication by the recommended route of administration, and delivering not more than 0.1 milliliter of the preparation per drop.
(iii) The tuaminoheptane sulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iv) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(v) The tuaminoheptane sulfate content of the preparation does not exceed 10 milligrams per milliliter.
(vi) The preparation is labeled with adequate directions for use in the temporary relief of nasal congestion.
(vii) The dosages recommended or suggested in the directions for use do not exceed the equivalent: For adults, 5 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for children 1 to 6 years of age, 3 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period; for infants under 1 year of age, 2 drops of a 1 percent solution per nostril per dose, and 5 doses in a 24-hour period.
(viii) The labeling bears, in juxtaposition with the dosage recommendations:
(
(
(17) [Reserved]
(18) Vibesate (a mixture of copolymers of hydroxy-vinyl chlorideacetate, sebacic acid, and modified maleic rosin ester) preparations meeting all the following conditions.
(i) The vibesate is prepared and packaged, with or without other drugs, solvents, and propellants, in a form suitable for self-medication by external application to the skin as a spray, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The vibesate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 13 percent by weight of vibesate.
(v) The preparation is labeled with adequate directions for use by external application as a dressing for minor burns, minor cuts, or other minor skin irritations.
(vi) The labeling bears in juxtaposition with the directions for use clear warning statements against:
(
(
(
(
(
(19) Pramoxine hydrochloride (4-
(i) The pramoxine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The pramoxine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of pramoxine hydrochloride.
(v) The preparation is labeled with adequate directions for use by external application to the skin for the temporary relief of pain or itching due to minor burns and sunburn, nonpoisonous insect bites, and minor skin irritations.
(vi) The directions for use recommend or suggest not more than four
(vii) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:
(
(
(
(
(20) Carbetapentane citrate (2-(2-diethylaminoethoxy)-ethyl-1-phenyl- cyclopentyl-1-carboxylate citrate) preparations meeting all the following conditions:
(i) The carbetanentane citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The carbetapentane citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, and application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of carbetapentane citrate per dosage unit; or if it is in liquid form, not more than 1.5 milligrams of carbetapentane citrate per milliliter.
(v) The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 30 milligrams of carbetapentane citrate per dose or 120 milligrams of carbetapentane citrate per 24-hour period; for children 4 to 12 years of age, 7.5 milligrams per dose or 30 milligrams per 24-hour period; for children 2 to 4 years of age, 4.0 milligrams per dose or 16.0 milligrams per 24-hour period.
(vii) The label bears a conspicuous warning to keep the drug out of the reach of children, and the labeling bears, in juxtaposition with the dosage recommendations:
(
(
(21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate) preparations meeting all the following conditions:
(i) The pamabrom is prepared with appropriate amounts of a suitable analgesic and with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The pamabrom and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 50 milligrams of pamabrom per dosage unit.
(v) The preparation is labeled with adequate directions for use in the temporary relief of the minor pains and discomforts that may occur a few days before and during the menstrual period.
(vi) The dosages recommended or suggested in the labeling do not exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour period.
(22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-piperidinium methylsulfate) preparations meeting all the following conditions:
(i) The diphemanil methylsulfate is prepared, with or without other drugs, in a dosage form suitable for use in self-medication by external application to the skin, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The diphemanil methylsulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 2.0 percent of diphemanil methylsulfate.
(v) The preparation is labeled with adequate directions for use by external application to the skin for the relief of symptoms of mild poison ivy, oak, and sumac and other minor irritations and itching of the skin.
(vi) The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for use, a clear warning statement, such as: “Caution: If redness, irritation, swelling, or pain persists or increases, discontinue use and consult physician.”
(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone hydrochloride; 4-
(i) The dyclonine hydrochloride is prepared, with or without other drugs, in a dosage form suitable for use as a cream or ointment in self-medication by external application to the skin, or rectally, and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The dyclonine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1.0 percent of dyclonine hydrochloride.
(v) The preparation is labeled with adequate directions for use:
(
(
(
(vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against:
(
(
(
(
(
(
(24) Chlorothen citrate (chloromethapyrilene citrate;
(i) The chlorothen citrate is prepared, with or without other drugs, in tablet or other dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The chlorothen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of chlorothen citrate per dosage unit.
(v) The preparation is labeled with adequate directions for use in the temporary relief of the symptoms of hay fever and/or the symptoms of other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150 milligrams of chlorothen citrate per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage recommendations:
(
(
(25) [Reserved]
(26) Methoxyphenamine hydrochloride (β-(
(i) The methoxyphenamine hydrochloride is prepared with appropriate amounts of a suitable antitussive, with or without other drugs, in a dosage form suitable for oral use in self-medication, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The methoxyphenamine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 3.5 milligrams of methoxyphenamine hydrochloride per milliliter.
(v) The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour period; for children 6 to 12 years of age, one-half of the maximum adult dose or dosage.
(vii) The label bears a conspicuous warning to keep the drug out of the reach of children, and the labeling bears, in juxtaposition with the dosage recommendations:
(
(
(
(27) Biphenamine hydrochloride (β-diethylaminoethyl-3-phenyl-2-hydroxybenzoate hydrochloride) preparations meeting all the following conditions:
(i) The biphenamine hydrochloride is prepared in a form suitable for use as a shampoo and contains no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.
(ii) The biphenamine hydrochloride meets its professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 1 percent of biphenamine hydrochloride.
(v) The preparation is labeled with adequate directions for use for the temporary relief of itching and scaling due to dandruff.
(vi) The label bears a conspicuous warning to keep the drug out of the reach of children.
(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium chloride ophthalmic preparations meeting all the following conditions:
(i) The tyloxapol and benzalkonium chloride are prepared, with other appropriate ingredients which are not drugs limited to prescription sale under the provisions of section 503(b)(1) of the act, as a sterile, isotonic aqueous solution suitable for use in self-medication on eye prostheses.
(ii) The preparation is so packaged as to volume and type of container as to afford adequate protection and be suitable for self-medication with a minimum risk of contamination of the solution during use. Any dispensing unit is sterile and so packaged as to maintain sterility until the package is opened.
(iii) The tyloxapol, benzalkonium chloride, and other ingredients used to prepare the isotonic aqueous solution
(iv) An application pursuant to section 505(b) of the act is approved for the drug.
(v) The preparation contains 0.25 percent of tyloxapol and 0.02 percent of benzalkonium chloride.
(vi) The label bears a conspicuous warning to keep the drug out of the reach of children and the labeling bears, in juxtaposition with the dosage recommendations, a clear warning that if irritation occurs, persists, or increases, use of the drug should be discontinued and a physician consulted. The labeling includes a statement that the dropper or other dispensing tip should not touch any surface, since this may contaminate the solution.
(29) [Reserved]
(b) [Reserved]
(a) A new drug may not be approved for marketing unless it has been shown to be safe and effective for its intended use(s). After approval, the applicant is required to establish and maintain records and make reports related to clinical experience or other data or information necessary to make or facilitate a determination of whether there are or may be grounds under section 505(e) of the act for suspending or withdrawing approval of the application. Some drugs, because of the nature of the condition for which they are intended, must be used for long periods of time—even a lifetime. To acquire necessary data for determining the safety and effectiveness of long-term use of such drugs, extensive animal and clinical tests are required as a condition of approval. Nonetheless, the therapeutic or prophylactic usefulness of such drugs may make it inadvisable in the public interest to delay the availability of the drugs for widespread clinical use pending completion of such long-term studies. In such cases, the Food and Drug Administration may approve the new drug application on condition that the necessary long-term studies will be conducted and the results recorded and reported in an organized fashion. The procedures required by paragraph (b) of this section will be followed in order to list such a drug in § 310.304.
(b) A proposal to require additional or continued studies with a drug for which a new drug application has been approved may be made by the Commissioner on his own initiative or on the petition of any interested person, pursuant to part 10 of this chapter. Prior to issuance of such a proposal, the applicant will be provided an opportunity for a conference with representatives of the Food and Drug Administration. When appropriate, investigators or other individuals may be invited to participate in the conference. All requirements for special studies, records, and reports will be published in § 310.304.
(a)
(b)
(c)
(1)
(ii) A person identified in paragraph (c)(1)(i) of this section is not required to submit a 15-day “Alert report” for an adverse drug experience obtained from a postmarketing study (whether or not conducted under an investigational new drug application) unless the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience.
(2)
(3)
(i) A copy of each adverse drug experience report;
(ii) The date the report was received by the packer or distributor;
(iii) The date the report was submitted to the manufacturer; and
(iv) The name and address of the manufacturer.
(4) Each report submitted to FDA under this section shall bear prominent identification as to its contents, i.e., “15-day Alert report,” or “15-day Alert report-followup.”
(5) A person identified in paragraph (c)(1)(i) of this section is not required to resubmit to FDA adverse drug experience reports forwarded to that person by FDA; however, the person must submit all
(d)
(2) Each completed FDA Form 3500A should pertain only to an individual patient.
(3) Instead of using Form FDA Form 3500A, a manufacturer, packer, or distributor may use a computer-generated FDA Form 3500A or other alternative format (e.g., a computer-generated tape or tabular listing) provided that:
(i) The content of the alternative format is equivalent in all elements of information to those specified in FDA Form 3500A, and
(ii) The format is agreed to in advance by MedWatch: The FDA Medical Products Reporting Program.
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the instructions for completing the form may be obtained from the Division of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. More than 10 copies of the form may be obtained by writing to the Consolidated Forms and Publications Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
(e)
(f)
(2) Manufacturers and packers may retain the records required in paragraph (f)(1) of this section as part of its complaint files maintained under § 211.198 of this chapter.
(3) Manufacturers, packers, and distributors shall permit any authorized FDA employee, at all reasonable times, to have access to and copy and verify the records established and maintained under this section.
(g)
(a)
(b)
(2) Patient package inserts for oral contraceptives dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first oral contraceptive and every 30 days thereafter, as long as the therapy continues.
(c)
(1) The name of the drug.
(2) A summary including a statement concerning the effectiveness of oral contraceptives in preventing pregnancy, the contraindications to the drug's use, and a statement of the risks and benefits associated with the drug's use.
(3) A statement comparing the effectiveness of oral contraceptives to other methods of contraception.
(4) A boxed warning concerning the increased risks associated with cigarette smoking and oral contraceptive use.
(5) A discussion of the contraindications to use, including information that the patient should provide to the prescriber before taking the drug.
(6) A statement of medical conditions that are not contraindications to use but deserve special consideration in connection with oral contraceptive use and about which the patient should inform the prescriber.
(7) A warning regarding the most serious side effects of oral contraceptives.
(8) A statement of other serious adverse reactions and potential safety hazards that may result from the use of oral contraceptives.
(9) A statement concerning common, but less serious side effects which may help the patient evaluate the benefits
(10) Information on precautions the patients should observe while taking oral contraceptives, including the following:
(i) A statement of risks to the mother and unborn child from the use of oral contraceptives before or during early pregnancy;
(ii) A statement concerning excretion of the drug in human milk and associated risks to the nursing infant;
(iii) A statement about laboratory tests which may be affected by oral contraceptives; and
(iv) A statement that identifies activities and drugs, foods, or other substances the patient should avoid because of their interactions with oral contraceptives.
(11) Information about how to take oral contraceptives properly, including information about what to do if the patient forgets to take the product, information about becoming pregnant after discontinuing use of the drug, a statement that the drug product has been prescribed for the use of the patient and should not be used for other conditions or given to others, and a statement that the patient's pharmacist or practitioner has a more technical leaflet about the drug product that the patient may ask to review.
(12) A statement of the possible benefits associated with oral contraceptive use.
(13) The following information about the drug product and the patient package insert:
(i) The name and place of business of the manufacturer, packer, or distributor, or the name and place of business of the dispenser of the product.
(ii) The date, identified as such, of the most recent revision of the patient package insert placed prominently immediately after the last section of the labeling.
(d)
(e)
(f)
(a) The drugs listed in this paragraph have been determined by rulemaking procedures to be new drugs within the meaning of section 201(p) of the act. An approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing the following drugs:
(1) Aerosol drug products for human use containing 1,1,1-trichloroethane.
(2) Aerosol drug products containing zirconium.
(3) Amphetamines (amphetamine, dextroamphetamine, and their salts, and levamfetamine and its salts) for human use.
(4) Camphorated oil drug products.
(5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4′,5-tribromosalicylanilide), dibromsalan (DBS, 4′, 5-dibromosalicylanilide), metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3′, 4,5′-tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products.
(6) Chloroform used as an ingredient (active or inactive) in drug products.
(7) Cobalt preparations intended for use by man.
(8) Intrauterine devices for human use for the purpose of contraception that incorporate heavy metals, drugs, or other active substances.
(9) Oral prenatal drugs containing fluorides intended for human use.
(10) Parenteral drug products in plastic containers.
(11) Sterilization of drugs by irradiation.
(12) Sweet spirits of nitre drug products.
(13) Thorium dioxide for drug use.
(14) Timed release dosage forms.
(15) Vinyl chloride as an ingredient, including propellant, in aerosol drug products.
(b) [Reserved]
(a) On January 8, 1963 (28 FR 183), the Commissioner of Food and Drugs exempted investigational radioactive new drugs from part 312 of this chapter provided they were shipped in complete conformity with the regulations issued by the Nuclear Regulatory Commission. This exemption also applied to investigational radioactive biologics.
(b) It is the opinion of the Nuclear Regulatory Commission, and the Food and Drug Administration that this exemption should not apply for certain specific drugs and that these drugs should be appropriately labeled for uses for which safety and effectiveness can be demonstrated by new drug applications or through licensing under the Public Health Service Act (42 U.S.C. 262
(c) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling. Such use may include, among others, the uses in this tabulation:
(d)(1) In view of the extent of experience with the isotopes listed in paragraph (c) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that such isotopes should not be distributed under investigational-use labeling when they are actually intended for use in medical practice.
(2) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, is terminated on March 3, 1972, except as provided in paragraph (d)(3) of this section.
(3) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (c) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or a “Investigational New Drug Application” was submitted prior to March 3, 1972, or for which biologic an application for product license or “Investigational New Drug Application” was submitted prior to March 3, 1972, is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.
(e) No exemption from section 505 of the act or from part 312 of this chapter is in effect or has been in effect for radioactive drugs prepared from accelerator-produced radioisotopes, naturally occurring isotopes, or nonradioactive substances used in conjunction with isotopes.
(f)(1) Based on its experience in regulating investigational radioactive pharmaceuticals, the Nuclear Regulatory Commission has compiled a list of reactor-produced isotopes for which it considers that applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for use as recommended in appropriate labeling; such use may include, among others, the uses in this tabulation:
(2) In view of the extent of experience with the isotopes listed in paragraph (f)(1) of this section, the Nuclear Regulatory Commission and the Food and Drug Administration conclude that they should not be distributed under investigational-use labeling when they are actually intended for use in medical practice.
(3) Any manufacturer or distributor interested in continuing to ship in interstate commerce drugs containing the isotopes listed in paragraph (f)(1) of this section for any of the indications listed, shall submit, on or before August 25, 1975 to the Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, a new drug application or a “Investigational New Drug Application” for each such drug for which the manufacturer or distributor does not have an approved new drug application pursuant to section 505(b) of the act. If the drug is a biologic, a “Investigational New Drug Application” or an application for a license under section 351 of the Public Health Service Act shall be submitted to the Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20014, in lieu of any submission to the Center for Drug Evaluation and Research.
(4) The exemption referred to in paragraph (a) of this section, as applied to any drug or biologic containing any of the isotopes listed in paragraph (f)(1) of this section, in the “chemical form” and intended for the uses stated, is terminated on August 26, 1975 except as provided in paragraph (f)(5) of this section.
(5)(i) Except as provided in paragraph (f)(5)(ii) of this section, the exemption referred to in paragraph (a) of this section, as applied to any drug containing any of the isotopes listed in paragraph (f)(1) of this section, in the “chemical form” and intended for the uses stated, for which drug a new drug application or “Investigational New Drug Application” was submitted to the Center for Drug Evaluation and Research on or before August 25, 1975 is terminated on August 20, 1976, unless an approvable notice was issued on or before August 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on November 20, 1976, whichever occurs first.
(ii) The exemption referred to in paragraph (a) of this section, as applied to any biologic containing any of the isotopes listed in paragraph (f)(1) of this section in the “chemical form” and intended for the uses stated, for which biologic an application for product license or “Investigational New Drug Application” was submitted to the Center for Biologics Evaluation and Research on or before August 25, 1975 is terminated on October 20, 1976, unless an approvable notice was issued on or before October 20, 1976, in which case the exemption is terminated either upon the subsequent issuance of a nonapprovable notice for the new drug application or on January 20, 1977, whichever occurs first.
(g) The exemption referred to in paragraph (a) of this section, as applied to any drug intended solely for investigational use as part of a research project, which use had been approved on or before July 25, 1975 in accordance with 10 CFR 35.11 (or equivalent regulation of an Agreement State) is terminated on February 20, 1976 if the manufacturer of such drug or the sponsor of the investigation of such drug submits on or before August 25, 1975 to the Food and Drug Administration, Bureau of Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following information:
(1) The research project title;
(2) A brief description of the purpose of the project;
(3) The name of the investigator responsible;
(4) The name and license number of the institution holding the specific license under 10 CFR 35.11 (or equivalent regulation of an Agreement State);
(5) The name and maximum amount per subject of the radionuclide used;
(6) The number of subjects involved; and
(7) The date on which the administration of the radioactive drugs is expected to be completed.
(h) The exemption referred to in paragraph (a) of this section, as applied to any drug not referred to in paragraphs (d), (f), and (g) of this section, is terminated on August 26, 1975.
(a) Any parenteral drug product packaged in a plastic immediate container is not generally recognized as safe and effective, is a new drug within the meaning of section 201(p) of the act, and requires an approved new drug application as a condition for marketing. An “Investigational New Drug Application” set forth in part 312 of this chapter is required for clinical investigations designed to obtain evidence of safety and effectiveness.
(b) As used in this section, the term “large volume parenteral drug product” means a terminally sterilized aqueous drug product packaged in a single-dose container with a capacity of 100 milliliters or more and intended to be administered or used intravenously in a human.
(c) Until the results of compatibility studies are evaluated, a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container on or after April 16, 1979, is misbranded unless its labeling contains a warning that includes the following information:
(1) A statement that additives may be incompatible.
(2) A statement that, if additive drugs are introduced into the parenteral system, aseptic techniques should be used and the solution should be thoroughly mixed.
(3) A statement that a solution containing an additive drug should not be stored.
(d) This section does not apply to a biological product licensed under the Public Health Service Act of July 1, 1944 (42 U.S.C. 201).
(a)
(b)
(2) In the case of estrogen drug products in bulk packages intended for multiple dispensing, and in the case of injectables in multiple-dose vials, a sufficient number of patient labeling pieces shall be included in or with each package to assure that one piece can be included with each package or dose dispensed or administered to every patient. Each bulk package shall be labeled with instructions to the dispensor to include one patient labeling piece with each package dispensed or, in the case of injectables, with each dose administered to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient labeling pieces to the dispensor.
(3) Patient package inserts for estrogens dispensed in acute-care hospitals or long-term care facilities will be considered to have been provided in accordance with this section if provided to the patient before administration of the first estrogen and every 30 days
(c)
(1) The name of the drug.
(2) The name and place of business of the manufacturer, packer, or distributor.
(3) A statement regarding the benefits and proper uses of estrogens.
(4) The contraindications to use, i.e., when estrogens should not be used.
(5) A description of the most serious risks associated with the use of estrogens.
(6) A brief summary of other side effects of estrogens.
(7) Instructions on how a patient may reduce the risks of estrogen use.
(8) The date, identified as such, of the most recent revision of the patient package insert.
(d)
(e)
(f)
(a) The University Group Diabetes Program clinical trial has reported an association between the administration of tolbutamide and increased cardiovascular mortality. The Food and Drug Administration has concluded that this reported association provides adequate basis for a warning in the labeling. In view of the similarities in chemical structure and mode of action, the Food and Drug Administration also believes it is prudent from a safety standpoint to consider that the possible increased risk of cardiovascular mortality from tolbutamide applies to all other sulfonylurea drugs as well. Therefore, the labeling for oral hypoglycemic drugs of the sulfonylurea class shall include a warning concerning the possible increased risk of cardiovascular mortality associated with such use, as set forth in paragraph (b) of this section.
(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class shall include in boldface type at the beginning of the “Warnings” section of the labeling the following statement:
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2
Although only one drug in the sulfonylurea class (tolbutamide) was included in this
Drug products containing elemental iron or iron salts as an active ingredient in solid oral dosage form, e.g., tablets or capsules shall meet the following requirements:
(a)
(b)
(2) If this temporary exemption is not extended or made permanent, such drug products shall be in compliance with the provisions of paragraph (a) of this section on or before July 15, 1998.
(c)
WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.
(2)(i) The warning statement required by paragraph (c)(1) of this section shall appear prominently and conspicuously on the information panel of the immediate container label.
(ii) If a drug product is packaged in unit-dose packaging, and if the immediate container bears labeling but not a label, the warning statement required by paragraph (c)(1) of this section shall appear prominently and conspicuously on the immediate container labeling in a way that maximizes the likelihood that the warning is intact until all of the dosage units to which it applies are used.
(3) Where the immediate container is not the retail package, the warning statement required by paragraph (c)(1) of this section shall also appear prominently and conspicuously on the information panel of the retail package label.
(4) The warning statement shall appear on any labeling that contains warnings.
(5) The warning statement required by paragraph (c)(1) of this section shall be set off in a box by use of hairlines.
(d) The iron-containing inert tablets supplied in monthly packages of oral contraceptives are categorically exempt from the requirements of paragraphs (a) and (c) of this section.
(a) Antihistamines, bromides, and scopolamine compounds, either singly or in combinations, have been marketed as ingredients in over-the-counter (OTC) drug products for use as daytime sedatives. The following claims have been made for daytime sedative products: “occasional simple nervous tension,” “nervous irritability,” “nervous tension headache,” “simple nervousness due to common every day overwork and fatigue,” “a relaxed feeling,” “calming down and relaxing,” “gently soothe away the tension,” “calmative,” “resolving that irritability that ruins your day,” “helps you relax,” “restlessness,” “when you're under occasional stress . . . helps you work relaxed.” Based on
(b) Any OTC drug product that is labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as an OTC daytime sedative (or any similar or related indication) is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC daytime sedative drug product introduced into interstate commerce after December 24, 1979, that is not in compliance with this section is subject to regulatory action.
(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and all other B-vitamins, dexpanthenol, estradiol and other topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20, polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat germ oil have been marketed as ingredients in OTC drug products for external use as hair growers or for hair loss prevention. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients intended for OTC external use as a hair grower or for hair loss prevention. Based on evidence currently available, all labeling claims for OTC hair grower and hair loss prevention drug products for external use are either false, misleading, or unsupported by scientific data. Therefore, any OTC drug product for external use containing an ingredient offered for use as a hair grower or for hair loss prevention cannot be considered generally recognized as safe and effective for its intended use.
(b) Any OTC drug product that is labeled, represented, or promoted for external use as a hair grower or for hair loss prevention is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC external use as a hair grower or for hair loss prevention is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Any product that bears labeling claims that it will arouse or increase sexual desire, or that it will improve sexual performance, is an aphrodisiac drug product. Anise, cantharides, don qual, estrogens, fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice, mandrake, methyltestosterone, minerals, nux vomica, Pega Palo, sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been present as ingredients in such drug products. Androgens (e.g., testosterone and methyltestosterone) and estrogens
(b) Any OTC drug product that is labeled, represented, or prompted for use as an aphrodisiac is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the act), for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an aphrodisiac is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an ingredient in over-the-counter (OTC) drug products for oral use as an insect repellent (an orally administered drug product intended to keep insects away). There is a lack of adequate data to establish the effectiveness of this, or any other ingredient for OTC oral use as an insect repellent. Labeling claims for OTC orally administered insect repellent drug products are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for orally administered OTC insect repellent drug products: “Oral mosquito repellent,” “mosquitos avoid you,” “bugs stay away,” “keep mosquitos away for 12 to 24 hours,” and “the newest way to fight mosquitos.” Therefore, any drug product containing ingredients offered for oral use as an insect repellent cannot be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted for oral use as an insect repellent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted OTC for oral use as an insect repellent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) Any such drug product in interstate commerce after December 17, 1985, that is not in compliance with
(a) The term “hormone” is used broadly to describe a chemical substance formed in some organ of the body, such as the adrenal glands or the pituitary, and carried to another organ or tissue, where it has a specific effect. Hormones include, for example, estrogens, progestins, androgens, anabolic steroids, and adrenal corticosteroids, and synthetic analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate have been present as ingredients in OTC drug products marketed for topical use as hormone creams. However, there is a lack of adequate data to establish effectiveness for any OTC drug use of these ingredients. Therefore, with the exception of those hormones identified in paragraph (e) of this section, any OTC drug product containing an ingredient offered for use as a topically applied hormone cannot be considered generally recognized as safe and effective for its intended use. The intended use of the product may be inferred from the product's labeling, promotional material, advertising, and any other relevant factor. The use of the word “hormone” in the text of the labeling or in the ingredient statement is an implied drug claim. The claim implied by the use of this term is that the product will have a therapeutic or some other physiological effect on the body. Therefore, reference to a product as a “hormone cream” or any statement in the labeling indicating that “hormones” are present in the product, or any statement that features or emphasizes the presence of a hormone ingredient in the product, will be considered to be a therapeutic claim for the product, or a claim that the product will affect the structure or function of the body, and will consequently cause the product to be a drug.
(b) Any OTC drug product that is labeled, represented, or promoted as a topically applied hormone-containing product for drug use, with the exception of those hormones identified in paragraph (e) of this section, is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a topically applied hormone-containing drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(e) This section does not apply to hydrocortisone and hydrocortisone acetate labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter.
(a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol, triclosan, and zinc oxide have been present in OTC boil treatment drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredient for OTC use for the treatment of boils. Treatment is defined as reducing the size of a boil or reducing an infection related to a boil. Treatment has involved the use of “drawing salves” for
(b) Any OTC drug product that is labeled, represented, or promoted for the treatment of boils is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any OTC boil treatment drug product is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product that contains aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(e) After May 16, 1994, any such OTC drug product that contains benzocaine, ichthammol, sulfur, or triclosan initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(f) This section does not apply to drug products that contain benzocaine labeled, represented, or promoted for OTC topical use in accordance with part 348 of this chapter.
(a) The amino acids glycine, alanine, and glutamic acid (alone or in combination) and the ingredient sabal have been present in over-the-counter (OTC) drug products to relieve the symptoms of benign prostatic hypertrophy, e.g., urinary urgency and frequency, excessive urinating at night, and delayed urination. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use in relieving the symptoms of benign prostatic hypertrophy. In addition, there is no definitive evidence that any drug product offered for the relief of the symptoms of benign prostatic hypertrophy would alter the obstructive or inflammatory signs and symptoms of this condition. Therefore, self-medication with OTC drug products might unnecessarily delay diagnosis and treatment of progressive obstruction and secondary infections. Based on evidence currently available, any OTC drug product containing ingredients offered for use in relieving the symptoms of benign prostatic hypertrophy cannot be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted to relieve the symptoms of benign prostatic hypertrophy is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use to relieve the symptoms of benign prostatic hypertrophy is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After August 27, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids as contained in Atropa belladonna and Datura stramonium have been present as ingredients in cough-cold drug products for use as an anticholinergic. Anticholinergic drugs have been marketed OTC in cough-cold drug products to relieve excessive secretions of the nose and eyes, symptoms that are commonly associated with hay fever, allergy, rhinitis, and the common cold. Atropine sulfate for oral use as an anticholinergic is probably safe at dosages that have been used in marketed cough-cold products (0.2 to 0.3 milligram); however, there are inadequate data to establish general recognition of the effectiveness of this ingredient. The belladonna alkaloids, which contain atropine (
(b) Any OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any cough-cold drug product labeled, represented, or promoted for OTC use as an anticholinergic is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC cough-cold drug product that is labeled, represented, or promoted for use as an anticholinergic may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application.
(a) Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing agents. Oral wound healing agents have been marketed as aids in the healing of minor oral wounds by means other than cleansing and irrigating, or by serving as a protectant. Allantoin, carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, and hydrogen peroxide in aqueous solution are safe for use as oral wound healing agents, but there are inadequate data to establish general recognition of the effectiveness of these ingredients as oral wound healing agents.
(b) Any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as an oral wound healing agent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any OTC drug product that is labeled, represented, or promoted for use as an oral wound healing agent may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved new drug application.
(a) Denatonium benzoate and sucrose octaacetate have been present in OTC nailbiting and thumbsucking deterrent drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these and any other ingredients (e.g., cayenne pepper) for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a nailbiting or thumbsucking deterrent cannot be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, and promoted as a nailbiting or thumbsucking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a nailbiting or thumbsucking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After March 2, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a)
(b) Any OTC drug product for oral administration that is labeled, represented, or promoted to treat or relieve the symptoms or discomfort of fever blisters and cold sores is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product for oral administration labeled,
(d) After December 30, 1992, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Any product that bears labeling claims such as for “temporary relief of discomfort from ingrown toenails,” or “ingrown toenail relief product,” or “ingrown toenail reliever,” or similar claims is considered an ingrown toenail relief drug product. Benzocaine, chlorobutanol, chloroxylenol, dibucaine, sodium sulfide, tannic acid, and urea have been present as ingredients in such products. There is lack of adequate data to establish general recognition of the safety and effectiveness of these or any other ingredients for OTC use for ingrown toenail relief. Based on evidence currently available, any OTC drug product containing ingredients offered for use for ingrown toenail relief cannot be generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for ingrown toenail relief is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Betaine hydrochloride, glutamic acid hydrochloride, diluted hydrochloric acid, and pepsin have been present as ingredients in over-the-counter (OTC) drug products for use as stomach acidifiers. Because of the lack of adequate data to establish the effectiveness of these or any other ingredients for use in treating achlorhydria and hypochlorhydria, and because such conditions are asymptomatic, any OTC drug product containing ingredients offered for use as a stomach acidifier cannot be considered generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted for use as a stomach acidifier is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, for which an approved new drug application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted as a stomach acidifier for OTC use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in
(a) Hypophosphatemia is a condition in which an abnormally low plasma level of phosphate occurs in the blood. This condition is not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hypophosphatemia cannot be considered generally recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of hypophosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of his chapter.
(d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Hyperphosphatemia is a condition in which an abnormally high plasma level of phosphate occurs in the blood. This condition in not amenable to self-diagnosis or self-treatment. Treatment of this condition should be restricted to the supervision of a physician. For this reason, any drug product containing ingredients offered for OTC use in the treatment of hyperphosphatemia cannot be considered generally recognized as safe and effective.
(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of hyperphosphatemia is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for use in the treatment of hyperphosphatemia is safe and effective for the purpose intended must comply with the requirements and procedures governing use of investigational new drugs set forth in part 312 of this chapter.
(d) After November 12, 1990, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Hemicellulase, pancreatin, and pancrelipase have been present as ingredients in exocrine pancreatic insufficiency drug products. Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin (protease), and lipase. Significant differences have been shown in the bioavailability of marketed exocrine pancreatic insufficiency drug products produced by different manufacturers. These differences raise a potential for serious risk to patients using these drug products. The bioavailability of pancreatic enzymes is dependent on the process used to manufacture the drug products. Information on this process is not included in an OTC drug monograph. Therefore,
(b) Any drug product that is labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use in the treatment of exocrine pancreatic insufficiency is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product that contains hemicellulase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(e) After October 24, 1995, any such OTC drug product that contains pancreatin or pancrelipase initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Any product that bears labeling claims that it “helps stop or reduce the cigarette urge,” “helps break the cigarette habit,” “helps stop or reduce smoking,” or similar claims is a smoking deterrent drug product. Cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or
(b) Any OTC drug product that is labeled, represented, or promoted as a smoking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a smoking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product containing cloves, coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), licorice root extract, menthol, methyl salicylate, quinine ascorbate, silver nitrate, and/or thymol initially introduced or
(a) A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses:
(1)
(2)
(ii)
(3)
(4)
(5) [Reserved]
(6)
(B)
(ii)
(B)
(iii)
(iv)
(B) Approved as of January 29, 1996. Any combination drug product containing theophylline (e.g., theophylline and ephedrine, or theophylline and ephedrine and phenobarbital).
(C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized metered-dose inhaler container.
(D) Approved as of October 29, 2001. Any oral bronchodilator active ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate, racephedrine hydrochloride, or any other ephedrine salt) in combination with any analgesic(s) oranalgesic-antipyretic(s), anticholinergic, antihistamine, oralantitussive, or stimulant active ingredient.
(7)
(8)
(ii)
(iii) Charcoal, activated
(9) [Reserved]
(10)
(ii)
(iii)
(iv)
Any ingredient(s) labeled with claims or directions for use in the treatment and/or prevention of diaper rash.
(v)
(vi)
(vii)
(11) [Reserved]
(12)
(ii)
(iii)
(iv)(A)
(iv)(B)
(C)
(13) [Reserved]
(14)
(a) * * *
(15)
(ii)
(16)
(17)
(18)
(ii)
(iii)
(iv)
(v)
(vi)
(19) [Reserved]
(20)
(21)
(i)
(ii)
(iii)
(iv)
(v)
(22)
(i)
(ii)
(iii) Any ingredient(s) labeled with claims or directions for use on the scalp or on the nails.
(iv)
(23)
(ii)
(24)
(ii)
(25)
(ii)
(26)
(ii)
(iii)
(iv)
(v)
(vi)
(vii)
(viii)
(ix)
(x)
(27)
(ii)
(28)
(ii)
(29)
(30) [Reserved]
(b) Any OTC drug product that is labeled, represented, or promoted for the uses specified and containing any active ingredient(s) as specified in paragraph (a) of this section is regarded as a new drug within the meaning of section 210(p) of the Federal Food, Drug, and Cosmetic Act (the Act), for which an approved new drug application under section 505 of the Act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the Act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for the OTC uses and containing any active ingredient(s) as specified in paragraph (a) of this section is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC drug product that is not in compliance with this section is subject to regulatory action if initially introduced or initially delivered for introduction into interstate commerce after the dates specified in paragraphs (d)(1) through (d)(29) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through (a)(2)(i), (a)(3) through (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), (a)(14) through (a)(15)(i), and (a)(16) through (a)(18) of this section.
(2) February 10, 1992, for products subject to paragraph (a)(20) of this section.
(3) December 4, 1992, for products subject to paragraph (a)(7) of this section
(4) February 28, 1990, for products subject to paragraph (a)(6)(iii) of this section, except those that contain ipecac.
(5) September 14, 1993, for products subject to paragraph (a)(6)(iii) of this section that contain ipecac.
(6) December 9, 1993, for products subject to paragraph (a)(6)(i)(B) of this section.
(7) March 6, 1989, for products subject to paragraph (a)(21) of this section, except those that contain ophthalmic anti-infective ingredients listed in paragraph (a)(21)(ii).
(8) June 18, 1993, for products subject to paragraph (a)(21) of this section that contain ophthalmic anti-infective ingredients.
(9) June 18, 1993, for products subject to paragraph (a)(10)(iv) of this section.
(10) June 18, 1993, for products subject to paragraph (a)(22)(i) of this section.
(11) November 10, 1993, for products subject to paragraphs (a)(8)(ii), (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except products that contain ferric subsulfate) through (a)(18)(vi), (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) of this section.
(12) March 2, 1994, for products subject to paragraph (a)(22)(iii) of this section.
(13) August 5, 1991, for products subject to paragraphs (a)(26) of this section, except for those that contain live yeast cell derivative.
(14) September 2, 1994, for products subject to paragraph (a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell derivative.
(15) September 23, 1994, for products subject to paragraph (a)(22)(iv) of this section.
(16) June 14, 1994, for products subject to paragraph (a)(25)(ii) of this section.
(17) [Reserved]
(18) August 15, 1995, for products subject to paragraph (a)(15)(ii) of this section.
(19) October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this section.
(20) January 29, 1996, for products subject to paragraph (a)(6)(iv)(B) of this section.
(21) April 21, 1994, for products subject to paragraph (a)(8)(iii) of this section.
(22) April 21, 1993, for products subject to paragraph (a)(18)(ii) of this section that contain ferric subsulfate.
(23) August 23, 1995, for products subject to paragraph (a)(6)(ii)(B) of this section.
(24) October 7, 1996, for products subject to paragraph (a)(2)(ii) of this section.
(25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C) of this section.
(26) February 22, 1999, for products subject to paragraphs (a)(23)(ii) and (a)(24)(ii) of this section.
(27) [Reserved]
(28) October 22, 1998, for products subject to paragraphs (a)(27) and (a)(28)(i) of this section.
(29) January 29, 1999, for products subject to paragraph (a)(12)(iv)(B) of this section.
(30) November 5, 2002, for products subject to paragraph (a)(12)(iv)(C) of this section.
(31) December 31, 2002, for products subject to paragraph (a)(29) of this section.
(32) [Reserved]
(33) October 29, 2001, for products subject to paragraph (a)(6)(iv)(D) of this section.
(34)-(35)[Reserved]
(36) November 5, 2002, for products subject to paragraph (a)(28)(ii) of this section.
For
At 61 FR 9571, Mar. 8, 1996, in § 310.545 in paragraph (a)(6)(ii)(B), the entry for “l-desoxyephedrine (topical)” was stayed until further notice.
(a) Quinine sulfate alone or in combination with vitamin E has been present in over-the-counter (OTC) drug products for the treatment and/or prevention of nocturnal leg muscle cramps, i.e., a condition of localized pain in the lower extremities usually occurring in middle life and beyond with no regular pattern concerning time or severity. There is a lack of adequate data to establish general recognition of the safety and effectiveness of quinine sulfate, vitamin E, or any other ingredients for OTC use in the treatment and/or prevention of nocturnal leg muscle cramps. In the doses used to treat or prevent this condition, quinine sulfate has caused adverse events such as transient visual and auditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea. Quinine sulfate may cause unpredictable serious and life-threatening hypersensitivity reactions requiring medical intervention and hospitalization; fatalities have been reported. The risk associated with use of quinine sulfate, in the absence of evidence of its effectiveness, outweighs any potential benefit in treating and/or preventing this benign, self-limiting condition. Based upon the adverse benefit-to-risk ratio, any drug product containing quinine or quinine sulfate cannot be considered generally recognized as safe for the treatment and/or prevention of nocturnal leg muscle cramps.
(b) Any OTC drug product that is labeled, represented, or promoted for the treatment and/or prevention of nocturnal leg muscle cramps is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or prevention of nocturnal leg muscle cramps is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.
(d) After February 22, 1995, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Quinine and quinine salts have been used OTC for the treatment and/or prevention of malaria, a serious and potentially life-threatening disease. Quinine is no longer the drug of choice for the treatment and/or prevention of most types of malaria. In addition, there are serious and complicating aspects of the disease itself and some potentially serious and life-threatening risks associated with the use of quinine at doses employed for the treatment of malaria. There is a lack of adequate data to establish general recognition of the safety of quinine drug products for OTC use in the treatment and/or prevention of malaria. Therefore, quinine or quinine salts cannot be safely and effectively used for the treatment and/or prevention of malaria except under the care and supervision of a doctor.
(b) Any OTC drug product containing quinine or quinine salts that is labeled, represented, or promoted for the treatment and/or prevention of malaria is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use for the treatment and/or
(d) After April 20, 1998, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
(a) Colloidal silver ingredients and silver salts have been marketed in over-the-counter (OTC) drug products for the treatment and prevention of numerous disease conditions. There are serious and complicating aspects to many of the diseases these silver ingredients purport to treat or prevent. Further, there is a lack of adequate data to establish general recognition of the safety and effectiveness of colloidal silver ingredients or silver salts for OTC use in the treatment or prevention of any disease. These ingredients and salts include, but are not limited to, silver proteins, mild silver protein, strong silver protein, silver, silver ion, silver chloride, silver cyanide, silver iodide, silver oxide, and silver phosphate.
(b) Any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any drug product containing colloidal silver or silver salts labeled, represented, or promoted for any OTC drug use is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs as set forth in part 312 of this chapter.
(d) After September 16, 1999, any such OTC drug product containing colloidal silver or silver salts initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.
21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 U.S.C. 262.
(a) This part contains procedures and requirements governing the use of investigational new drugs, including procedures and requirements for the submission to, and review by, the Food and Drug Administration of investigational new drug applications (IND's). An investigational new drug for which an IND is in effect in accordance with this part is exempt from the premarketing approval requirements that are otherwise applicable and may be shipped lawfully for the purpose of conducting clinical investigations of that drug.
(b) References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.
(a)
(b)
(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;
(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;
(iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; and
(v) The investigation is conducted in compliance with the requirements of § 312.7.
(2)(i) A clinical investigation involving an in vitro diagnostic biological product listed in paragraph (b)(2)(ii) of this section is exempt from the requirements of this part if (
(ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (
(3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements of this part if shipped in accordance with § 312.160.
(4) FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.
(5) A clinical investigation involving use of a placebo is exempt from the requirements of this part if the investigation does not otherwise require submission of an IND.
(6) A clinical investigation involving an exception from informed consent under § 50.24 of this chapter is not exempt from the requirements of this part.
(c)
(d)
(e)
(a) The definitions and interpretations of terms contained in section 201 of the Act apply to those terms when used in this part:
(b) The following definitions of terms also apply to this part:
(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement “Caution: New Drug—Limited by Federal (or United States) law to investigational use.”
(b) The label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated.
(a)
(b)
(c)
(d)
(2)
(3)
(4)
(a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be submitted either in an IND or in an information amendment to an IND. In an emergency, a request may be made by telephone or other rapid communication means. A waiver request is required to contain at least one of the following:
(1) An explanation why the sponsor's compliance with the requirement is unnecessary or cannot be achieved;
(2) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds that the sponsor's noncompliance would not pose a significant and unreasonable risk to human subjects of the investigation and that one of the following is met:
(1) The sponsor's compliance with the requirement is unnecessary for the agency to evaluate the application, or compliance cannot be achieved;
(2) The sponsor's proposed alternative satisfies the requirement; or
(3) The applicant's submission otherwise justifies a waiver.
(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to § 312.2(a).
(b) A sponsor shall not begin a clinical investigation subject to § 312.2(a) until the investigation is subject to an IND which is in effect in accordance with § 312.40.
(c) A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent under § 50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide a written determination 30 days after FDA receives the IND or earlier.
An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:
(a)
(2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.
(b)
(c)
(a) FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety. Therefore, although FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA's review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.
(b) The amount of information on a particular drug that must be submitted in an IND to assure the accomplishment of the objectives described in paragraph (a) of this section depends upon such factors as the novelty of the drug, the extent to which it has been studied previously, the known or suspected risks, and the developmental phase of the drug.
(c) The central focus of the initial IND submission should be on the general investigational plan and the protocols for specific human studies. Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting the status of studies being conducted under the IND and should update the general investigational plan for the coming year.
(d) The IND format set forth in § 312.23 should be followed routinely by sponsors in the interest of fostering an efficient review of applications. Sponsors are expected to exercise considerable discretion, however, regarding the content of information submitted in each section, depending upon the kind of drug being studied and the nature of the available information. Section 312.23 outlines the information needed for a commercially sponsored IND for a new molecular entity. A sponsor-investigator who uses, as a research tool, an investigational new drug that is already subject to a manufacturer's IND or marketing application should follow the same general format, but ordinarily may, if authorized by the manufacturer, refer to the manufacturer's IND or marketing application in providing the technical information supporting the proposed clinical investigation. A sponsor-investigator who uses an investigational drug not subject to
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:
(1)
(i) The name, address, and telephone number of the sponsor, the date of the application, and the name of the investigational new drug.
(ii) Identification of the phase or phases of the clinical investigation to be conducted.
(iii) A commitment not to begin clinical investigations until an IND covering the investigations is in effect.
(iv) A commitment that an Institutional Review Board (IRB) that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed changes in the research activity in accordance with the requirements of part 56.
(v) A commitment to conduct the investigation in accordance with all other applicable regulatory requirements.
(vi) The name and title of the person responsible for monitoring the conduct and progress of the clinical investigations.
(vii) The name(s) and title(s) of the person(s) responsible under § 312.32 for review and evaluation of information relevant to the safety of the drug.
(viii) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer—in lieu of a listing of the specific obligations transferred—may be submitted.
(ix) The signature of the sponsor or the sponsor's authorized representative. If the person signing the application does not reside or have a place of business within the United States, the IND is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.
(2)
(3)
(ii) A brief summary of previous human experience with the drug, with reference to other IND's if pertinent, and to investigational or marketing experience in other countries that may be relevant to the safety of the proposed clinical investigation(s).
(iii) If the drug has been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness, identification of the country(ies) where the drug was withdrawn and the reasons for the withdrawal.
(iv) A brief description of the overall plan for investigating the drug product for the following year. The plan should include the following: (
(4) [Reserved]
(5)
(i) A brief description of the drug substance and the formulation, including the structural formula, if known.
(ii) A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans.
(iv) A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies. (Reprints of published articles on such studies may be appended when useful.)
(v) A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug.
(6)
(ii) In Phases 2 and 3, detailed protocols describing all aspects of the study should be submitted. A protocol for a Phase 2 or 3 investigation should be designed in such a way that, if the sponsor anticipates that some deviation from the study design may become necessary as the investigation progresses, alternatives or contingencies to provide for such deviation are built into the protocols at the outset. For example, a protocol for a controlled short-term study might include a plan for an early crossover of nonresponders to an alternative therapy.
(iii) A protocol is required to contain the following, with the specific elements and detail of the protocol reflecting the above distinctions depending on the phase of study:
(
(
(
(
(
(
(
(7)
(ii) It should be emphasized that the amount of information to be submitted depends upon the scope of the proposed clinical investigation. For example, although stability data are required in all phases of the IND to demonstrate that the new drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical investigation, if very short-term tests are proposed, the supporting stability data can be correspondingly limited.
(iii) As drug development proceeds and as the scale or production is changed from the pilot-scale production appropriate for the limited initial clinical investigations to the larger-scale production needed for expanded clinical trials, the sponsor should submit information amendments to supplement the initial information submitted on the chemistry, manufacturing, and control processes with information appropriate to the expanded scope of the investigation.
(iv) Reflecting the distinctions described in this paragraph (a)(7), and based on the phase(s) to be studied, the submission is required to contain the following:
(
(
(
(
(
(8)
(i)
(ii)
(
(iii) For each nonclinical laboratory study subject to the good laboratory practice regulations under part 58, a statement that the study was conducted in compliance with the good laboratory practice regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance.
(9)
(i) If the investigational drug has been investigated or marketed previously, either in the United States or other countries, detailed information about such experience that is relevant to the safety of the proposed investigation or to the investigation's rationale. If the durg has been the subject of controlled trials, detailed information on such trials that is relevant to an assessment of the drug's effectiveness for the proposed investigational use(s) should also be provided. Any published material that is relevant to the safety of the proposed investigation or to an assessment of the drug's effectiveness for its proposed investigational use should be provided in full. Published material that is less directly relevant may be supplied by a bibliography.
(ii) If the drug is a combination of drugs previously investigated or marketed, the information required under paragraph (a)(9)(i) of this section should be provided for each active drug component. However, if any component in such combination is subject to an approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is not required to submit published material concerning that active drug component unless such material relates directly to the proposed investigational use (including publications relevant to component-component interaction).
(iii) If the drug has been marketed outside the United States, a list of the countries in which the drug has been marketed and a list of the countries in which the drug has been withdrawn from marketing for reasons potentially related to safety or effectiveness.
(10)
(i)
(ii)
(iii)
(iv)
(11)
(b)
(c)
(d)
(e)
(f)
Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. This section sets forth the provisions under which new protocols may be submitted and changes in previously submitted protocols may be made. Whenever a sponsor intends to conduct a clinical investigation with an exception from informed consent for emergency research as set forth in § 50.24 of this chapter, the sponsor shall submit a separate IND for such investigation.
(a)
(b)
(i) Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that in the current protocol, or any significant increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.
(2)(i) A protocol change under paragraph (b)(1) of this section may be made provided two conditions are met:
(
(
(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately provided FDA is subsequently notified by protocol amendment and the reviewing IRB is notified in accordance with § 56.104(c).
(c)
(d)
(1)(i) In the case of a new protocol, a copy of the new protocol and a brief description of the most clinically significant differences between it and previous protocols.
(ii) In the case of a change in protocol, a brief description of the change and reference (date and number) to the submission that contained the protocol.
(iii) In the case of a new investigator, the investigator's name, the qualifications to conduct the investigation, reference to the previously submitted protocol, and all additional information about the investigator's study as is required under § 312.23(a)(6)(iii)(
(2) Reference, if necessary, to specific technical information in the IND or in a concurrently submitted information amendment to the IND that the sponsor relies on to support any clinically significant change in the new or amended protocol. If the reference is made to supporting information already in the IND, the sponsor shall identify by name, reference number, volume, and page number the location of the information.
(3) If the sponsor desires FDA to comment on the submission, a request for such comment and the specific questions FDA's response should address.
(e)
(a)
(1) New toxicology, chemistry, or other technical information; or
(2) A report regarding the discontinuance of a clinical investigation.
(b)
(1) A statement of the nature and purpose of the amendment.
(2) An organized submission of the data in a format appropriate for scientific review.
(3) If the sponsor desires FDA to comment on an information amendment, a request for such comment.
(c)
(a)
(b)
(c)
(A) Any adverse experience associated with the use of the drug that is both serious and unexpected; or
(B) Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification shall be made as soon as possible and in no event later than 15 calendar days after the sponsor's initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a narrative format (foreign events may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological studies shall be submitted in a narrative format) and shall bear prominent identification of its contents, i.e., “IND Safety Report.” Each written notification to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND. If FDA determines that additional data are needed, the agency may require further data to be submitted.
(ii) In each written IND safety report, the sponsor shall identify all safety reports previously filed with the IND concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of the previouos, similar reports.
(2)
(3)
(4) A sponsor of a clinical study of a marketed drug is not required to make a safety report for any adverse experience associated with use of the drug that is not from the clinical study itself.
(d)
(2) Followup information to a safety report shall be submitted as soon as the relevant information is available.
(3) If the results of a sponsor's investigation show that an adverse drug experience not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor shall report such experience in a written safety report as soon as possible, but in no event later than 15 calendar days after the determination is made.
(4) Results of a sponsor's investigation of other safety information shall be submitted, as appropriate, in an information amendment or annual report.
(e)
A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation that includes:
(a)
(1) The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement identifying the patient population, and a statement as to whether the study is completed.
(2) The total number of subjects initially planned for inclusion in the study; the number entered into the study to date, tabulated by age group, gender, and race; the number whose participation in the study was completed as planned; and the number who dropped out of the study for any reason.
(3) If the study has been completed, or if interim results are known, a brief description of any available study results.
(b)
(1) A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.
(2) A summary of all IND safety reports submitted during the past year.
(3) A list of subjects who died during participation in the investigation, with the cause of death for each subject.
(4) A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related.
(5) A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including, for example, information about dose response, information from controlled trails, and information about bioavailability.
(6) A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings.
(7) A summary of any significant manufacturing or microbiological changes made during the past year.
(c) A description of the general investigational plan for the coming year to replace that submitted 1 year earlier. The general investigational plan shall contain the information required under § 312.23(a)(3)(iv).
(d) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure.
(e) A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment.
(f) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country.
(g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment, or meeting.
(a)
(b)
(i) The drug is intended to treat a serious or immediately life-threatening disease;
(ii) There is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population;
(iii) The drug is under investigation in a controlled clinical trial under an IND in effect for the trial, or all clinical trials have been completed; and
(iv) The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence.
(2)
(3)
(A) May be effective for its intended use in its intended patient population; or
(B) Would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury.
(ii) For the purpose of this section, an “immediately life-threatening” disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.
(c)
(d)
(a)
(1) A treatment protocol is required to contain the following:
(i) The intended use of the drug.
(ii) An explanation of the rationale for use of the drug, including, as appropriate, either a list of what available regimens ordinarily should be tried before using the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available marketed treatments.
(iii) A brief description of the criteria for patient selection.
(iv) The method of administration of the drug and the dosages.
(v) A description of clinical procedures, laboratory tests, or other measures to monitor the effects of the drug and to minimize risk.
(2) A treatment protocol is to be supported by the following:
(i) Informational brochure for supplying to each treating physician.
(ii) The technical information that is relevant to safety and effectiveness of the drug for the intended treatment purpose. Information contained in the sponsor's IND may be incorporated by reference.
(iii) A commitment by the sponsor to assure compliance of all participating investigators with the informed consent requirements of 21 CFR part 50.
(3) A licensed practioner who receives an investigational drug for treatment use under a treatment protocol is an “investigator” under the protocol and is responsible for meeting all applicable investigator responsibilities under this part and 21 CFR parts 50 and 56.
(b)
(i) A cover sheet (Form FDA 1571) meeting § 312.23(g)(1).
(ii) Information (when not provided by the sponsor) on the drug's chemistry, manufacturing, and controls, and prior clinical and nonclinical experience with the drug submitted in accordance with § 312.23. A sponsor of a clinical investigation subject to an IND who supplies an investigational drug to a licensed medical practitioner for purposes of a separate treatment clinical investigation shall be deemed to authorize the incorporation-by-reference of the technical information contained in the sponsor's IND into the medical practitioner's treatment IND.
(iii) A statement of the steps taken by the practitioner to obtain the drug under a treatment protocol from the drug sponsor.
(iv) A treatment protocol containing the same information listed in paragraph (a)(1) of this section.
(v) A statement of the practitioner's qualifications to use the investigational drug for the intended treatment use.
(vi) The practitioner's statement of familiarity with information on the drug's safety and effectiveness derived from previous clinical and nonclinical experience with the drug.
(vii) Agreement to report to FDA safety information in accordance with § 312.32.
(2) A licensed practitioner who submits a treatment IND under this section is the sponsor-investigator for such IND and is responsible for meeting all applicable sponsor and investigator responsibilities under this part and 21 CFR parts 50 and 56.
Need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND in accordance with § 312.23 or
(a) At any time a sponsor may withdraw an effective IND without prejudice.
(b) If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or otherwise disposed of at the request of the sponsor in accordance with § 312.59.
(c) If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all participating investigators, and all reviewing Institutional Review Boards, together with the reasons for such withdrawal.
(a) An investigational new drug may be used in a clinical investigation if the following conditions are met:
(1) The sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect under paragraph (b) of this section; and the sponsor complies with all applicable requirements in this part and parts 50 and 56 with respect to the conduct of the clinical investigations; and
(2) Each participating investigator conducts his or her investigation in compliance with the requirements of this part and parts 50 and 56.
(b) An IND goes into effect:
(1) Thirty days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold under § 312.42; or
(2) On earlier notification by FDA that the clinical investigations in the IND may begin. FDA will notify the sponsor in writing of the date it receives the IND.
(c) A sponsor may ship an investigational new drug to investigators named in the IND:
(1) Thirty days after FDA receives the IND; or
(2) On earlier FDA authorization to ship the drug.
(d) An investigator may not administer an investigational new drug to human subjects until the IND goes into effect under paragraph (b) of this section.
(a) FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about FDA's need for more data or information.
(b) On the sponsor's request, FDA will provide advice on specific matters relating to an IND. Examples of such advice may include advice on the adequacy of technical data to support an
(c) Unless the communication is accompanied by a clinical hold order under § 312.42, FDA communications with a sponsor under this section are solely advisory and do not require any modification in the planned or ongoing clinical investigations or response to the agency.
(a)
(b)
(i) Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;
(ii) The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND;
(iii) The investigator brochure is misleading, erroneous, or materially incomplete; or
(iv) The IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.
(v) The IND is for the study of an investigational drug intended to treat a life-threatening disease or condition that affects both genders, and men or women with reproductive potential who have the disease or condition being studied are excluded from eligibility because of a risk or potential risk from use of the investigational drug of reproductive toxicity (i.e., affecting reproductive organs) or developmental toxicity (i.e., affecting potential offspring). The phrase “women with reproductive potential” does not include pregnant women. For purposes of this paragraph, “life-threatening illnesses or diseases” are defined as “diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted.” The clinical hold would not apply under this paragraph to clinical studies conducted:
(A) Under special circumstances, such as studies pertinent only to one gender (e.g., studies evaluating the excretion of a drug in semen or the effects on menstrual function);
(B) Only in men or women, as long as a study that does not exclude members of the other gender with reproductive potential is being conducted concurrently, has been conducted, or will take place within a reasonable time agreed upon by the agency; or
(C) Only in subjects who do not suffer from the disease or condition for which the drug is being studied.
(2)
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v) of this section apply; or
(ii) The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.
(3) Clinical hold of a treatment IND or treatment protocol.
(i)
(A) The pertinent criteria in § 312.34(b) for permitting the treatment use to begin are not satisfied; or
(B) The treatment protocol or treatment IND does not contain the information required under § 312.35 (a) or (b)
(ii)
(A) There becomes available a comparable or satisfactory alternative drug or other therapy to treat that stage of the disease in the intended patient population for which the investigational drug is being used;
(B) The investigational drug is not under investigation in a controlled clinical trial under an IND in effect for the trial and not all controlled clinical trials necessary to support a marketing application have been completed, or a clinical study under the IND has been placed on clinical hold:
(C) The sponsor of the controlled clinical trial is not pursuing marketing approval with due diligence;
(D) If the treatment IND or treatment protocol is intended for a serious disease, there is insufficient evidence of safety and effectiveness to support such use; or
(E) If the treatment protocol or treatment IND was based on an immediately life-threatening disease, the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug:
(
(
(iii) FDA may place a proposed or ongoing treatment IND or treatment protocol on clinical hold if it finds that any of the conditions in paragraph (b)(4)(i) through (b)(4)(viii) of this section apply.
(4)
(i) Any of the conditions in paragraph (b)(1) or (b)(2) of this section apply; or
(ii) There is reasonable evidence the investigation that is not designed to be adequate and well-controlled is impeding enrollment in, or otherwise interfering with the conduct or completion of, a study that is designed to be an adequate and well-controlled investigation of the same or another investigational drug; or
(iii) Insufficient quantities of the investigational drug exist to adequately conduct both the investigation that is not designed to be adequate and well-controlled and the investigations that are designed to be adequate and well-controlled; or
(iv) The drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness; or
(v) Another drug under investigation or approved for the same indication and available to the same patient population has demonstrated a better potential benefit/risk balance; or
(vi) The drug has received marketing approval for the same indication in the same patient population; or
(vii) The sponsor of the study that is designed to be an adequate and well-controlled investigation is not actively pursuing marketing approval of the investigational drug with due diligence; or
(viii) The Commissioner determines that it would not be in the public interest for the study to be conducted or continued. FDA ordinarily intends that clinical holds under paragraphs (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this section would only apply to additional enrollment in nonconcurrently controlled trials rather than eliminating continued access to individuals already receiving the investigational drug.
(5)
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or
(ii) The pertinent criteria in § 50.24 of this chapter for such an investigation to begin or continue are not submitted or not satisfied.
(6) Clinical hold of any investigation involving an exception from informed consent under § 50.23(d) of this chapter.
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section apply; or
(ii) A determination by the President to waive the prior consent requirement for the administration of an investigational new drug has not been made.
(c)
(d)
(e)
(f)
(g)
(a)
(b)
(i) Human subjects would be exposed to an unreasonable and significant risk of illness or unjury.
(ii) The IND does not contain sufficient information required under § 312.23 to assess the safety to subjects of the clinical investigations.
(iii) The methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety.
(iv) The clinical investigations are being conducted in a manner substantially different than that described in the protocols submitted in the IND.
(v) The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation or permitted by § 312.7.
(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.
(vii) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with § 312.32 or fails to make any other report required under this part.
(viii) The sponsor fails to submit an accurate annual report of the investigations in accordance with § 312.33.
(ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.
(x) The IND has remained on inactive status for 5 years or more.
(xi) The sponsor fails to delay a proposed investigation under the IND or to suspend an ongoing investigation that has been placed on clinical hold under § 312.42(b)(4).
(2)
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi) of this section apply; or
(ii) The investigational plan or protocol(s) is not reasonable as a bona fide scientific plan to determine whether or not the drug is safe and effective for use; or
(iii) There is convincing evidence that the drug is not effective for the purpose for which it is being investigated.
(3) FDA may propose to terminate a treatment IND if it finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (x) of this section apply; or
(ii) Any of the conditions in § 312.42(b)(3) apply.
(c)
(2) On such notification, the sponsor may provide a written explanation or correction or may request a conference with FDA to provide the requested explanation or correction. If the sponsor does not respond to the notification within the allocated time, the IND shall be terminated.
(3) If the sponsor responds but FDA does not accept the explanation or correction submitted, FDA shall inform the sponsor in writing of the reason for the nonacceptance and provide the sponsor with an opportunity for a regulatory hearing before FDA under part 16 on the question of whether the IND should be terminated. The sponsor's request for a regulatory hearing must be made within 10 days of the sponsor's receipt of FDA's notification of nonacceptance.
(d)
(a) If no subjects are entered into clinical studies for a period of 2 years or more under an IND, or if all investigations under an IND remain on clinical hold for 1 year or more, the IND may be placed by FDA on inactive status. This action may be taken by FDA either on request of the sponsor or on FDA's own initiative. If FDA seeks to act on its own initiative under this section, it shall first notify the sponsor in writing of the proposed inactive status. Upon receipt of such notification, the sponsor shall have 30 days to respond as to why the IND should continue to remain active.
(b) If an IND is placed on inactive status, all investigators shall be so notified and all stocks of the drug shall be returned or otherwise disposed of in accordance with § 312.59.
(c) A sponsor is not required to submit annual reports to an IND on inactive status. An inactive IND is, however, still in effect for purposes of the public disclosure of data and information under § 312.130.
(d) A sponsor who intends to resume clinical investigation under an IND placed on inactive status shall submit a protocol amendment under § 312.30 containing the proposed general investigational plan for the coming year and appropriate protocols. If the protocol amendment relies on information previously submitted, the plan shall reference such information. Additional information supporting the proposed investigation, if any, shall be submitted in an information amendment. Notwithstanding the provisions of § 312.30, clinical investigations under an IND on inactive status may only resume (1) 30 days after FDA receives the protocol amendment, unless FDA notifies the sponsor that the investigations described in the amendment are subject to a clinical hold under § 312.42, or (2) on earlier notification by FDA that the clinical investigations described in the protocol amendment may begin.
(e) An IND that remains on inactive status for 5 years or more may be terminated under § 312.44.
(a)
(b)
(1)
(ii)
(iii)
(iv)
(v)
(2)
(i) A brief summary of the clinical studies to be submitted in the application.
(ii) A proposed format for organizing the submission, including methods for presenting the data.
(iii) Information on the status of needed or ongoing pediatric studies.
(iv) Any other information for discussion at the meeting.
(a)
(b)
(c)
(2) The “end-of-Phase 2” and “pre-NDA” meetings described in § 312.47(b) will also provide a timely forum for discussing and resolving scientific and medical issues on which the sponsor disagrees with the agency.
(3) In requesting a meeting designed to resolve a scientific or medical dispute, applicants may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee members or other consultants, as designated by the agency. Applicants may rely on, and may bring to any meeting, their own consultants. For major scientific and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of its standing advisory committees for its consideration and recommendations.
Sponsors are responsibile for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug. Additional specific responsibilities of sponsors are described elsewhere in this part.
(a) A sponsor may transfer responsibility for any or all of the obligations set forth in this part to a contract research organization. Any such transfer shall be described in writing. If not all obligations are transferred, the writing is required to describe each of the obligations being assumed by the contract research organization. If all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Any obligation not covered by the written description shall be deemed not to have been transferred.
(b) A contract research organization that assumes any obligation of a sponsor shall comply with the specific regulations in this chapter applicable to this obligation and shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under these regulations. Thus, all references to “sponsor” in this part apply to a contract research organization to the extent that it assumes one or more obligations of the sponsor.
(a)
(b)
(c)
(1) A signed investigator statement (Form FDA-1572) containing:
(i) The name and address of the investigator;
(ii) The name and code number, if any, of the protocol(s) in the IND identifying the study(ies) to be conducted by the investigator;
(iii) The name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be conducted;
(iv) The name and address of any clinical laboratory facilities to be used in the study;
(v) The name and address of the IRB that is responsible for review and approval of the study(ies);
(vi) A commitment by the investigator that he or she:
(
(
(
(
(
(
(
(vii) A commitment by the investigator that, for an investigation subject to an institutional review requirement under part 56, an IRB that complies with the requirements of that part will be responsible for the initial and continuing review and approval of the clinical investigation and that the investigator will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others, and will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to the human subjects.
(viii) A list of the names of the subinvestigators (e.g., research fellows, residents) who will be assisting the investigator in the conduct of the investigation(s).
(2)
(3)
(ii) For Phase 2 or 3 investigations, an outline of the study protocol including an approximation of the number of subjects to be treated with the drug and the number to be employed as controls, if any; the clinical uses to be investigated; characteristics of subjects by age, sex, and condition; the kind of clinical observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a description of case report forms to be used.
(4)
(d)
(a) The sponsor shall monitor the progress of all investigations involving an exception from informed consent under § 50.24 of this chapter. When the sponsor receives from the IRB information concerning the public disclosures required by § 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter, the sponsor promptly shall submit to the IND file and to Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, copies of the information that was disclosed, identified by the IND number.
(b) The sponsor also shall monitor such investigations to identify when an IRB determines that it cannot approve the research because it does not meet the criteria in the exception in § 50.24(a) of this chapter or because of other relevant ethical concerns. The sponsor promptly shall provide this information in writing to FDA, investigators who are asked to participate in this or a substantially equivalent clinical investigation, and other IRB's that are asked to review this or a substantially equivalent investigation.
(a) Before the investigation begins, a sponsor (other than a sponsor-investigator) shall give each participating clinical investigator an investigator brochure containing the information described in § 312.23(a)(5).
(b) The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means. Important safety information is required to be relayed to investigators in accordance with § 312.32.
(a) The sponsor shall monitor the progress of all clinical investigations being conducted under its IND.
(b) A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA-1572), the general investigational plan, or the requirements of this part or other applicable parts shall promptly either secure compliance or discontinue shipments of the investigational new drug to the investigator and end the investigator's participation in the investigation. If the investigator's participation in the investigation is ended, the sponsor shall require that the investigator dispose of or return the investigational drug in accordance with the requirements of § 312.59 and shall notify FDA.
(c) The sponsor shall review and evaluate the evidence relating to the
(d) A sponsor who determines that its investigational drug presents an unreasonable and significant risk to subjects shall discontinue those investigations that present the risk, notify FDA, all institutional review boards, and all investigators who have at any time participated in the investigation of the discontinuance, assure the disposition of all stocks of the drug outstanding as required by § 312.59, and furnish FDA with a full report of the sponsor's actions. The sponsor shall discontinue the investigation as soon as possible, and in no event later than 5 working days after making the determination that the investigation should be discontinued. Upon request, FDA will confer with a sponsor on the need to discontinue an investigation.
(a) A sponsor shall maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment.
(b) A sponsor shall maintain complete and accurate records showing any financial interest in § 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this chapter paid to clinical investigators by the sponsor of the covered study. A sponsor shall also maintain complete and accurate records concerning all other financial interests of investigators subject to part 54 of this chapter.
(c) A sponsor shall retain the records and reports required by this part for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified.
(d) A sponsor shall retain reserve samples of any test article and reference standard identified in, and used in any of the bioequivalence or bioavailability studies described in, § 320.38 or § 320.63 of this chapter, and release the reserve samples to FDA upon request, in accordance with, and for the period specified in § 320.38.
(a)
(b)
The sponsor shall assure the return of all unused supplies of the investigational drug from each individual investigator whose participation in the investigation is discontinued or terminated. The sponsor may authorize alternative disposition of unused supplies of the investigational drug provided this alternative disposition does not expose humans to risks from the drug. The sponsor shall maintain written records of any disposition of the drug in accordance with § 312.57.
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in §§ 50.23 or 50.24 of this chapter. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.
An investigator shall administer the drug only to subjects under the investigator's personal supervision or under the supervision of a subinvestigator responsible to the investigator. The investigator shall not supply the investigational drug to any person not authorized under this part to receive it.
(a)
(b)
(c)
(a)
(b)
(c)
(d)
An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
An investigator shall upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to § 312.62. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual results obtained.
If the investigational drug is subject to the Controlled Substances Act, the investigator shall take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution.
(a) If FDA has information indicating that an investigator (including a sponsor-investigator) has repeatedly or deliberately failed to comply with the requirements of this part, part 50, or part 56 of this chapter, or has submitted to FDA or to the sponsor false information in any required report, the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investigator written notice of the matter complained of and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference. If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research, the investigator will be given an opportunity for a regulatory hearing under part 16 on the question of whether the investigator is entitled to receive investigational new drugs.
(b) After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements of this part, part 50, or part 56 of this chapter, or has deliberately or repeatedly submitted false information to FDA or to the sponsor in any required report, the Commissioner will notify the investigator and the sponsor
(c) Each IND and each approved application submitted under part 314 containing data reported by an investigator who has been determined to be ineligible to receive investigational drugs will be examined to determine whether the investigator has submitted unreliable data that are essential to the continuation of the investigation or essential to the approval of any marketing application.
(d) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is reasonably safe to continue the investigation, the Commissioner will notify the sponsor who shall have an opportunity for a regulatory hearing under part 16. If a danger to the public health exists, however, the Commissioner shall terminate the IND immediately and notify the sponsor of the determination. In such case, the sponsor shall have an opportunity for a regulatory hearing before FDA under part 16 on the question of whether the IND should be reinstated.
(e) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued approval of the drug product for which the data were submitted cannot be justified, the Commissioner will proceed to withdraw approval of the drug product in accordance with the applicable provisions of the act.
(f) An investigator who has been determined to be ineligible to receive investigational drugs may be reinstated as eligible when the Commissioner determines that the investigator has presented adequate assurances that the investigator will employ investigatioal drugs solely in compliance with the provisions of this part and of parts 50 and 56.
21 U.S.C. 351, 352, 353, 355, 371; 42 U.S.C. 262.
The purpose of this section is to establish procedures designed to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternative therapy exists. As stated § 314.105(c) of this chapter, while the statutory standards of safety and effectiveness apply to all drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those drugs, demand flexibility in applying the standards. The Food and Drug Administration (FDA) has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses. These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated. The procedure outlined in this section should be interpreted consistent with that purpose.
This section applies to new drug and biological products that are being studied for their safety and effectiveness in treating life-threatening or severely-debilitating diseases.
(a) For purposes of this section, the term “life-threatening” means:
(1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and
(2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival.
(b) For purposes of this section, the term “severely debilitating” means diseases or conditions that cause major irreversible morbidity.
(c) Sponsors are encouraged to consult with FDA on the applicability of these procedures to specific products.
For products intended to treat life-threatening or severely-debilitating illnesses, sponsors may request to meet with FDA-reviewing officials early in the drug development process to review and reach agreement on the design of necessary preclinical and clinical studies. Where appropriate, FDA will invite to such meetings one or more outside expert scientific consultants or advisory committee members. To the extent FDA resources permit, agency reviewing officials will honor requests for such meetings
(a)
(b)
If the preliminary analysis of phase 2 test results appears promising, FDA may ask the sponsor to submit a treatment protocol to be reviewed under the procedures and criteria listed in §§ 312.34 and 312.35. Such a treatment protocol, if requested and granted, would normally remain in effect while the complete data necessary for a marketing application are being assembled by the sponsor and reviewed by FDA (unless grounds exist for clinical hold of ongoing protocols, as provided in § 312.42(b)(3)(ii)).
(a) FDA's application of the statutory standards for marketing approval shall recognize the need for a medical risk-benefit judgment in making the final decision on approvability. As part of this evaluation, consistent with the statement of purpose in § 312.80, FDA will consider whether the benefits of the drug outweigh the known and potential risks of the drug and the need to answer remaining questions about risks and benefits of the drug, taking into consideration the severity of the disease and the absence of satisfactory alternative therapy.
(b) In making decisions on whether to grant marketing approval for products that have been the subject of an end-of-phase 1 meeting under § 312.82, FDA will usually seek the advice of outside expert scientific consultants or advisory committees. Upon the filing of such a marketing application under § 314.101 or part 601 of this chapter, FDA will notify the members of the relevant
(c) If FDA concludes that the data presented are not sufficient for marketing approval, FDA will issue (for a drug) a not approvable letter pursuant to § 314.120 of this chapter, or (for a biologic) a deficiencies letter consistent with the biological product licensing procedures. Such letter, in describing the deficiencies in the application, will address why the results of the research design agreed to under § 312.82, or in subsequent meetings, have not provided sufficient evidence for marketing approval. Such letter will also describe any recommendations made by the advisory committee regarding the application.
(d) Marketing applications submitted under the procedures contained in this section will be subject to the requirements and procedures contained in part 314 or part 600 of this chapter, as well as those in this subpart.
Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain postmarketing (phase 4) studies to delineate additional information about the drug's risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.
At the discretion of the agency, FDA may undertake focused regulatory research on critical rate-limiting aspects of the preclinical, chemical/manufacturing, and clinical phases of drug development and evaluation. When initiated, FDA will undertake such research efforts as a means for meeting a public health need in facilitating the development of therapies to treat life-threatening or severely debilitating illnesses.
For drugs covered under this section, the Commissioner and other agency officials will monitor the progress of the conduct and evaluation of clinical trials and be involved in facilitating their appropriate progress.
All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed to ensure the safety of clinical testing and the safety of products following marketing approval apply to drugs covered by this section. This includes the requirements for informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter). These safeguards further include the review of animal studies prior to initial human testing (§ 312.23), and the monitoring of adverse drug experiences through the requirements of IND safety reports (§ 312.32), safety update reports during agency review of a marketing application (§ 314.50 of this chapter), and postmarketing adverse reaction reporting (§ 314.80 of this chapter).
(a)
(b)
(1) If an IND is in effect for the drug under § 312.40 and each person who receives the drug is an investigator named in the application; or
(2) If FDA authorizes shipment of the drug for use in a clinical investigation. Authorization may be obtained as follows:
(i) Through submission to the International Affairs Staff (HFY-50), Associate Commissioner for Health Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, of a written request from the person that seeks to export the drug. A request must provide adequate information about the drug to satisfy FDA that the drug is appropriate for the proposed investigational use in humans, that the drug will be used for investigational purposes only, and that the drug may be legally used by that consignee in the importing country for the proposed investigational use. The request shall specify the quantity of the drug to be shipped per shipment and the frequency of expected shipments. If FDA authorizes exportation under this paragraph, the agency shall concurrently notify the government of the importing country of such authorization.
(ii) Through submission to the International Affairs Staff (HFY-50), Associate Commissioner for Health Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, of a formal request from an authorized official of the government of the country to which the drug is proposed to be shipped. A request must specify that the foreign government has adequate information about the drug and the proposed investigational use, that the drug will be used for investigational purposes only, and that the foreign government is satisfied that the drug may legally be used by the intended consignee in that country. Such a request shall specify the quantity of drug to be shipped per shipment and the frequency of expected shipments.
(iii) Authorization to export an investigational drug under paragraph (b)(2)(i) or (ii) of this section may be revoked by FDA if the agency finds that the conditions underlying its authorization are not longer met.
(3) This paragraph applies only where the drug is to be used for the purpose of clinical investigation.
(4) This paragraph does not apply to the export of new drugs (including biological products, antibiotic drugs, and insulin) approved or authorized for export under section 802 of the act (21 U.S.C. 382) or section 351(h)(1)(A) of the Public Health Service Act (42 U.S.C. 262(h)(1)(A)).
(a)
(b)
(1) A description of the investigator's qualifications;
(2) A description of the research facilities;
(3) A detailed summary of the protocol and results of the study, and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records;
(4) A description of the drug substance and drug product used in the study, including a description of components, formulation, specifications, and bioavailability of the specific drug product used in the clinical study, if available; and
(5) If the study is intended to support the effectiveness of a drug product, information showing that the study is adequate and well controlled under § 314.126.
(c)
(2) For each foreign clinical study submitted under this section, the sponsor shall explain how the research conformed to the ethical principles contained in the “Declaration of Helsinki” or the foreign country's standards, whichever were used. If the foreign country's standards were used, the sponsor shall explain in detail how those standards differ from the “Declaration of Helsinki” and how they offer greater protection.
(3) When the research has been approved by an independent review committee, the sponsor shall submit to FDA documentation of such review and approval, including the names and qualifications of the members of the committee. In this regard, a “review committee” means a committee composed of scientists and, where practicable, individuals who are otherwise qualified (e.g., other health professionals or laymen). The investigator may not vote on any aspect of the review of his or her protocol by a review committee.
(4) The “Declaration of Helsinki” states as follows:
It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this mission.
The Declaration of Geneva of the World Medical Association binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient.”
The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research.
Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.
Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.
1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature.
2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed.
3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent.
4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.
5. Every biomedical research project involving human subjects should be preceded
6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.
7. Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Physicians should cease any investigation if the hazards are found to outweigh the potential benefits.
8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.
9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject's freely-given informed consent, preferably in writing.
10. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case the informed consent should be obtained by a physician who is not engaged in the investigation and who is completely independent of this official relationship.
11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation.
Whenever the minor child is in fact able to give a consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian.
12. The research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with.
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing health or alleviating suffering.
2. The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods.
3. In any medical study, every patient—including those of a control group, if any—should be assured of the best proven diagnostic and therapeutic method.
4. The refusal of the patient to participate in a study must never interfere with the physician-patient relationship.
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee (I, 2).
6. The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.
1. In the purely scientific application of medical research carried out on a human being, it is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out.
2. The subjects should be volunteers—either healthy persons or patients for whom the experimental design is not related to the patient's illness.
3. The investigator or the investigating team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual.
4. In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.
(a) The existence of an investigational new drug application will not be disclosed by FDA unless it has previously been publicly disclosed or acknowledged.
(b) The availability for public disclosure of all data and information in an investigational new drug application for a new drug will be handled in accordance with the provisions established in § 314.430 for the confidentiality of data and information in applications submitted in part 314. The availability for public disclosure of all data and information in an investigational new drug application for a biological product will be governed by the provisions of §§ 601.50 and 601.51.
(c) Notwithstanding the provisions of § 314.430, FDA shall disclose upon request to an individual to whom an investigational new drug has been given a copy of any IND safety report relating to the use in the individual.
(d) The availability of information required to be publicly disclosed for investigations involving an exception from informed consent under § 50.24 of this chapter will be handled as follows: Persons wishing to request the publicly disclosable information in the IND that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, shall submit a request under the Freedom of Information Act.
(a) Except as provided in paragraph (b) of this section, a sponsor shall send an initial IND submission to the Central Document Room, Center for Drug Evaluation and Research, Food and Drug Administration, Park Bldg., Rm. 214, 12420 Parklawn Dr., Rockville, MD 20852. On receiving the IND, FDA will inform the sponsor which one of the divisions in the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research is responsible for the IND. Amendments, reports, and other correspondence relating to matters covered by the IND should be directed to the appropriate division. The outside wrapper of each submission shall state what is contained in the submission, for example, “IND Application”, “Protocol Amendment”, etc.
(b) Applications for the products listed below should be submitted to the Division of Biological Investigational New Drugs (HFB-230), Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892. (1) Products subject to the licensing provisions of the Public Health Service Act of July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201
(c) All correspondence relating to biological products for human use which are also radioactive drugs shall be submitted to the Division of Oncology and Radiopharmaceutical Drug Products (HFD-150), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, except that applications for coupled antibodies shall be submitted in accordance with paragraph (b) of this section.
(d) All correspondence relating to export of an investigational drug under § 312.110(b)(2) shall be submitted to the International Affairs Staff (HFY-50), Office of Health Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain requirements of this part.
(b) The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) maintain lists of guidance documents that apply to the centers' regulations. The lists are maintained on
(a)
CAUTION: Contains a new drug for investigational use only in laboratory research animals, or for tests in vitro. Not for use in humans.
(ii) A person may ship a biological product for investigational in vitro diagnostic use that is listed in § 312.2(b)(2)(ii) if it is labeled as follows:
CAUTION: Contains a biological product for investigational in vitro diagnostic tests only.
(2) A person shipping a drug under paragraph (a) of this section shall use due diligence to assure that the consignee is regularly engaged in conducting such tests and that the shipment of the new drug will actually be used for tests in vitro or in animals used only for laboratory research.
(3) A person who ships a drug under paragraph (a) of this section shall maintain adequate records showing the name and post office address of the expert to whom the drug is shipped and the date, quantity, and batch or code mark of each shipment and delivery. Records of shipments under paragraph (a)(1)(i) of this section are to be maintained for a period of 2 years after the shipment. Records and reports of data and shipments under paragraph (a)(1)(ii) of this section are to be maintained in accordance with § 312.57(b). The person who ships the drug shall upon request from any properly authorized officer or employee of the Food and Drug Administration, at reasonable times, permit such officer or employee to have access to and copy and verify records required to be maintained under this section.
(b)
(1) The sponsor of the investigation has failed to comply with any of the conditions for shipment established under this section; or
(2) The continuance of the investigation is unsafe or otherwise contrary to the public interest or the drug is used for purposes other than bona fide scientific investigation. FDA will notify the person shipping the drug of its finding and invite immediate correction. If correction is not immediately made, the person shall have an opportunity for a regulatory hearing before FDA pursuant to part 16.
(c)
21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 356a, 356b, 356c, 371, 374, 379e.
(a) This part sets forth procedures and requirements for the submission to, and the review by, the Food and Drug Administration of applications and abbreviated applications to market a new drug under section 505 of the Federal Food, Drug, and Cosmetic Act, as well as amendments, supplements, and postmarketing reports to them.
(b) This part does not apply to drug products subject to licensing by FDA under the Public Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201
(c) References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.
The purpose of this part is to establish an efficient and thorough drug review process in order to: (a) Facilitate the approval of drugs shown to be safe and effective; and (b) ensure the disapproval of drugs not shown to be safe and effective. These regulations are also intended to establish an effective system for FDA's surveillance of marketed drugs. These regulations shall be construed in light of these objectives.
(a) The definitions and interpretations contained in section 201 of the act apply to those terms when used in this part.
(b) The following definitions of terms apply to this part:
Applications and supplements to approved applications are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the application are required: An archival copy, a review copy, and a field copy.An application for a new chemical entity will generally contain an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labeling, including, if applicable, any Medication Guide required under part 208 of this chapter. Other applications will generally contain only some of those items, and information will be limited to that needed to support the particular submission. These include an application of the type described in section 505(b)(2) of the act, an amendment, and a supplement. The application is required to contain reports of all investigations of the drug product sponsored by the applicant, and all other information about the drug pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source. FDA will maintain
(a)
(1) The name and address of the applicant; the date of the application; the application number if previously issued (for example, if the application is a resubmission, an amendment, or a supplement); the name of the drug product, including its established, proprietary, code, and chemical names; the dosage form and strength; the route of administration; the identification numbers of all investigational new drug applications that are referenced in the application; the identification numbers of all drug master files and other applications under this part that are referenced in the application; and the drug product's proposed indications for use.
(2) A statement whether the submission is an original submission, a 505(b)(2) application, a resubmission, or a supplement to an application under § 314.70.
(3) A statement whether the applicant proposes to market the drug product as a prescription or an over-the-counter product.
(4) A check-list identifying what enclosures required under this section the applicant is submitting.
(5) The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application. If the person signing the application does not reside or have a place of business within the United States, the application is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.
(b)
(c)
(2) The summary is required to contain the following information:
(i) The proposed text of the labeling, including, if applicable, any Medication Guide required under part 208 of this chapter, for the drug, with annotations to the information in the summary and technical sections of the application that support the inclusion of each statement in the labeling, and, if the application is for a prescription drug, statements describing the reasons for omitting a section or subsection of the labeling format in § 201.57 of this chapter.
(ii) A statement identifying the pharmacologic class of the drug and a discussion of the scientific rationale for the drug, its intended use, and the potential clinical benefits of the drug product.
(iii) A brief description of the marketing history, if any, of the drug outside the United States, including a list of the countries in which the drug has been marketed, a list of any countries in which the drug has been withdrawn from marketing for any reason related to safety or effectiveness, and a list of countries in which applications for marketing are pending. The description is required to describe both marketing by the applicant and, if known, the marketing history of other persons.
(iv) A summary of the chemistry, manufacturing, and controls section of the application.
(v) A summary of the nonclinical pharmacology and toxicology section of the application.
(vi) A summary of the human pharmacokinetics and bioavailability section of the application.
(vii) A summary of the microbiology section of the application (for anti-infective drugs only).
(viii) A summary of the clinical data section of the application, including the results of statistical analyses of the clinical trials.
(ix) A concluding discussion that presents the benefit and risk considerations related to the drug, including a discussion of any proposed additional studies or surveillance the applicant intends to conduct postmarketing.
(d)
(1)
(i)
(ii)(
(
(
(iii)
(iv) The applicant may, at its option, submit a complete chemistry, manufacturing, and controls section 90 to 120 days before the anticipated submission of the remainder of the application. FDA will review such early submissions as resources permit.
(v) Except for a foreign applicant, the applicant shall include a statement certifying that the field copy of the application has been provided to the applicant's home FDA district office.
(2)
(i) Studies of the pharmacological actions of the drug in relation to its proposed therapeutic indication and studies that otherwise define the pharmacologic properties of the drug or are pertinent to possible adverse effects.
(ii) Studies of the toxicological effects of the drug as they relate to the drug's intended clinical uses, including, as appropriate, studies assessing the drug's acute, subacute, and chronic toxicity; carcinogenicity; and studies of toxicities related to the drug's particular mode of administration or conditions of use.
(iii) Studies, as appropriate, of the effects of the drug on reproduction and on the developing fetus.
(iv) Any studies of the absorption, distribution, metabolism, and excretion of the drug in animals.
(v) For each nonclinical laboratory study subject to the good laboratory practice regulations under part 58 a statement that it was conducted in compliance with the good laboratory practice regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance.
(3)
(i) A description of each of the bioavailability and pharmacokinetic studies of the drug in humans performed by or on behalf of the applicant that includes a description of the analytical and statistical methods used in each study and a statement with respect to each study that it either was conducted in compliance with the institutional review board regulations in part 56, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in part 50.
(ii) If the application describes in the chemistry, manufacturing, and controls section specifications or analytical methods needed to assure the bioavailability of the drug product or drug substance, or both, a statement in this section of the rationale for establishing the specification or analytical methods, including data and information supporting the rationale.
(iii) A summarizing discussion and analysis of the pharmacokinetics and metabolism of the active ingredients and the bioavailability or bioequivalence, or both, of the drug product.
(4)
(i) A description of the biochemical basis of the drug's action on microbial physiology.
(ii) A description of the antimicrobial spectra of the drug, including results of in vitro preclinical studies to demonstrate concentrations of the drug required for effective use.
(iii) A description of any known mechanisms of resistance to the drug, including results of any known epidemiologic studies to demonstrate prevalence of resistance factors.
(iv) A description of clinical microbiology laboratory methods (for example, in vitro sensitivity discs) needed for effective use of the drug.
(5)
(i) A description and analysis of each clinical pharmacology study of the drug, including a brief comparison of the results of the human studies with the animal pharmacology and toxicology data.
(ii) A description and analysis of each controlled clinical study pertinent to a proposed use of the drug, including the protocol and a description of the statistical analyses used to evaluate the study. If the study report is an interim analysis, this is to be noted and a projected completion date provided. Controlled clinical studies that have not been analyzed in detail for any reason (e.g., because they have been discontinued or are incomplete) are to be included in this section, including a copy of the protocol and a brief description of the results and status of the study.
(iii) A description of each uncontrolled clinical study, a summary of the results, and a brief statement explaining why the study is classified as uncontrolled.
(iv) A description and analysis of any other data or information relevant to an evaluation of the safety and effectiveness of the drug product obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from clinical investigations, including controlled and uncontrolled studies of uses of the drug other than those proposed in the application, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers.
(v) An integrated summary of the data demonstrating substantial evidence of effectiveness for the claimed indications. Evidence is also required to support the dosage and administration section of the labeling, including support for the dosage and dose interval recommended. The effectiveness data shall be presented by gender, age, and racial subgroups and shall identify any modifications of dose or dose interval needed for specific subgroups. Effectiveness data from other subgroups of the population of patients treated, when appropriate, such as patients with renal failure or patients with different levels of severity of the disease, also shall be presented.
(vi) A summary and updates of safety information, as follows:
(
(
(vii) If the drug has a potential for abuse, a description and analysis of studies or information related to abuse of the drug, including a proposal for scheduling under the Controlled Substances Act. A description of any studies related to overdosage is also required, including information on dialysis, antidotes, or other treatments, if known.
(viii) An integrated summary of the benefits and risks of the drug, including a discussion of why the benefits exceed the risks under the conditions stated in the labeling.
(ix) A statement with respect to each clinical study involving human subjects that it either was conducted in compliance with the institutional review board regulations in part 56, or was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted in compliance with the informed consent regulations in part 50.
(x) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer—in lieu of a listing of the specific obligations transferred—may be submitted.
(xi) If original subject records were audited or reviewed by the sponsor in the course of monitoring any clinical study to verify the accuracy of the case reports submitted to the sponsor, a list identifying each clinical study so audited or reviewed.
(6)
(i) A copy of the information submitted under paragraph (d)(5)(ii) of this section concerning the description and analysis of each controlled clinical study, and the documentation and supporting statistical analyses used in evaluating the controlled clinical studies.
(ii) A copy of the information submitted under paragraph (d)(5)(vi)(
(7)
(e)
(i) Four representative samples of the following, each sample in sufficient quantity to permit FDA to perform three times each test described in the application to determine whether the drug substance and the drug product meet the specifications given in the application:
(
(
(
(ii) Samples of the finished market package, if requested by FDA.
(2) The applicant shall submit the following in the archival copy of the application:
(i) Three copies of the analytical methods and related descriptive information contained in the chemistry, manufacturing, and controls section under paragraph (d)(1) of this section for the drug substance and the drug product that are necessary for FDA's laboratories to perform all necessary tests on the samples and to validate the applicant's analytical methods. The related descriptive information includes a description of each sample; the proposed regulatory specifications for the drug; a detailed description of the methods of analysis; supporting data for accuracy, specificity, precision and ruggedness; and complete results of the applicant's tests on each sample.
(ii) Copies of the label and all labeling for the drug product (including, if applicable, any Medication Guide required under part 208 of this chapter) for the drug product (4 copies of draft labeling or 12 copies of final printed labeling).
(f)
(1)
(2)
(3)
(4) Applicants are invited to meet with FDA before submitting an application to discuss the presentation and format of supporting information. If the applicant and FDA agree, the applicant may submit tabulations of patient data and case report forms in a form other than hard copy, for example, on microfiche or computer tapes.
(g)
(1) The applicant ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously is required to identify the file by name, reference number, volume, and page number in the agency's records where the information can be found. A reference to information submitted to the agency by a person other than the applicant is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information.
(2) The applicant shall submit an accurate and complete English translation of each part of the application that is not in English. The applicant shall submit a copy of each original literature publication for which an English translation is submitted.
(3) If an applicant who submits a new drug application under section 505(b) of the act obtains a “right of reference or use,” as defined under § 314.3(b), to an investigation described in clause (A) of section 505(b)(1) of the act, the applicant shall include in its application a written statement signed by the owner of the data from each such investigation that the applicant may rely on in support of the approval of its application, and provide FDA access to, the underlying raw data that provide the basis for the report of the investigation submitted in its application.
(h)
(i)
(i)
(
(
(
(
(B) If the drug on which investigations that are relied upon by the applicant were conducted is itself a licensed generic drug of a patented drug first approved under section 505(b) of the act, the appropriate patent certification under this section with respect to each patent that claims the first-approved patented drug or that claims an approved use for such a drug.
(ii)
(iii)
(B) If the labeling of the drug product for which the applicant is seeking approval includes an indication that, according to the patent information submitted under section 505(b) or (c) of the act and § 314.53 or in the opinion of the applicant, is claimed by a use patent, the applicant shall submit an applicable certification under paragraph (i)(1)(i) of this section.
(2)
(3)
(4)
(5)
(6)
(i)
(ii)
(iii)
(B) An applicant is not required to amend a submitted certification when information on an otherwise applicable patent is submitted after the effective date of approval for the 505(b)(2) application.
(j)
(1) A statement that the applicant is claiming exclusivity.
(2) A reference to the appropriate paragraph under § 314.108 that supports its claim.
(3) If the applicant claims exclusivity under § 314.108(b)(2), information to show that, to the best of its knowledge or belief, a drug has not previously been approved under section 505(b) of the act containing any active moiety in the drug for which the applicant is seeking approval.
(4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the following information to show that the application contains “new clinical investigations” that are “essential to approval of the application or supplement” and were “conducted or sponsored by the applicant:”
(i)
(ii)
(iii)
(k)
(l)
(2) The applicant shall submit a review copy of the application. Each of the technical sections, described in paragraphs (d)(1) through (d)(6) of this section, in the review copy is required to be separately bound with a copy of the application form required under paragraph (a) of this section and a copy of the summary required under paragraph (c) of this section.
(3) The applicant shall submit a field copy of the application that contains the technical section described in paragraph (d)(1) of this section, a copy of the application form required under paragraph (a) of this section, a copy of the summary required under paragraph (c) of this section, and a certification that the field copy is a true copy of the technical section described in paragraph (d)(1) of this section contained in the archival and review copies of the application.
(4) The applicant may obtain from FDA sufficient folders to bind the archival, the review, and the field copies of the application.
For
(a)
(1) Each owner of the patent that is the subject of the certification or the representative designated by the owner to receive the notice. The name and address of the patent owner or its representative may be obtained from the United States Patent and Trademark Office; and
(2) The holder of the approved application under section 505(b) of the act for each drug product which is claimed by the patent or a use of which is claimed by the patent and for which the applicant is seeking approval, or, if the application holder does not reside or maintain a place of business within the United States, the application holder's attorney, agent, or other authorized official. The name and address of the application holder or its attorney, agent, or authorized official may be obtained from the Division of Drug Information Resources (HFD-80), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(3) This paragraph does not apply to a use patent that claims no uses for which the applicant is seeking approval.
(b)
(c)
(1) A statement that a 505(b)(2) application submitted by the applicant has been filed by FDA.
(2) The application number.
(3) The established name, if any, as defined in section 502(e)(3) of the act, of the proposed drug product.
(4) The active ingredient, strength, and dosage form of the proposed drug product.
(5) The patent number and expiration date, as submitted to the agency or as known to the applicant, of each patent alleged to be invalid, unenforceable, or not infringed.
(6) A detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid, unenforceable, or will not be infringed. The applicant shall include in the detailed statement:
(i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation.
(7) If the applicant does not reside or have a place of business in the United States, the name and address of an agent in the United States authorized to accept service of process for the applicant.
(d)
(e)
(f)
(a)
(b)
(c)
(i) Patent number and the date on which the patent will expire.
(ii) Type of patent, i.e., drug, drug product, or method of use.
(iii) Name of the patent owner.
(iv) If the patent owner or applicant does not reside or have a place of business within the United States, the name of an agent (representative) of the patent owner or applicant who resides or maintains a place of business within the United States authorized to receive notice of patent certification under section 505(b)(3) and (j)(2)(B) of the act and §§ 314.52 and 314.95.
(2)
The undersigned declares that Patent No. ____ covers the formulation, composition, and/or method of use of (
(ii)
(3)
(4)
(d)
(2)
(A) To change the formulation;
(B) To add a new indication or other condition of use, including a change in route of administration;
(C) To change the strength;
(D) To make any other patented change regarding the drug, drug product, or any method of use.
(ii) If the applicant submits a supplement for one of the changes listed under paragraph (d)(2)(i) of this section and existing patents for which information has already been submitted to FDA claim the changed product, the applicant shall submit a certification with the supplement identifying the patents that claim the changed product.
(iii) If the applicant submits a supplement for one of the changes listed under paragraph (d)(2)(i) of this section and no patents, including previously submitted patents, claim the changed product, it shall so certify.
(iv) The applicant shall comply with the requirements for amendment of formulation or composition and method of use patent information under paragraphs (c)(2)(ii) and (d)(3) of this section.
(3)
(4)
(5)
(6)
(e)
(f)
(a) The act does not permit approval of an abbreviated new drug application for a new indication, nor does it permit approval of other changes in a listed drug if investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the change. Any person seeking approval of a drug product that represents a modification of a listed drug (e.g., a new indication or new dosage form) and for which investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the changes may, except as provided in paragraph (b) of this section, submit a 505(b)(2) application. This application need contain only that information needed to support the modification(s) of the listed drug.
(1) The applicant shall submit a complete archival copy of the application that contains the following:
(i) The information required under § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and (g), except that § 314.50(d)(1)(ii)(
(ii) The information required under § 314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) as needed to support the safety and effectiveness of the drug product.
(iii) Identification of the listed drug for which FDA has made a finding of safety and effectiveness and on which finding the applicant relies in seeking approval of its proposed drug product by established name, if any, proprietary name, dosage form, strength, route of administration, name of listed drug's application holder, and listed drug's approved application number.
(iv) If the applicant is seeking approval only for a new indication and not for the indications approved for the listed drug on which the applicant relies, a certification so stating.
(v) Any patent information required under section 505(b)(1) of the act with respect to any patent which claims the drug for which approval is sought or a method of using such drug and to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug product.
(vi) Any patent certification or statement required under section 505(b)(2) of the act with respect to any relevant patents that claim the listed drug or that claim any other drugs on which
(vii) If the applicant believes the change for which it is seeking approval is entitled to a period of exclusivity, the information required under § 314.50(j).
(2) The applicant shall submit a review copy that contains the technical sections described in § 314.50(d)(1), except that § 314.50(d)(1)(ii)(
(3) The information required by § 314.50 (d)(2), (d)(4) (if an anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on which the applicant relies shall be satisfied by reference to the listed drug under paragraph (a)(1)(iii) of this section.
(4) The applicant shall submit a field copy of the application that contains the technical section described in § 314.50(d)(1), a copy of the information required under § 314.50(a) and (c), and certification that the field copy is a true copy of the technical section described in § 314.50(d)(1) contained in the archival and review copies of the application.
(b) An application may not be submitted under this section for a drug product whose only difference from the reference listed drug is that:
(1) The extent to which its active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug; or
(2) The rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the reference listed drug.
(a)
(b)
(2) If FDA determines that there is an adequate justification for temporarily delaying the submission of assessments of pediatric safety and effectiveness, the drug product may be approved for use in adults subject to the requirement that the applicant submit the required assessments within a specified time.
(c)
(2)
(i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients and is not likely to be used in a substantial number of pediatric patients;
(ii) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed; or
(iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in all pediatric age groups.
(3)
(i) The drug product does not represent a meaningful therapeutic benefit over existing treatments for pediatric patients in that age group, and is not likely to be used in a substantial number of patients in that age group;
(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed;
(iii) There is evidence strongly suggesting that the drug product would be ineffective or unsafe in that age group; or
(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.
(4)
(5)
(i) If approved, the drug would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared to marketed products adequately labeled for that use in the relevant pediatric population. Examples of how improvement might be demonstrated include, for example, evidence of increased effectiveness in treatment, prevention, or diagnosis of disease, elimination or substantial reduction of a treatment-limiting drug reaction, documented enhancement of compliance, or evidence of safety and effectiveness in a new subpopulation; or
(ii) The drug is in a class of drugs or for an indication for which there is a need for additional therapeutic options.
(d)
(a) Except as provided in paragraph (b) of this section, the applicant may submit an amendment to an application that is filed under § 314.100, but not
(b)(1) An unapproved application may not be amended if all of the following conditions apply:
(i) The unapproved application is for a drug for which a previous application has been approved and granted a period of exclusivity in accordance with section 505(c)(3)(D)(ii) of the act that has not expired;
(ii) The applicant seeks to amend the unapproved application to include a published report of an investigation that was conducted or sponsored by the applicant entitled to exclusivity for the drug;
(iii) The applicant has not obtained a right of reference to the investigation described in paragraph (b)(1)(ii) of this section; and
(iv) The report of the investigation described in paragraph (b)(1)(ii) of this section would be essential to the approval of the unapproved application.
(2) The submission of an amendment described in paragraph (b)(1) of this section will cause the unapproved application to be deemed to be withdrawn by the applicant under § 314.65 on the date of receipt by FDA of the amendment. The amendment will be considered a resubmission of the application, which may not be accepted except as provided in accordance with section 505(c)(3)(D)(ii) of the act.
(c) The applicant shall submit a field copy of each amendment to § 314.50(d)(1). The applicant, other than a foreign applicant, shall include in its submission of each such amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant's home FDA district office.
An applicant may at any time withdraw an application that is not yet approved by notifying the Food and Drug Administration in writing. The agency will consider an applicant's failure to respond within 10 days to an approvable letter under § 314.110 or a not approvable letter under § 314.120 to be a request by the applicant to withdraw the application. A decision to withdraw the application is without prejudice to refiling. The agency will retain the application and will provide a copy to the applicant on request under the fee schedule in § 20.42 of FDA's public information regulations.
(a)
(b)
(1)
(i) To relax the limits for a specification;
(ii) To establish a new regulatory analytical method;
(iii) To delete a specification or regulatory analytical method;
(iv) To change the synthesis of the drug substance, including a change in solvents and a change in the route of synthesis.
(v) To use a different facility or establishment to manufacture the drug substance, where: (
(2)
(i) To add or delete an ingredient, or otherwise to change the composition of the drug product, other than deletion of an ingredient intended only to affect the color of the drug product;
(ii) To relax the limits for a specification;
(iii) To establish a new regulatory analytical method;
(iv) To delete a specification or regulatory analytical method;
(v) To change the method of manufacture of the drug product, including changing or relaxing an in-process control;
(vi) To use a different facility or establishment, including a different contract laboratory or labeler, to manufacture, process, or pack the drug product;
(vii) To change the container and closure system for the drug product (for example, glass to high density polyethylene (HDPE), or HDPE to polyvinyl chloride) or change a specification or regulatory analytical method for the container and closure system;
(viii) To change the size of the container, except for solid dosage forms, without a change in the container and closure system.
(ix) To extend the expiration date of the drug product based on data obtained under a new or revised stability testing protocol that has not been approved in the application.
(x) To establish a new procedure for reprocessing a batch of the drug product that fails to meet specifications.
(xi) To add a code imprint by printing with ink on a solid oral dosage form drug product.
(xii) To add a code imprint by embossing, debossing, or engraving on a modified release solid oral dosage form drug product.
(3)
(ii) If applicable, any change to a Medication Guide required under part 208 of this chapter, except for changes in the information specified in § 208.20(b)(8)(iii) and (b)(8)(iv).
(c)
(1) Adds a new specification or test method or changes in the methods, facilities (except a change to a new facility), or controls to provide increased assurance that the drug will have the characteristics of identity, strength, quality, and purity which it purports or is represented to possess;
(2) Changes labeling to accomplish any of the following:
(i) To add or strengthen a contraindication, warning, precaution, or adverse reaction;
(ii) To add or strengthen a statement about drug abuse, dependence, or overdosage; or
(iii) To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the product.
(iv) To delete false, misleading, or unsupported indications for use or claims for effectiveness.
(3) To use a different facility or establishment to manufacture the drug substance, where: (i) The manufacturing process in the new facility or establishment does not differ materially from that in the former facility or establishment, and (ii) the new facility or establishment has received a satisfactory current good manufacturing practice (CGMP) inspection within the previous 2 years covering that manufacturing process.
(d)
(1) Any change made to comply with an official compendium.
(2) A change in the labeling concerning the description of the drug product or in the information about how the drug product is supplied, that does not involve a change in the dosage strength or dosage form.
(3) An editorial or similar minor change in labeling.
(4) The deletion of an ingredient intended only to affect the color of the drug product.
(5) An extension of the expiration date based upon full shelf-life data obtained from a protocol approved in the application.
(6) A change within the container and closure system for the drug product (for example, a change from one high density polyethylene (HDPE) to another HDPE), except a change in container size for nonsolid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium.
(7) The addition or deletion of an alternate analytical method.
(8) A change in the size of a container for a solid dosage form, without a change from one container and closure system to another.
(9) The addition by embossing, debossing, or engraving of a code imprint to a solid oral dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint.
(e)
(f)
(g)
(1)
(ii) These changes include, but are not limited to:
(A) Changes in the qualitative or quantitative formulation or other specifications as provided in the approved application or in the regulations;
(B) Changes requiring completion of an appropriate human study to demonstrate the equivalence of the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;
(C) Changes in the virus or adventitious agent removal or inactivation method(s);
(D) Changes in the source material or cell line;
(E) Establishment of a new master cell bank or seed; and
(F) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation.
(iii) The applicant must obtain approval of the supplement from FDA prior to distribution of the product made using the change. Except for submissions under paragraph (g)(4) of this section, the following shall be contained in the supplement:
(A) A detailed description of the proposed change;
(B) The product(s) involved;
(C) The manufacturing site(s) or area(s) affected;
(D) A description of the methods used and studies performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;
(E) The data derived from such studies;
(F) Relevant validation protocols and data; and
(G) A reference list of relevant standard operating procedures (SOP's).
(2)
(ii) These changes include, but are not limited to:
(A) Change in the site of testing from one facility to another;
(B) An increase or decrease in production scale during finishing steps that involves new or different equipment; and
(C) Replacement of equipment with that of similar, but not identical, design and operating principle that does not affect the process methodology or process operating parameters.
(iii) Pending approval of the supplement by FDA, and except as provided in paragraph (g)(2)(v) of this section, distribution of the product made using the change may begin not less than 30 days after receipt of the supplement by FDA. The information listed in paragraph (g)(1)(iii)(A) through (g)(1)(iii)(G) of this section shall be contained in the supplement.
(iv) If within 30 days following FDA's receipt of the supplement, FDA informs the applicant that either:
(A) The change requires approval prior to distribution of the product in
(B) Any of the information required under paragraph (g)(2)(iii) of this section is missing; the applicant shall not distribute the product made using the change until FDA determines that compliance with this section is achieved.
(v) In certain circumstances, FDA may determine that, based on experience with a particular type of change, the supplement for such change is usually complete and provides the proper information, and on particular assurances that the proposed change has been appropriately submitted, the product made using the change may be distributed immediately upon receipt of the supplement by FDA. These circumstances may include substantial similarity with a type of change regularly involving a “Supplement—Changes Being Effected” supplement, or a situation in which the applicant presents evidence that the proposed change has been validated in accordance with an approved protocol for such change under paragraph (g)(4) of this section.
(3)
(ii) These changes include, but are not limited to:
(A) Any change made to comply with an official compendium that is consistent with FDA requirements;
(B) The deletion of an ingredient intended only to affect the color of the product;
(C) An extension of an expiration date based upon full shelf life data obtained from a protocol approved in the application;
(D) A change within the container and closure system for solid dosage forms, based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium;
(E) A change in the size of a container for a solid dosage form, without a change from one container and closure system to another;
(F) The addition by embossing, debossing, or engraving of a code imprint to a solid dosage form drug product other than a modified release dosage form, or a minor change in an existing code imprint; and
(G) The addition or deletion of an alternate analytical method.
(4) An applicant may submit one or more protocols describing the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. Any such protocols, or change to a protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution of the product which, if approved, may justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect.
(a) Only the applicant may submit a supplement to an application.
(b) All procedures and actions that apply to an application under § 314.50 also apply to supplements, except that the information required in the supplement is limited to that needed to support the change. A supplement is required to contain an archival copy and a review copy that include an application form and appropriate technical sections, samples, and labeling; except that a supplement for a change other than a change in labeling is required also to contain a field copy.
(c) All procedures and actions that apply to applications under this part, including actions by applicants and the Food and Drug Administration, also apply to supplements.
(a) An applicant may transfer ownership of its application. At the time of transfer the new and former owners are required to submit information to the Food and Drug Administration as follows:
(1) The former owner shall submit a letter or other document that states that all rights to the application have been transferred to the new owner.
(2) The new owner shall submit an application form signed by the new owner and a letter or other document containing the following:
(i) The new owner's commitment to agreements, promises, and conditions made by the former owner and contained in the application;
(ii) The date that the change in ownership is effective; and
(iii) Either a statement that the new owner has a complete copy of the approved application, including supplements and records that are required to be kept under § 314.81, or a request for a copy of the application from FDA's files. FDA will provide a copy of the application to the new owner under the fee schedule in § 20.42 of FDA's public information regulations.
(b) The new owner shall advise FDA about any change in the conditions in the approved application under § 314.70, except the new owner may advise FDA in the next annual report about a change in the drug product's label or labeling to change the product's brand or the name of its manufacturer, packer, or distributor.
(a)
(b)
(c)
(1)(i)
(ii)
(iii)
(A) A copy of each adverse drug experience report;
(B) The date the report was received by the nonapplicant;
(C) The date the report was submitted to the applicant; and
(D) The name and address of the applicant.
(iv)
(2)
(ii) Each periodic report is required to contain: (
(iii) Periodic reporting, except for information regarding 15-day Alert reports, does not apply to adverse drug experience information obtained from postmarketing studies (whether or not conducted under an investigational new drug application), from reports in the scientific literature, and from foreign marketing experience.
(d)
(2) As with all reports submitted under paragraph (c)(1)(i) of this section, reports based on the scientific literature shall be submitted on FDA Form 3500A or comparable format as prescribed by paragraph (f) of this section. In cases where the applicant believes that preparing the FDA Form 3500A constitutes an undue hardship, the applicant may arrange with the Division of Pharmacovigilance and Epidemiology for an acceptable alternative reporting format.
(e)
(2) The applicant shall separate and clearly mark reports of adverse drug experiences that occur during a postmarketing study as being distinct from those experiences that are being reported spontaneously to the applicant.
(f)
(2) Each completed FDA Form 3500A should refer only to an individual patient or a single attached publication.
(3) Instead of using FDA Form 3500A, an applicant may use a computer-generated FDA Form 3500A or other alternative format (e.g., a computer-generated tape or tabular listing) provided that: (i) The content of the alternative format is equivalent in all elements of information to those specified in FDA
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the instructions for completing the form may be obtained from the Division of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. More than 10 copies of the form may be obtained by writing to the Consolidated Forms and Publications Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
(g)
(h)
(i)
(j)
(k)
(a)
(b)
(1)
(i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article.
(ii) Information concerning any bacteriological contamination, or any significant chemical, physical, or other
(2)
(i)
(ii)
(iii)
(iv)
(
(v)
(vi)
(
(
(vii)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(viii)
(ix)
(3)
(ii)
(iii)
(
(
(
(
(
(
(c)
(2)
(d)
(a) An applicant may ask the Food and Drug Administration to waive under this section any requirement that applies to the applicant under §§ 314.50 through 314.81. An applicant may ask FDA to waive under § 314.126(c) any criteria of an adequate and well-controlled study described in § 314.126(b). A waiver request under this section is required to be submitted with supporting documentation in an application, or in an amendment or supplement to an application. The waiver request is required to contain one of the following:
(1) An explanation why the applicant's compliance with the requirement is unnecessary or cannot be achieved;
(2) A description of an alternative submission that satisfies the purpose of the requirement; or
(3) Other information justifying a waiver.
(b) FDA may grant a waiver if it finds one of the following:
(1) The applicant's compliance with the requirement is unnecessary for the agency to evaluate the application or compliance cannot be achieved;
(2) The applicant's alternative submission satisfies the requirement; or
(3) The applicant's submission otherwise justifies a waiver.
(a) Abbreviated applications are suitable for the following drug products within the limits set forth under § 314.93:
(1) Drug products that are the same as a listed drug. A “listed drug” is defined in § 314.3. For determining the suitability of an abbreviated new drug application, the term “same as” means identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use, except that conditions of use for which approval cannot be granted because of exclusivity or an existing patent may be omitted. If a listed drug has been voluntarily withdrawn from or not offered for sale by its manufacturer, a person who wishes to submit an abbreviated new drug application for the drug shall comply with § 314.122.
(2) [Reserved]
(3) Drug products that have been declared suitable for an abbreviated new drug application submission by FDA through the petition procedures set forth under § 10.30 of this chapter and § 314.93.
(b) FDA will publish in the list listed drugs for which abbreviated applications may be submitted. The list is available from the Superintendent of Documents, U.S. Government Printing
(a) The only changes from a listed drug for which the agency will accept a petition under this section are those changes described in paragraph (b) of this section. Petitions to submit abbreviated new drug applications for other changes from a listed drug will not be approved.
(b) A person who wants to submit an abbreviated new drug application for a drug product which is not identical to a listed drug in route of administration, dosage form, and strength, or in which one active ingredient is substituted for one of the active ingredients in a listed combination drug, must first obtain permission from FDA to submit such an abbreviated application.
(c) To obtain permission to submit an abbreviated new drug application for a change described in paragraph (b) of this section, a person must submit and obtain approval of a petition requesting the change. A person seeking permission to request such a change from a reference listed drug shall submit a petition in accordance with §10.20 of this chapter and in the format specified in § 10.30 of this chapter. The petition shall contain the information specified in § 10.30 of this chapter and any additional information required by this section. If any provision of § 10.20 or § 10.30 of this chapter is inconsistent with any provision of this section, the provisions of this section apply.
(d) The petitioner shall identify a listed drug and include a copy of the proposed labeling for the drug product that is the subject of the petition and a copy of the approved labeling for the listed drug. The petitioner may, under limited circumstances, identify more than one listed drug, for example, when the proposed drug product is a combination product that differs from the combination reference listed drug with regard to an active ingredient, and the different active ingredient is an active ingredient of a listed drug. The petitioner shall also include information to show that:
(1) The active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those of the reference listed drug.
(2) The drug product can be expected to have the same therapeutic effect as the reference listed drug when administered to patients for each condition of use in the reference listed drug's labeling for which the applicant seeks approval.
(3) If the proposed drug product is a combination product with one different active ingredient, including a different ester or salt, from the reference listed drug, that the different active ingredient has previously been approved in a listed drug or is a drug that does not meet the definition of “new drug” in section 201(b) of the act.
(e) No later than 90 days after the date a petition that is permitted under paragraph (a) of this section is submitted, FDA will approve or disapprove the petition.
(1) FDA will approve a petition properly submited under this section unless it finds that:
(i) Investigations must be conducted to show the safety and effectiveness of the drug product or of any of its active ingredients, its route of administration, dosage form, or strength which differs from the reference listed drug; or
(ii) For a petition that seeks to change an active ingredient, the drug product that is the subject of the petition is not a combination drug; or
(iii) For a combination drug product that is the subject of the petition and has an active ingredient different from the reference listed drug:
(A) The drug product may not be adequately evaluated for approval as safe and effective on the basis of the information required to be submitted under § 314.94; or
(B) The petition does not contain information to show that the different active ingredient of the drug product is of the same pharmacological or therapeutic class as the ingredient of the reference listed drug that is to be changed and that the drug product can be expected to have the same therapeutic effect as the reference listed
(C) The different active ingredient is not an active ingredient in a listed drug or a drug that meets the requirements of section 201(p) of the act; or
(D) The remaining active ingredients are not identical to those of the listed combination drug; or
(iv) Any of the proposed changes from the listed drug would jeopardize the safe or effective use of the product so as to necessitate significant labeling changes to address the newly introduced safety or effectiveness problem; or
(v) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons.
(2) For purposes of this paragraph, “investigations must be conducted” means that information derived from animal or clinical studies is necessary to show that the drug product is safe or effective. Such information may be contained in published or unpublished reports.
(3) If FDA approves a petition submitted under this section, the agency's response may describe what additional information, if any, will be required to support an abbreviated new drug application for the drug product. FDA may, at any time during the course of its review of an abbreviated new drug application, request additional information required to evaluate the change approved under the petition.
(f) FDA may withdraw approval of a petition if the agency receives any information demonstrating that the petition no longer satisfies the conditions under paragraph (e) of this section.
Abbreviated applications are required to be submitted in the form and contain the information required under this section. Three copies of the application are required, an archival copy, a review copy, and a field copy. FDA will maintain guidance documents on the format and content of applications to assist applicants in their preparation.
(a)
(1)
(2)
(3)
(i) The name of the reference listed drug, including its dosage form and strength. For an abbreviated new drug application based on an approverd petition under §10.30 of this chapter or §314.93, the reference listed drug must be the same as the listed drug approved in the petition.
(ii) A statement as to whether, according to the information published in the list, the reference listed drug is entitled to a period of marketing exclusivity under section 505(j)(4)(D) of the act.
(iii) For an abbreviated new drug application based on an approved petition under § 10.30 of this chapter or § 314.93, a reference to FDA-assigned docket number for the petition and a copy of FDA's correspondence approving the petition.
(4)
(ii) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.
(5)
(A) A statement that the active ingredient of the proposed drug product is the same as that of the reference listed drug.
(B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.
(ii) For a combination drug product, information to show that the active ingredients are the same as those of the reference listed drug except for any different active ingredient that has been the subject of an approved petition, as follows:
(A) A statement that the active ingredients of the proposed drug product are the same as those of the reference listed drug, or if one of the active ingredients differs from one of the active ingredients of the reference listed drug and the abbreviated application is submitted under the approval of a petition under § 314.93 to vary such active ingredient, information to show that the other active ingredients of the drug product are the same as the other active ingredients of the reference listed drug, information to show that the different active ingredient is an active ingredient of another listed drug or of a drug that does not meet the definition of “new drug” in section 201(p) of the act, and such other information about the different active ingredient that FDA may require.
(B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.
(6)
(A) A statement that the route of administration, dosage form, and strength of the proposed drug product are the same as those of the reference listed drug.
(B) A reference to the applicant's annotated proposed labeling and to the currently approved labeling for the reference listed drug provided under paragraph (a)(8) of this section.
(ii) If the route of administration, dosage form, or strength of the drug product differs from the reference listed drug and the abbreviated application is submitted under an approved petition under § 314.93, such information about the different route of administration, dosage form, or strength that FDA may require.
(7)
(ii) If the abbreviated new drug application is submitted under a petition approved under § 314.93, the results of any bioavailability of bioequivalence testing required by the agency, or any other information required by the agency to show that the active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those in the reference listed drug and that the proposed drug product can be expected to have the same therapeutic effect as the reference listed drug. If the proposed drug product contains a different active ingredient than the reference listed drug, FDA will consider the proposed drug product to have the same therapeutic effect as the reference listed drug if the applicant provides information demonstrating that:
(A) There is an adequate scientific basis for determining that substitution of the specific proposed dose of the different active ingredient for the dose of the member of the same pharmacological or therapeutic class in the reference listed drug will yield a resulting drug product whose safety and effectiveness have not been adversely affected.
(B) The unchanged active ingredients in the proposed drug product are bioequivalent to those in the reference listed drug.
(C) The different active ingredient in the proposed drug product is bioequivalent to an approved dosage form containing that ingredient and approved for the same indication as the proposed drug product or is bioequivalent to a drug product offered for that indication which does not meet the definition of “new drug” under section 201(p) of the act.
(iii) For each in vivo bioequivalence study contained in the abbreviated new drug application, a description of the analytical and statistical methods used in each study and a statement with respect to each study that it either was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to the regulations under § 56.104 or § 56.105 of this chapter and that each study was conducted in compliance with the informed consent regulations in part 50 of this chapter.
(8)
(ii)
(iii)
(iv)
(9)
(ii)
(iii)
(iv)
(v)
(10)
(11)
(12)
(
(
(
(
I, (
(B) If the abbreviated new drug application refers to a listed drug that is itself a licensed generic product of a patented drug first approved under section 505(b) of the act, the appropriate patent certification under paragraph (a)(12)(i) of this section with respect to
(ii)
In the opinion and to the best knowledge of (
(iii)
(B) If the labeling of the drug product for which the applicant is seeking approval includes an indication that, according to the patent information submitted under section 505(b) or (c) of the act and § 314.53 or in the opinion of the applicant, is claimed by a use patent, an applicable certification under paragraph (a)(12)(i) of this section.
(iv)
(v)
(vi)
(vii)
(viii)
(A)
(B)
(C)
(
(13)
(b)
(c) [Reserved]
(d)
(2) For abbreviated new drug applications, the applicant shall submit a review copy of the abbreviated application that contains two separate sections. One section shall contain the information described under paragraphs (a)(2) through (a)(6), (a)(8), and (a)(9) of this section 505(j)(2)(A)(vii) of the act and one copy of the analytical methods and descriptive information needed by FDA's laboratories to perform tests on samples of the proposed drug product
(3) [Reserved]
(4) The applicant may obtain from FDA sufficient folders to bind the archival, the review, and the field copies of the abbreviated application.
(5) The applicant shall submit a field copy of the abbreviated application that contains the technical section described in paragraph (a)(9) of this section, a copy of the application form required under paragraph (a)(1) of this section, and a certification that the field copy is a true copy of the technical section described in paragraph (a)(9) of this section contained in the archival and review copies of the abbreviated application.
(a)
(1) Each owner of the patent which is the subject of the certification or the representative designated by the owner to receive the notice. The name and address of the patent owner or its representative may be obtained from the United States Patent and Trademark Office; and
(2) The holder of the approved application under section 505(b) of the act for the listed drug that is claimed by the patent and for which the applicant is seeking approval, or, if the application holder does not reside or maintain a place of business within the United States, the application holder's attorney, agent, or other authorized official. The name and address of the application holder or its attorney, agent, or authorized official may be obtained from the Division of Drug Information Resources (HFD-80), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(3) This paragraph does not apply to a use patent that claims no uses for which the applicant is seeking approval.
(b)
(c)
(1) A statement that FDA has received an abbreviated new drug application submitted by the applicant containing any required bioavailability or bioequivalence data or information.
(2) The abbreviated application number.
(3) The established name, if any, as defined in section 502(e)(3) of the act, of the proposed drug product.
(4) The active ingredient, strength, and dosage form of the proposed drug product.
(5) The patent number and expiration date, as submitted to the agency or as known to the applicant, of each patent alleged to be invalid, unenforceable, or not infringed.
(6) A detailed statement of the factual and legal basis of the applicant's opinion that the patent is not valid, unenforceable, or will not be infringed.
(i) For each claim of a patent alleged not to be infringed, a full and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or unenforceable, a full and detailed explanation of the grounds supporting the allegation.
(7) If the applicant does not reside or have a place of business in the United States, the name and address of an agent in the United States authorized to accept service of process for the applicant.
(d)
(e)
(f)
(a)
(2) Submission of an amendment containing significant data or information constitutes an agreement between FDA and the applicant to extend the review period only for the time necessary to review the significant data or information and for no more than 180 days.
(3) Submission of an amendment containing significant data or information to resolve deficiencies in the application as set forth in a not approvable letter issued under § 314.120 constitutes an agreement between FDA and the applicant under section 505(j)(4)(A) of the act to extend the date by which the agency is required to reach a decision on the abbreviated new drug application only for the time necessary to review the significant data or information and for no more than 180 days.
(b) The applicant shall submit a field copy of each amendment to § 314.94(a)(9). The applicant, other than a foreign applicant, shall include in its submission of each such amendment to FDA a statement certifying that a field copy of the amendment has been sent to the applicant's home FDA district office.
The applicant shall comply with the requirements of §§ 314.70 and 314.71 regarding the submission of supplemental applications and other changes to an approved abbreviated application.
(a) Except as provided in paragraph (b) of this section, each applicant having an approved abbreviated new drug application under § 314.94 that is effective shall comply with the requirements of § 314.80 regarding the reporting and recordkeeping of adverse drug experiences.
(b) Each applicant shall submit one copy of each report required under § 314.80 to the Division of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(c) Each applicant shall make the reports required under § 314.81 and section 505(k) of the act for each of its approved abbreviated applications.
(a) An applicant shall comply with the requirements of § 314.65 regarding withdrawal by the applicant of an unapproved abbreviated application and § 314.72 regarding a change in ownership of an abbreviated application.
(b) An applicant may ask FDA to waive under this section any requirement that applies to the applicant under §§ 314.92 through 314.99. The applicant shall comply with the requirements for a waiver under § 314.90.
(a) Within 180 days of receipt of an application for a new drug under section 505(b) of the act, or of an abbreviated application for a new drug under section 505(j) of the act, FDA will review it and send the applicant either an approval letter under § 314.105, or an approvable letter under § 314.110, or a not approvable letter under § 314.120. This 180-day period is called the “review clock.”
(b) During the review period, an applicant may withdraw an application under § 314.65 or an abbreviated application under § 314.99 and later resubmit it. FDA will treat the resubmission as a new application or abbreviated application.
(c) The review clock may be extended by mutual agreement between FDA and an applicant or as provided in §§ 314.60 and 314.96, as the result of a major amendment.
(a)(1) Within 60 days after FDA receives an application, the agency will determine whether the application may be filed. The filing of an application means that FDA has made a threshold determination that the application is sufficiently complete to permit a substantive review.
(2) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for refusing to file the application apply, the agency will file the application and notify the applicant in writing. The date of filing will be the date 60 days after the date FDA received the application. The date of filing begins the 180-day period described in section 505(c) of the act. This 180-day period is called the “filing clock.”
(3) If FDA refuses to file the application, the agency will notify the applicant in writing and state the reason under paragraph (d) or (e) of this section for the refusal. If FDA refuses to file the application under paragraph (d) of this section, the applicant may request in writing within 30 days of the date of the agency's notification an informal conference with the agency about whether the agency should file the application. If, following the informal conference, the applicant requests that FDA file the application (with or without amendments to correct the deficiencies), the agency will file the application over protest under paragraph (a)(2) of this section, notify the applicant in writing, and review it as filed. If the application is filed over protest, the date of filing will be the date 60 days after the date the applicant requested the informal conference. The applicant need not resubmit a copy of an application that is filed over protest. If FDA refuses to file the application under paragraph (e) of this section, the applicant may amend the application and resubmit it, and the
(b)(1) An abbreviated new drug application will be reviewed after it is submitted to determine whether the abbreviated application may be received. Receipt of an abbreviated new drug application means that FDA has made a threshold determination that the abbreviated application is sufficiently complete to permit a substantive review.
(2) If FDA finds that none of the reasons in paragraphs (d) and (e) of this section for considering the abbreviated new drug application not to have been received applies, the agency will receive the abbreviated new drug application and notify the applicant in writing.
(3) If FDA considers the abbreviated new drug application not to have been received under paragraph (d) or (e) of this section, FDA will notify the applicant, ordinarily by telephone. The applicant may then:
(i) Withdraw the abbreviated new drug application under § 314.99; or
(ii) Amend the abbreviated new drug application to correct the deficiencies; or
(iii) Take no action, in which case FDA will refuse to receive the abbreviated new drug application.
(c) [Reserved]
(d) FDA may refuse to file an application or may not consider an abbreviated new drug application to be received if any of the following applies:
(1) The application does not contain a completed application form.
(2) The application is not submitted in the form required under § 314.50 or § 314.94.
(3) The application or abbreviated application is incomplete because it does not on its face contain information required under section 505(b), section 505(j), or section 507 of the act and § 314.50 or § 314.94.
(4) The applicant fails to submit a complete environmental assessment, which addresses each of the items specified in the applicable format under § 25.40 of this chapter or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under § 25.30 or § 25.31 of this chapter.
(5) The application or abbreviated application does not contain an accurate and complete English translation of each part of the application that is not in English.
(6) The application does not contain a statement for each nonclinical laboratory study that it was conducted in compliance with the requirements set forth in part 58 of this chapter, or, for each study not conducted in compliance with part 58 of this chapter, a brief statement of the reason for the noncompliance.
(7) The application does not contain a statement for each clinical study that it was conducted in compliance with the institutional review board regulations in part 56 of this chapter, or was not subject to those regulations, and that it was conducted in compliance with the informed consent regulations in part 50 of this chapter, or, if the study was subject to but was not conducted in compliance with those regulations, the application does not contain a brief statement of the reason for the noncompliance.
(8) The drug product that is the subject of the submission is already covered by an approved application or abbreviated application and the applicant of the submission:
(i) Has an approved application or abbreviated application for the same drug product; or
(ii) Is merely a distributor and/or repackager of the already approved drug product.
(9) The application is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the act.
(e) The agency will refuse to file an application or will consider an abbreviated new drug application not to have been received if any of the following applies:
(1) The drug product is subject to licensing by FDA under the Public Health Service Act (42 U.S.C. 201
(2) In the case of a 505(b)(2) application or an abbreviated new drug application, the drug product contains the same active moiety as a drug that:
(i) Was approved after September 24, 1984, in an application under section 505(b) of the act, and
(ii) Is entitled to a 5-year period of exclusivity under section 505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act and § 314.108(b)(2), unless the 5-year exclusivity period has elapsed or unless 4 years of the 5-year period have elapsed and the application or abbreviated application contains a certification of patent invalidity or noninfringement described in § 314.50(i)(1)(i)(A)(
(f)(1) Within 180 days after the date of filing, plus the period of time the review period was extended (if any), FDA will either:
(i) Approve the application; or
(ii) Issue a notice of opportunity for hearing if the applicant asked FDA to provide it an opportunity for a hearing on an application in response to an approvable letter or a not approvable letter.
(2) Within 180 days after the date of receipt, plus the period of time the review clock was extended (if any), FDA will either approve or disapprove the abbreviated new drug application. If FDA disapproves the abbreviated new drug application, FDA will issue a notice of opportunity for hearing if the applicant asked FDA to provide it an opportunity for a hearing on an abbreviated new drug application in response to a not approvable letter.
(3) This paragraph does not apply to applications or abbreviated applications that have been withdrawn from FDA review by the applicant.
(a)
(b)
(c)
(d)
(e)
(a)
(b)
(c)
(2) When scientific or medical disputes arise at other times during the review process, applicants should discuss the matter directly with the responsible reviewing officials. If necessary, applicants may request a meeting with the appropriate reviewing officials and management representatives in order to seek a resolution. Ordinarily, such meetings would be held first with the Division Director, then with the Office Director, and finally with the Center Director if the matter is still unresolved. Requests for such meetings shall be directed to the director of the division responsible for reviewing the application or abrreviated application. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times.
(3) In requesting a meeting designed to resolve a scientific or medical dispute, applicants may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion,
The Food and Drug Administration will inform the Drug Enforcement Administration under section 201(f) of the Controlled Substances Act (21 U.S.C. 801) when an application or abbreviated application is submitted for a drug that appears to have an abuse potential.
(a) The Food and Drug Administration will approve an application and send the applicant an approval letter if none of the reasons in § 314.125 for refusing to approve the application applies.An approval becomes effective on the date of the issuance of the approval letter, except with regard to an approval under section 505(b)(2) of the act with a delayed effective date. An approval with a delayed effective date is tentative and does not become final until the effective date. A new drug product or antibiotic approved under this paragraph may not be marketed until an approval is effective.
(b) FDA will approve an application and issue the applicant an approval letter (rather than an approvable letter under § 314.110) on the basis of draft labeling if the only deficiencies in the application concern editorial or similar minor deficiencies in the draft labeling. Such approval will be conditioned upon the applicant incorporating the specified labeling changes exactly as directed, and upon the applicant submitting to FDA a copy of the final printed labeling prior to marketing.
(c) FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling, and an abbreviated application after it determines that the drug meets the statutory standards for manufacturing and controls, labeling, and, where applicable, bioequivalence. While the statutory standards apply to all drugs, the many kinds of drugs that are subject to the statutory standards and the wide range of uses for those drugs demand flexibility in applying the standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards. FDA makes its views on drug products and classes of drugs available through guidance documents, recommendations, and other statements of policy.
(d) FDA will approve an abbreviated new drug application and send the applicant an approval letter if none of the reasons in § 314.127 for refusing to approve the abbreviated new drug application applies. The approval becomes effective on the date of the issuance of the agency's approval letter unless the approval letter provides for a delayed effective date. An approval with a delayed effective date is tentative and does not become final until the effective date. A new drug product approved under this paragraph may not be introduced or delivered for introduction into interstate commerce until approval of the abbreviated new drug application is effective. Ordinarily, the effective date of approval will be stated in the approval letter.
(a)
(b)
(c)
(a)
(b)
(1)
(i) There are no relevant patents; or
(ii) The applicant is aware of a relevant patent but the patent information required under section 505 (b) or (c) of the act has not been submitted to FDA; or
(iii) The relevant patent has expired; or
(iv) The relevant patent is invalid, unenforceable, or will not be infringed.
(2)
(3)
(B) If the patented drug product qualifies for 5 years of exclusive marketing under § 314.108(b)(2) and the patent owner or its representative or the exclusive patent licensee brings suit for patent infringement during the 1-year period beginning 4 years after the date the patented drug was approved and within 45 days of receipt by the patent owner of the notice of certification, the approval may be made effective at the expiration of the 7
(ii) If before the expiration of the 30-month period, or 7
(iii) If before the expiration of the 30-month period, or 7
(iv) If before the expiration of the 30-month period, or 7
(v) In order for an approval to be made effective under paragraph (b)(3) of this section, the applicant must receive an approval letter from the agency indicating that the application has received final approval. Tentative approval of an application does not constitute “approval” of an application and cannot, absent a final approval letter from the agency, result in an effective approval under paragraph (b)(3) of this section.
(4)
(c)
(i) The date the applicant submitting the first application first commences commercial marketing of its drug product; or
(ii) The date of a decision of the court holding the relevant patent invalid, unenforceable, or not infringed.
(2) For purposes of paragraph (c)(1) of this section, the “applicant submitting the first application” is the applicant that submits an application that is both substantially complete and contains a certification that the patent was invalid, unenforceable, or not infringed prior to the submission of any other application for the same listed drug that is both substantially complete and contains the same certification. A “substantially complete” application must contain the results of any required bioequivalence studies, or, if applicable, a request for a waiver of such studies.
(3) For purposes of paragraph (c)(1) of this section, if FDA concludes that the applicant submitting the first application is not actively pursuing approval of its abbreviated application, FDA will make the approval of subsequent abbreviated applications immediately effective if they are otherwise eligible for an immediately effective approval.
(4) For purposes of paragraph (c)(1)(i) of this section, the applicant submitting the first application shall notify FDA of the date that it commences commercial marketing of its drug product. Commercial marketing commences with the first date of introduction or delivery for introduction into interstate commerce outside the control of the manufacturer of a drug product, except for investigational use under part 312 of this chapter, but does not include transfer of the drug product for reasons other than sale within the control of the manufacturer or application holder. If an applicant does not promptly notify FDA of such date, the effective date of approval shall be deemed to be the date of the commencement of first commercial marketing.
(d)
(e)
(f)
(2) The abbreviated new drug applicant or the 505(b)(2) applicant shall notify FDA immediately of the filing of any legal action filed within 45 days of receipt of the notice of certification. If the applicant submitting the abbreviated new drug application or the 505(b)(2) application or patent owner or its representative does not notify FDA in writing before the expiration of the 45-day time period or the completion of the agency's review of the application, whichever occurs later, that a legal action for patent infringement was filed within 45 days of receipt of the notice of certification, approval of the abbreviated new drug application or the 505(b)(2) application will be made effective immediately upon expiration of the 45 days or upon completion of the agency's review and approval of the application, whichever is later. The notification to FDA of the legal action shall include:
(i) The abbreviated new drug application or 505(b)(2) application number.
(ii) The name of the abbreviated new drug or 505(b)(2) application applicant.
(iii) The established name of the drug product or, if no established name exists, the name(s) of the active ingredient(s), the drug product's strength, and dosage form.
(iv) A certification that an action for patent infringement identified by number, has been filed in an appropriate court on a specified date.
The applicant of an abbreviated new drug application shall send the notification to FDA's Office of Generic Drugs (HFD-600). A 505(b)(2) applicant shall send the notification to the appropriate division in the Center for Drug Evaluation and Research reviewing the application. A patent owner or its representative may also notify FDA of the filing of any legal action for patent infringement. The notice should contain the information and be sent to the offices or divisions described in this paragraph.
(3) If the patent owner or approved application holder who is an exclusive patent licensee waives its opportunity to file a legal action for patent infringement within 45 days of a receipt of the notice of certification and the patent owner or approved application holder who is an exclusive patent licensee submits to FDA a valid waiver before the 45 days elapse, approval of the abbreviated new drug application or the 505(b)(2) application will be made effective upon completion of the agency's review and approval of the application. FDA will only accept a waiver in the following form:
(
(a)
(b)
(2) If a drug product that contains a new chemical entity was approved after September 24, 1984, in an application submitted under section 505(b) of the act, no person may submit a 505(b)(2) application or abbreviated new drug application under section 505(j) of the act for a drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved new drug application, except that the 505(b)(2) application or abbreviated application may be submitted after 4 years if it contains a certification of patent invalidity or noninfringement described in § 314.50(i)(1)(i)(A)(
(3) The approval of a 505(b)(2) application or abbreviated application described in paragraph (b)(2) of this section will become effective as provided in § 314.107(b)(1) or (b)(2), unless the
(4) If an application:
(i) Was submitted under section 505(b) of the act;
(ii) Was approved after September 24, 1984;
(iii) Was for a drug product that contains an active moiety that has been previously approved in another application under section 505(b) of the act; and
(iv) Contained reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the applicant that were essential to approval of the application, the agency will not make effective for a period of 3 years after the date of approval of the application the approval of a 505(b)(2) application or an abbreviated new drug application for the conditions of approval of the original application, or an abbreviated new drug application submitted pursuant to an approved petition under section 505(j)(2)(C) of the act that relies on the information supporting the conditions of approval of an original new drug application.
(5) If a supplemental application:
(i) Was approved after September 24, 1984; and
(ii) Contained reports of new clinical investigations (other than bioavailability studies) that were conducted or sponsored by the applicant that were essential to approval of the supplemental application, the agency will not make effective for a period of 3 years after the date of approval of the supplemental application the approval of a 505(b)(2) application or an abbreviated new drug application for a change, or an abbreviated new drug application submitted pursuant to an approved petition under section 505(j)(2)(C) of the act that relies on the information supporting a change approved in the supplemental new drug application.
(a) In selected circumstances, it is useful at the end of the review period for the Food and Drug Administration to indicate to the applicant that the application or abbreviated application is basically approvable providing certain issues are resolved. An approvable letter may be issued in such circumstances. FDA will send the applicant an approvable letter if the application or abbreviated application substantially meets the requirements of this part and the agency believes that it can approve the application or abbreviated application if specific additional information or material is submitted or specific conditions (for example, certain changes in labeling) are agreed to by the applicant. The approvable letter will describe the information or material FDA requires or the conditions the applicant is asked to meet. As a practical matter, the approvable letter will serve in most instances as a mechanism for resolving outstanding issues on drugs that are about to be approved and marketed. For an application, the applicant shall, within 10 days after the date of the approvable letter:
(1) Amend the application or notify FDA of an intent to file an amendment. The filing of an amendment or notice of intent to file an amendment constitutes an agreement by the applicant to extend the review period for 45 days after the date FDA receives the amendment. The extension is to permit the agency to review the amendment;
(2) Withdraw the application. FDA will consider the applicant's failure to respond within 10 days to an approvable letter to be a request by the applicant to withdraw the application under § 314.65. A decision to withdraw an application is without prejudice to a refiling;
(3) For a new drug application, ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the application
(4) [Reserved]
(5) Notify FDA that the applicant agrees to an extension of the review period under section 505(c) of the act, so that the applicant can determine whether to respond further under paragraph (a)(1), (a)(2), or (a)(3) of this section. The applicant's notice is required to state the length of the extension. FDA will honor any reasonable request for such an extension. FDA will consider the applicant's failure to respond further within the extended review period to be a request to withdraw the application under § 314.65. A decision to withdraw an application is without prejudice to a refiling.
(b) FDA will send the applicant of an abbreviated new drug application an approvable letter only if the application substantially meets the requirements of this part and the agency believes that it can approve the abbreviated application if minor deficiencies (e.g., labeling deficiencies) are corrected. The approvable letter will describe the deficiencies and state a time period within which the applicant must respond. Unless the applicant corrects the deficiencies by amendment within the specified time period, FDA will refuse to approve the abbreviated application under § 314.127. Within 10 days after the date of the approvable letter, the applicant may also ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the abbreviated new drug application. Applicants who request a hearing shall submit the request to the Associate Director for Policy (HFD-5), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(a) The Food and Drug Administration will send the applicant a not approvable letter if the agency believes that the application may not be approved for one of the reasons given in § 314.125 or the abbreviated new drug application may not be approved for one of the reasons given in § 314.127. The not approvable letter will describe the deficiencies in the application or abbreviated application. Except as provided in paragraph (b) of this section, within 10 days after the date of the not approvable letter, the applicant shall:
(1) Amend the application or abbreviated application or notify FDA of an intent to file an amendment. The filing of an amendment or a notice of intent to file an amendment constitutes an agreement by the applicant to extend the review period under § 314.60 or § 314.96;
(2) Withdraw the application or abbreviated application. Except as provided in paragraph (b) of this section, FDA will consider the applicant's failure to respond within 10 days to a not approvable letter to be a request by the applicant to withdraw the application under § 314.65 or abbreviated application under § 314.99. A decision to withdraw the application or abbreviated application is without prejudice to refiling;
(3) For a new drug application or an abbreviated application, ask the agency to provide the applicant an opportunity for a hearing on the question of whether there are grounds for denying approval of the application under section 505(d) or (j)(3) of the act. The applicant shall submit the request to the Associate Director for Policy (HFD-5), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Within 60 days of the date of the not approvable letter, or within a different
(4) [Reserved]
(5) Notify FDA that the applicant agrees to an extension of the review period under section 505(c)(1) or (j)(4)(A) of the act, so that the applicant can determine whether to respond further under paragraph (a)(1), (a)(2), or (a)(3) of this section. The applicant's notice is required to state the length of the extension. FDA will honor any reasonable request for such an extension. FDA will consider the applicant's failure to respond further within the extended review period to be a request to withdraw the application under § 314.65 or abbreviated application under § 314.99. A decision to withdraw an application or abbreviated application is without prejudice to a refiling.
(b) With the exception of a request for an opportunity for a hearing under paragraph (a)(3) of this section, the 10-day time period in this section for responding to a not approvable letter does not apply to abbreviated new drug applications. FDA may consider the applicant's failure to respond within 180 days to a not approvable letter to be a request by the applicant to withdraw the abbreviated new drug application under § 314.99.
(a) An abbreviated new drug application that refers to, or a petition under section 505(j)(2)(C) of the act and § 314.93 that relies on, a listed drug that has been voluntarily withdrawn from sale in the United States must be accompanied by a petition seeking a determination whether the listed drug was withdrawn for safety or effectiveness reasons. The petition must be submitted under §§ 10.25(a) and 10.30 of this chapter and must contain all evidence available to the petitioner concerning the reasons for the withdrawal from sale.
(b) When a petition described in paragraph (a) of this section is submitted, the agency will consider the evidence in the petition and any other evidence before the agency, and determine whether the listed drug is withdrawn from sale for safety or effectiveness reasons, in accordance with the procedures in § 314.161.
(c) An abbreviated new drug application described in paragraph (a) of this section will be disapproved, under § 314.127(a)(11), and a 505(j)(2)(C) petition described in paragraph (a) of this section will be disapproved, under § 314.93(e)(1)(iv), unless the agency determines that the withdrawal of the listed drug was not for safety or effectiveness reasons.
(d) Certain drug products approved for safety and effectiveness that were no longer marketed on September 24, 1984, are not included in the list. Any person who wishes to obtain marketing approval for such a drug product under an abbreviated new drug application must petition FDA for a determination whether the drug product was withdrawn from the market for safety or effectiveness reasons and request that the list be amended to include the drug product. A person seeking such a determination shall use the petition procedures established in § 10.30 of this chapter. The petitioner shall include in the petition information to show that the drug product was approved for safety and effectiveness and all evidence available to the petitioner concerning the reason that marketing of the drug product ceased.
(a) The Food and Drug Administration will refuse to approve the application and for a new drug give the applicant written notice of an opportunity for a hearing under § 314.200 on the
(1) FDA sends the applicant an approvable or a not approvable letter under § 314.110 or § 314.120;
(2) The applicant requests an opportunity for hearing for a new drug on the question of whether the application is approvable; and
(3) FDA finds that any of the reasons given in paragraph (b) of this section apply.
(b) FDA may refuse to approve an application for any of the following reasons:
(1) The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product are inadequate to preserve its identity, strength, quality, purity, stability, and bioavailability.
(2) The investigations required under section 505(b) of the act do not include adequate tests by all methods reasonably applicable to show whether or not the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.
(3) The results of the tests show that the drug is unsafe for use under the conditions prescribed, recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for use under those conditions.
(4) There is insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.
(5) There is a lack of substantial evidence consisting of adequate and well-controlled investigations, as defined in § 314.126, that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling.
(6) The proposed labeling is false or misleading in any particular.
(7) The application contains an untrue statement of a material fact.
(8) The drug product's proposed labeling does not comply with the requirements for labels and labeling in part 201.
(9) The application does not contain bioavailability or bioequivalence data required under part 320 of this chapter.
(10) A reason given in a letter refusing to file the application under § 314.101(d), if the deficiency is not corrected.
(11) The drug will be manufactured or processed in whole or in part in an establishment that is not registered and not exempt from registration under section 510 of the act and part 207.
(12) The applicant does not permit a properly authorized officer or employee of the Department of Health and Human Services an adequate opportunity to inspect the facilities, controls, and any records relevant to the application.
(13) The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product do not comply with the current good manufacturing practice regulations in parts 210 and 211.
(14) The application does not contain an explanation of the omission of a report of any investigation of the drug product sponsored by the applicant, or an explanation of the omission of other information about the drug pertinent to an evaluation of the application that is received or otherwise obtained by the applicant from any source.
(15) A nonclinical laboratory study that is described in the application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling was not conducted in compliance with the good laboratory practice regulations in part 58 of this chapter and no reason for the noncompliance is provided or, if it is, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.
(16) Any clinical investigation involving human subjects described in the application, subject to the institutional review board regulations in part 58 of this chapter or informed consent regulations in part 50 of this chapter, was not conducted in compliance with those regulations such that the rights or safety of human subjects were not adequately protected.
(17) The applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.
(18) For a new drug, the application failed to contain the patent information required by section 505(b)(1) of the act.
(c) For drugs intended to treat life-threatening or severely-debilitating illnesses that are developed in accordance with §§ 312.80 through 312.88 of this chapter, the criteria contained in paragraphs (b) (3), (4), and (5) of this section shall be applied according to the considerations contained in § 312.84 of this chapter.
(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been developed over a period of years and are recognized by the scientific community as the essentials of an adequate and well-controlled clinical investigation. The Food and Drug Administration considers these characteristics in determining whether an investigation is adequate and well-controlled for purposes of section 505 of the act. Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is “substantial evidence” to support the claims of effectiveness for new drugs. Therefore, the study report should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a determination of whether the characteristics of an adequate and well-controlled study are present.
(b) An adequate and well-controlled study has the following characteristics:
(1) There is a clear statement of the objectives of the investigation and a summary of the proposed or actual methods of analysis in the protocol for the study and in the report of its results. In addition, the protocol should contain a description of the proposed methods of analysis, and the study report should contain a description of the methods of analysis ultimately used. If the protocol does not contain a description of the proposed methods of analysis, the study report should describe how the methods used were selected.
(2) The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol for the study and report of results should describe the study design precisely; for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of control are recognized:
(i)
(ii)
(iii)
(iv)
(v)
(3) The method of selection of subjects provides adequate assurance that they have the disease or condition being studied, or evidence of susceptibility and exposure to the condition against which prophylaxis is directed.
(4) The method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of the groups with respect to pertinent variables such as age, sex, severity of disease, duration of disease, and use of drugs or therapy other than the test drug. The protocol for the study and the report of its results should describe how subjects were assigned to groups. Ordinarily, in a concurrently controlled study, assignment is by randomization, with or without stratification.
(5) Adequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data. The protocol and report of the study should describe the procedures used to accomplish this, such as blinding.
(6) The methods of assessment of subjects' response are well-defined and reliable. The protocol for the study and the report of results should explain the variables measured, the methods of observation, and criteria used to assess response.
(7) There is an analysis of the results of the study adequate to assess the effects of the drug. The report of the study should describe the results and the analytic methods used to evaluate them, including any appropriate statistical methods. The analysis should assess, among other things, the comparability of test and control groups with respect to pertinent variables, and the effects of any interim data analyses performed.
(c) The Director of the Center for Drug Evaluation and Research may, on the Director's own initiative or on the petition of an interested person, waive in whole or in part any of the criteria in paragraph (b) of this section with respect to a specific clinical investigation, either prior to the investigation or in the evaluation of a completed study. A petition for a waiver is required to set forth clearly and concisely the specific criteria from which waiver is sought, why the criteria are not reasonably applicable to the particular clinical investigation, what alternative procedures, if any, are to be, or have been employed, and what results have been obtained. The petition is also required to state why the clinical investigations so conducted will yield, or have yielded, substantial evidence of effectiveness, notwithstanding nonconformance with the criteria for which waiver is requested.
(d) For an investigation to be considered adequate for approval of a new drug, it is required that the test drug be standardized as to identity, strength, quality, purity, and dosage
(e) Uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness. Such studies carefully conducted and documented, may provide corroborative support of well-controlled studies regarding efficacy and may yield valuable data regarding safety of the test drug. Such studies will be considered on their merits in the light of the principles listed here, with the exception of the requirement for the comparison of the treated subjects with controls. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.
(a) FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of the act for any of the following reasons:
(1) The methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity.
(2) Information submitted with the abbreviated new drug application is insufficient to show that each of the proposed conditions of use has been previously approved for the listed drug referred to in the application.
(3)(i) If the reference listed drug has only one active ingredient, information submitted with the abbreviated new drug application is insufficient to show that the active ingredient is the same as that of the reference listed drug;
(ii) If the reference listed drug has more than one active ingredient, information submitted with the abbreviated new drug application is insufficient to show that the active ingredients are the same as the active ingredients of the reference listed drug; or
(iii) If the reference listed drug has more than one active ingredient and if the abbreviated new drug application is for a drug product that has an active ingredient different from the reference listed drug:
(A) Information submitted with the abbreviated new drug application is insufficient to show:
(
(
(B) No petition to submit an abbreviated application for the drug product with the different active ingredient was approved under § 314.93.
(4)(i) If the abbreviated new drug application is for a drug product whose route of administration, dosage form, or strength purports to be the same as that of the listed drug referred to in the abbreviated new drug application, information submitted in the abbreviated new drug application is insufficient to show that the route of administration, dosage form, or strength is the same as that of the reference listed drug; or
(ii) If the abbreviated new drug application is for a drug product whose route of administration, dosage form, or strength is different from that of the listed drug referred to in the application, no petition to submit an abbreviated new drug application for the drug product with the different route of administration, dosage form, or strength was approved under § 314.93.
(5) If the abbreviated new drug application was submitted under the approval of a petition under § 314.93, the abbreviated new drug application did not contain the information required by FDA with respect to the active ingredient, route of administration, dosage form, or strength that is not the same as that of the reference listed drug.
(6)(i) Information submitted in the abbreviated new drug application is insufficient to show that the drug product is bioequivalent to the listed drug referred to in the abbreviated new drug application; or
(ii) If the abbreviated new drug application was submitted under a petition approved under § 314.93, information
(7) Information submitted in the abbreviated new drug application is insufficient to show that the labeling proposed for the drug is the same as the labeling approved for the listed drug referred to in the abbreviated new drug application except for changes required because of differences approved in a petition under § 314.93 or because the drug product and the reference listed drug are produced or distributed by different manufacturers or because aspects of the listed drug's labeling are protected by patent, or by exclusivity, and such differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, nonprotected conditions of use.
(8)(i) Information submitted in the abbreviated new drug application of any other information available to FDA shows that:
(A) The inactive ingredients of the drug product are unsafe for use, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug product; or
(B) The composition of the drug product is unsafe, as described in paragraph (a)(8)(ii) of this section, under the conditions prescribed, recommended, or suggested in the proposed labeling because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.
(ii)(A) FDA will consider the inactive ingredients or composition of a drug product unsafe and refuse to approve an abbreviated new drug application under paragraph (a)(8)(i) of this section if, on the basis of information available to the agency, there is a reasonable basis to conclude that one or more of the inactive ingredients of the proposed drug or its composition raises serious questions of safety or efficacy. From its experience with reviewing inactive ingredients, and from other information available to it, FDA may identify changes in inactive ingredients or composition that may adversely affect a drug product's safety or efficacy. The inactive ingredients or composition of a proposed drug product will be considered to raise serious questions of safety or efficacy if the product incorporates one or more of these changes. Examples of the changes that may raise serious questions of safety or efficacy include, but are not limited to, the following:
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(B) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the abbreviated new drug application unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the
(C) FDA will consider an inactive ingredient in, or the composition of, a drug product intended for ophthalmic or otic use unsafe and will refuse to approve the abbreviated new drug application unless it contains the same inactive ingredients, other than preservatives, buffers, substances to adjust tonicity, or thickening agents, in the same concentration as the listed drug, and if it differs from the listed drug in a preservative, buffer, substance to adjust tonicity, or thickening agent, the application contains sufficient information to demonstrate that the difference does not affect the safety or efficacy of the drug product and the labeling does not claim any therapeutic advantage over or difference from the listed drug.
(9) Approval of the listed drug referred to in the abbreviated new drug application has been withdrawn or suspended for grounds described in § 314.150(a) or FDA has published a notice of opportunity for hearing to withdraw approval of the reference listed drug under § 314.150(a).
(10) Approval of the listed drug referred to in the abbreviated new drug application has been withdrawn under § 314.151 or FDA has proposed to withdraw approval of the reference listed drug under § 314.151(a).
(11) FDA has determined that the reference listed drug has been withdrawn from sale for safety or effectiveness reasons under § 314.161, or the reference listed drug has been voluntarily withdrawn from sale and the agency has not determined whether the withdrawal is for safety or effectiveness reasons, or approval of the reference listed drug has been suspended under § 314.153, or the agency has issued an initial decision proposing to suspend the reference listed drug under § 314.153(a)(1).
(12) The abbreviated new drug application does not meet any other requirement under section 505(j)(2)(A) of the act.
(13) The abbreviated new drug application contains an untrue statement of material fact.
(b) FDA may refuse to approve an abbreviated application for a new drug if the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.63 of this chapter that is contained in the abbreviated new drug application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer of employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.
(a) The Food and Drug Administration will notify the applicant, and, if appropriate, all other persons who manufacture or distribute identical, related, or similar drug products as defined in §§ 310.6 and 314.151(a) of this chapter and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application or abbreviated new drug application under section 505(e) of the act and under the procedure in § 314.200, if any of the following apply:
(1) The Secretary of Health and Human Services has suspended the approval of the application or abbreviated application for a new drug on a finding that there is an imminent hazard to the public health. FDA will promptly afford the applicant an expedited hearing following summary suspension on a finding of imminent hazard to health.
(2) FDA finds:
(i) That clinical or other experience, tests, or other scientific data show that the drug is unsafe for use under the conditions of use upon the basis of which the application or abbreviated application was approved; or
(ii) That new evidence of clinical experience, not contained in the application or not available to FDA until after
(iii) Upon the basis of new information before FDA with respect to the drug, evaluated together with the evidence available when the application or abbreviated application was approved, that there is a lack of substantial evidence from adequate and well-controlled investigations as defined in § 314.126, that the drug will have the effect it is purported or represented to have under the conditions of use prescribed, recommended, or suggested in its labeling; or
(iv) That the application or abbreviated application contains any untrue statement of a material fact; or
(v) That the patent information prescribed by section 505(c) of the act was not submitted within 30 days after the receipt of written notice from FDA specifying the failure to submit such information; or
(b) FDA may notify the applicant, and, if appropriate, all other persons who manufacture or distribute identical, related, or similar drug products as defined in § 310.6, and for a new drug afford an opportunity for a hearing on a proposal to withdraw approval of the application or abbreviated new drug application under section 505(e) of the act and under the procedure in § 314.200, if the agency finds:
(1) That the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain required records or to make required reports under section 505(k) or 507(g) of the act and § 314.80, § 314.81, or § 314.98, or that the applicant has refused to permit access to, or copying or verification of, its records.
(2) That on the basis of new information before FDA, evaluated together with the evidence available when the application or abbreviated application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to ensure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the agency.
(3) That on the basis of new information before FDA, evaluated together with the evidence available when the application or abbreviated application was approved, the labeling of the drug, based on a fair evaluation of all material facts, is false or misleading in any particular, and the labeling was not corrected by the applicant within a reasonable time after receipt of written notice from the agency.
(4) That the applicant has failed to comply with the notice requirements of section 510(j)(2) of the act.
(5) That the applicant has failed to submit bioavailability or bioequivalence data required under part 320 of this chapter.
(6) The application or abbreviated application does not contain an explanation of the omission of a report of any investigation of the drug product sponsored by the applicant, or an explanation of the omission of other information about the drug pertinent to an evaluation of the application or abbreviated application that is received or otherwise obtained by the applicant from any source.
(7) That any nonclinical laboratory study that is described in the application or abbreviated application and that is essential to show that the drug is safe for use under the conditions prescribed, recommended, or suggested in its labeling was not conducted in compliance with the good laboratory practice regulations in part 58 of this chapter and no reason for the noncompliance was provided or, if it was, the differences between the practices used in conducting the study and the good laboratory practice regulations do not support the validity of the study.
(8) Any clinical investigation involving human subjects described in the application or abbreviated application, subject to the institutional review board regulations in part 56 of this
(9) That the applicant or contract research organization that conducted a bioavailability or bioequivalence study described in § 320.38 or § 320.63 of this chapter that is contained in the application or abbreviated application refuses to permit an inspection of facilities or records relevant to the study by a properly authorized officer or employee of the Department of Health and Human Services or refuses to submit reserve samples of the drug products used in the study when requested by FDA.
(10) That the labeling for the drug product that is the subject of the abbreviated new drug application is no longer consistent with that for the listed drug referred to in the abbreviated new drug application, except for differences approved in the abbreviated new drug application or those differences resulting from:
(i) A patent on the listed drug issued after approval of the abbreviated new drug application; or
(ii) Exclusivity accorded to the listed drug after approval of the abbreviated new drug application that do not render the drug product less safe or effective than the listed drug for any remaining, nonprotected condition(s) of use.
(c) FDA will withdraw approval of an application or abbreviated application if the applicant requests its withdrawal because the drug subject to the application or abbreviated application is no longer being marketed, provided none of the conditions listed in paragraphs (a) and (b) of this section applies to the drug. FDA will consider a written request for a withdrawal under this paragraph to be a waiver of an opportunity for hearing otherwise provided for in this section. Withdrawal of approval of an application or abbreviated application under this paragraph is without prejudice to refiling.
(d) FDA may notify an applicant that it believes a potential problem associated with a drug is sufficiently serious that the drug should be removed from the market and may ask the applicant to waive the opportunity for hearing otherwise provided for under this section, to permit FDA to withdraw approval of the application or abbreviated application for the product, and to remove voluntarily the product from the market. If the applicant agrees, the agency will not make a finding under paragraph (b) of this section, but will withdraw approval of the application or abbreviated application in a notice published in the
(a) Approval of an abbreviated new drug application approved under § 314.105(d) may be withdrawn when the agency withdraws approval, under § 314.150(a) or under this section, of the approved drug referred to in the abbreviated new drug application. If the agency proposed to withdraw approval of a listed drug under § 314.150(a), the holder of an approved application for the listed drug has a right to notice and opportunity for hearing. The published notice of opportunity for hearing will identify all drug products approved under § 314.105(d) whose applications are subject to withdrawal under this section if the listed drug is withdrawn, and will propose to withdraw such drugs. Holders of approved applications for the identified drug products will be provided notice and an opportunity to respond to the proposed withdrawal of their applications as described in paragraphs (b) and (c) of this section.
(b)(1) The published notice of opportunity for hearing on the withdrawal of the listed drug will serve as notice to holders of identified abbreviated new drug applications of the grounds for the proposed withdrawal.
(2) Holders of applications for drug products identified in the notice of opportunity for hearing may submit written comments on the notice of opportunity for hearing issued on the proposed withdrawal of the listed drug. If an abbreviated new drug application
(3) Except as provided in paragraphs (c) and (d) of this section, the approval of an abbreviated new drug application for a drug product identified in the notice of opportunity for hearing on the withdrawal of a listed drug will be withdrawn when the agency has completed the withdrawal of approval of the listed drug.
(c)(1) If the holder of an application for a drug identified in the notice of opportunity for hearing has submitted timely comments but does not have an opportunity to participate in a hearing because a hearing is not requested or is settled, the submitted comments will be considered by the agency, which will issue an initial decision. The initial decision will respond to the comments, and contain the agency's decision whether there are grounds to withdraw approval of the listed drug and of the abbreviated new drug applications on which timely comments were submitted. The initial decision will be sent to each abbreviated new drug application holder that has submitted comments.
(2) Abbreviated new drug application holders to whom the initial decision was sent may, within 30 days of the issuance of the initial decision, submit written objections.
(3) The agency may, at its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions.
(4) If there are no timely objections to the initial decision, it will become final at the expiration of 30 days.
(5) If timely objections are submitted, they will be reviewed and responded to in a final decision.
(6) The written comments received, the initial decision, the evidence relied on in the comments and in the initial decision, the objections to the initial decision, and, if a limited oral hearing has been held, the transcript of that hearing and any documents submitted therein, shall form the record upon which the agency shall make a final decision.
(7) Except as provided in paragraph (d) of this section, any abbreviated new drug application whose holder submitted comments on the notice of opportunity for hearing shall be withdrawn upon the issuance of a final decision concluding that the listed drug should be withdrawn for grounds as described in § 314.150(a). The final decision shall be in writing and shall constitute final agency action, reviewable in a judicial proceeding.
(8) Documents in the record will be publicly available in accordance with § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public display in the Dockets Management Branch (HFA-305), Food and Drug Administration, room. 1-23, 12420 Parklawn Dr., Rockville, MD 20857, promptly upon receipt in that office.
(d) If the agency determines, based upon information submitted by the holder of an abbreviated new drug application, that the grounds for withdrawal of the listed drug are not applicable to a drug identified in the notice of opportunity for hearing, the final decision will state that the approval of the abbreviated new drug application for such drug is not withdrawn.
If the Food and Drug Administration withdraws approval of an application or abbreviated application for a new drug, FDA will publish a notice in the
(a)
(1) The Secretary of the Department of Health and Human Services, under the imminent hazard authority of section 505(e) of the act or the authority of this paragraph, suspends approval of a listed drug referred to in the abbreviated new drug application, for the period of the suspension;
(2) The agency, in the notice described in paragraph (b) of this section, or in any subsequent written notice given an abbreviated new drug application holder by the agency, concludes that the risk of continued marketing and use of the drug is inappropriate, pending completion of proceedings to withdraw or suspend approval under § 314.151 or paragraph (b) of this section; or
(3) The agency, under the procedures set forth in paragraph (b) of this section, issues a final decision stating the determination that the abbreviated application is suspended because the listed drug on which the approval of the abbreviated new drug application depends has been withdrawn from sale for reasons of safety or effectiveness or has been suspended under paragraph (b) of this section. The suspension will take effect on the date stated in the decision and will remain in effect until the agency determines that the marketing of the drug has resumed or that the withdrawal is not for safety or effectiveness reasons.
(b)
(2) Each abbreviated new drug application holder will have 30 days from the issuance of the initial decision to present, in writing, comments and information bearing on the initial decision. If no comments or information is received, the initial decision will become final at the expiration of 30 days.
(3) Comments and information received within 30 days of the issuance of the initial decision will be considered by the agency and responded to in a final decision.
(4) The agency may, in its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions.
(5) If the final decision affirms the agency's initial decision that the listed drug was withdrawn for reasons of safety or effectiveness, the decision will be published in the
(6) If the agency determines in its final decision that the listed drug was withdrawn for reasons of safety or effectiveness but, based upon information submitted by the holder of an abbreviated new drug application, also determines that the reasons for the withdrawal of the listed drug are not relevant to the safety and effectiveness of the drug subject to such abbreviated new drug application, the final decision will state that the approval of such abbreviated new drug application is not suspended.
(7) Documents in the record will be publicly available in accordance with § 10.20(j) of this chapter. Documents available for examination or copying will be placed on public display in the
Upon the Food and Drug Administration's own initiative or upon request of an applicant, FDA may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval. FDA will publish a notice in the
(a) A determination whether a listed drug that has been voluntarily withdrawn from sale was withdrawn for safety or effectiveness reasons may be made by the agency at any time after the drug has been voluntarily withdrawn from sale, but must be made:
(1) Prior to approving an abbreviated new drug application that refers to the listed drug;
(2) Whenever a listed drug is voluntarily withdrawn from sale and abbreviated new drug applications that referred to the listed drug have been approved; and
(3) When a person petitions for such a determination under §§ 10.25(a) and 10.30 of this chapter.
(b) Any person may petition under §§ 10.25(a) and 10.30 of this chapter for a determination whether a listed drug has been voluntarily withdrawn for safety or effectiveness reasons. Any such petition must contain all evidence available to the petitioner concerning the reason that the drug is withdrawn from sale.
(c) If the agency determines that a listed drug is withdrawn from sale for safety or effectiveness reasons, the agency will, except as provided in paragraph (d) of this section, publish a notice of the determination in the
(d) If the agency determines under paragraph (a) of this section that a listed drug is withdrawn from sale for safety and effectiveness reasons and there are approved abbreviated new drug applications that are subject to suspension under section 505(j)(5) of the act, FDA will initiate a proceeding in accordance with § 314.153(b).
(e) A drug that the agency determines is withdrawn for safety or effectiveness reasons will be removed from the list, under § 314.162. The drug may be relisted if the agency has evidence that marketing of the drug has resumed or that the withdrawal is not for safety or effectiveness reasons. A determination that the drug is not withdrawn for safety or effectiveness reasons may be made at any time after its removal from the list, upon the agency's initiative, or upon the submission of a petition under §§ 10.25(a) and 10.30 of this chapter. If the agency determines that the drug is not withdrawn for safety or effectiveness reasons, the agency shall publish a notice of this determination in the
(a) FDA will remove a previously approved new drug product from the list for the period stated when:
(1) The agency withdraws or suspends approval of a new drug application or an abbreviated new drug application under § 314.150(a) or § 314.151 or under the imminent hazard authority of section 505(e) of the act, for the same period as the withdrawal or suspension of the application; or
(2) The agency, in accordance with the procedures in § 314.153(b) or § 314.161, issues a final decision stating that the listed drug was withdrawn from sale for safety or effectiveness reasons, or suspended under § 314.153(b), until the agency determines that the withdrawal from the market has ceased or is not for safety or effectiveness reasons.
(b) FDA will publish in the
(c) At the end of the period specified in paragraph (a)(1) or (a)(2) of this section, FDA will relist a drug that has been removed from the list. The agency will publish in the
All drugs, including those the Food and Drug Administration approves under section 505 of the act and this part, are subject to the adulteration and misbranding provisions in sections 501, 502, and 503 of the act. FDA is authorized to regulate approved new drugs by regulations issued through informal rulemaking under sections 501, 502, and 503 of the act.
(a)
(1) The notice may be general (that is, simply summarizing in a general way the information resulting in the notice) or specific (that is, either referring to specific requirements in the statute and regulations with which there is a lack of compliance, or providing a detailed description and analysis of the specific facts resulting in the notice).
(2) FDA will publish the notice in the
(3) It is the responsibility of every manufacturer and distributor of a drug product to review every notice of opportunity for a hearing published in the
(b) FDA will provide the notice of opportunity for a hearing to applicants and to other persons subject to the notice under § 310.6, as follows:
(1) To any person who has submitted an application or abbreviated application, by delivering the notice in person or by sending it by registered or certified mail to the last address shown in the application or abbreviated application.
(2) To any person who has not submitted an application or abbreviated application but who is subject to the notice under § 310.6 of this chapter, by
(c)(1)
(2) FDA will not consider data or analyses submitted after 60 days in determining whether a hearing is warranted unless they are derived from well-controlled studies begun before the date of the notice of opportunity for hearing and the results of the studies were not available within 60 days after the date of publication of the notice. Nevertheless, FDA may consider other studies on the basis of a showing by the person requesting a hearing of inadvertent omission and hardship. The person requesting a hearing shall list in the request for hearing all studies in progress, the results of which the person intends later to submit in support of the request for a hearing. The person shall submit under paragraph (c)(1)(ii) of this section a copy of the complete protocol, a list of the participating investigators, and a brief status report of the studies.
(3) Any other interested person who is not subject to the notice of opportunity for a hearing may also submit comments on the proposal to withdraw approval of the application or abbreviated application. The comments are requested to be submitted within the time and under the conditions specified in this section.
(d) The person requesting a hearing is required to submit under paragraph (c)(1)(ii) of this section the studies (including all protocols and underlying raw data) on which the person relies to justify a hearing with respect to the drug product. Except, a person who requests a hearing on the refusal to approve an application is not required to submit additional studies and analyses if the studies upon which the person relies have been submitted in the application and in the format and containing the summaries required under § 314.50.
(1) If the grounds for FDA's proposed action concern the effectiveness of the drug, each request for hearing is required to be supported only by adequate and well-controlled clinical studies meeting all of the precise requirements of § 314.126 and, for combination drug products, § 300.50, or by other studies not meeting those requirements for which a waiver has been previously granted by FDA under § 314.126. Each person requesting a hearing shall submit all adequate and well-controlled clinical studies on the drug product, including any unfavorable analyses, views, or judgments with respect to the studies. No other data, information, or studies may be submitted.
(2) The submission is required to include a factual analysis of all the studies submitted. If the grounds for FDA's proposed action concern the effectiveness of the drug, the analysis is required to specify how each study accords, on a point-by-point basis, with each criterion required for an adequate well-controlled clinical investigation established under § 314.126 and, if the product is a combination drug product, with each of the requirements for a combination drug established in § 300.50, or the study is required to be accompanied by an appropriate waiver previously granted by FDA. If a study concerns a drug or dosage form or condition of use or mode of administration other than the one in question, that fact is required to be clearly stated. Any study conducted on the final marketed form of the drug product is required to be clearly identified.
(3) Each person requesting a hearing shall submit an analysis of the data upon which the person relies, except that the required information relating either to safety or to effectiveness may be omitted if the notice of opportunity for hearing does not raise any issue with respect to that aspect of the drug; information on compliance with § 300.50 may be omitted if the drug product is not a combination drug product. A financial certification or disclosure statement or both as required by part 54 of this chapter must accompany all clinical data submitted. FDA can most efficiently consider submissions made in the following format.
I. Safety data.
A. Animal safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
B. Human safety data.
1. Individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a determination about the safety of each individual active component.
2. Combinations of the individual active components.
a. Controlled studies.
b. Partially controlled or uncontrolled studies.
c. Documented case reports.
d. Pertinent marketing experiences that may influence a determination about the safety of each individual active component.
II. Effectiveness data.
A. Individual active components: Controlled studies, with an analysis showing clearly how each study satisfies, on a point-by-point basis, each of the criteria required by § 314.126.
B. Combinations of individual active components.
1. Controlled studies with an analysis showing clearly how each study satisfies on a point-by-point basis, each of the criteria required by § 314.126.
2. An analysis showing clearly how each requirement of § 300.50 has been satisfied.
III. A summary of the data and views setting forth the medical rationale and purpose for the drug and its ingredients and the scientific basis for the conclusion that the drug and its ingredients have been proven safe and/or effective for the intended use. If there is an absence of controlled studies in the material submitted or the requirements of any element of § 300.50 or § 314.126 have not been fully met, that fact is required to be stated clearly and a waiver obtained under § 314.126 is required to be submitted.
IV. A statement signed by the person responsible for such submission that it includes in full (or incorporates by reference as permitted in § 314.200(c)(2)) all studies and information specified in § 314.200(d).
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(e)
(1) A contention that a drug product is generally recognized as safe and effective within the meaning of section 201(p) of the act is required to be supported by submission of the same quantity and quality of scientific evidence that is required to obtain approval of an application for the product, unless
(2) A contention that a drug product is exempt from part or all of the new drug provisions of the act under the exemption for products marketed before June 25, 1938, contained in section 201(p) of the act, or under section 107(c) of the Drug Amendments of 1962, is required to be supported by evidence of past and present quantitative formulas, labeling, and evidence of marketing. A person who makes such a contention should submit the formulas, labeling, and evidence of marketing in the following format.
I. Formulation.
A. A copy of each pertinent document or record to establish the exact quantitative formulation of the drug (both active and inactive ingredients) on the date of initial marketing of the drug.
B. A statement whether such formulation has at any subsequent time been changed in any manner. If any such change has been made, the exact date, nature, and rationale for each change in formulation, including any deletion or change in the concentration of any active ingredient and/or inactive ingredient, should be stated, together with a copy of each pertinent document or record to establish the date and nature of each such change, including, but not limited to, the formula which resulted from each such change. If no such change has been made, a copy of representative documents or records showing the formula at representative points in time should be submitted to support the statement.
II. Labeling.
A. A copy of each pertinent document or record to establish the identity of each item of written, printed, or graphic matter used as labeling on the date the drug was initially marketed.
B. A statement whether such labeling has at any subsequent time been discontinued or changed in any manner. If such discontinuance or change has been made, the exact date, nature, and rationale for each discontinuance or change and a copy of each pertinent document or record to establish each such discontinuance or change should be submitted, including, but not limited to, the labeling which resulted from each such discontinuance or change. If no such discontinuance or change has been made, a copy of representative documents or records showing labeling at representative points in time should be submitted to support the statement.
III. Marketing.
A. A copy of each pertinent document or record to establish the exact date the drug was initially marketed.
B. A statement whether such marketing has at any subsequent time been discontinued. If such marketing has been discontinued, the exact date of each such discontinuance should be submitted, together with a copy of each pertinent document or record to establish each such date.
IV. Verification.
A statement signed by the person responsible for such submission, that all appropriate records have been searched and to the best of that person's knowledge and belief it includes a true and accurate presentation of the facts.
(3) The Food and Drug Administration will not find a drug product, including any active ingredient, which is identical, related, or similar, as described in § 310.6, to a drug product, including any active ingredient for which an application is or at any time has been effective or deemed approved, or approved under section 505 of the act, to be exempt from part or all of the new drug provisions of the act.
(4) A contention that a drug product is not a new drug for any other reason is required to be supported by submission of the factual records, data, and information that are necessary and appropriate to support the contention.
(5) It is the responsibility of every person who manufactures or distributes a drug product in reliance upon a “grandfather” provision of the act to maintain files that contain the data and information necessary fully to document and support that status.
(f)
(g)
(1) Where a specific notice of opportunity for hearing (as defined in paragraph (a)(1) of this section) is used, the Commissioner will enter summary judgment against a person who requests a hearing, making findings and conclusions, denying a hearing, if it conclusively appears from the face of the data, information, and factual analyses in the request for the hearing that there is no genuine and substantial issue of fact which precludes the refusal to approve the application or abbreviated application or the withdrawal of approval of the application or abbreviated application; for example, no adequate and well-controlled clinical investigations meeting each of the precise elements of § 314.126 and, for a combination drug product, § 300.50 of this chapter, showing effectiveness have been identified. Any order entering summary judgment is required to set forth the Commissioner's findings and conclusions in detail and is required to specify why each study submitted fails to meet the requirements of the statute and regulations or why the request for hearing does not raise a genuine and substantial issue of fact.
(2) When following a general notice of opportunity for a hearing (as defined in paragraph (a)(1) of this section) the Director of the Center for Drug Evaluation and Research concludes that summary judgment against a person requesting a hearing should be considered, the Director will serve upon the person requesting a hearing by registered mail a proposed order denying a hearing. This person has 60 days after receipt of the proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.
(3) When following a general or specific notice of opportunity for a hearing a person requesting a hearing submits data or information of a type required by the statute and regulations, and the Director of the Center for Drug Evaluation and Research concludes that summary judgment against the person should be considered, the Director will serve upon the person by registered mail a proposed order denying a hearing. The person has 60 days after receipt of the proposed order to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing.
(4) If review of the data, information, and analyses submitted show that the grounds cited in the notice are not
(5) If the Commissioner grants a hearing, it will begin within 90 days after the expiration of the time for requesting the hearing unless the parties otherwise agree in the case of denial of approval, and as soon as practicable in the case of withdrawal of approval.
(6) The Commissioner will grant a hearing if there exists a genuine and substantial issue of fact or if the Commissioner concludes that a hearing would otherwise be in the public interest.
(7) If the manufacturer or distributor of an identical, related, or similar drug product requests and is granted a hearing, the hearing may consider whether the product is in fact identical, related, or similar to the drug product named in the notice of opportunity for a hearing.
(8) A request for a hearing, and any subsequent grant or denial of a hearing, applies only to the drug products named in such documents.
(h) FDA will issue a notice withdrawing approval and declaring all products unlawful for drug products subject to a notice of opportunity for a hearing, including any identical, related, or similar drug product under § 310.6, for which an opportunity for a hearing is waived or for which a hearing is denied. The Commissioner may defer or stay the action pending a ruling on any related request for a hearing or pending any related hearing or other administrative or judicial proceeding.
Parts 10 through 16 apply to hearings relating to new drugs under section 505 (d) and (e) of the act.
(a) The Commissioner of Food and Drugs will certify the transcript and record. In any case in which the Commissioner enters an order without a hearing under § 314.200(g), the record certified by the Commissioner is required to include the requests for hearing together with the data and information submitted and the Commissioner's findings and conclusion.
(b) A manufacturer or distributor of an identical, related, or similar drug product under § 310.6 may seek judicial review of an order withdrawing approval of a new drug application, whether or not a hearing has been held, in a United States court of appeals under section 505(h) of the act.
(a)
(2) A drug substance intended for use in the manufacture, processing, or repacking of a new drug may be imported into the United States if it complies with the labeling exemption in § 201.122 pertaining to shipments of drug substances in domestic commerce.
(b)
(2) A new drug substance that is covered by an application approved under this part for use in the manufacture of an approved drug product may be exported by the applicant or any person listed as a supplier in the approved application, provided the drug substance intended for export meets the specifications of, and is shipped with a copy
(3) Insulin or an antibiotic drug may be exported without regard to the requirements in section 802 of the act if the insulin or antibiotic drug meets the requirements of section 801(e)(1) of the act.
(a) A drug master file is a submission of information to the Food and Drug Administration by a person (the drug master file holder) who intends it to be used for one of the following purposes: To permit the holder to incorporate the information by reference when the holder submits an investigational new drug application under part 312 or submits an application or an abbreviated application or an amendment or supplement to them under this part, or to permit the holder to authorize other persons to rely on the information to support a submission to FDA without the holder having to disclose the information to the person. FDA ordinarily neither independently reviews drug master files nor approves or disapproves submissions to a drug master file. Instead, the agency customarily reviews the information only in the context of an application under part 312 or this part. A drug master file may contain information of the kind required for any submission to the agency, including information about the following:
(1) [Reserved]
(2) Drug substance, drug substance intermediate, and materials used in their preparation, or drug product;
(3) Packaging materials;
(4) Excipient, colorant, flavor, essence, or materials used in their preparation;
(5) FDA-accepted reference information. (A person wishing to submit information and supporting data in a drug master file (DMF) that is not covered by Types II through IV DMF's must first submit a letter of intent to the Drug Master File Staff, Food and Drug Administration, 12229 Wilkins Ave., Rockville, MD 20852). FDA will then contact the person to discuss the proposed submission.
(b) An investigational new drug application or an application, abbreviated application, amendment, or supplement may incorporate by reference all or part of the contents of any drug master file in support of the submission if the holder authorizes the incorporation in writing. Each incorporation by reference is required to describe the incorporated material by name, reference number, volume, and page number of the drug master file.
(c) A drug master file is required to be submitted in two copies. The agency has prepared guidance that provides information about how to prepare a well-organized drug master file. If the drug master file holder adds, changes, or deletes any information in the file, the holder shall notify in writing, each person authorized to reference that information. Any addition, change, or deletion of information in a drug master file (except the list required under paragraph (d) of this section) is required to be submitted in two copies and to describe by name, reference number, volume, and page number the information affected in the drug master file.
(d) The drug master file is required to contain a complete list of each person currently authorized to incorporate by reference any information in the file, identifying by name, reference number, volume, and page number the information that each person is authorized to incorporate. If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies.
(e) The public availability of data and information in a drug master file, including the availability of data and information in the file to a person authorized to reference the file, is determined under part 20 and § 314.430.
(a) The Food and Drug Administration will determine the public availability of any part of an application or abbreviated application under this section and part 20 of this chapter. For purposes of this section, the application or abbreviated application includes all data and information submitted with or incorporated by reference in the application or abbreviated application, including investigational new drug applications, drug master files under § 314.420, supplements submitted under § 314.70 or § 314.97, reports under § 314.80 or § 314.98, and other submissions. For purposes of this section, safety and effectiveness data include all studies and tests of a drug on animals and humans and all studies and tests of the drug for identity, stability, purity, potency, and bioavailability.
(b) FDA will not publicly disclose the existence of an application or abbreviated application before an approvable letter is sent to the applicant under § 314.110, unless the existence of the application or abbreviated application has been previously publicly disclosed or acknowledged. The Center for Drug Evaluation and Research will maintain and make available for public disclosure a list of applications or abbreviated applications for which the agency has sent an approvable letter to the applicant.
(c) If the existence of an unapproved application or abbreviated application has not been publicly disclosed or acknowledged, no data or information in the application or abbreviated application is available for public disclosure.
(d)(1) If the existence of an application or abbreviated application has been publicly disclosed or acknowledged before the agency sends an approval letter to the applicant, no data or information contained in the application or abbreviated application is available for public disclosure before the agency sends an approval letter, but the Commissioner may, in his or her discretion, disclose a summary of selected portions of the safety and effectiveness data that are appropriate for public consideration of a specific pending issue; for example, for consideration of an open session of an FDA advisory committee.
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make available to the public upon request the information in the investigational new drug application that was required to be filed in Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations involving an exception from informed consent under § 50.24 of this chapter. Persons wishing to request this information shall submit a request under the Freedom of Information Act.
(e) After FDA sends an approval letter to the applicant, the following data and information in the application or abbreviated application are immediately available for public disclosure, unless the applicant shows that extraordinary circumstances exist. A list of approved applications and abbreviated applications, entitled “Approved Drug Products with Therapeutic Equivalence Evaluations,” is available from the Government Printing Office, Washington, DC 20402. This list is updated monthly.
(1) [Reserved]
(2) If the application applies to a new drug, all safety and effectiveness data previously disclosed to the public as set forth in § 20.81 and a summary or summaries of the safety and effectiveness data and information submitted with or incorporated by reference in the application. The summaries do not constitute the full reports of investigations under section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) on which the safety or effectiveness of the drug may be approved. The summaries consist of the following:
(i) For an application approved before July 1, 1975, internal agency records that describe safety and effectiveness data and information, for example, a summary of the basis for approval or internal reviews of the data and information, after deletion of the following:
(
(
(ii) For an application approved on or after July 1, 1975, a Summary Basis of Approval (SBA) document that contains a summary of the safety and effectiveness data and information evaluated by FDA during the drug approval process. The SBA is prepared in one of the following ways:
(
(
(3) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61.
(4) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information after deletion of the following:
(i) Names and any information that would identify the person using the product.
(ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution.
(5) A list of all active ingredients and any inactive ingredients previously disclosed to the public as set forth in § 20.81.
(6) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and is shown to fall within the exemption established for trade secrets and confidential commercial information in § 20.61.
(7) All correspondence and written summaries of oral discussions between FDA and the applicant relating to the application, under the provisions of part 20.
(f) All safety and effectiveness data and information which have been submitted in an application and which have not previously been disclosed to the public are available to the public, upon request, at the time any one of the following events occurs unless extraordinary circumstances are shown:
(1) No work is being or will be undertaken to have the application approved.
(2) A final determination is made that the application is not approvable and all legal appeals have been exhausted.
(3) Approval of the application is withdrawn and all legal appeals have been exhausted.
(4) A final determination has been made that the drug is not a new drug.
(5) For applications submitted under section 505(b) of the act, the effective date of the approval of the first abbreviated application submitted under section 505(j) of the act which refers to such drug, or the date on which the approval of an abbreviated application under section 505(j) of the act which refers to such drug could be made effective if such an abbreviated application had been submitted.
(6) For abbreviated applications submitted under section 505(j) of the act, when FDA sends an approval letter to the applicant.
(g) The following data and information in an application or abbreviated application are not available for public disclosure unless they have been previously disclosed to the public as set forth in § 20.81 of this chapter or they relate to a product or ingredient that has been abandoned and they do not represent a trade secret or confidential commercial or financial information under § 20.61 of this chapter:
(1) Manufacturing methods or processes, including quality control procedures.
(2) Production, sales distribution, and similar data and information, except that any compilation of that data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.
(3) Quantitative or semiquantitative formulas.
(h) The compilations of information specified in § 20.117 are available for public disclosure.
(a) Applicants shall send applications, abbreviated applications, and other correspondence relating to matters covered by this part, except for products listed in paragraph (b) of this section, to the Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, and directed to the appropriate office identified below:
(1) Except as provided in paragraph (a)(4) of this section, an application under § 314.50 or § 314.54 submitted for filing should be directed to the Document and Records Section, 12420 Parklawn Dr., Rockville, MD 20852. Applicants may obtain folders for binding applications from the Consolidated Forms and Publications Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785. After FDA has filed the application, the agency will inform the applicant which division is responsible for the application. Amendments, supplements, resubmissions, requests for waivers, and other correspondence about an application that has been filed should be directed to the appropriate division.
(2) Except as provided in paragraph (a)(4) of this section, an abbreviated application under § 314.94, and amendments, supplements, and resubmissions should be directed to the Office of Generic Drugs (HFD-600), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Items sent by parcel post or overnight courier service should be directed to the Office of Generic Drugs (HFD-600), Center for Drug Evaluation and Research, Food and Drug Administration, Metro Park North II, 7500 Standish Place, rm. 150, Rockville, MD 20855. Correspondence not associated with an application should be addressed specifically to the intended office or division and to the person as follows: Center for Drug Evaluation and Research, Food and Drug Administration, Attn: [
(3) A request for an opportunity for a hearing under § 314.110 or § 314.120 on the question of whether there are grounds for denying approval of an application, except an application under paragraph (b) of this section, should be directed to the Associate Director for Policy (HFD-5).
(4) The field copy of an application, an abbreviated application, amendments, supplements, resubmissions, requests for waivers, and other correspondence about an application and an abbreviated application shall be sent to the applicant's home FDA district office, except that a foreign applicant shall send the field copy to the appropriate address identified in paragraphs (a)(1) and (a)(2) of this section.
(b) Applicants shall send applications and other correspondence relating to matters covered by this part for the drug products listed below to the Division of Product Certification (HFB-240), Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20892, except applicants shall send a request for an opportunity for a hearing under § 314.110 or § 314.120 on the question of whether there are grounds for denying approval of an application to the Director, Center for Biologics Evaluation and Research (HFB-1), at the same address.
(1) Ingredients packaged together with containers intended for the collection, processing, or storage of blood and blood components.
(2) Urokinase products.
(3) Plasma volume expanders and hydroxyethyl starch for leukapheresis.
(a) FDA has made available guidance documents under § 10.115 of this chapter to help you to comply with certain requirements of this part.
(b) The Center for Drug Evaluation and Research (CDER) maintains a list of guidance documents that apply to CDER's regulations. The list is maintained on the Internet and is published annually in the
This subpart applies to certain new drug products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy).
FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.
(a) If FDA concludes that a drug product shown to be effective can be safely used only if distribution or use is restricted, FDA will require such postmarketing restrictions as are needed to assure safe use of the drug product, such as:
(1) Distribution restricted to certain facilities or physicians with special training or experience; or
(2) Distribution conditioned on the performance of specified medical procedures.
(b) The limitations imposed will be commensurate with the specific safety concerns presented by the drug product.
(a) For new drugs approved under §§ 314.510 and 314.520, FDA may withdraw approval, following a hearing as provided in part 15 of this chapter, as modified by this section, if:
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the required postmarketing study with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to assure safe use of the drug product;
(4) The applicant fails to adhere to the postmarketing restrictions agreed upon;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use.
(b)
(c)
(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the
(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.
(d)
(e)
(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of the Center may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.
(f)
Drug products approved under this program are subject to the postmarketing recordkeeping and safety reporting applicable to all approved drug products, as provided in §§ 314.80 and 314.81.
For drug products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
If FDA determines after approval that the requirements established in § 314.520, § 314.530, or § 314.550 are no longer necessary for the safe and effective use of a drug product, it will so notify the applicant. Ordinarily, for drug products approved under § 314.510, these requirements will no longer apply when FDA determines that the required postmarketing study verifies and describes the drug product's clinical benefit and the drug product would be appropriate for approval under traditional procedures. For drug products approved under § 314.520, the restrictions would no longer apply when FDA determines that safe use of the drug product can be assured through appropriate labeling. FDA also retains the
This subpart applies to certain new drug products that have been studied for their safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances. This subpart applies only to those new drug products for which: Definitive human efficacy studies cannot be conducted because it would be unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance; and field trials to study the product's effectiveness after an accidental or hostile exposure have not been feasible. This subpart does not apply to products that can be approved based on efficacy standards described elsewhere in FDA's regulations (e.g., accelerated approval based on surrogate markers or clinical endpoints other than survival or irreversible morbidity), nor does it address the safety evaluation for the products to which it does apply.
(a) FDA may grant marketing approval for a new drug product for which safety has been established and for which the requirements of § 314.600 are met based on adequate and well-controlled animal studies when the results of those animal studies establish that the drug product is reasonably likely to produce clinical benefit in humans. In assessing the sufficiency of animal data, the agency may take into account other data, including human data, available to the agency. FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when:
(1) There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;
(2) The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;
(3) The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and
(4) The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.
(b) Approval under this subpart will be subject to three requirements:
(1)
(2)
(i) Distribution restricted to certain facilities or health care practitioners with special training or experience;
(ii) Distribution conditioned on the performance of specified medical procedures, including medical followup; and
(iii) Distribution conditioned on specified recordkeeping requirements.
(3)
(a)
(1) A postmarketing clinical study fails to verify clinical benefit;
(2) The applicant fails to perform the postmarketing study with due diligence;
(3) Use after marketing demonstrates that postmarketing restrictions are inadequate to ensure safe use of the drug product;
(4) The applicant fails to adhere to the postmarketing restrictions applied at the time of approval under this subpart;
(5) The promotional materials are false or misleading; or
(6) Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use.
(b)
(c)
(2) If the applicant files a timely request for a hearing, the agency will publish a notice of hearing in the
(3) An applicant who requests a hearing under this section must, within 30 days of receipt of the notice of opportunity for a hearing, submit the data and information upon which the applicant intends to rely at the hearing.
(d)
(e)
(1) An advisory committee duly constituted under part 14 of this chapter will be present at the hearing. The committee will be asked to review the issues involved and to provide advice and recommendations to the Commissioner of Food and Drugs.
(2) The presiding officer, the advisory committee members, up to three representatives of the applicant, and up to three representatives of CDER may question any person during or at the conclusion of the person's presentation. No other person attending the hearing may question a person making a presentation. The presiding officer may, as a matter of discretion, permit questions to be submitted to the presiding officer for response by a person making a presentation.
(f)
Drug products approved under this subpart are subject to the postmarketing recordkeeping and safety reporting requirements applicable to all approved drug products, as provided in §§ 314.80 and 314.81.
For drug products being considered for approval under this subpart, unless otherwise informed by the agency, applicants must submit to the agency for consideration during the preapproval review period copies of all promotional materials, including promotional labeling as well as advertisements, intended for dissemination or publication within 120 days following marketing approval. After 120 days following marketing approval, unless otherwise informed by the agency, the applicant must submit promotional materials at least 30 days prior to the intended time of initial dissemination of the labeling or initial publication of the advertisement.
If FDA determines after approval under this subpart that the requirements established in §§ 314.610(b)(2), 314.620, and 314.630 are no longer necessary for the safe and effective use of a drug product, FDA will so notify the applicant. Ordinarily, for drug products approved under § 314.610, these requirements will no longer apply when FDA determines that the postmarketing study verifies and describes the drug product's clinical benefit. For drug products approved under § 314.610, the restrictions would no longer apply when FDA determines that safe use of the drug product can be ensured through appropriate labeling. FDA also retains the discretion to remove specific postapproval requirements upon review of a petition submitted by the sponsor in accordance with § 10.30 of this chapter.
21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374, 379e; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).
The regulations in this part apply to radiopharmaceuticals intended for in vivo administration for diagnostic and monitoring use. They do not apply to radiopharmaceuticals intended for therapeutic purposes. In situations where a particular radiopharmaceutical is proposed for both diagnostic and therapeutic uses, the radiopharmaceutical must be evaluated taking into account each intended use.
For purposes of this part,
(a) An article that is intended for use in the diagnosis or monitoring of a disease or a manifestation of a disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons; or
(b) Any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of such article as defined in paragraph (a) of this section.
FDA's determination of the safety and effectiveness of a diagnostic radiopharmaceutical includes consideration of the following:
(a) The proposed use of the diagnostic radiopharmaceutical in the practice of medicine,
(b) The pharmacological and toxicological activity of the diagnostic
(c) The estimated absorbed radiation dose of the diagnostic radiopharmaceutical.
(a) For diagnostic radiopharmaceuticals, the categories of proposed indications for use include, but are not limited to, the following:
(1) Structure delineation;
(2) Functional, physiological, or biochemical assessment;
(3) Disease or pathology detection or assessment; and
(4) Diagnostic or therapeutic patient management.
(b) Where a diagnostic radiopharmaceutical is not intended to provide disease-specific information, the proposed indications for use may refer to a biochemical, physiological, anatomical, or pathological process or to more than one disease or condition.
(a) The effectiveness of a diagnostic radiopharmaceutical is assessed by evaluating its ability to provide useful clinical information related to its proposed indications for use. The method of this evaluation varies depending upon the proposed indication(s) and may use one or more of the following criteria:
(1) The claim of structure delineation is established by demonstrating in a defined clinical setting the ability to locate anatomical structures and to characterize their anatomy.
(2) The claim of functional, physiological, or biochemical assessment is established by demonstrating in a defined clinical setting reliable measurement of function(s) or physiological, biochemical, or molecular process(es).
(3) The claim of disease or pathology detection or assessment is established by demonstrating in a defined clinical setting that the diagnostic radiopharmaceutical has sufficient accuracy in identifying or characterizing the disease or pathology.
(4) The claim of diagnostic or therapeutic patient management is established by demonstrating in a defined clinical setting that the test is useful in diagnostic or therapeutic patient management.
(5) For a claim that does not fall within the indication categories identified in § 315.4, the applicant or sponsor should consult FDA on how to establish the effectiveness of the diagnostic radiopharmaceutical for the claim.
(b) The accuracy and usefulness of the diagnostic information is determined by comparison with a reliable assessment of actual clinical status. A reliable assessment of actual clinical status may be provided by a diagnostic standard or standards of demonstrated accuracy. In the absence of such diagnostic standard(s), the actual clinical status must be established in another manner, e.g., patient followup.
(a) Factors considered in the safety assessment of a diagnostic radiopharmaceutical include, among others, the following:
(1) The radiation dose;
(2) The pharmacology and toxicology of the radiopharmaceutical, including any radionuclide, carrier, or ligand;
(3) The risks of an incorrect diagnostic determination;
(4) The adverse reaction profile of the drug;
(5) Results of human experience with the radiopharmaceutical for other uses; and
(6) Results of any previous human experience with the carrier or ligand of the radiopharmaceutical when the same chemical entity as the carrier or ligand has been used in a previously studied product.
(b) The assessment of the adverse reaction profile includes, but is not limited to, an evaluation of the potential of the diagnostic radiopharmaceutical, including the carrier or ligand, to elicit the following:
(1) Allergic or hypersensitivity responses,
(2) Immunologic responses,
(3) Changes in the physiologic or biochemical function of the target and nontarget tissues, and
(4) Clinically detectable signs or symptoms.
(c)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA
(i) Pharmacology data,
(ii) Toxicology data,
(iii) Clinical adverse event data, and
(iv) Radiation safety assessment.
(2) The amount of new safety data required will depend on the characteristics of the product and available information regarding the safety of the diagnostic radiopharmaceutical, and its carrier or ligand, obtained from other studies and uses. Such information may include, but is not limited to, the dose, route of administration, frequency of use, half-life of the ligand or carrier, half-life of the radionuclide, and results of clinical and preclinical studies. FDA will establish categories of diagnostic radiopharmaceuticals based on defined characteristics relevant to risk and will specify the amount and type of safety data that are appropriate for each category (e.g., required safety data may be limited for diagnostic radiopharmaceuticals with a well established, low-risk profile). Upon reviewing the relevant product characteristics and safety information, FDA will place each diagnostic radiopharmaceutical into the appropriate safety risk category.
(d) Radiation safety assessment. The radiation safety assessment must establish the radiation dose of a diagnostic radiopharmaceutical by radiation dosimetry evaluations in humans and appropriate animal models. The maximum tolerated dose need not be established.
21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.
(a) This part implements sections 525, 526, 527, and 528 of the act and provides procedures to encourage and facilitate the development of drugs for rare diseases or conditions, including biological products and antibiotics. This part sets forth the procedures and requirements for:
(1) Submissions to FDA of:
(i) Requests for recommendations for investigations of drugs for rare diseases or conditions;
(ii) Requests for designation of a drug for a rare disease or condition; and
(iii) Requests for gaining exclusive approval for a drug product for a rare disease or condition.
(2) Allowing a sponsor to provide an investigational drug product under a treatment protocol to patients who need the drug for treatment of a rare disease or condition.
(b) This part does not apply to food, medical devices, or drugs for veterinary use.
(c) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.
The purpose of this part is to establish standards and procedures for determining eligibility for the benefits provided for in section 2 of the Orphan Drug Act, including written recommendations for investigations of orphan drugs, a 7-year period of exclusive marketing, and treatment use of investigational orphan drugs. This part is also intended to satisfy Congress' requirements that FDA promulgate procedures for the implementation of sections 525(a) and 526(a) of the act.
(a) The definitions and interpretations contained in section 201 of the act apply to those terms when used in this part.
(b) The following definitions of terms apply to this part:
(1)
(2)
(3)
(i) Greater effectiveness than an approved orphan drug (as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs; in most cases, direct comparative clinical trials would be necessary; or
(ii) Greater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects. In some cases, direct comparative clinical trials will be necessary; or
(iii) In unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care.
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(i) If it is a drug composed of small molecules, a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate or clathrate has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.
(ii) If it is a drug composed of large molecules (macromolecules), a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. This criterion will be applied as follows to different kinds of macromolecules:
(A) Two protein drugs would be considered the same if the only differences in structure between them were due to post-translational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.
(B) Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications, unless the subsequent drug could be shown to be clinically superior.
(C) Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars), unless the subsequent drug were shown to be clinically superior.
(D) Closely related, complex partly definable drugs with similar therapeutic intent, such as two live viral vaccines for the same indication, would be considered the same unless the subsequent drug was shown to be clinically superior.
(14)
All correspondence and requests for FDA action pursuant to the provisions of this rule should be addressed as follows: Office of Orphan Products Development (HF-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(a) A sponsor's request for written recommendations from FDA concerning the nonclinical and clinical investigations necessary for approval of a marketing application shall be submitted in the form and contain the information required in this section. FDA may require the sponsor to submit information in addition to that specified in paragraph (b) of this section if FDA determines that the sponsor's initial request does not contain
(b) A sponsor shall submit two copies of a completed, dated, and signed request for written recommendations that contains the following:
(1) The sponsor's name and address.
(2) A statement that the sponsor is requesting written recommendations on orphan-drug development under section 525 of the act.
(3) The name of the sponsor's primary contact person and/or resident agent, and the person's title, address, and telephone number.
(4) The generic name and trade name, if any, of the drug and a list of the drug product's components or description of the drug product's formulation, and chemical and physical properties.
(5) The proposed dosage form and route of administration.
(6) A description of the disease or condition for which the drug is proposed to be investigated and the proposed indication or indications for use for such disease or condition.
(7) Current regulatory and marketing status and history of the drug product, including:
(i) Whether the product is the subject of an IND or a marketing application (if the product is the subject of an IND or a marketing application, the IND or marketing application numbers should be stated and the investigational or approved indication or indications for use specified);
(ii) Known marketing experience or investigational status outside the United States;
(iii) So far as is known or can be determined, all indications previously or currently under investigation anywhere;
(iv) All adverse regulatory actions taken by the United States or foreign authorities.
(8) The basis for concluding that the drug is for a disease or condition that is rare in the United States, including the following:
(i) The size and other known demographic characteristics of the patient population affected and the source of this information.
(ii) For drugs intended for diseases or conditions affecting 200,000 or more people in the United States, or for a vaccine, diagnostic drug, or preventive drug that would be given to 200,000 or more persons per year, a summary of the sponsor's basis for believing that the disease or condition described in paragraph (b)(6) of this section occurs so infrequently that there is no reasonable expectation that the costs of drug development and marketing will be recovered in future sales of the drug in the United States. The estimated costs and sales data should be submitted as provided for in § 316.21(c).
(9) A summary and analysis of available data on the pharmacologic effects of the drug.
(10) A summary and analysis of available nonclinical and clinical data pertinent to the drug and the disease to be studied including copies of pertinent published reports. When a drug proposed for orphan drug designation is intended to treat a life-threatening or severely debilitating illness, especially where no satisfactory alternative therapy exists, the sponsor may wish voluntarily to provide this information. A sponsor of such a drug may be entitled to expeditious development, evaluation, and marketing under 21 CFR part 312, subpart E.
(11) An explanation of how the data summarized and analyzed under paragraphs (b)(9) and (b)(10) of this section support the rationale for use of the drug in the rare disease or condition.
(12) A definition of the population from which subjects will be identified for clinical trials, if known.
(13) A detailed outline of any protocols under which the drug has been or is being studied for the rare disease or condition and a summary and analysis of any available data from such studies.
(14) The sponsor's proposal as to the scope of nonclinical and clinical investigations needed to establish the safety and effectiveness of the drug.
(15) Detailed protocols for each proposed United States or foreign clinical investigation, if available.
(16) Specific questions to be addressed by FDA in its recommendations for nonclinical laboratory studies and clinical investigations.
(a) FDA will provide the sponsor with written recommendations concerning the nonclinical laboratory studies and clinical investigations necessary for approval of a marketing application if none of the reasons described in § 316.14 for refusing to do so applies.
(b) When a sponsor seeks written recommendations at a stage of drug development at which advice on any clinical investigations, or on particular investigations would be premature, FDA's response may be limited to written recommendations concerning only nonclinical laboratory studies, or only certain of the clinical studies (e.g., Phase 1 studies as described in § 312.21 of this chapter). Prior to providing written recommendations for the clinical investigations required to achieve marketing approval, FDA may require that the results of the nonclinical laboratory studies or completed early clinical studies be submitted to FDA for agency review.
(a) FDA may refuse to provide written recommendations concerning the nonclinical laboratory studies and clinical investigations necessary for approval of a marketing application for any of the following reasons:
(1) The information required to be submitted by § 316.10(b) has not been submitted, or the information submitted is incomplete.
(2) There is insufficient information about:
(i) The drug to identify the active moiety and its physical and chemical properties, if these characteristics can be determined; or
(ii) The disease or condition to determine that the disease or condition is rare in the United States; or
(iii) The reasons for believing that the drug may be useful for treating the rare disease or condition with that drug; or
(iv) The regulatory and marketing history of the drug to determine the scope and type of investigations that have already been conducted on the drug for the rare disease or condition; or
(v) The plan of study for establishing the safety and effectiveness of the drug for treatment of the rare disease or condition.
(3) The specific questions for which the sponsor seeks the advice of the agency are unclear or are not sufficiently specific.
(4) On the basis of the information submitted and on other information available to the agency, FDA determines that the disease or condition for which the drug is intended is not rare in the United States.
(5) On the basis of the information submitted and on other information available to the agency, FDA determines that there is an inadequate basis for permitting investigational use of the drug under part 312 of this chapter for the rare disease or condition.
(6) The request for information contains an untrue statement of material fact.
(b) A refusal to provide written recommendations will be in writing and will include a statement of the reason for FDA's refusal. Where practicable, FDA will describe the information or material it requires or the conditions the sponsor must meet for FDA to provide recommendations.
(c) Within 90 days after the date of a letter from FDA requesting additional information or material or setting forth the conditions that the sponsor is asked to meet, the sponsor shall either:
(1) Provide the information or material or amend the request for written recommendations to meet the conditions sought by FDA; or
(2) Withdraw the request for written recommendations. FDA will consider a sponsor's failure to respond within 90 days to an FDA letter requesting information or material or setting forth conditions to be met to be a withdrawal of the request for written recommendations.
(a) A sponsor that submits a request for orphan-drug designation of a drug for a specified rare disease or condition shall submit each request in the form
(b) A sponsor shall submit two copies of a completed, dated, and signed request for designation that contains the following:
(1) A statement that the sponsor requests orphan-drug designation for a rare disease or condition, which shall be identified with specificity.
(2) The name and address of the sponsor; the name of the sponsor's primary contact person and/or resident agent including title, address, and telephone number; the generic and trade name, if any, of the drug or drug product; and the name and address of the source of the drug if it is not manufactured by the sponsor.
(3) A description of the rare disease or condition for which the drug is being or will be investigated, the proposed indication or indications for use of the drug, and the reasons why such therapy is needed.
(4) A description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition, including all data from nonclinical laboratory studies, clinical investigations, and other relevant data that are available to the sponsor, whether positive, negative, or inconclusive. Copies of pertinent unpublished and published papers are also required.
(5) Where the sponsor of a drug that is otherwise the same drug as an already-approved orphan drug seeks orphan-drug designation for the subsequent drug for the same rare disease or condition, an explanation of why the proposed variation may be clinically superior to the first drug.
(6) Where a drug is under development for only a subset of persons with a particular disease or condition, a demonstration that the subset is medically plausible.
(7) A summary of the regulatory status and marketing history of the drug in the United States and in foreign countries, e.g., IND and marketing application status and dispositions, what uses are under investigation and in what countries; for what indication is the drug approved in foreign countries; what adverse regulatory actions have been taken against the drug in any country.
(8) Documentation, with appended authoritative references, to demonstrate that:
(i) The disease or condition for which the drug is intended affects fewer than 200,000 people in the United States or, if the drug is a vaccine, diagnostic drug, or preventive drug, the persons to whom the drug will be administered in the United States are fewer than 200,000 per year as specified in § 316.21(b), or
(ii) For a drug intended for diseases or conditions affecting 200,000 or more people, or for a vaccine, diagnostic drug, or preventive drug to be administered to 200,000 or more persons per year in the United States, there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the United States as specified in § 316.21(c).
(9) A statement as to whether the sponsor submitting the request is the real party in interest of the development and the intended or actual production and sales of the product.
(c) Any of the information previously provided by the sponsor to FDA under subpart B of this part may be referenced by specific page or location if it duplicates information required elsewhere in this section.
(a) So that FDA can determine whether a drug qualifies for orphan-drug designation under section 526(a) of
(1) Documentation as described in paragraph (b) of this section that the number of people affected by the disease or condition for which the drug product is indicated is fewer than 200,000 persons; or
(2) Documentation as described in paragraph (c) of this section that demonstrates that there is no reasonable expectation that the sales of the drug will be sufficient to offset the costs of developing the drug for the U.S. market and the costs of making the drug available in the United States.
(b) For the purpose of documenting that the number of people affected by the disease or condition for which the drug product is indicated is less than 200,000 persons, “prevalence” is defined as the number of persons in the United States who have been diagnosed as having the disease or condition at the time of the submission of the request for orphan-drug designation. To document the number of persons in the United States who have the disease or condition for which the drug is to be indicated, the sponsor shall submit to FDA evidence showing:
(1) The estimated prevalence of the disease or condition for which the drug is being developed, together with a list of the sources (including dates of information provided and literature citations) for the estimate;
(2) Upon request by FDA, the estimated prevalence of any other disease or condition for which the drug has already been approved or for which the drug is currently being developed, together with an explanation of the bases of these estimates; and
(3) The estimated number of people to whom the drug will be administered annually if the drug is a vaccine or is a drug intended for diagnosis or prevention of a rare disease or condition, together with an explanation of the bases of these estimates (including dates of information provided and literature citations).
(c) When submitting documentation that there is no reasonable expectation that costs of research and development of the drug for the disease or condition can be recovered by sales of the drug in the United States, the sponsor shall submit to FDA:
(1) Data on all costs that the sponsor has incurred in the course of developing the drug for the U.S. market. These costs shall include, but are not limited to, nonclinical laboratory studies, clinical studies, dosage form development, record and report maintenance, meetings with FDA, determination of patentability, preparation of designation request, IND/marketing application preparation, distribution of the drug under a “treatment” protocol, licensing costs, liability insurance, and overhead and depreciation. Furthermore, the sponsor shall demonstrate the reasonableness of the cost data. For example, if the sponsor has incurred costs for clinical investigations, the sponsor shall provide information on the number of investigations, the years in which they took place, and on the scope, duration, and number of patients that were involved in each investigation.
(2) If the drug was developed wholly or in part outside the United States, in addition to the documentation listed in paragraph (c)(1) of this section:
(i) Data on and justification for all costs that the sponsor has incurred outside of the United States in the course of developing the drug for the U.S. market. The justification, in addition to demonstrating the reasonableness of the cost data, must also explain the method that was used to determine which portion of the foreign development costs should be applied to the U.S. market, and what percent these costs are of total worldwide development costs. Any data submitted to foreign government authorities to support drug pricing determinations must be included with this information.
(ii) Data that show which foreign development costs were recovered through cost recovery procedures that are allowed during drug development in some foreign countries. For example, if the sponsor charged patients for the drug during clinical investigations, the revenues collected by the sponsor must be reported to FDA.
(3) In cases where the drug has already been approved for marketing for any indication or in cases where the drug is currently under investigation
(4) A statement of and justification for any development costs that the sponsor expects to incur after the submission of the designation request. In cases where the extent of these future development costs are not clear, the sponsor should request FDA's advice and assistance in estimating the scope of nonclinical laboratory studies and clinical investigations and other data that are needed to support marketing approval. Based on these recommendations, a cost estimate should be prepared.
(5) A statement of and justification for production and marketing costs that the sponsor has incurred in the past and expects to incur during the first 7 years that the drug is marketed.
(6) An estimate of and justification for the expected revenues from sales of the drug in the United States during its first 7 years of marketing. The justification should assume that the total market for the drug is equal to the prevalence of the disease or condition that the drug will be used to treat. The justification should include:
(i) An estimate of the expected market share of the drug in each of the first 7 years that it is marketed, together with an explanation of the basis for that estimate;
(ii) A projection of and justification for the price at which the drug will be sold; and
(iii) Comparisons with sales of similarly situated drugs, where available.
(7) The name of each country where the drug has already been approved for marketing for any indication, the dates of approval, the indication for which the drug is approved, and the annual sales and number of prescriptions in each country since the first approval date.
(8) A report of an independent certified public accountant in accordance with Statement on Standards for Attestation established by the American Institute of Certified Public Accountants on agreed upon procedures performed with respect to the data estimates and justifications submitted pursuant to this section. Cost data shall be determined in accordance with generally accepted accounting principles.
(d) A sponsor that is requesting orphan-drug designation for a drug designed to treat a disease or condition that affects 200,000 or more persons shall, at FDA's request, allow FDA or FDA-designated personnel to examine at reasonable times and in a reasonable manner all relevant financial records and sales data of the sponsor and manufacturer.
Every foreign sponsor that seeks orphan-drug designation shall name a permanent resident of the United States as the sponsor's agent upon whom service of all processes, notices, orders, decisions, requirements, and other communications may be made on behalf of the sponsor. Notifications of changes in such agents or changes of address of agents should preferably be provided in advance, but not later than 60 days after the effective date of such changes. The permanent-resident agent may be an individual, firm, or domestic corporation and may represent any number of sponsors. The name of the permanent-resident agent shall be provided to: Office of Orphan Products Development (HF-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
(a) A sponsor may request orphan-drug designation at any time in the drug development process prior to the submission of a marketing application for the drug product for the orphan indication.
(b) A sponsor may request orphan-drug designation of an already approved drug product for an unapproved use without regard to whether the prior marketing approval was for an orphan-drug indication.
(a) FDA will grant the request for orphan-drug designation if none of the reasons described in § 316.25 for requiring or permitting refusal to grant such a request applies.
(b) When a request for orphan-drug designation is granted, FDA will notify the sponsor in writing and will publicize the orphan-drug designation in accordance with § 316.28.
(a) FDA will refuse to grant a request for orphan-drug designation if any of the following reasons apply:
(1) The drug is not intended for a rare disease or condition because:
(i) There is insufficient evidence to support the estimate that the drug is intended for treatment of a disease or condition in fewer than 200,000 people in the United States, or that the drug is intended for use in prevention or in diagnosis in fewer than 200,000 people annually in the United States; or
(ii) Where the drug is intended for prevention, diagnosis, or treatment of a disease or condition affecting 200,000 or more people in the United States, the sponsor has failed to demonstrate that there is no reasonable expectation that development and production costs will be recovered from sales of the drug for the orphan indication in the United States. A sponsor's failure to comply with § 316.21 shall constitute a failure to make the demonstration required in this paragraph.
(2) There is insufficient information about the drug, or the disease or condition for which it is intended, to establish a medically plausible basis for expecting the drug to be effective in the prevention, diagnosis, or treatment of that disease or condition.
(3) A drug that is otherwise the same drug as one that already has orphan-drug exclusive approval for the same rare disease or condition and the sponsor has not submitted a medically plausible hypothesis for the possible clinical superiority of the subsequent drug.
(b) FDA may refuse to grant a request for orphan-drug designation if the request for designation contains an untrue statement of material fact or omits material information.
(a) At any time prior to approval of a marketing application for a designated orphan drug, the sponsor holding designation may apply for an amendment to the indication stated in the orphan-drug designation if the proposed change is due to new and unexpected findings in research on the drugs, information arising from FDA recommendations, or unforeseen developments in treatment or diagnosis of the disease or condition.
(b) FDA will grant the amendment if it finds that the initial designation request was made in good faith and that the amendment is intended to conform the orphan-drug designation indication to the results of unanticipated research findings, to unforeseen developments in the treatment or diagnosis of the disease or condition, or to changes based on FDA recommendations, and that, as of the date of the submission of the amendment request, the amendment would not result in exceeding the prevalence or cost recovery thresholds in § 316.21 (a)(1) or (a)(2) upon which the drug was originally designated.
(a) A sponsor may transfer ownership of or any beneficial interest in the orphan-drug designation of a drug to a new sponsor. At the time of the transfer, the new and former owners are required to submit the following information to FDA:
(1) The former owner or assignor of rights shall submit a letter or other document that states that all or some rights to the orphan-drug designation of the drug have been transferred to the new owner or assignee and that a complete copy of the request for orphan-drug designation, including any amendments to the request, supplements to the granted request, and correspondence relevant to the orphan-drug designation, has been provided to the new owner or assignee.
(2) The new owner or assignee of rights shall submit a statement accepting orphan-drug designation and a letter or other document containing the following:
(i) The date that the change in ownership or assignment of rights is effective;
(ii) A statement that the new owner has a complete copy of the request for orphan-drug designation including any amendments to the request, supplements to the granted request, and correspondence relevant to the orphan-drug designation; and
(iii) A specific description of the rights that have been assigned and those that have been reserved. This may be satisfied by the submission of either a list of rights assigned and reserved or copies of all relevant agreements between assignors and assignees; and
(iv) The name and address of a new primary contact person or resident agent.
(b) No sponsor may relieve itself of responsibilities under the Orphan Drug Act or under this part by assigning rights to another person without:
(1) Assuring that the sponsor or the assignee will carry out such responsibilities; or
(2) Obtaining prior permission from FDA.
Each month FDA will update a publically available list of drugs designated as orphan drugs. A cumulative, updated list of all designated drugs will be provided annually. These will be placed on file at the FDA Dockets Management Branch, and will contain the following information:
(a) The name and address of the manufacturer and sponsor;
(b) The generic name and trade name, if any, of the drug and the date of the granting of orphan-drug designation;
(c) The rare disease or condition for which orphan-drug designation was granted; and
(d) The proposed indication for use of the drug.
(a) FDA may revoke orphan-drug designation for any drug if the agency finds that:
(1) The request for designation contained an untrue statement of material fact; or
(2) The request for designation omitted material information required by this part; or
(3) FDA subsequently finds that the drug in fact had not been eligible for orphan-drug designation at the time of submission of the request therefor.
(b) For an approved drug, revocation of orphan-drug designation also suspends or withdraws the sponsor's exclusive marketing rights for the drug but not the approval of the drug's marketing application.
(c) Where a drug has been designated as an orphan drug because the prevalence of a disease or condition (or, in the case of vaccines, diagnostic drugs, or preventive drugs, the target population) is under 200,000 in the United States at the time of designation, its designation will not be revoked on the ground that the prevalence of the disease or condition (or the target population) becomes more than 200,000 persons.
Within 14 months after the date on which a drug was designated as an orphan drug and annually thereafter until marketing approval, the sponsor of a designated drug shall submit a brief progress report to the FDA Office of Orphan Products Development on the drug that includes:
(a) A short account of the progress of drug development including a review of preclinical and clinical studies initiated, ongoing, and completed and a short summary of the status or results of such studies.
(b) A description of the investigational plan for the coming year, as well as any anticipated difficulties in development, testing, and marketing; and
(c) A brief discussion of any changes that may affect the orphan-drug status of the product. For example, for products nearing the end of the approval process, sponsors should discuss any
(a) After approval of a sponsor's marketing application for a designated orphan-drug product for treatment of the rare disease or condition concerning which orphan-drug designation was granted, FDA will not approve another sponsor's marketing application for the same drug before the expiration of 7 years from the date of such approval as stated in the approval letter from FDA, except that such a marketing application can be approved sooner if, and such time as, any of the following occurs:
(1) Withdrawal of exclusive approval or revocation of orphan-drug designation by FDA under any provision of this part; or
(2) Withdrawal for any reason of the marketing application for the drug in question; or
(3) Consent by the holder of exclusive approval to permit another marketing application to gain approval; or
(4) Failure of the holder of exclusive approval to assure a sufficient quantity of the drug under section 527 of the act and § 316.36.
(b) If a sponsor's marketing application for a drug product is determined not to be approvable because approval is barred under section 527 of the act until the expiration of the period of exclusive marketing of another drug product, FDA will so notify the sponsor in writing.
(a) FDA will send the sponsor (or, the permanent-resident agent, if applicable) timely written notice recognizing exclusive approval once the marketing application for a designated orphan-drug product has been approved. The written notice will inform the sponsor of the requirements for maintaining orphan-drug exclusive approval for the full 7-year term of exclusive approval.
(b) When a marketing application is approved for a designated orphan drug that qualifies for exclusive approval, FDA will publish in its publication entitled “Approved Drug Products with Therapeutic Equivalence Evaluations” information identifying the sponsor, the drug, and the date of termination of the orphan-drug exclusive approval. A subscription to this publication and its monthly cumulative supplements is available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325.
(a) Under section 527 of the act, whenever the Director has reason to believe that the holder of exclusive approval cannot assure the availability of sufficient quantities of an orphan drug to meet the needs of patients with the disease or condition for which the drug was designated, the Director will so notify the holder of this possible insufficiency and will offer the holder one of the following options, which must be exercised by a time that the Director specifies:
(1) Provide the Director in writing, or orally, or both, at the Director's discretion, views and data as to how the holder can assure the availability of sufficient quantities of the orphan drug within a reasonable time to meet the needs of patients with the disease or condition for which the drug was designated; or
(2) Provide the Director in writing the holder's consent for the approval of other marketing applications for the same drug before the expiration of the 7-year period of exclusive approval.
(b) If, within the time that the Director specifies, the holder fails to consent to the approval of other marketing applications and if the Director finds that the holder has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated, the Director will issue a written order withdrawing the drug product's exclusive approval. This
Prospective investigators seeking to obtain treatment use of designated orphan drugs may do so as provided in § 312.34 of this chapter.
FDA's Office of Orphan Products Development will maintain and make publicly available a list of guidance documents that apply to the regulations in this part. The list is maintained on the Internet and is published annually in the
(a) FDA will not publicly disclose the existence of a request for orphan-drug designation under section 526 of the act prior to final FDA action on the request unless the existence of the request has been previously publicly disclosed or acknowledged.
(b) Whether or not the existence of a pending request for designation has been publicly disclosed or acknowledged, no data or information in the request are available for public disclosure prior to final FDA action on the request.
(c) Upon final FDA action on a request for designation, FDA will determine the public availability of data and information in the request in accordance with part 20 and § 314.430 of this chapter and other applicable statutes and regulations.
(d) In accordance with § 316.28, FDA will make a cumulative list of all orphan drug designations available to the public and update such list monthly.
(e) FDA will not publicly disclose the existence of a pending marketing application for a designated orphan drug for the use for which the drug was designated unless the existence of the application has been previously publicly disclosed or acknowledged.
(f) FDA will determine the public availability of data and information contained in pending and approved marketing applications for a designated orphan drug for the use for which the drug was designated in accordance with part 20 and § 314.430 of this chapter and other applicable statutes and regulations.
21 U.S.C. 321, 351, 352, 355, 371.
(a)
(b)
(c)
(d)
(e)
(f)
(a) Any person submitting a full new drug application to the Food and Drug Administration (FDA) shall include in the application either:
(1) Evidence measuring the in vivo bioavailability of the drug product that is the subject of the application; or
(2) Information to permit FDA to waive the submission of evidence measuring in vivo bioavailability.
(b) Any person submitting an abbreviated new drug application to FDA shall include in the application either:
(1) Evidence demonstrating that the drug product that is the subject of the abbreviated new drug application is bioequivalent to the reference listed drug (defined in § 314.3(b) of this chapter); or
(2) Information to show that the drug product is bioequivalent to the reference listed drug which would permit FDA to waive the submission of evidence demonstrating in vivo bioequivalence as provided in paragraph (f) of this section.
(c) Any person submitting a supplemental application to FDA shall include in the supplemental application the evidence or information set forth in paragraphs (a) and (b) of this section if the supplemental application proposes any of the following changes:
(1) A change in the manufacturing site or a change in the manufacturing process, including a change in product formulation or dosage strength, beyond the variations provided for in the approved application.
(2) A change in the labeling to provide for a new indication for use of the drug product, if clinical studies are required to support the new indication for use.
(3) A change in the labeling to provide for a new dosage regimen or for an additional dosage regimen for a special patient population, e.g., infants, if clinical studies are required to support the new or additional dosage regimen.
(d) FDA may approve a full new drug application, or a supplemental application proposing any of the changes set forth in paragraph (c) of this section, that does not contain evidence of in vivo bioavailability or information to permit waiver of the requirement for in vivo bioavailability data, if all of the following conditions are met.
(1) The application is otherwise approvable.
(2) The application agrees to submit, within the time specified by FDA, either:
(i) Evidence measuring the in vivo bioavailability and demonstrating the in vivo bioequivalence of the drug product that is the subject of the application; or
(ii) Information to permit FDA to waive measurement of in vivo bioavailability.
(e) Evidence measuring the in vivo bioavailability and demonstrating the in vivo bioequivalence of a drug product shall be obtained using one of the approaches for determining bioavailability set forth in § 320.24.
(f) Information to permit FDA to waive the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence shall meet the criteria set forth in § 320.22.
(g) Any person holding an approved full or abbreviated new drug application shall submit to FDA a supplemental application containing new evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of the drug product that is the subject of the application if notified by FDA that:
(1) There are data demonstrating that the dosage regimen in the labeling is based on incorrect assumptions or facts regarding the pharmacokinetics of the drug product and that following this dosage regimen could potentially result in subtherapeutic or toxic levels; or
(2) There are data measuring significant intra-batch and batch-to-batch variability, e.g., plus or minus 25 percent, in the bioavailability of the drug product.
(h) The requirements of this section regarding the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence apply only to a full or abbreviated new drug application or a supplemental application for a finished dosage formulation.
(a) Any person submitting a full or abbreviated new drug application, or a supplemental application proposing any of the changes set forth in § 320.21(c), may request FDA to waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of the drug product that is the subject of the application. An applicant shall submit a request for waiver with the application. Except as provided in paragraph (f) of this section, FDA shall waive the requirement for the submission of evidence of in vivo bioavailability or bioequivalence if the drug product meets any of the provisions of paragraphs (b), (c), (d), or (e) of this section.
(b) For certain drug products, the in vivo bioavailability or bioequivalence of the drug product may be self-evident. FDA shall waive the requirement for the submission of evidence obtained in vivo measuring the bioavailability or demonstrating the bioequivalence of these drug products. A drug product's in vivo bioavailability or bioequivalence may be considered self-evident based on other data in the application if the product meets one of the following criteria:
(1) The drug product:
(i) Is a parenteral solution intended solely for administration by injection, or an ophthalmic or otic solution; and
(ii) Contains the same active and inactive ingredients in the same concentration as a drug product that is the subject of an approved full new drug application or abbreviated new drug application.
(2) The drug product:
(i) Is administered by inhalation as a gas, e.g., a medicinal or an inhalation anesthetic; and
(ii) Contains an active ingredient in the same dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application.
(3) The drug product:
(i) Is a solution for application to the skin, an oral solution, elixir, syrup, tincture, a solution for aerosolization or nebulization, a nasal solution, or similar other solubilized form; and
(ii) Contains an active drug ingredient in the same concentration and dosage form as a drug product that is the subject of an approved full new drug application or abbreviated new drug application; and
(iii) Contains no inactive ingredient or other change in formulation from the drug product that is the subject of the approved full new drug application or abbreviated new drug application that may significantly affect absorption of the active drug ingredient or active moiety for products that are systemically absorbed, or that may significantly affect systemic or local availability for products intended to act locally.
(c) FDA shall waive the requirement for the submission of evidence measuring the in vivo bioavailability or demonstrating the in vivo bioequivalence of a solid oral dosage form (other than a delayed release or extended release dosage form) of a drug product determined to be effective for at least one indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such a drug product under § 310.6 of this chapter unless FDA has evaluated the drug product under the criteria set forth in § 320.33, included the drug product in the Approved Drug Products with Therapeutic Equivalence Evaluations List, and rated the drug product as having a known or potential bioequivalence problem. A drug product so rated reflects a determination by FDA that an in vivo bioequivalence study is required.
(d) For certain drug products, bioavailability may be measured or bioequivalence may be demonstrated by evidence obtained in vitro in lieu of in
(1) [Reserved]
(2) The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another drug product for which the same manufacturer has obtained approval and the conditions in paragraphs (d)(2)(i) through (d)(2)(iii) of this section are met:
(i) The bioavailability of this other drug product has been measured;
(ii) Both drug products meet an appropriate in vitro test approved by FDA; and
(iii) The applicant submits evidence showing that both drug products are proportionally similar in their active and inactive ingredients.
(iv) Paragraph (d) of this section does not apply to delayed release or extended release products.
(3) The drug product is, on the basis of scientific evidence submitted in the application, shown to meet an in vitro test that has been correlated with in vivo data.
(4) The drug product is a reformulated product that is identical, except for a different color, flavor, or preservative that could not affect the bioavailability of the reformulated product, to another drug product for which the same manufacturer has obtained approval and the following conditions are met:
(i) The bioavailability of the other product has been measured; and
(ii) Both drug products meet an appropriate in vitro test approved by FDA.
(e) FDA, for good cause, may waive a requirement for the submission of evidence of in vivo bioavailability or bioequivalence if waiver is compatible with the protection of the public health. For full new drug applications, FDA may defer a requirement for the submission of evidence of in vivo bioavailability if deferral is compatible with the protection of the public health.
(f) FDA, for good cause, may require evidence of in vivo bioavailability or bioequivalence for any drug product if the agency determines that any difference between the drug product and a listed drug may affect the bioavailability or bioequivalence of the drug product.
(a)(1) The in vivo bioavailability of a drug product is measured if the product's rate and extent of absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, urinary excretion rates, or pharmacological effects, do not indicate a significant difference from the reference material's rate and extent of absorption. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
(2) Statistical techniques used shall be of sufficient sensitivity to detect differences in rate and extent of absorption that are not attributable to subject variability.
(3) A drug product that differs from the reference material in its rate of absorption, but not in its extent of absorption, may be considered to be bioavailable if the difference in the rate of absorption is intentional, is appropriately reflected in the labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug product.
(b) Two drug products will be considered bioequivalent drug products if they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the active moiety under similar experimental conditions, either single dose or multiple dose. Some pharmaceutical
(a) Bioavailability may be measured or bioequivalence may be demonstrated by several in vivo and in vitro methods. FDA may require in vivo or in vitro testing, or both, to measure the bioavailability of a drug product or establish the bioequivalence of specific drug products. Information on bioequivalence requirements for specific products is included in the current edition of FDA's publication “Approved Drug Products with Therapeutic Equivalence Evaluations” and any current supplement to the publication. The selection of the method used to meet an in vivo or in vitro testing requirement depends upon the purpose of the study, the analytical methods available, and the nature of the drug product. Applicants shall conduct bioavailability and bioequivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in paragraph (b) of this section. The method used must be capable of measuring bioavailability or establishing bioequivalence, as appropriate, for the product being tested.
(b) The following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, are acceptable for determining the bioavailability or bioequivalence of a drug product.
(1)(i) An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is measured as a function of time. This approach is particularly applicable to dosage forms intended to deliver the active moiety to the bloodstream for systemic distribution within the body; or
(ii) An in vitro test that has been correlated with and is predictive of human in vivo bioavailability data; or
(2) An in vivo test in humans in which the urinary excretion of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time. The intervals at which measurements are taken should ordinarily be as short as possible so that the measure of the rate of elimination is as accurate as possible. Depending on the nature of the drug product, this approach may be applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section. This method is not appropriate where urinary excretion is not a significant mechanism of elimination.
(3) An in vivo test in humans in which an appropriate acute pharmacological effect of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time if such effect can be measured with sufficient accuracy, sensitivity, and reproducibility. This approach is applicable to the category of dosage forms described in paragraph (b)(1)(i) of this section only when appropriate methods are not available for measurement of the concentration of the moiety, and, when appropriate, its active metabolite(s), in biological fluids or excretory products but a method is available for the measurement of an appropriate acute pharmacological effect. This approach may be particularly applicable to dosage forms that are not intended to deliver the active moiety to the bloodstream for systemic distribution.
(4) Well-controlled clinical trials that establish the safety and effectiveness of the drug product, for purposes of measuring bioavailability, or appropriately designed comparative clinical trials, for purposes of demonstrating bioequivalence. This approach is the least accurate, sensitive, and reproducible of the general approaches for measuring bioavailability or demonstrating bioequivalence. For dosage forms intended to deliver the active
(5) A currently available in vitro test acceptable to FDA (usually a dissolution rate test) that ensures human in vivo bioavailability.
(6) Any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence.
(c) FDA may, notwithstanding prior requirements for measuring bioavailability or establishing bioequivalence, require in vivo testing in humans of a product at any time if the agency has evidence that the product:
(1) May not produce therapeutic effects comparable to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably;
(2) May not be bioequivalent to a pharmaceutical equivalent or alternative with which it is intended to be used interchangeably; or
(3) Has greater than anticipated potential toxicity related to pharmacokinetic or other characteristics.
(a)
(2) An in vivo bioavailability study is generally done in a normal adult population under standardized conditions. In some situations, an in vivo bioavailability study in humans may preferably and more properly be done in suitable patients. Critically ill patients shall not be included in an in vivo bioavailability study unless the attending physician determines that there is a potential benefit to the patient.
(b)
(1) The scientific questions to be answered.
(2) The nature of the reference material and the dosage form to be tested.
(3) The availability of analytical methods.
(4) Benefit-risk considerations in regard to testing in humans.
(c)
(d)
(i) The bioavailability of the formulation proposed for marketing; and
(ii) The essential pharmacokinetic characteristics of the active drug ingredient or therapeutic moiety, such as the rate of absorption, the extent of absorption, the half-life of the therapeutic moiety in vivo, and the rate of excretion and/or metabolism. Dose proportionality of the active drug ingredient or the therapeutic moiety needs to be established after single-dose administration and in certain instances after multiple-dose administration. This characterization is a necessary part of the investigation of the drug to support drug labeling.
(2) The reference material in such a bioavailability study should be a solution or suspension containing the same quantity of the active drug ingredient or therapeutic moiety as the formulation proposed for marketing.
(3) The reference material should be administered by the same route as the
(e)
(i) Measure the bioavailability of the new formulation, new dosage form, or new salt or ester relative to an appropriate reference material; and
(ii) Define the pharmacokinetic parameters of the new formulation, new dosage form, or new salt or ester to establish dosage recommendation.
(2) The selection of the reference material(s) in such a bioavailability study depends upon the scientific questions to be answered, the data needed to establish comparability to a currently marketed drug product, and the data needed to establish dosage recommendations.
(3) The reference material should be taken from a current batch of a drug product that is the subject of an approved new drug application and that contains the same active drug ingredient or therapeutic moiety, if the new formulation, new dosage form, or new salt or ester is intended to be comparable to or to meet any comparative labeling claims made in relation to the drug product that is the subject of an approved new drug application.
(f)
(i) The drug product meets the extended release claims made for it.
(ii) The bioavailability profile established for the drug product rules out the occurrence of any dose dumping.
(iii) The drug product's steady-state performance is equivalent to a currently marketed nonextended release or extended release drug product that contains the same active drug ingredient or therapeutic moiety and that is subject to an approved full new drug application.
(iv) The drug product's formulation provides consistent pharmacokinetic performance between individual dosage units.
(2) The reference material(s) for such a bioavailability study shall be chosen to permit an appropriate scientific evaluation of the extended release claims made for the drug product. The reference material shall be one of the following or any combination thereof:
(i) A solution or suspension of the active drug ingredient or therapeutic moiety.
(ii) A currently marketed noncontrolled release drug product containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labeling of the noncontrolled release drug product.
(iii) A currently marketed extended release drug product subject to an approved full new drug application containing the same active drug ingredient or therapeutic moiety and administered according to the dosage recommendations in the labeling proposed for the extended release drug product.
(iv) A reference material other than one set forth in paragraph (f)(2) (i), (ii) or (iii) of this section that is appropriate for valid scientific reasons.
(g)
(2) The reference material in such a bioavailability study should be two or
(3) The Food and Drug Administration may permit a bioavailability study involving a combination drug product to determine the rate and extent of absorption of selected, but not all, active drug ingredients or therapeutic moieties in the combination drug product. The Food and Drug Administration may permit this determination if the pharmacokinetics and the interactions of the active drug ingredients or therapeutic moieties in the combination drug product are well known and the therapeutic activity of the combination drug product is generally recognized to reside in only one of the active drug ingredients or therapeutic moieties, e.g., ampicillin in an ampicillin-probenecid combination drug product.
(h)
(1) The study measures the therapeutic or acute pharmacological effect of the active drug ingredient or therapeutic moiety; or
(2) The study is a clinical trial to establish the safety and effectiveness of the drug product.
(i)
(2) Samples of the drug product to be tested shall be manufactured using the same equipment and under the same conditions as those used for full-scale production.
(a)
(2) The test product and the reference material should be administered to subjects in the fasting state, unless some other approach is more appropriate for valid scientific reasons.
(b)
(2) Unless some other approach is appropriate for valid scientific reasons, the drug elimination period should be either:
(i) At least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured in the blood or urine; or
(ii) At least three times the half-life of decay of the acute pharmacological effect.
(c)
(i) The peak concentration in the blood of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured; and
(ii) The total area under the curve for a time period at least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured.
(2) In a study comparing oral dosage forms, the sampling times should be identical.
(3) In a study comparing an intravenous dosage form and an oral dosage
(i) The distribution and elimination phase of the intravenous dosage form; and
(ii) The absorption and elimination phase of the oral dosage form.
(4) In a study comparing drug delivery systems other than oral or intravenous dosage forms with an appropriate reference standard, the sampling times should be based on valid scientific reasons.
(d)
(e)
(2) The use of an acute pharmacological effect to determine bioavailability may further require demonstration of dose-related response. In such a case, bioavailability may be determined by comparison of the dose-response curves as well as the total area under the acute pharmacological effect-time curves for any given dose.
(a)
(2) The test product and the reference material should be administered to subjects in the fasting or nonfasting state, depending upon the conditions reflected in the proposed labeling of the test product.
(3) A multiple-dose study may be required to determine the bioavailability of a drug product in the following circumstances:
(i) There is a difference in the rate of absorption but not in the extent of absorption.
(ii) There is excessive variability in bioavailability from subject to subject.
(iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood resulting from a single dose is too low for accurate determination by the analytical method.
(iv) The drug product is an extended release dosage form.
(b)
(2) A multiple-dose study is not required to be of crossover design if the study is to establish dose proportionality under a multiple-dose regimen or to establish the pharmacokinetic profile of a new drug product, a new drug delivery system, or a extended release dosage form.
(3) If a drug elimination period is required, unless some other approach is more appropriate for valid scientific reasons, the drug elimination period should be either:
(i) At least five times the half-life of the active drug ingredient or therapeutic moiety, or its active metabolite(s), measured in the blood or urine; or
(ii) At least five times the half-life of decay of the acute pharmacological effect.
(c)
(d)
(2) Whenever comparison of the test product and the reference material is to be based on cumulative urinary excretion-time curves at steady state, appropriate dosage administration and sampling should be carried out to document attainment of steady state.
(3) A more complete characterization of the blood concentration or urinary excretion rate during the absorption and elimination phases of a single dose administered at steady-state is encouraged to permit estimation of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain pharmacokinetic information, e.g., half-life or blood clearance, that is essential in preparing adequate labeling for the drug product.
(e)
(2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a multiple-dose steady-state study is directly proportional to the fraction of the dose absorbed and is equal to the corresponding “zero to infinity” area under the curve for a single-dose study. Therefore, when steady-state conditions are achieved, a comparison of blood concentrations during a dosing interval may be used to define the fraction of the active drug ingredient or therapeutic moiety absorbed.
(3) Other methods based on valid scientific reasons should be used to determine the bioavailability of a drug product having dose-dependent kinetics (non-linear system).
(f)
Correlation of in vivo bioavailability data with an acute pharmacological effect or clinical evidence of safety and effectiveness may be required if needed to establish the clinical significance of a special claim, e.g., in the case of a extended release preparation.
(a) The analytical method used in an in vivo bioavailability or bioequivalence study to measure the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, or the method used to measure an acute pharmacological effect shall be demonstrated to be accurate and of sufficient sensitivity to measure, with appropriate precision, the actual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), achieved in the body.
(b) When the analytical method is not sensitive enough to measure accurately the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products produced by a single dose of the test product, two or more single doses may be given together to produce higher concentration if the requirements of § 320.31 are met.
(a) The Commissioner of Food and Drugs strongly recommends that, to avoid the conduct of an improper study and unnecessary human research, any person planning to conduct a bioavailability or bioequivalence study submit the proposed protocol for the study to FDA for review prior to the initiation of the study.
(b) FDA may review a proposed protocol for a bioavailability or bioequivalence study and will offer advice with respect to whether the following conditions are met:
(1) The design of the proposed bioavailability or bioequivalence study is appropriate.
(2) The reference material to be used in the bioavailability or bioequivalence study is appropriate.
(3) The proposed chemical and statistical analytical methods are adequate.
(c)(1) General inquiries relating to in vivo bioavailability requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology and Biopharmaceutics (HFD-850), 5600 Fishers Lane, Rockville, MD 20857.
(2) General inquiries relating to bioequivalence requirements and methodology shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Bioequivalence (HFD-650), 7500 Standish Pl., Rockville, MD 20855-2773.
(a) Any person planning to conduct an in vivo bioavailability or bioequivalence study in humans shall submit an “Investigational New Drug Application” (IND) if:
(1) The test product contains a new chemical entity as defined in § 314.108(a) of this chapter; or
(2) The study involves a radioactively labeled drug product; or
(3) The study involves a cytotoxic drug product.
(b) Any person planning to conduct a bioavailability or bioequivalence study in humans using a drug product that contains an already approved, non-new chemical entity shall submit an IND if the study is one of the following:
(1) A single-dose study in normal subjects or patients where either the maximum single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or abbreviated new drug application.
(2) A multiple-dose study in normal subjects or patients where either the single or total daily dose exceeds that specified in the labeling of the drug product that is the subject of an approved new drug application or abbreviated new drug application.
(3) A multiple-dose study on a extended release product on which no single-dose study has been completed.
(c) The provisions of parts 50, 56, and 312 of this chapter are applicable to any bioavailability or bioequivalence study in humans conducted under an IND.
(d) A bioavailability or bioequivalence study in humans other than one described in paragraphs (a) through (c) of this section is exempt from the requirements of part 312 of this chapter if the following conditions are satisfied:
(1) If the study is one described under § 320.38(b) or § 320.63, the person conducting the study, including any contract research organization, shall retain reserve samples of any test article and reference standard used in the study and release the reserve samples to FDA upon request, in accordance with, and for the period specified in, § 320.38; and
(2) An in vivo bioavailability or bioequivalence study in humans shall be conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter, and informed consent set forth in part 50 of this chapter.
(a) The Food and Drug Administration, on its own initiative or in response to a petition by an interested person, may propose and promulgate a regulation to establish a bioequivalence requirement for a product not subject to section 505(j) of the act if it finds there is well-documented evidence that specific pharmaceutical equivalents or pharmaceutical alternatives intended to be used interchangeably for the same therapeutic effect:
(1) Are not bioequivalent drug products; or
(2) May not be bioequivalent drug products based on the criteria set forth in § 320.33; or
(3) May not be bioequivalent drug products because they are members of a class of drug products that have close structural similarity and similar physicochemical or pharmacokinetic properties to other drug products in the same class that FDA finds are not bioequivalent drug products.
(b) FDA shall include in a proposed rule to establish a bioequivalence requirement the evidence and criteria set forth in § 320.33 that are to be considered in determining whether to issue the proposal. If the rulemaking is proposed in response to a petition, FDA shall include in the proposal a summary and analysis of the relevant information that was submitted in the petition as well as other available information to support the establishment of a bioequivalence requirement.
(c) FDA, on its own initiative or in response to a petition by an interested person, may propose and promulgate an amendment to a bioequivalence requirement established under this subpart.
The Commissioner of Food and Drugs shall consider the following factors, when supported by well-documented evidence, to identify specific pharmaceutical equivalents and pharmaceutical alternatives that are not or may not be bioequivalent drug products.
(a) Evidence from well-controlled clinical trials or controlled observations in patients that such drug products do not give comparable therapeutic effects.
(b) Evidence from well-controlled bioequivalence studies that such products are not bioequivalent drug products.
(c) Evidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2-fold difference in median lethal dose (LD
(d) Competent medical determination that a lack of bioequivalence would have a serious adverse effect in the treatment or prevention of a serious disease or condition.
(e) Physicochemical evidence that:
(1) The active drug ingredient has a low solubility in water, e.g., less than 5 milligrams per 1 milliliter, or, if dissolution in the stomach is critical to absorption, the volume of gastric fluids required to dissolve the recommended dose far exceeds the volume of fluids present in the stomach (taken to be 100 milliliters for adults and prorated for infants and children).
(2) The dissolution rate of one or more such products is slow, e.g., less than 50 percent in 30 minutes when tested using either a general method specified in an official compendium or a paddle method at 50 revolutions per minute in 900 milliliters of distilled or deionized water at 37° C, or differs significantly from that of an appropriate reference material such as an identical drug product that is the subject of an approved full new drug application.
(3) The particle size and/or surface area of the active drug ingredient is critical in determining its bioavailability.
(4) Certain physical structural characteristics of the active drug ingredient, e.g., polymorphic forms, conforms, solvates, complexes, and crystal
(5) Such drug products have a high ratio of excipients to active ingredients, e.g., greater than 5 to 1.
(6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic excipients and lubricants, either may be required for absorption of the active drug ingredient or therapeutic moiety or, alternatively, if present, may interfere with such absorption.
(f) Pharmacokinetic evidence that:
(1) The active drug ingredient, therapeutic moiety, or its precursor is absorbed in large part in a particular segment of the gastrointestinal tract or is absorbed from a localized site.
(2) The degree of absorption of the active drug ingredient, therapeutic moiety, or its precursor is poor, e.g., less than 50 percent, ordinarily in comparison to an intravenous dose, even when it is administered in pure form, e.g., in solution.
(3) There is rapid metabolism of the therapeutic moiety in the intestinal wall or liver during the process of absorption (first-class metabolism) so the therapeutic effect and/or toxicity of such drug product is determined by the rate as well as the degree of absorption.
(4) The therapeutic moiety is rapidly metabolized or excreted so that rapid dissolution and absorption are required for effectiveness.
(5) The active drug ingredient or therapeutic moiety is unstable in specific portions of the gastrointestinal tract and requires special coatings or formulations, e.g., buffers, enteric coatings, and film coatings, to assure adequate absorption.
(6) The drug product is subject to dose dependent kinetics in or near the therapeutic range, and the rate and extent of absorption are important to bioequivalence.
(a) If the Commissioner determines that individual batch testing by the Food and Drug Administration is necessary to assure that all batches of the same drug product meet an appropriate in vitro test, he shall include in the bioequivalence requirement a requirement for manufacturers to submit samples of each batch to the Food and Drug Administration and to withhold distribution of the batch until notified by the Food and Drug Administration that the batch may be introduced into interstate commerce.
(b) The Commissioner will ordinarily terminate a requirement for a manufacturer to submit samples for batch testing on a finding that the manufacturer has produced four consecutive batches that were tested by the Food and Drug Administration and found to meet the bioequivalence requirement, unless the public health requires that batch testing be extended to additional batches.
If a bioequivalence requirement specifies a currently available in vitro test or an in vitro bioequivalence standard comparing the drug product to a reference standard, the manufacturer shall conduct the test on a sample of each batch of the drug product to assure batch-to-batch uniformity.
(a) All records of in vivo or in vitro tests conducted on any marketed batch of a drug product to assure that the product meets a bioequivalence requirement shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitted to the Food and Drug Administration on request.
(b) Any person who contracts with another party to conduct a bioequivalence study from which the data are intended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study sufficient accurate financial information to allow the submission of complete and
(a) The applicant of an application or supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioavailability testing was performed under contract, the contract research organization shall retain an appropriately identified reserve sample of the drug product for which the applicant is seeking approval (test article) and of the reference standard used to perform an in vivo bioavailability study in accordance with and for the studies described in paragraph (b) of this section that is representative of each sample of the test article and reference standard provided by the applicant for the testing.
(b) Reserve samples shall be retained for the following test articles and reference standards and for the studies described:
(1) If the formulation of the test article is the same as the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article used to conduct an in vivo bioavailability study comparing the test article to a reference oral solution, suspension, or injection.
(2) If the formulation of the test article differs from the formulation(s) used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article's claimed indications, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to the formulation(s) (reference standard) used in the clinical studies.
(3) For a new formulation, new dosage form, or a new salt or ester of an active drug ingredient or therapeutic moiety that has been approved for marketing, a reserve sample of the test article and of the reference standard used to conduct an in vivo bioequivalence study comparing the test article to a marketed product (reference standard) that contains the same active drug ingredient or therapeutic moiety.
(c) Each reserve sample shall consist of a sufficient quantity to permit FDA to perform five times all of the release tests required in the application or supplemental application.
(d) Each reserve sample shall be adequately identified so that the reserve sample can be positively identified as having come from the same sample as used in the specific bioavailability study.
(e) Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.
(f) Authorized FDA personnel will ordinarily collect reserve samples directly from the applicant or contract research organization at the storage site during a preapproval inspection. If authorized FDA personnel are unable to collect samples, FDA may require the applicant or contract research organization to submit the reserve samples to the place identified in the agency's request. If FDA has not collected
(g) Upon release of the reserve samples to FDA, the applicant or contract research organization shall provide a written assurance that, to the best knowledge and belief of the individual executing the assurance, the reserve samples came from the same samples as used in the specific bioavailability or bioequivalence study identified by the agency. The assurance shall be executed by an individual authorized to act for the applicant or contract research organization in releasing the reserve samples to FDA.
(h) A contract research organization may contract with an appropriate, independent third party to provide storage of reserve samples provided that the sponsor of the study has been notified in writing of the name and address of the facility at which the reserve samples will be stored.
(i) If a contract research organization conducting a bioavailability or bioequivalence study that requires reserve sample retention under this section or § 320.63 goes out of business, it shall transfer its reserve samples to an appropriate, independent third party, and shall notify in writing the sponsor of the study of the transfer and provide the study sponsor with the name and address of the facility to which the reserve samples have been transferred.
The applicant of an abbreviated application or a supplemental application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence testing was performed under contract, the contract research organization shall retain reserve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application. The applicant or contract research organization shall retain the reserve samples in accordance with, and for the period specified in, § 320.38 and shall release the reserve samples to FDA upon request in accordance with § 320.38.
Secs. 201, 301, 501, 502, 503, 505, 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371).
Reference in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b)
(a) Any over-the-counter (OTC) drug product intended for oral ingestion
(b) For any OTC drug product intended for oral ingestion and labeled for use by adults and children 12 years of age and over, the amount of alcohol in the product shall not exceed 10 percent.
(c) For any OTC drug product intended for oral ingestion and labeled for use by children 6 to under 12 years of age, the amount of alcohol in the product shall not exceed 5 percent.
(d) For any OTC drug product intended for oral ingestion and labeled for use by children under 6 years of age, the amount of alcohol in the product shall not exceed 0.5 percent.
(e) The Food and Drug Administration will grant an exemption from paragraphs (b), (c), and (d) of this section where appropriate, upon petition under the provisions of § 10.30 of this chapter. Appropriate cause, such as a specific solubility or manufacturing problem, must be adequately documented in the petition. Decisions with respect to requests for exemption shall be maintained in a permanent file for public review by the Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
(f) Ipecac syrup is exempt from the provisions of paragraph (d) of this section.
(g) The following drugs are temporarily exempt from the provisions of paragraphs (b), (c), and (d) of this section:
(1) Aromatic Cascara Fluidextract.
(2) Cascara Sagrada Fluidextract.
(3) Orally ingested homeopathic drug products.
(a) The amount (percentage) of alcohol present in a product shall be stated in terms of percent volume of absolute alcohol at 60 °F (15.56 °C) in accordance with § 201.10(d)(2) of this chapter.
(b) A statement expressing the amount (percentage) of alcohol present in a product shall appear prominently and conspicuously on the “principal display panel,” as defined in § 201.60 of this chapter. For products whose principal display panel is on the immediate container label and that are not marketed in another retail package (e.g., an outer box), the statement of the percentage of alcohol present in the product shall appear prominently and conspicuously on the “principal display panel” of the immediate container label.
(c) For products whose principal display panel is on the retail package and the retail package is not the immediate container, the statement of the percentage of alcohol present in the product shall also appear on the immediate container label; it may appear anywhere on that label in accord with section 502(e) of the Federal Food, Drug, and Cosmetic Act.
(d) The statement expressing the amount (percentage) of alcohol present in the product shall be in a size reasonably related to the most prominent printed matter on the panel or label on which it appears, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.
(e) For a product to state in its labeling that it is “alcohol free,” it must contain no alcohol (0 percent).
(f) For any OTC drug product intended for oral ingestion containing over 5 percent alcohol and labeled for use by adults and children 12 years of age and over, the labeling shall contain the following statement in the directions section: “Consult a physician for use in children under 12 years of age.”
(g) For any OTC drug product intended for oral ingestion containing over 0.5 percent alcohol and labeled for use by children ages 6 to under 12 years of age, the labeling shall contain the following statement in the directions section: “Consult a physician for use in children under 6 years of age.”
(h) When the direction regarding age in paragraph (e) or (f) of this section differs from an age-limiting direction contained in any OTC drug monograph
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
An over-the-counter (OTC) drug listed in this subchapter is generally recognized as safe and effective and is not misbranded if it meets each of the conditions contained in this part and each of the conditions contained in any applicable monograph. Any product which fails to conform to each of the conditions contained in this part and in an applicable monograph is liable to regulatory action.
(a) The product is manufactured in compliance with current good manufacturing practices, as established by parts 210 and 211 of this chapter.
(b) The establishment(s) in which the drug product is manufactured is registered, and the drug product is listed, in compliance with part 207 of this chapter. It is requested but not required that the number assigned to the product pursuant to part 207 of this chapter appear on all drug labels and in all drug labeling. If this number is used, it shall be placed in the manner set forth in part 207 of this chapter.
(c)(1) The product is labeled in compliance with chapter V of the Federal Food, Drug, and Cosmetic Act (the act) and subchapter C
(2) The “Uses” section of the label and labeling of the product shall contain the labeling describing the “Indications” that have been established in an applicable OTC drug monograph or alternative truthful and nonmisleading statements describing only those indications for use that have been established in an applicable monograph, subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act. Any other labeling under this subchapter and subchapter C
(d) The advertising for the product prescribes, recommends, or suggests its use only under the conditions stated in the labeling.
(e) The product contains only suitable inactive ingredients which are
(f) The product container and container components meet the requirements of § 211.94 of this chapter.
(g) The labeling for all drugs contains the general warning: “Keep out of reach of children.” [highlighted in bold type]. The labeling of drugs shall also state as follows: For drugs used by oral administration, “In case of overdose, get medical help or contact a Poison Control Center right away”; for drugs used topically, rectally, or vaginally and not intended for oral ingestion, “If swallowed, get medical help or contact a Poison Control Center right away”; and for drugs used topically and intended for oral use, “If more than used for” (insert intended use, e.g., pain) “is accidentally swallowed, get medical help or contact a Poison Control Center right away.” The Food and Drug Administration will grant an exemption from these general warnings where appropriate upon petition, which shall be maintained in a permanent file for public review by the Dockets Management Branch, Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
(h) Where no maximum daily dosage limit for an active ingredient is established in this part, it is used in a product at a level that does not exceed the amount reasonably required to achieve its intended effect.
(i) The following terms may be used interchangeably in the labeling of OTC drug products, provided such use does not alter the meaning of the labeling that has been established and identified in an applicable monograph or by regulation. The following terms shall not be used to change in any way the title, headings, and subheadings required under § 201.66(c)(1) through (c)(9) of this chapter:
(1) “Abdominal” or “stomach” (in context only).
(2) “Administer” or “give”.
(3) “Aggravate(s)” or “make(s) worse”.
(4) “Application of this product” or “applying”.
(5) “Are uncertain” or “do not know”.
(6) “Ask” or “consult” or “contact”.
(7) “Asking” or “consulting”.
(8) “Assistance” or “help” or “aid”.
(9) “Associated with” or “due to” or “caused by”.
(10) “Avoid contact with eyes” or “do not get into eyes”.
(11) “Avoid inhaling” or “do not inhale”.
(12) “Before a doctor is consulted” or “without first consulting your doctor” or “consult your doctor before”.
(13) “Beverages” or “drinks”.
(14) “Clean” or “cleanse”.
(15) “Consulting” or “advising”.
(16) “Continue(s)” or “persist(s)” or “is persistent” or “do(es) not go away” or “last(s)”.
(17) “Daily” or “every day”.
(18) “Develop(s)” or “begin(s)” or “occur(s)”.
(19) “Difficulty” or “trouble”.
(20) “Difficulty in urination” or “trouble urinating”.
(21) “Discard” or “throw away”.
(22) “Discontinue” or “stop” or “quit”.
(23) “Doctor” or “physician”.
(24) “Drowsiness” or “the drowsiness effect”.
(25) “Drowsiness may occur” or “you may get drowsy”.
(26) “Enlargement of the” or “an enlarged”.
(27) “Especially in children” or especially children”.
(28) “Exceed” or “use more than” or “go beyond”.
(29) “Exceed recommended dosage” or “use more than directed”.
(30) “Excessive” or “too much”.
(31) “Excitability may occur” or “you may get excited”.
(32) “Experience” or “feel”.
(33) “For relief of” or “relieves”.
(34) “For temporary reduction of” or “temporarily reduces”.
(35) “For the temporary relief of” or “temporarily relieves”.
(36) “For the treatment of” or “treats”.
(37) “Frequently” or “often”.
(38) “Give to” or “use in”.
(39) “Immediately” or “right away” or “directly”.
(40) “Immediately” or “as soon as”.
(41) “Immediately following” or “right after”.
(42) “Improve(s)” or “get(s) better” or “make(s) better”.
(43) “Increased” or “more”.
(44) “Increase your risk of” or “cause”.
(45) “Indication(s)” or “Use(s)”.
(46) “Inhalation” or “puff”.
(47) “In persons who” or “if you” or “if the child”.
(48) “Instill” or “put”.
(49) “Is (are) accompanied by” or “you also have” (in context only) or “(optional: that) occur(s) with”.
(50) “Longer” or “more”.
(51) “Lung” or “pulmonary”.
(52) “Medication(s)” or “medicine(s)” or “drug(s)”.
(53) “Nervousness, dizziness, or sleeplessness occurs” or “you get nervous, dizzy, or sleepless”.
(54) “Not to exceed” or “do not exceed” or “not more than”.
(55) “Obtain(s)” or “get(s)”.
(56) “Passages” or “passageways” or “tubes”.
(57) “Perforation of” or “hole in”.
(58) “Persistent” or “that does not go away” or “that continues” or “that lasts”.
(59) “Per day” or “daily”.
(60) “Presently” or “now”.
(61) “Produce(s)” or “cause(s)”.
(62) “Prompt(ly)” or “quick(ly)” or “right away”.
(63) “Reduce” or “minimize”.
(64) “Referred to as” or “of”.
(65) “Sensation” or “feeling”.
(66) “Solution” or “liquid”.
(67) “Specifically” or “definitely”.
(68) “Take” or “use” or “give”.
(69) “Tend(s) to recur” or “reoccur(s)” or “return(s)” or “come(s) back”.
(70) “To avoid contamination” or “avoid contamination” or “do not contaminate”.
(71) “To help” or “helps”.
(72) “Unless directed by a doctor” or “except under the advice of a doctor” or “unless told to do so by a doctor”.
(73) “Use caution” or “be careful”.
(74) “Usually” or “generally” (in context only).
(75) “You” (“Your”) or “the child” (“the child's”).
(76) “You also have” or “occurs with”.
(77) “When practical” or “if possible”.
(78) “Whether” or “if”.
(79) “Worsen(s)” or “get(s) worse” or “make(s) worse”.
(j) The following connecting terms may be deleted from the labeling of OTC drug products, provided such deletion does not alter the meaning of the labeling that has been established and identified in an applicable monograph or by regulation. The following terms shall not be used to change in any way the specific title, headings, and subheadings required under § 201.66(c)(1) through (c)(9) of this chapter:
(l) “And”.
(2) “As may occur with”.
(3) “Associated” or “to be associated”.
(4) “Consult a doctor”.
(5) “Discontinue use”.
(6) “Drug Interaction Precaution”.
(7) “Due to”.
(8) “Except under the advice and supervision of a physician”.
(9) “If this occurs”.
(10) “In case of”.
(11) “Notice”.
(12) “Or”.
(13) “Occurring with”.
(14) “Or as directed by a doctor”.
(15) “Such as”.
(16) “Such as occurs with”.
(17) “Tends to”.
(18) “This product”.
(19) “Unless directed by a doctor”.
(20) “While taking this product” or “before taking this product”.
(21) “Within”.
A pregnancy-nursing warning for OTC drugs is set forth under § 201.63 of this chapter.
A requirement to imprint an identification code on solid oral dosage form drug products is set forth under part 206 of this chapter.
Monographs promulgated pursuant to the provisions of this part shall be established in this part 330 and following parts and shall cover the following designated categories:
(a) Antacids.
(b) Laxatives.
(c) Antidiarrheal products.
(d) Emetics.
(e) Antiemetics.
(f) Antiperspirants.
(g) Sunburn prevention and treatment products.
(h) Vitamin-mineral products.
(i) Antimicrobial products.
(j) Dandruff products.
(k) Oral hygiene aids.
(l) Hemorrhoidal products.
(m) Hematinics.
(n) Bronchodilator and antiasthmatic products.
(o) Analgesics.
(p) Sedatives and sleep aids.
(q) Stimulants.
(r) Antitussives.
(s) Allergy treatment products.
(t) Cold remedies.
(u) Antirheumatic products.
(v) Ophthalmic products.
(w) Contraceptive products.
(x) Miscellaneous dermatologic products.
(y) Dentifrices and dental products such as analgesics, antiseptics, etc.
(z) Miscellaneous (all other OTC drugs not falling within one of the above therapeutic categories).
For purposes of classifying over-the-counter (OTC) drugs as drugs generally recognized among qualified experts as safe and effective for use and as not misbranded drugs, the following regulations shall apply:
(a)
(2)
I. Label(s) and all labeling (preferably mounted and filed with the other data—facsimile labeling is acceptable in lieu of actual container labeling).
II. A statement setting forth the quantities of active ingredients of the drug.
III. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
IV. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports. Identify expected or frequently reported side effects.
4. Pertinent marketing experiences that may influence a determination as to the safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports. Identify expected or frequently reported side effects.
4. Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports. Identify expected or frequently reported side effects.
4. Pertinent marketing experiences that may influence a determination as to the safety of the finished drug product.
5. Pertinent medical and scientific literature.
V. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports. Identify expected or frequently reported side effects.
4. Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports. Identify expected or frequently reported side effects.
4. Pertinent marketing experiences that may influence a determination on the efficacy of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports. Identify expected or frequently reported side effects.
4. Pertinent marketing experiences that may influence a determination on the efficacy of the finished drug product.
5. Pertinent medical and scientific literature.
VI. A summary of the data and views setting forth the medical rationale and purpose (or lack thereof) for the drug and its ingredients and the scientific basis (or lack thereof) for the conclusion that the drug and its ingredients have been proven safe and effective for the intended use. If there is an absence of controlled studies in the material submitted, an explanation as to why such studies are not considered necessary must be included.
VII. An official United States Pharmacopeia (USP)-National Formulary (NF) drug monograph for the active ingredient(s) or botanical drug substance(s), or a proposed standard for inclusion in an article to be recognized in an official USP-NF drug monograph for the active ingredient(s) or botanical drug substance(s). Include information showing that the official or proposed compendial monograph for the active ingredient or botanical drug substance is consistent with the active ingredient or botanical drug substance used in the studies establishing safety and effectiveness and with the active ingredient or botanical drug substance marketed in the OTC product(s) to a material extent and for a material time. If differences exist, explain why.
(3)
(4)
(i) Safety means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for harm which may result from abuse under conditions of widespread availability. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the drug is safe under the prescribed, recommended, or suggested conditions of use. This proof shall include results of significant human experience during marketing. General recognition of safety shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.
(ii) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed. Proof of effectiveness shall consist of controlled clinical investigations as defined in § 314.126(b) of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the drug or essential to the validity of the investigation and that an alternative method of investigation is adequate to substantiate effectiveness. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered. General recognition of effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.
(iii) The benefit-to-risk ratio of a drug shall be considered in determining safety and effectiveness.
(iv) An OTC drug may combine two or more safe and effective active ingredients and may be generally recognized as safe and effective when each active ingredient makes a contribution to the claimed effect(s); when combining of the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients; and when the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent therapy for a significant proportion of the target population.
(v) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall state the intended uses and results of the product; adequate directions for proper use; and warnings against unsafe use, side effects, and adverse reactions in such terms as to render them likely to be read and understood by the ordinary individual, including individuals of low comprehension, under customary conditions of purchase and use.
(vi) A drug shall be permitted for OTC sale and use by the laity unless, because of its toxicity or other potential for harmful effect or because of the
(5)
(i) A recommended monograph or monographs covering the category of OTC drugs and establishing conditions under which the drugs involved are generally recognized as safe and effective and not misbranded (Category I). This monograph may include any conditions relating to active ingredients, labeling indications, warnings and adequate directions for use, prescription or OTC status, and any other conditions necessary and appropriate for the safety and effectiveness of drugs covered by the monograph.
(ii) A statement of active ingredients, labeling claims or other statements, or other conditions reviewed and excluded from the monograph on the basis of the panel's determination that they would result in the drug's not being generally recognized as safe and effective or would result in misbranding (Category II).
(iii) A statement of active ingredients, labeling claims or other statements, or other conditions reviewed and excluded from the monograph on the basis of the panel's determination that the available data are insufficient to classify such condition under either paragraph (a)(5) (i) or (ii) of this section and for which further testing is therefore required (Category III). The report may recommend the type of further testing required and the time period within which it might reasonably be concluded.
(6)
(i) A monograph or monographs establishing conditions under which a category of OTC drugs or a specific or specific OTC drugs are generally recognized as safe and effective and not misbranded (Category I).
(ii) A statement of the conditions excluded from the monograph on the basis of the Commissioner's determination that they would result in the drug's not being generally recognized as safe and effective or would result in misbranding (Category II).
(iii) A statement of the conditions excluded from the monograph on the basis of the Commissioner's determination that the available data are insufficient to classify such conditions under either paragraph (a)(6)(i) or (ii) of this section (Category III).
(iv) The full report(s) of the panel to the Commissioner. The proposed order shall specify a reasonable period of time within which conditions falling within paragraph (a)(6)(iii) of this section may be continued in marketed products while the data necessary to support them are being obtained for evaluation by the Food and Drug Administration. The summary minutes of the panel meetings shall be made available to interested persons upon request. Any interested person may, within 90 days after publication of the proposed order in the
(7)
(i) After reviewing all comments, reply comments, and any new data and information or, alternatively, after reviewing a panel's recommendations, the Commissioner shall publish in the
(ii) The Commissioner may also publish in the
(iii) Within 12 months after publishing a tentative order pursuant to paragraph (a)(7)(i) of this section, any interested person may file with the Dockets Management Branch, Food and Drug Administration, new data and information to support a condition excluded from the monograph in the tentative order.
(iv) Within 60 days after the final day for submission of new data and information, comments on the new data and information may be filed with the Dockets Management Branch, Food and Drug Administration.
(v) New data and information submitted after the time specified in this paragraph but prior to the establishment of a final monograph will be considered as a petition to amend the monograph and will be considered by the Commissioner only after a final monograph has been published in the
(8)
(9)
(10)
(ii) The Commissioner shall make all decisions and issue all orders pursuant to this section solely on the basis of the administrative record, and shall not consider data or information not included as part of the administrative record.
(iii) The administrative record shall consist solely of the following material: All notices and orders published in the
(11)
(12)
(ii) A new drug application may be submitted in lieu of a petition to amend the OTC drug monograh only if the drug product with the condition that is the subject of the new drug application has not been marketed on an interim basis (such as under the provisions of paragraph (a)(6)(iii) of this section), all clinical testing has been conducted pursuant to a new drug application plan, and no marketing of the
(b)
(c) Information and data submitted under this section shall include, with respect to each nonclinical laboratory study contained in the application, either a statement that the study was conducted in compliance with the good laboratory practice regulations set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.
(d) [Reserved]
(e)
(f)
A new drug application requesting approval of an OTC drug deviating in any respect from a monograph that has become final shall be in the form required by § 314.50 of this chapter, but shall include a statement that the product meets all conditions of the applicable monograph except for the deviation for which approval is requested and may omit all information except that pertinent to the deviation.
(a) There were 420 OTC drugs reviewed in the Drug Efficacy Study (a review of drugs introduced to the market through new drug procedures between 1938 and 1962). A careful review has been made of the reports on these drugs to determine those drugs for which implementation may be deferred without significant risk to the public health, pending review by appropriate OTC drug advisory review panels and promulgation of a monograph.
(b) On and after April 20, 1972, a number of notices were published in the
(1) The requirements of the following DESI announcements are not deferred (the reference document may also pertain to prescription drugs):
(i) Certain Surgical Sutures (DESI 4725), published in the
(ii) Absorbable Dusting Powder (DESI 6264), published in the
(iii) Certain Insulin Preparations (DESI 4286), published in the
(iv) Sulfo-Van Ointment (DESI 2230), published in the
(v) Antiperspirants and Deodorants Containing Neomycin Sulfate (DESI 11048) for which an order revoking provisions for certification or release was published in the
(vi) Thorexin Cough Medicine (DESI 11160) for which a notice of opportunity for hearing was published in the
(vii) Antibiotic susceptibility discs (DESI 90235) for which an order providing for certain discs to be certified and removing provisions for certification of other discs was published in the
(2) Deferral of requirements is not appropriate when an announcement has been published and has been followed by a final order classifying a drug either as lacking substantial evidence of effectiveness or as not shown to be safe. These products will be removed from the market, if they have not already been removed. Regulatory action will also be undertaken against identical, similar and related products (21 CFR 310.6). Deferral of requirements is not appropriate for the following (the referenced document may also pertain to prescription drugs):
(i) Certain Sulfonamide-Decongestant Nasal Preparation (DESI 4850), for which notice of withdrawal of approval of new drug applications was published in the
(ii) Eskay's Theranates, containing strychnine, sodium, and calcium glycerophosphates, thiamine hydrochloride, alcohol, and phosphoric acid (DESI 2220), for which notice of withdrawal of approval of the new drug application was published in the
(iii) The following topical drugs (DESI 1726), for which notice of withdrawal of new drug applications was published in the
(
(
(iv) Menacyl Tablets, containing aspirin, menadione, and ascorbic acid (DESI 6363), for which notice of withdrawal of approval of the new drug application was published in the
(v) Curad Medicated Adhesive Bandage containing sulfathiazole (DESI 4964), for which notice of withdrawal of approval of the new drug application was published in the
(vi) Drugs Containing Rutin, Quercetin, Hesperidin, or any Bioflavonoids (DESI 5960), for which notice of withdrawal of approval of new drug applications was published in the
(vii) Antibiotics in Combination with Other Drugs for Nasal Use (DESI 7561), for which an order revoking provision for certification was published in the
(viii) Antibiotic Troches (DESI 8328), for which an order revoking provision for certification was published in the
(ix) Certain Drugs Containing Oxyphenisatin or Oxyphenisatin Acetate (DESI 10732), for which notices of withdrawal of approval of new drug applications were published in the
(x) Curad Medicated Adhesive Bandage containing tyrothricin-nitrofurazone (DESI 6898), for which an order revoking provision for certification was published March 14, 1972 (37 FR 5294), and confirmed in the
(xi) Candette Cough Gel (DESI 11562), for which notice of withdrawal of approval of the new drug application was published in the
(xii) Certain OTC Multiple-Vitamin Preparations for Oral Use containing excessive amounts of vitamin D and/or vitamin A (DESI 97), for which notice of withdrawal of approval of the new drug applications was published in the
(xiii) Certain Sulfonamide-Containing Preparations for Topical Ophthalmic or Otic Use (DESI 368, for which a notice of withdrawal of approval was published in the
(xiv) Those parts of the publication entitled “Certain Mouthwash and Gargle Preparations” (DESI 2855) pertaining to Tyrolaris Mouthwash, containing tyrothricin, panthenol, and alcohol, for which an order revoking provision for certification was published in the
(c) Manufacturers and distributors should take notice that the information on OTC drugs provided by the Drug Efficacy Study review is valuable information as to the deficiencies in the data available to support indications for use. They are encouraged to perform studies to obtain adequate evidence of effectiveness for the review of OTC drugs which is already in progress. In the interim it is in the public interest that manufacturers and distributors of all OTC drugs effect changes in their formulations and/or labeling to bring the products into conformity with current medical knowledge and experience.
(d) Manufacturers and distributors of OTC drugs may be reluctant to make appropriate formulation and/or labeling changes for fear of losing the protection of the so-called “grandfather” provisions of the 1938 Federal Food, Drug, and Cosmetic Act (sec. 201(p)(1)) and the 1962 amendments to the act (sec. 107(c) of those amendments). To encourage and facilitate prompt changes, the Food and Drug Administration will not take legal action against any OTC drug, other than those not deferred, based on a charge that the product is a new drug and not grandfathered under the act as a result of the changes if the changes in formulation and/or labeling are of the following kind:
(1) The addition to the labeling of warning, contraindications, side effects, and/or precaution information.
(2) The deletion from the labeling of false, misleading, or unsupported indications for use or claims of effectiveness.
(3) Changes in the components or composition of the drug that will give increased assurance that the drug will have its intended effect, yet not raise or contribute any added safety questions.
(4) Changes in the components or composition of the drug which may reasonably be concluded to improve the safety of the drug, without diminishing its effectiveness.
(e) The forbearance from legal action for lack of grandfather protection is an interim procedure designed to encourage appropriate change in formulation and/or labeling during the time period required to review the various classes of OTC drugs. At such time as an applicable OTC drug monograph becomes effective, the interim procedure will automatically be terminated and any appropriate regulatory action will be initiated.
(a) Before the publication in the
(2) An active ingredient at a dosage level higher than that available in an OTC drug product on December 4, 1975, shall be regarded as a new drug within the meaning of section 201(p) of the act for which an approved new drug application is required.
(b)(1) An OTC drug product that contains: (i) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or
(ii) An active ingredient at a dosage level higher than that available in an OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category I (conditions subject to § 330.10(a)(6)(i)) shall be regarded as a new drug within the meaning of section 201(p) of the act for which an approved new drug application is required if marketed for OTC use prior to the date of publication in the
(2) An OTC drug product covered by paragraph (b)(1) of this section which is marketed after the date of publication in the
(c) An OTC drug product that contains: (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or
(2) An active ingredient at a dosage level higher than that available in any OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category II (conditions subject to § 330.10(a)(6)(ii)), may be marketed only after:
(i) The Center for Drug Evaluation and Research or the Commissioner tentatively determines that the ingredient is generally recognized as safe and effective, and the Commissioner states by notice in the
(ii) The ingredient is determined by the Commissioner to be generally recognized as safe and effective and is included in the appropriate published OTC drug final monograph; or
(iii) A new drug application for the product has been approved.
(d) An OTC drug product that contains: (1) An active ingredient limited, on or after May 11, 1972, to prescription use for the indication and route of administration under consideration by an OTC advisory review panel, and not thereafter exempted from such limitation pursuant to § 310.200 of this chapter, or
(2) An active ingredient at a dosage level higher than that available in any OTC drug product on December 4, 1975, which ingredient and/or dosage level is classified by the panel in category III (conditions subject to § 330.10(a)(6)(iii)), may be marketed only after:
(i) The Center for Drug Evaluation and Research or the Commissioner tentatively determines that the ingredient is generally recognized as safe and effective, and the Commissioner states by notice in the
(ii) The ingredient is determined by the Commissioner to be generally recognized as safe and effective and is included in the appropriate published OTC drug final monograph; or
(iii) A new drug application for the product has been approved.
(e) This section applies only to conditions under consideration as part of the OTC drug review initiated on May 11, 1972, and evaluated under the procedures set forth in § 330.10. Section 330.14(h) applies to the marketing of all conditions under consideration and evaluated using the criteria and procedures set forth in § 330.14.
(a)
(b)
(1) The condition must be marketed for OTC purchase by consumers. If the condition is marketed in another country in a class of OTC drug products that may be sold only in a pharmacy, with or without the personal involvement of a pharmacist, it must be established that this marketing restriction does not indicate safety concerns about the condition's toxicity or other potentiality for harmful effect, the method of its use, or the collateral measures necessary to its use.
(2) The condition must have been marketed OTC for a minimum of 5 continuous years in the same country and in sufficient quantity, as determined in paragraphs (c)(2)(ii), (c)(2)(iii), and (c)(2)(iv) of this section. Depending on the condition's extent of marketing in only one country with 5 continuous years of marketing, marketing in more than one country may be necessary.
(c)
(1) Basic information about the condition that includes a description of the active ingredient(s) or botanical drug substance(s), pharmacologic class(es), intended OTC use(s), OTC strength(s) and dosage form(s), route(s) of administration, directions for use, and the applicable existing OTC drug monograph(s) under which the condition would be marketed or the request and rationale for creation of a new OTC drug monograph(s).
(i) A detailed chemical description of the active ingredient(s) that includes a full description of the drug substance, including its physical and chemical characteristics, the method of synthesis (or isolation) and purification of the drug substance, and any specifications and analytical methods necessary
(ii) For a botanical drug substance(s), a detailed description of the botanical ingredient (including proper identification of the plant, plant part(s), alga, or macroscopic fungus used; a certificate of authenticity; and information on the grower/supplier, growing conditions, harvest location and harvest time); a qualitative description (including the name, appearance, physical/chemical properties, chemical constituents, active constituent(s) (if known), and biological activity (if known)); a quantitative description of the chemical constituents, including the active constituent(s) or other chemical marker(s) (if known and measurable); the type of manufacturing process (
(iii) Reference to the current edition of the U.S. Pharmacopeia (USP)-National Formulary (NF) or foreign compendiums may help satisfy the requirements in this section.
(2) A list of all countries in which the condition has been marketed. Include the following information for each country. (For a condition that has been marketed OTC in 5 or more countries with a minimum of 5 continuous years of marketing in at least one country, the sponsor may submit information in accordance with paragraph (c)(4) of this section):
(i) How the condition has been marketed (e.g., OTC general sales direct-to-consumer; sold only in a pharmacy, with or without the personal involvement of a pharmacist; dietary supplement; or cosmetic). If the condition has been marketed as a nonprescription pharmacy-only product, establish that this marketing restriction does not indicate safety concerns about its toxicity or other potentiality for harmful effect, the method of its use, or the collateral measures necessary to its use.
(ii) The cumulative total number of dosage units (e.g., tablets, capsules, ounces) sold for each dosage form of the condition. Manufacturers or suppliers of OTC active ingredients may provide dosage unit information as the total weight of active ingredient sold. List the various package sizes for each dosage form in which the condition is marketed OTC. Provide an estimate of the minimum number of potential consumer exposures to the condition using one of the following calculations:
(A) Divide the total number of dosage units sold by the number of dosage units in the largest package size marketed, or
(B) Divide the total weight of the active ingredient sold by the total weight of the active ingredient in the largest package size marketed.
(iii) A description of the population demographics (percentage of various racial/ethnic groups) and the source(s) from which this information has been compiled, to ensure that the condition's use(s) can be reasonably extrapolated to the U.S. population.
(iv) If the use pattern (
(v) A description of the country's system for identifying adverse drug experiences, especially those found in OTC marketing experience, including method of collection if applicable.
(3) A statement of how long the condition has been marketed in each country and how long the current product labeling has been in use, accompanied by a copy of the current product labeling. All labeling that is not in English must be translated to English in accordance with § 10.20(c)(2) of this chapter. State whether the current product labeling has or has not been authorized, accepted, or approved by a regulatory body in each country where the condition is marketed.
(4) For a condition that has been marketed OTC in five or more countries with a minimum of 5 continuous years of marketing in at least one country, the sponsor may select at least five of these countries from which to submit information in accord with paragraphs (c)(2)(i) through (c)(2)(iv) of this section. Selected countries must include the country with a minimum of 5 continuous years of OTC marketing,
(5) A list of all countries where the condition is marketed only as a prescription drug and the reasons why its marketing is restricted to prescription in these countries.
(6) A list of all countries in which the condition has been withdrawn from marketing or in which an application for OTC marketing approval has been denied. Include the reasons for such withdrawal or application denial.
(7) The information requested in paragraphs (c)(2), (c)(2)(i) through (c)(2)(iv), and (c)(3) of this section must be provided in a table format. The labeling required by paragraph (c)(3) of this section must be attached to the table.
(8) For OTC drugs that have been marketed for more than 5 years in the United States under a new drug application, the information requested in paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), (c)(3), and (c)(5) of this section need not be provided.
(d)
(e)
(f)
(1) All data and information listed in § 330.10(a)(2) under the outline “OTC Drug Review Information,” items III through VII.
(2) All serious adverse drug experiences as defined in §§ 310.305 and 314.80 of this chapter, from each country where the condition has been or is currently marketed as a prescription drug or as an OTC drug or product. Provide individual adverse drug experience reports (FDA Form 3500A or equivalent) along with a summary of all serious adverse drug experiences and expected or frequently reported side effects for the condition. Individual reports that are not in English must be translated to English in accordance with § 10.20(c)(2) of this chapter.
(g)
(1) If the agency uses an advisory review panel to evaluate the data, the panel may submit its recommendations in its official minutes of meeting(s) or by a report under the provisions of § 330.10(a)(5).
(2) The agency may act on an advisory review panel's recommendations using the procedures in §§ 330.10(a)(2) and 330.10(a)(6) through (a)(10).
(3) If the condition is initially determined to be generally recognized as safe and effective for OTC use in the United States, the agency will propose to include it in an appropriate OTC drug monograph(s), either by amending an existing monograph(s) or establishing a new monograph(s), if necessary.
(4) If the condition is initially determined not to be generally recognized as safe and effective for OTC use in the United States, the agency will inform the sponsor and other interested parties who have submitted data of its determination by letter, a copy of which will be placed on public display in the docket established in the Dockets Management Branch. The agency will publish a notice of proposed rulemaking to include the condition in § 310.502 of this chapter.
(5) Interested parties will have an opportunity to submit comments and new data. The agency will subsequently publish a final rule (or reproposal if necessary) in the
(h)
(i)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
An over-the-counter antacid product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the following conditions and each of the general conditions established in § 330.1 of this chapter.
(a) The active antacid ingredients of the product consist of one or more of the ingredients permitted in § 331.11 within any maximum daily dosage limit established, each ingredient is included at a level that contributes at least 25 percent of the total acid neutralizing capacity of the product, and the finished product contains at least 5 meq of acid neutralizing capacity as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18. The method established in § 331.20 shall be used to determine the percent contribution of each antacid active ingredient.
(b) This section does not apply to an antacid ingredient specifically added as a corrective to prevent a laxative or constipating effect.
(a) Aluminum-containing active ingredients:
(1) Basic aluminum carbonate gel.
(2) Aluminum hydroxide (or as aluminum hydroxide-hexitol stabilized polymer, aluminum hydroxide-magnesium carbonate codried gel, aluminum hydroxide-magnesium trisilicate codried gel, aluminum-hydroxide sucrose powder hydrated).
(3) Dihydroxyaluminum aminoacetate and dihydroxyaluminum aminoacetic acid.
(4) Aluminum phosphate gel when used as part of an antacid combination product and contributing at least 25 percent of the total acid neutralizing capacity; maximum daily dosage limit is 8 grams.
(5) Dihydroxyaluminum sodium carbonate.
(b) Bicarbonate-containing active ingredients: Bicarbonate ion; maximum daily dosage limit 200 mEq. for persons up to 60 years old and 100 mEq. for persons 60 years or older.
(c) Bismuth-containing active ingredients:
(1) Bismuth aluminate.
(2) Bismuth carbonate.
(3) Bismuth subcarbonate.
(4) Bismuth subgallate.
(5) Bismuth subnitrate.
(d) Calcium-containing active ingredients: Calcium, as carbonate or phosphate; maximum daily dosage limit 160 mEq. calcium (e.g., 8 grams calcium carbonate).
(e) Citrate-containing active ingredients: Citrate ion, as citric acid or salt; maximum daily dosage limit 8 grams.
(f) Glycine (aminoacetic acid).
(g) Magnesium-containing active ingredients:
(1) Hydrate magnesium aluminate activated sulfate.
(2) Magaldrate.
(3) Magnesium aluminosilicates.
(4) Magnesium carbonate.
(5) Magnesium glycinate.
(6) Magnesium hydroxide.
(7) Magnesium oxide.
(8) Magnesium trisilicate.
(h) Milk solids, dried.
(i) Phosphate-containing active ingredients:
(1) Aluminum phosphate; maximum daily dosage limit 8 grams.
(2) Mono or dibasic calcium salt; maximum daily dosage limit 2 grams.
(3) Tricalcium phosphate; maximum daily dosage limit 24 grams.
(j) Potassium-containing active ingredients:
(1) Potassium bicarbonate (or carbonate when used as a component of an effervescent preparation); maximum daily dosage limit 200 mEq. of bicarbonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years or older.
(2) Sodium potassium tartrate.
(k) Sodium-containing active ingredients:
(1) Sodium bicarbonate (or carbonate when used as a component of an effervescent preparation); maximum daily dosage limit 200 mEq. of sodium for persons up to 60 years old and 100 mEq. of sodium for persons 60 years or older, and 200 mEq. of bicarbonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for persons 60 years or older. That part of the warning required by § 330.1(g), which states, “Keep this and all drugs out of the reach of children” is not required on a product which contains only sodium bicarbonate powder and which is intended primarily for other than drug uses.
(2) Sodium potassium tartrate.
(l) Silicates:
(1) Magnesium aluminosilicates.
(2) Magnesium trisilicate.
(m) Tartrate-containing active ingredients. Tartaric acid or its salts; maximum daily dosage limit 200 mEq. (15 grams) of tartrate.
(a) An antacid may contain any generally recognized as safe and effective nonantacid laxative ingredient to correct for constipation caused by the antacid. No labeling claim of the laxative effect may be used for such a product.
(b) An antacid may contain any generally recognized as safe and effective analgesic ingredient(s), if it is indicated for use solely for the concurrent symptoms involved, e.g., headache and acid indigestion, and is marketed in a form intended for ingestion as a solution.
(c) An antacid may contain any generally recognized as safe and effective antiflatulent ingredient if it is indicated for use solely for the concurrent symptoms of gas associated with heartburn, sour stomach or acid indigestion.
To determine the percent contribution of an antacid active ingredient, place an accurately weighed amount of the antacid active ingredient equal to the amount present in a unit dose of the product into a 250-milliliter (mL) beaker. If wetting is desired, add not more than 5 mL of alcohol (neutralized to an apparent pH of 3.5), and mix to wet the sample thoroughly. Add 70 mL of water, and mix on a magnetic stirrer at 300 ±30 r.p.m. for 1 minute. Analyze the acid neutralizing capacity of the sample according to the procedure provided in the United States Pharmacopeia 23/National Formulary 18 and calculate the percent contribution of the antacid active ingredient in the total product as follows:
Percent contribution =(Total mEq. Antacid Active Ingredient×100)/(Total mEq. Antacid Product).
The formulation or mode of administration of certain products may require a modification of the United States Pharmacopeia 23/National Formulary 18 acid neutralizing capacity test. Any proposed modification and the data to support it shall be submitted as a petition under the rules established in § 10.30 of this chapter. All information submitted will be subject to the disclosure rules in part 20 of this chapter.
(a)
(b)
(c)
(1) “Do not take more than (maximum recommended daily dosage, broken down by age groups if appropriate, expressed in units such as tablets or teaspoonfuls) in a 24-hour period, or use the maximum dosage of this product for more than 2 weeks, except under the advice and supervision of a physician.”
(2) For products which cause constipation in 5 percent or more of persons who take the maximum recommended dosage: “May cause constipation.”
(3) For products which cause laxation in 5 percent or more of persons who take the maximum recommended dosage: “May have laxative effect.”
(4) For products containing more than 50 mEq. of magnesium in the recommended daily dosage: “Do not use this product except under the advice and supervision of a physician if you have kidney disease.”
(5) For products containing more than 25 mEq. potassium in the maximum recommended daily dose: “Do not use this product except under the advice and supervision of a physician if you have kidney disease.”
(6) For products containing more than 5 gm per day lactose in a maximum daily dosage: “Do not use this product except under advice and supervision of a physician if you are allergic to milk or milk products.”
(d)
(e)
(f)
(g) [Reserved]
(h) The word “doctor” may be substituted for the word “physician” in any of the labeling statements in this section.
(a) The labeling of the product provided to health professionals (but not to the general public):
(1) Shall contain the neutralizing capacity of the product as calculated using the procedure set forth in United States Pharmacopeia 23/National Formulary 18 expressed in terms of the dosage recommended per minimum
(2) May contain an indication for the symptomatic relief of hyperacidity associated with the diagnosis of peptic ulcer, gastritis, peptic esophagitis, gastric hyperacidity, and hiatal hernia.
(3)
(4)
(ii) Aluminum forms insoluble complexes with phosphate in the gastrointestinal tract, thus decreasing phosphate absorption. Prolonged use of aluminum-containing antacids by normophosphatemic patients may result in hypophosphatemia if phosphate intake is not adequate. In its more severe forms, hypophosphatemia can lead to anorexia, malaise, muscle weakness, and osteomalacia.
(b) Professional labeling for an antacid-antiflatulent combination may contain the information allowed for health professionals for antacids and antiflatulents.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
An over-the-counter antiflatulent product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the following conditions and each of the general conditions established in § 330.1 of this chapter.
As used in this part:
Simethicone; maximum daily dose 500 mg. There is no dosage limitation at this time for professional labeling.
An antiflatulent may contain any generally recognized as safe and effective antacid ingredient(s) if it is indicated for use solely for the concurrent symptoms of gas associated with heartburn, sour stomach or acid indigestion.
(a)
(b)
(1) (Select one of the following: “Alleviates or Relieves”) “the symptoms referred to as gas.”
(2) (Select one of the following: “Alleviates” or “Relieves”) (select one or more of the following: “bloating,” “pressure,” “fullness,” or “stuffed feeling”) “commonly referred to as gas.”
(c)
(a) The labeling of the product provided to health professionals (but not to the general public) may contain as additional indications postoperative gas pain or for use in endoscopic examination.
(b) Professional labeling for an antiflatulent-antacid combination may contain information allowed for health professionals for antacids and antiflatulents.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter first aid antibiotic drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each of the general conditions established in § 330.1.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
The product consists of any of the following active ingredients within the specified concentration established for each ingredient and in the specified dosage form:
(a) Bacitracin ointment containing, in each gram, 500 units of bacitracin in a suitable ointment base.
(b) Bacitracin zinc ointment containing, in each gram, 500 units of bacitracin zinc in a suitable ointment base.
(c) Chlortetracycline hydrochloride ointment containing, in each gram, 30 milligrams of chlortetracycline hydrochloride in a suitable ointment base.
(d) Neomycin sulfate ointment containing, in each gram, 3.5 milligrams of neomycin in a suitable water soluble or oleaginous ointment base.
(e) Neomycin sulfate cream containing, in each gram, 3.5 milligrams of neomycin in a suitable cream base.
(f) Tetracycline hydrochloride ointment containing, in each gram, 30 milligrams of tetracycline hydrochloride in a suitable ointment base.
The following combinations are permitted provided each active ingredient is present within the established concentration and in the specified dosage form, and the product is labeled in accordance with § 333.160.
(a)
(2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:
(i) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B;
(3) Bacitracin-polymyxin B sulfate topical aerosol containing, in each gram, 500 units of bacitracin and 5,000 units of polymyxin B in a suitable vehicle, packaged in a pressurized container with suitable inert gases.
(4) Bacitracin zinc-neomycin sulfate ointment containing, in each gram, 500 units of bacitracin and 3.5 milligrams of neomycin in a suitable ointment base.
(5) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:
(i) 400 units of bacitracin, 3 milligrams of neomycin, and 8,000 units of polymyxin B; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B; or
(iii) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of polymyxin B; or
(iv) 500 units of bacitracin, 3.5 milligrams of neomycin, and 10,000 units of polymyxin B;
(6) Bacitracin zinc-polymyxin B sulfate ointment containing, in each gram, 500 units of bacitracin and 10,000 units of polymyxin B in a suitable ointment base.
(7) Bacitracin zinc-polymyxin B sulfate topical aerosol containing, in each gram, 120 units of bacitracin and 2,350 units of polymyxin B in a suitable vehicle, packaged in a pressurized container with suitable inert gases.
(8) Bacitracin zinc-polymyxin B sulfate topical powder containing, in each gram, 500 units of bacitracin and 10,000 units of polymyxin B in a suitable base.
(9) Neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, 3.5 milligrams of neomycin and 5,000 units of polymyxin B in a suitable water miscible base.
(10) Neomycin sulfate-polymyxin B sulfate cream containing, in each gram, 3.5 milligrams of neomycin and 10,000 units of polymyxin B in a suitable vehicle.
(11) Oxytetracycline hydrochloride-polymyxin B sulfate ointment containing, in each gram, 30 milligrams of oxytetracycline and 10,000 units of polymyxin B in a suitable ointment base.
(12) Oxytetracycline hydrochloride-polymyxin B sulfate topical powder containing, in each gram, 30 milligrams of oxytetracycline and 10,000 units of polymyxin B with a suitable filler.
(b)
(1) Bacitracin ointment containing, in each gram, 500 units of bacitracin and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable ointment base.
(2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:
(i) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient.
(3) Bacitracin-polymyxin B sulfate topical aerosol containing, in each gram, 500 units of bacitracin and 5,000 units of polymyxin B and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable vehicle, packaged in a pressurized container with suitable inert gases.
(4) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment containing, in each gram, in a suitable ointment base the following:
(i) 400 units of bacitracin, 3 milligrams of neomycin, 8,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or
(ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or
(iii) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient; or
(iv) 500 units of bacitracin, 3.5 milligrams of neomycin, 10,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient;
(5) Bacitracin zinc-polymyxin B sulfate ointment containing, in each gram, 500 units of bacitracin, 10,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local anesthetic active ingredient in a suitable ointment base.
(6) Neomycin sulfate-polymyxin B sulfate cream containing, in each gram, 3.5 milligrams of neomycin, 10,000 units of polymyxin B, and any single generally recognized as safe and effective amine or “caine”-type local
(a)
(b)
(c)
(1) “For external use only. Do not use in the eyes or apply over large areas of the body. In case of deep or puncture wounds, animal bites, or serious burns, consult a doctor.”
(2)
(3)
(d)
(2)
(3)
(e) The word “doctor” may be substituted for the word “physician” in any of the labeling statements in this subpart.
Statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.
(a)
(b)
(1)
(2)
(c)
(d)
(a) An over-the-counter antifungal drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each general condition established in § 330.1 of this chapter.
(b) Reference in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
(a)
(b)
(c)
(d)
(e)
(f)
The active ingredient of the product consists of any one of the following within the specified concentration established for each ingredient:
(a) Clioquinol 3 percent.
(b) Haloprogin 1 percent.
(c) Miconazole nitrate 2 percent.
(d) Povidone-iodine 10 percent.
(e) Tolnaftate 1 percent.
(f) Undecylenic acid, calcium undecylenate, copper undecylenate, and zinc undecylenate may be used individually or in any ratio that provides a total undecylenate concentration of 10 to 25 percent.
(g) Clotrimazole 1 percent.
(a)
(b)
(1)
(A) “Athlete's foot,” athlete's foot (dermatophytosis),” “athlete's foot (tinea pedis),” or “tinea pedis (athlete's foot)”;
(B) “Jock itch,” “jock itch (tinea cruris),” or “tinea cruris (jock itch)”; or
(C) “Ringworm,” “ringworm (tinea corporis),” or “tinea corporis (ringworm).”)
(ii) In addition to the information identified in paragraph (b)(1)(i) of this section, the labeling of the product may contain the following statement: (Select one of the following: “Relieves,” “For relief of,” “For effective relief of,” or “Soothes,”) (select one or more of the following: “Itching,” “scaling,” “cracking,” “burning,” “redness,” “soreness,” “irritation,” “discomfort,” “chafing associated with jock itch,” “itchy, scaly skin between the toes,” or “itching, burning feet”).
(2)
(ii) In addition to the information identified in paragraph (b)(2)(i) of this section, the labeling of the product may contain the following statement: “Clears up most athlete's foot infection and with daily use helps keep it from coming back.”
(c)
(1)
(ii) “For external use only.”
(iii) “Avoid contact with the eyes.”
(2)
(3)
(4)
(5)
(ii) “Do not use for diaper rash.”
(d)
(1)
(2)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
The labeling provided to health professionals (but not to the general public) may contain the following additional indication:
(a)
(b) [Reserved]
(a) An over-the-counter acne drug product in a form suitable for topical application is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each general condition established in § 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
(a)
(b)
(c)
(d)
(e)
(f)
The active ingredient of the product consists of any of the following when labeled according to § 333.350.
(a) Resorcinol 2 percent when combined in accordance with § 333.320(a).
(b) Resorcinol monoacetate 3 percent when combined in accordance with § 333.320(b).
(c) Salicylic acid 0.5 to 2 percent.
(d) Sulfur 3 to 10 percent.
(e) Sulfur 3 to 8 percent when combined in accordance with § 333.320.
(a) Resorcinol identified in § 333.310(a) when combined with sulfur identified in § 333.310(e) provided the product is labeled according to § 333.350.
(b) Resorcinol monoacetate identified in § 333.310(b) when combined with sulfur identified in § 333.310(e) provided the product is labeled according to § 333.350.
(a)
(b)
(1) “For the” (select one of the following: “management” or “treatment”) “of acne.”
(2) In addition to the information identified in paragraph (b)(1) of this section, the labeling of the product may contain any one or more of the following statements:
(i) (Select one of the following: “Clears,” “Clears up,” “Clears up most,” “Dries,” “Dries up,” “Dries and clears,” “Helps clear,” “Helps clear up,” “Reduces the number of,” or “Reduces the severity of”) (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”) which may be followed by “and allows skin to heal.”
(ii) “Penetrates pores to” (select one of the following: “eliminate most,” “control,” “clear most,” or “reduce the number of”) (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”).
(iii) “Helps keep skin clear of new” (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”).
(iv) “Helps prevent new” (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”) which may be followed by “from forming.”
(v) “Helps prevent the development of new” (select one or more of the following: “acne blemishes,” “acne pimples,” “blackheads,” or “whiteheads”).
(c)
(1)
(ii) “Using other topical acne medications at the same time or immediately following use of this product may increase dryness or irritation of the skin. If this occurs, only one medication should be used unless directed by a doctor.”
(2)
(3)
(d)
(1) “Cleanse the skin thoroughly before applying medication. Cover the entire affected area with a thin layer one to three times daily. Because excessive drying of the skin may occur, start
(2) The directions described in paragraph (d)(1) of this section are intended for products that are applied and left on the skin. Other products, such as soaps or masks, may be applied and removed and should have appropriate directions.
(3)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter antiemetic drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
The active ingredient of the product consists of any of the following when used within the dosage limits established for each ingredient in § 336.50(d):
(a) Cyclizine hydrochloride.
(b) Dimenhydrinate.
(c) Diphenhydramine hydrochloride.
(d) Meclizine hydrochloride.
(a)
(b)
(c)
(1)
(ii)
(2)
(3)
(4)
(5)
(6)
(7)
(d)
(1)
(2)
(3)
(4)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
At 67 FR 72559, Dec. 6, 2002, § 336.50 was amended by adding paragraph (c)(8), effective Dec. 8, 2003. For the convenience of the user, the added text is set forth as follows:
(c) * * *
(8)
The labeling provided to health professionals (but not to the general public) may contain the following additional indications.
(a)
(b)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter nighttime sleep-aid drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
The active ingredient of the product consists of any of the following when used within the dosage limits established for each ingredient in § 338.50(d):
(a) Diphenhydramine hydrochloride.
(b) Diphenhydramine citrate.
(a)
(b)
(1) (“Helps you” or “Reduces time to”) “fall asleep if you have difficulty falling asleep.”
(2) “For relief of occasional sleeplessness.”
(3) “Helps to reduce difficulty falling asleep.”
(c)
(1) “Do not give to children under 12 years of age.”
(2) “If sleeplessness persists continuously for more than 2 weeks, consult your doctor. Insomnia may be a symptom of serious underlying medical illness.”
(3) “Do not take this product, unless directed by a doctor, if you have a breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due to enlargement of the prostate gland.”
(4) “Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor.”
(d)
(1)
(2)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
At 67 FR 72559, Dec. 6, 2002, § 338.50 was amended by adding paragraph (c)(5), effective Dec. 8, 2003. For the convenience of the user, the added text is set forth as follows:
(c) * * *
(5) “Do not use [bullet]
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter stimulant drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
The active ingredient of the product consists of caffeine when used within the dosage limits established in § 340.50(d).
(a)
(b)
(c)
(1) “The recommended dose of this product contains about as much caffeine as a cup of coffee. Limit the use of caffeine-containing medications, foods, or beverages while taking this product because too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heart beat.”
(2) “For occasional use only. Not intended for use as a substitute for sleep. If fatigue or drowsiness persists or continues to recur, consult a” (select one of the following: “physician” or “doctor”).
(3) “Do not give to children under 12 years of age.”
(d)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter cold, cough, allergy, bronchodilator, or antiasthmatic drug product in a form suitable for oral, inhalant, or topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
The active ingredient of the product consists of any of the following when used within the dosage limits established for each ingredient:
(a) Brompheniramine maleate.
(b) Chlorcyclizine hydrochloride.
(c) Chlorpheniramine maleate.
(d) Dexbrompheniramine maleate.
(e) Dexchlorpheniramine maleate.
(f) Diphenhydramine citrate.
(g) Diphenhydramine hydrochloride.
(h) Doxylamine succinate.
(i) Phenindamine tartrate.
(j) Pheniramine maleate.
(k) Pyrilamine maleate.
(l) Thonzylamine hydrochloride.
(m) Triprolidine hydrochloride.
The active ingredients of the product consist of any of the following when used within the dosage limits and in the dosage forms established for each ingredient in § 341.74(d):
(a)
(2)
(i) Codeine.
(ii) Codeine phosphate.
(iii) Codeine sulfate.
(3) Dextromethorphan.
(4) Dextromethorphan hydrobromide.
(5) Diphenhydramine citrate.
(6) Diphenhydramine hydrochloride.
(b)
(1) Camphor.
(2) Menthol.
The active ingredients of the product consist of any of the following when used within the dosage limits established for each ingredient:
(a) Ephedrine.
(b) Ephedrine hydrochloride.
(c) Ephedrine sulfate.
(d) Epinephrine.
(e) Epinephrine bitartrate.
(f) Racephedrine hydrochloride.
(g) Racepinephrine hydrochloride.
The active ingredient of the product is guaifenesin when used within the dosage limits established in § 341.78(d).
The active ingredient of the product consists of any of the following when used within the dosage limits and in
(a)
(2) Pseudoephedrine hydrochloride.
(3) Pseudoephedrine sulfate.
(b)
(2) Ephedrine.
(3) Ephedrine hydrochloride.
(4) Ephedrine sulfate.
(5) [Reserved]
(6) Naphazoline hydrochloride.
(7) Oxymetazoline hydrochloride.
(8) Phenylephrine hydrochloride.
(9) Propylhexedrine.
(10) Xylometazoline hydrochloride.
The following combinations are permitted provided each active ingredient is present within the dosage limits established in parts 341, 343, and 356 of this chapter and the product is labeled in accordance with §§ 341.70 or 341.85:
(a) Any single antihistamine active ingredient identified in § 341.12 may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(b) Any single antihistamine active ingredient identified in § 341.12 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85.
(c) Any single antihistamine active ingredient identified in § 341.12 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(d) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).
(e) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) and any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).
(f) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85(c)(4). Diphenhydramine citrate in §§ 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in §§ 341.12(g) and 341.14(a)(6) may be both the antihistamine and the antitussive active ingredient provided that the product is labeled according to § 341.70(a).
(g) Any single antihistamine active ingredient identified in § 341.12(a) through (e) and (h) through (m) may be combined with any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) and any
(h) Any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) may be combined with any single expectorant active ingredient identified in § 341.18 provided that the product is labeled according to § 341.85.
(i) Any single oral antitussive active ingredient identified in § 341.14(a) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85.
(j) Any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any single expectorant active ingredient identified in § 341.18 provided that the product is labeled according to § 341.85.
(k) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient, or any combination of anesthetic/analgesic active ingredients provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth. Menthol in § 341.14(b)(2) and part 356 of this chapter may be both the antitussive and the anesthetic/analgesic active ingredient provided that the product is labeled according to § 341.70(b).
(l) Any single oral antitussive active ingredient identified in § 341.14(a) may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(m) Any single oral antitussive active ingredient identified in § 341.14(a) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(n) Any single oral antitussive active ingredient identified in § 341.14(a)(1) through (a)(4) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any single expectorant active ingredient identified in § 341.18 and any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(o) Any single expectorant active ingredient identified in § 341.18 may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(p) Any single expectorant active ingredient identified in § 341.18 may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) provided that the product is labeled according to § 341.85.
(q) Any single expectorant active ingredient identified in § 341.18 may be
(r) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single analgesic-antipyretic active ingredient, or any combination of acetaminophen with other analgesic-antipyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to § 341.85.
(s) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient identified, or any combination of anesthetic/analgesic active ingredients provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85.
(t) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any single antitussive active ingredient identified in § 341.14(a) or (b)(2) and any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient, or any combination of anesthetic/analgesic active ingredients provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.
(u) Camphor identified in § 341.14(b)(1) may be combined with menthol identified in § 341.14(b)(2) and eucalyptus oil (1.2 to 1.3 percent) provided that the product is available only in a suitable ointment vehicle and provided that the product is labeled according to § 341.85.
(v) Levmetamfetamine identified in § 341.20(b)(1) may be combined with aromatics (camphor (54 milligrams (mg)), menthol (80 mg), methyl salicylate (11 mg), and lavender oil (4 mg)) provided that the product is available only as a nasal inhaler and provided that the product is labeled according to § 341.85.
(w) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.
(x) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85.
(y) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.
(z) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient or any combination of anesthetic/analgesic active ingredients and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is
(aa) Any single oral nasal decongestant active ingredient identified in § 341.20(a) may be combined with any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient or any combination of oral anesthetic/analgesic active ingredients and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85.
(bb) Any single antitussive active ingredient identified in § 341.14(a) or (b)(2) may be combined with any single oral nasal decongestant active ingredient identified in § 341.20(a) and any generally recognized as safe and effective single oral anesthetic/analgesic active ingredient identified or any combination of anesthetic/analgesic active ingredients and any generally recognized as safe and effective single oral demulcent active ingredient provided that the product is available in either a liquid (to be swallowed) or a solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to § 341.85. If the combination contains a topical antitussive, the product must be formulated in a solid dosage form to be dissolved in the mouth.
At 67 FR 78168, Dec. 23, 2002, § 341.40 was added, effective Dec. 23, 2004.
The statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.
(a)
(b) (Reserved)
At 67 FR 78170, Dec. 23, 2002, § 341.70 was amended by adding paragraph (b), effective Dec. 23, 2004. For the convenience of the user, the added text is set forth as follows:
(b)
(a)
(b)
(1) “Temporarily” (select one of the following: “relieves,” “alleviates,” “decreases,” “reduces,” or “dries”) “runny nose and” (select one of the following: “relieves,” “alleviates,” “decreases,” or “reduces”) “sneezing, itching of the nose or throat, and itchy, watery eyes due to hay fever” (which may be followed by one or both of the following: “or other upper respiratory allergies” or “(allergic rhinitis)”).
(2) “For the temporary relief of runny nose, sneezing, itching of the nose or throat, and itchy, watery eyes due to hay fever” (which may be followed by one or both of the following: “or other upper respiratory allergies” or “(allergic rhinitis)”).
(c)
(1) “May cause excitability especially in children.”
(2) “Do not take this product, unless directed by a doctor, if you have a breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due to enlargement of the prostate gland.”
(3)
(4)
(5)
(6)
(i) “Do not give this product to children who have a breathing problem such as chronic bronchitis, or who have glaucoma, without first consulting the child's doctor.”
(ii)
(iii)
(d)
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
At 67 FR 72559, Dec. 6, 2002, § 341.72 was amended by adding paragraphs (c)(6)(iv) and (c)(7), effective Dec. 8, 2003. For the convenience of the user, the added text is set forth as follows:
(c) * * *
(6) * * *
(iv)
(7)
(a)
(b)
(1) “Temporarily” (select one of the following: “alleviates,” “calms,” “controls,” “decreases,” “quiets,” “reduces,” “relieves,” or “suppresses”) “cough due to” (select one of the following: “minor bronchial irritation” or “minor throat and bronchial irritation”) (select one of the following: “as
(2) “Temporarily” (select one of the following: “alleviates,” “calms,” “controls,” “decreases,” “quiets,” “reduces,” “relieves,” or “suppresses”) “cough” (select one of the following: “as may occur with,” “associated with,” or “occurring with”) (select one of the following: “A cold,” “the common cold,” or “inhaled irritants”).
(3) In addition to the required information identified in paragraphs (b) (1) and (2) of this section, the labeling of the product may contain any (one or more) of the following statements:
(i) “Cough suppressant which temporarily” (select one of the following: “Alleviates,” “controls,” “decreases,” “reduces,” “relieves,” or “suppresses”) “the impulse to cough.”
(ii) “Temporarily helps you cough less.”
(iii) “Temporarily helps to” (select one of the following: “Alleviate,” “control,” “decrease,” “reduce,” “relieve,” or “suppress”) “the cough reflex that causes coughing.”
(iv) “Temporarily” (select one of the following: “Alleviates,” “controls,” “decreases,” “reduces,” “relieves,” or “suppresses”) “the intensity of coughing.”
(v) (Select one of the following: “Alleviates,” “Controls,” “Decreases,” “Reduces,” “Relieves,” or “Suppresses”) (select one of the following: “Cough,” “the impulse to cough,” or “your cough”) “to help you” (select one of the following: “Get to sleep,” “sleep,” or “rest”).
(vi)
(vii)
(
(c)
(1)
(2)
(3)
(4)
(ii)
(iii)
(iv)
(v)
(vi)
(vii)
(viii)
(B) “May cause marked drowsiness. Sedatives and tranquilizers may increase the drowsiness effect. Do not give this product to children who are taking sedatives or tranquilizers, without first consulting the child's doctor.”
(ix)
(B) “May cause marked drowsiness; alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery.”
(5)
(ii)
(iii)
(iv)
(v)
(vi)
(vii)
(d)
(1)
(ii)
(iii)
(iv)
(v)
(2)
(ii)
(iii)
(iv)
(v)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
(f)
At 67 FR 72559, Dec. 6, 2002, § 341.74 was amended by adding paragraphs (c)(4)(viii)(C) and (c)(4)(ix)(C), effective Dec. 8, 2003. For the convenience of the user, the added text is set forth as follows:
(c) * * *
(4) * * *
(viii) * * *
(C) “Do not use [bullet]
(ix) * * *
(C) “Do not use [bullet] with any other product containing diphenhydramine, even one used on skin”.
(a)
(b)
(1) “For temporary relief of shortness of breath, tightness of chest, and wheezing due to bronchial asthma.”
(2) In addition to the required information identified in paragraph (b)(1) of this section, the labeling of the product may contain one or more of the following statements:
(i) “For the” (select one of the following: “temporary relief” or “symptomatic control”) “of bronchial asthma.”
(ii) “Eases breathing for asthma patients” (which may be followed by: “by reducing spasms of bronchial muscles”).
(c)
(1) “Do not use this product unless a diagnosis of asthma has been made by a doctor.”
(2) “Do not use this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor.”
(3) “Do not use this product if you have ever been hospitalized for asthma or if you are taking any prescription drug for asthma unless directed by a doctor.”
(4)
(5)
(ii) “Some users of this product may experience nervousness, tremor, sleeplessness, nausea, and loss of appetite. If these symptoms persist or become worse, consult your doctor.”
(6)
(ii) “Do not continue to use this product, but seek medical assistance
(iii)
(d)
(1)
(2)
(a)
(b)
(c)
(1) “A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by a fever, rash, or persistent headache, consult a doctor.”
(2)
(3)
(d)
(e) The word “physician” may be substituted for the word “doctor” in any
(a)
(b)
(1) (Select one of the following: “For the temporary relief of nasal congestion” or “Temporarily relieves nasal congestion”) (which may be followed by any of the following in paragraphs (b)(1) (i), (ii), and (iii) of this section):
(i) “due to” (select one of the following: “the common cold” or “a cold”).
(ii) “due to” (select one of the following: “hay fever,” “hay fever (allergic rhinitis),” “hay fever or other upper respiratory allergies,” or “hay fever or other upper respiratory allergies (allergic rhinitis)”).
(iii) “associated with sinusitis.”
(2) In addition to the information identified in paragraph (b)(1) of this section, the labeling of the product may contain any (one or more) of the following statements:
(i) (Select one of the following: “For the temporary relief of” or “Temporarily relieves”) (select one of the following: “stuffy nose,” “stopped up nose,” “nasal stuffiness,” or “clogged up nose.”)
(ii) (Select one of the following: “Reduces swelling of,” “Decongests,” or “Helps clear”) “nasal passages; shrinks swollen membranes.”
(iii) “Temporarily restores freer breathing through the nose.”
(iv) “Helps decongest sinus openings and passages; temporarily relieves sinus congestion and pressure.”
(v) “Promotes nasal and/or sinus drainage; temporarily relieves sinus congestion and pressure.”
(c)
(1)
(B) “If symptoms do not improve within 7 days or are accompanied by fever, consult a doctor.”
(C) “Do not take this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor.”
(D)
(ii)
(B) “If symptoms do not improve within 7 days or are accompanied by fever, consult a doctor.”
(C) “Do not give this product to a child who has heart disease, high blood
(D)
(iii)
(2)
(B) “This product may cause temporary discomfort such as burning, stinging, sneezing, or an increase in nasal discharge.”
(C) “The use of this container by more than one person may spread infection.”
(ii)
(iii)
(B) “Do not use this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor.”
(iv)
(v)
(vi)
(vii)
(viii)
(B) “Do not use this product in a child who has heart disease, high blood pressure, thyroid disease, or diabetes unless directed by a doctor.”
(ix)
(x)
(d)
(1)
(ii)
(2)
(ii)
(B)
(iii)
(
(B)
(
(iv)
(
(B)
(v)
(
(
(
(B)
(
(
(vi)
(vii)
(
(B)
(
(viii)
(B) “Keep inhaler tightly closed.”
The statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.
(a)
(1)
(2) [Reserved]
(b)
(1)
(i) The labeling for the analgesic-antipyretic ingredients states “[bullet] temporarily relieves [bullet] minor aches and pains [bullet] headache” and “[bullet] temporarily reduces fever”.
(ii) The labeling for the cough-cold ingredient(s) may follow a separate bullet(s) or may be combined with the relieves part of the indication in paragraph (b)(1)(i) of this section.
(2)
(i) The labeling for the analgesic-antipyretic ingredients states “[bullet] temporarily relieves [bullet] minor aches and pains [bullet] headache”.
(ii) The indication(s) for the cough-cold ingredient(s) consists of the labeling for antihistamines in § 341.72(b)(1) or (b)(2) and/or nasal decongestants in § 341.80(b)(1)(ii) and/or (b)(1)(iii), as appropriate, and the labeling for any other cough-cold ingredient present in the combination. This labeling may follow a separate bullet(s) or may be combined with the indication in paragraph (b)(2)(i) of this section.
(3)
(4)
(5)
(6)
(7)
(c)
(1)
(i)
(ii)
(iii)
(2)
(i)
(ii)
(iii)
(3)
(i)
(ii)
(iii)
(4)
(5)
(6)
(d)
(1)
(2)
(3)
At 67 FR 78170, Dec. 23, 2002, § 341.85 was added, effective Dec. 23, 2004.
The labeling of the product provided to health professionals (but not to the general public) may contain the following additional dosage information for products containing the active ingredients identified below:
(a)
(b)
(c)
(2) Parents should be instructed to obtain and use a calibrated measuring device for administering the drug to the child, to use extreme care in measuring the dosage, and not exceed the recommended daily dosage.
(3) A dispensing device (such as a dropper calibrated for age or weight) should be dispensed along with the product when it is intended for use in children 2 to under 6 years of age to prevent possible overdose due to improper measuring of the dose.
(4) Codeine is not recommended for use in children under 2 years of age. Children under 2 years may be more susceptible to the respiratory depressant effects of codeine, including respiratory arrest, coma, and death.
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k)
(l)
(m)
(n)
(o)
(p)
(q)
(r)
(s)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter analgesic-antipyretic drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part in addition to each of the general conditions established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a) Aspirin.
(b) Buffered aspirin. Aspirin identified in paragraph (a) of this section may be buffered with any antacid ingredient(s) identified in § 331.11 of this chapter provided that the finished product contains at least 1.9 milliequivalents of acid-neutralizing capacity per 325 milligrams of aspirin as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18.
(a) Aspirin.
(b) Buffered aspirin. Aspirin identified in paragraph (a) of this section may be buffered with any antacid ingredient(s) identified in § 331.11 of this chapter provided that the finished product contains at least 1.9 milliequivalents of acid-neutralizing capacity per 325 milligrams of aspirin as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18.
Combinations containing aspirin must meet the standards of an acceptable dissolution test, as set forth in § 343.90. The following combinations are permitted: Aspirin identified in §§ 343.12 and 343.13 may be combined with any antacid ingredient identified in § 331.11 of this chapter or any combination of antacids permitted in accordance with § 331.10(a) of this chapter provided that the finished product meets the requirements of § 331.10 of this chapter and is marketed in a form intended for ingestion as a solution.
The labeling of an over-the-counter drug product written for health professionals (but not for the general public) shall consist of the following:
(a)
(1) The labeling contains the following prescribing information under the heading “Comprehensive Prescribing Information” and the subheadings “Description,” “Clinical Pharmacology,” “Clinical Studies,” “Animal Toxicology,” “Indications and Usage,” “Contraindications,” “Warnings,” “Precautions,” “Adverse Reactions,” “Drug Abuse and Dependence,” “Overdosage,” “Dosage and Administration,” and “How Supplied” in the exact language and the exact order provided as follows:
(
At higher doses aspirin is an effective anti-inflammatory agent, partially due to inhibition of inflammatory mediators via cyclo-oxygenase inhibition in peripheral tissues. In vitro studies suggest that other mediators of inflammation may also be suppressed by aspirin administration, although the precise mechanism of action has not been elucidated. It is this nonspecific suppression of cyclo-oxygenase activity in peripheral tissues following large doses that leads to its primary side effect of gastric irritation. (See
The acute oral 50 percent lethal dose in rats is about 1.5 g/kilogram (kg) and in mice 1.1 g/kg. Renal papillary necrosis and decreased urinary concentrating ability occur in rodents chronically administered high doses. Dose-dependent gastric mucosal injury occurs in rats and humans. Mammals may develop aspirin toxicosis associated with GI symptoms, circulatory effects, and central nervous system depression. (See
Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.
Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature. (See
Aspirin is nonnarcotic. There is no known potential for addiction associated with the use of aspirin.
Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 μg/mL. Plasma concentrations of aspirin above 300 μg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 μg/mL. (See
Severity of aspirin intoxication is determined by measuring the blood salicylate level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained.
In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia.
Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children.
Each dose of aspirin should be taken with a full glass of water unless patient is fluid restricted. Anti-inflammatory and analgesic dosages should be individualized. When aspirin is used in high doses, the development of tinnitus may be used as a clinical sign of elevated plasma salicylate levels except in patients with high frequency hearing loss.
(
REV: October 23, 1998.
(2) In addition to, and immediately preceding, the labeling required under paragraph (a)(1) of this section, the professional labeling may contain the following highlights of prescribing information in the exact language and exact format provided, but only when accompanied by the comprehensive prescribing information required in paragraph (a)(1) of this section.
(b) [Reserved]
(a) [Reserved]
(b)
(c)
(d)
(e)
(f)
(g)
(h)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter topical otic drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part in addition to each of the general conditions established in § 330.1.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b)
(c)
(d)
The active ingredient of the product consists of carbamide peroxide 6.5 percent formulated in an anhydrous glycerin vehicle.
The active ingredient of the product consists of isopropyl alcohol 95 percent in an anhydrous glycerin 5 percent base.
(a)
(b)
(c)
(1) “Do not use if you have ear drainage or discharge, ear pain, irritation, or rash in the ear or are dizzy; consult a doctor.”
(2) “Do not use if you have an injury or perforation (hole) of the ear drum or after ear surgery unless directed by a doctor.”
(3) “Do not use for more than 4 days; if excessive earwax remains after use of this product, consult a doctor.”
(4) “Avoid contact with the eyes.”
(d)
(a)
(b)
(c)
(1) “Flammable [in bold type]: Keep away from fire or flame.”
(2) “Do not use [in bold type] in the eyes.”
(3) “Ask a doctor before use if you have [in bold type] [bullet] ear drainage or discharge [bullet] pain, irritation, or rash in the ear [bullet] had ear surgery [bullet] dizziness.”
(4) “Stop use and ask a doctor if [in bold type] irritation (too much burning) or pain occurs.”
(d)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter anorectal drug product in a form suitable for external (topical) or intrarectal (rectal) administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 212 unless otherwise noted.
As used in this part:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
The active ingredient of the product consists of any of the following when used in the concentration or within the concentration range established for each ingredient:
(a) Benzocaine 5 to 20 percent.
(b) Benzyl alcohol 1 to 4 percent.
(c) Dibucaine 0.25 to 1 percent.
(d) Dibucaine hydrochloride 0.25 to 1 percent.
(e) Dyclonine hydrochloride 0.5 to 1 percent.
(f) Lidocaine 2 to 5 percent.
(g) Pramoxine hydrochloride 1 percent.
(h) Tetracaine 0.5 to 1 percent.
(i) Tetracaine hydrochloride 0.5 to 1 percent.
The active ingredient of the product consists of any of the following when used in the concentration or within the concentration range established for each ingredient.
(a) Ephedrine sulfate 0.1 to 1.25 percent.
(b) Epinephrine 0.005 to 0.01 percent.
(c) Epinephrine hydrochloride 0.005 to 0.01 percent.
(d) Phenylephrine hydrochloride 0.25 percent.
(a) The following active ingredients may be used as the sole protectant active ingredient in a product if the ingredient as identified constitutes 50 percent or more by weight of the final product. In addition, the following active ingredients may be used in concentrations of less than 50 percent by weight only when used in combinations in accordance with § 346.22 (a), (b), or (n).
(1) Aluminum hydroxide gel.
(2) Cocoa butter.
(3) Glycerin in a 20- to 45-percent (weight/weight) aqueous solution so that the final product contains not less than 10 and not more than 45 percent glycerin (weight/weight). Any combination product containing glycerin must contain at least this minimum amount of glycerin.
(4) Hard fat.
(5) Kaolin.
(6) Lanolin.
(7) Mineral oil.
(8) Petrolatum.
(9) Topical starch.
(10) White petrolatum.
(b) The following active ingredients may not be used as a sole protectant ingredient but may be used in combination with one, two, or three other protectant active ingredients in accordance with § 346.22 (a), (b), (n), and (o) and with the following limitations:
(1) Calamine not to exceed 25 percent by weight per dosage unit (based on the zinc oxide content of calamine).
(2) Cod liver oil, provided that the product is labeled so that the amount of the product that is used in a 24-hour period represents a quantity that provides 10,000 U.S.P. units of vitamin A and 400 U.S.P. units of cholecalciferol.
(3) Shark liver oil, provided that the product is labeled so that the amount of the product that is used in a 24-hour period represents a quantity that provides 10,000 U.S.P. units of vitamin A and 400 U.S.P. units of cholecalciferol.
(4) Zinc oxide not to exceed 25 percent by weight per dosage unit.
The active ingredient of the product consists of any of the following when used within the concentration range established for each ingredient:
(a) Camphor 0.1 to 3 percent.
(b) Juniper tar 1 to 5 percent.
(c) Menthol 0.1 to 1 percent.
The active ingredient of the product consists of any of the following when used within the concentration range established for each ingredient:
(a) Calamine, within a concentration range of 5 to 25 percent by weight per dosage unit (based on the zinc oxide content of calamine).
(b) Witch hazel, 10 to 50 percent.
(c) Zinc oxide, within a concentration range of 5 to 25 percent by weight per dosage unit.
The active ingredient of the product consists of any of the following when used within the concentration range established for each ingredient:
(a) Alcloxa 0.2 to 2 percent.
(b) Resorcinol 1 to 3 percent.
(a) Any two, three, or four protectants identified in § 346.14(a) may be combined, except aluminum hydroxide gel in § 346.14(a)(1) and kaolin in § 346.14(a)(5) may not be combined with any ingredient in § 346.14(a) (2), (4), (6), (7), (8) and (10), and (b) (2) and (3), provided that the combined percentage by weight of all protectants in the combination is at least 50 percent of the
(b) Any single anorectal ingredient identified in § 346.10, 346.12, 346.16, 346.18, or 346.20 may be combined with up to four protectants in accordance with paragraph (a) of this section.
(c) Any single local anesthetic identified in § 346.10 may be combined with any single vasoconstrictor identified in § 346.12.
(d) Any single local anesthetic identified in § 346.10 may be combined with any single astringent identified in § 346.18.
(e) Any single local anesthetic identified in § 346.10 may be combined with any single keratolytic identified in § 346.20.
(f) Any single vasoconstrictor identified in § 346.12 may be combined with any single astringent identified in § 346.18.
(g) Any single analgesic, anesthetic, and antipruritic identified in § 346.16 may be combined with any single astringent identified in § 346.18.
(h) Any single analgesic, anesthetic, and antipruritic identified in § 346.16 may be combined with any single keratolytic identified in § 346.20.
(i) Any single astringent identified in § 346.18 may be combined with any single keratolytic identified in § 346.20.
(j) Any single local anesthetic identified in § 346.10 may be combined with any single vasoconstrictor identified in § 346.12 and with any single astringent identified in § 346.18.
(k) Any single local anesthetic identified in § 346.10 may be combined with any single astringent identified in § 346.18 and with any single keratolytic identified in § 346.20.
(l) Any single vasoconstrictor identified in § 346.12 may be combined with any single analgesic, anesthetic, and antipruritic identified in § 346.16 and with any single astringent identified in § 346.18.
(m) Any single analgesic, anesthetic, and antipruritic identified in § 346.16 may be combined with any single astringent identified in § 346.18 and with any single keratolytic identified in § 346.20.
(n) Any combination of ingredients listed in paragraphs (c) through (m) of this section may be combined with up to four protectants in accordance with paragraph (a) of this section.
(o) Any product containing calamine for use as a protectant and/or as an astringent and/or containing zinc oxide for use as a protectant and/or as an astringent may not have a total weight of zinc oxide exceeding 25 percent by weight per dosage unit.
The labeling of the product contains the following information for anorectal ingredients identified in §§ 346.10, 346.12, 346.14, 346.16, 346.18, and 346.20, and for combinations of anorectal ingredients identified in § 346.22. Unless otherwise specified, the labeling in this subpart is applicable to anorectal drug products for both external and intrarectal use.
(a)
(b)
(1) (“For the temporary relief of,” “Gives temporary relief of,” or “Helps
(2)
(i)
(ii)
(A) “Temporarily reduces the swelling associated with” (select one of the following: “irritated hemorrhoidal tissue and other anorectal disorders” or “irritation in hemorrhoids and other anorectal disorders”).
(B) “Temporarily shrinks hemorrhoidal tissue.”
(iii)
(A) “Temporarily forms a protective coating over inflamed tissues to help prevent drying of tissues.”
(B) “Temporarily protects irritated areas.”
(C) “Temporarily relieves burning.”
(D) “Provides temporary relief from skin irritations.”
(E) “Temporarily provides a coating for relief of anorectal discomforts.”
(F) “Temporarily protects the inflamed, irritated anorectal surface” (select one of the following: “to help make bowel movements less painful” or “from irritation and abrasion during bowel movement”).
(G) “Temporarily protects inflamed perianal skin.”
(H) “Temporarily relieves the symptoms of perianal skin irritation.”
(iv)
(v)
(A) “For the temporary relief of” (select one or both of the following: “pain” or “burning”).
(B) “Can help distract from pain.”
(C) “May provide a cooling sensation.”
(vi)
(A) “Aids in protecting irritated anorectal areas.”
(B) “Temporary relief of” (select one or both of the following: “irritation” or “burning”).
(vii)
(c)
(1) “If condition worsens or does not improve within 7 days, consult a doctor.”
(2) “Do not exceed the recommended daily dosage unless directed by a doctor.”
(3) “In case of bleeding, consult a doctor promptly.”
(4)
(5)
(6)
(7)
(ii) “Ask a doctor or pharmacist before use if you are [bullet]
(iii)
(8)
(9)
(d)
(1) “
(2)
(3)
(4)
(5)
(6)
(i)
(ii)
(7)
(8)
(9)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
Indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.
(a)
(b)
(c)
(d)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter skin protectant drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b) [Reserved]
The active ingredient of the product consists of any one of the following within the specified concentration established for each ingredient:
(a) Aluminum acetate, 0.13 to 0.5 percent (depending on the formulation and concentration of the marketed product, the manufacturer must provide adequate directions so that the resulting solution to be used by the consumer contains 0.13 to 0.5 percent aluminum acetate).
(b) Aluminum sulfate, 46 to 63 percent (the concentration is based on the anhydrous equivalent).
(c) Witch hazel.
(a)
(b)
(1)
(2)
(3)
(c)
(1) “For external use only. Avoid contact with the eyes.”
(2)
(3)
(d)
(1)
(ii)
(2)
(3)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter external analgesic drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b) [Reserved]
The active ingredient of the product consists of any of the following within the specified concentration established for each ingredient:
(a)
(2) Lidocaine in a metered spray with approximately 10 milligrams per spray.
(b) [Reserved]
(a)
(1)
(2) [Reserved]
(b)
(1)
(ii) “For temporary male genital desensitization, helping to slow the onset of ejaculation.”
(iii) “Helps in temporarily” (select one of the following: “retarding the onset of,” “slowing the onset of,” or “prolonging the time until”) followed by “ejaculation.”
(iv) “For reducing oversensitivity in the male in advance of intercourse.”
(2) [Reserved]
(c)
(1)
(ii) “Avoid contact with the eyes.”
(iii) “If you or your partner develop a rash or irritation, such as burning or itching, discontinue use. If symptoms persist, consult a doctor.”
(2) [Reserved]
(d)
(1)
(ii)
(2) [Reserved]
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter ophthalmic drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in § 330.1.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
The active ingredient and its concentration in the product is as follows: Zinc sulfate, 0.25 percent.
The active ingredients of the product consist of any of the following, within the established concentrations for each ingredient:
(a) Cellulose derivatives:
(1) Carboxymethylcellulose sodium, 0.2 to 2.5 percent.
(2) Hydroxyethyl cellulose, 0.2 to 2.5 percent.
(3) Hydroxypropyl methylcellulose, 0.2 to 2.5 percent.
(4) Methylcellulose, 0.2 to 2.5 percent.
(b) Dextran 70, 0.1 percent when used with another polymeric demulcent agent in this section.
(c) Gelatin, 0.01 percent.
(d) Polyols, liquid:
(1) Glycerin, 0.2 to 1 percent.
(2) Polyethylene glycol 300, 0.2 to 1 percent.
(3) Polyethylene glycol 400, 0.2 to 1 percent.
(4) Polysorbate 80, 0.2 to 1 percent.
(5) Propylene glycol, 0.2 to 1 percent.
(e) Polyvinyl alcohol, 0.1 to 4 percent.
(f) Povidone, 0.1 to 2 percent.
The active ingredients of the product consist of any of the following:
(a) Lanolin preparations:
(1) Anhydrous lanolin, 1 to 10 percent in combination with one or more oleaginous emollient agents included in the monograph.
(2) Lanolin, 1 to 10 percent in combination with one or more oleaginous emollient agents included in the monograph.
(b) Oleaginous ingredients:
(1) Light mineral oil, up to 50 percent in combination with one or more other emollient agents included in the monograph.
(2) Mineral oil, up to 50 percent in combination with one or more other emollient agents included in the monograph.
(3) Paraffin, up to 5 percent in combination with one or more other emollient agents included in the monograph.
(4) Petrolatum, up to 100 percent.
(5) White ointment, up to 100 percent.
(6) White petrolatum, up to 100 percent.
(7) White wax, up to 5 percent in combination with one or more other emollient agents included in the monograph.
(8) Yellow wax, up to 5 percent in combination with one or more other emollient agents included in the monograph.
The active ingredient and its concentration in the product is as follows: Sodium chloride, 2 to 5 percent.
The active ingredient of the product consists of one of the following, within the established concentration for each ingredient:
(a) Ephedrine hydrochloride, 0.123 percent.
(b) Naphazoline hydrochloride, 0.01 to 0.03 percent.
(c) Phenylephrine hydrochloride, 0.08 to 0.2 percent.
(d) Tetrahydrozoline hydrochloride, 0.01 to 0.05 percent.
The active ingredient of the product is purified water. The productalso contains suitable tonicity agents to establish isotonicity with tears,suitable agents for establishing pH and buffering to achieve the same pH astears, and a suitable preservative agent.
The following combinations are permitted provided each active ingredient is present within the established concentration, and the product is labeled in accordance with § 349.79.
(a) Any single ophthalmic astringent active ingredient identified in § 349.10
(b) Any two or three ophthalmic demulcent active ingredients identified in § 349.12 may be combined.
(c) Any single ophthalmic demulcent active ingredient identified in § 349.12 or any ophthalmic demulcent combination identified in paragraph (b) of this section may be combined with any single ophthalmic vasoconstrictor identified in § 349.18.
(d) Any single ophthalmic astringent active ingredient identified in § 349.10 may be combined with any single ophthalmic vasoconstrictor active ingredient identified in § 349.18 and any single ophthalmic demulcent identified in § 349.12 or ophthalmic demulcent combination identified in paragraph (b) of this section.
(e) Any two or more emollient active ingredients identified in § 349.14 may be combined as necessary to give the product proper consistency for application to the eye.
(a) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this part.
(b) Where applicable, indications in this part applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable. Other truthful and nonmisleading statements, describing only the indications for use that have been established and listed in this part, may also be used, as provided in § 330.1(c)(2), subject to the provisions of section 502 of the act relating to misbranding and the prohibition in section 301(d) of the act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the act.
(c) The labeling of the product contains the following warnings, under the heading “Warnings”:
(1)
(2)
(3)
(a)
(b)
(c)
(1) “If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours, discontinue use and consult a doctor.”
(2) “If solution changes color or becomes cloudy, do not use.”
(d)
(a)
(b)
(1) “For the temporary relief of burning and irritation due to dryness of the eye.”
(2) “For the temporary relief of discomfort due to minor irritations of the eye or to exposure to wind or sun.”
(3) “For use as a protectant against further irritation or to relieve dryness of the eye.”
(4) “For use as a lubricant to prevent further irritation or to relieve dryness of the eye.”
(c)
(1) “If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours, discontinue use and consult a doctor.”
(2) “If solution changes color or becomes cloudy, do not use.”
(d)
(a)
(b)
(1) “For the temporary relief of burning and irritation due to dryness of the eye.”
(2) “For the temporary relief of discomfort due to minor irritations of the eye or to exposure to wind or sun.”
(3) “For use as a protectant against further irritation or to relieve dryness of the eye.”
(4) “For use as a lubricant to prevent further irritation or to relieve dryness of the eye.”
(c)
(d)
(a)
(b)
(c)
(1) “Do not use this product except under the advice and supervision of a doctor. If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists, consult a doctor.”
(2) “This product may cause temporary burning and irritation on being instilled into the eye.”
(3) “If solution changes color or becomes cloudy, do not use.”
(d)
(a)
(b)
(c)
(1) “If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours, discontinue use and consult a doctor.”
(2) “Ask a doctor before use if you have [in bold type] narrow angle glaucoma.”
(3) “Overuse of this product may produce increased redness of the eye.”
(4) “If solution changes color or becomes cloudy, do not use.”
(5) “When using this product [in bold type] pupils may become enlarged temporarily.”
(d)
(a)
(b)
(1) “For” (select one of the following: “flushing,” “irrigating,” “cleansing,” “washing,” or “bathing”) “the eye to remove” (select one or more of the following: “loose foreign material,” “air pollutants (smog or pollen),” or “chlorinated water”).
(2) “For” (select one of the following: “flushing,” “irrigating,” “cleansing,” “washing,” or “bathing”) “the eye to help relieve” (select one or more of the following: “irritation,” “discomfort,” “burning,” “stinging,” “smarting,” or “itching”) “by removing” (select one or more of the following: “loose foreign material,” “air pollutants (smog or pollen),” or “chlorinated water”).
(c)
(1) “If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists, consult a doctor.”
(2) “Obtain immediate medical treatment for all open wounds in or near the eyes.”
(3) “If solution changes color or becomes cloudy, do not use.”
(d)
(1)
(2)
Statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.
(a)
(b)
(c)
(d)
The labeling of any OTC ophthalmic demulcent drug product provided to health professionals (but not to the general public) may contain instructions for the use of these products in professional eye examinations (i.e. gonioscopy, electroretinography).
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
At 64 FR 27687, May 21, 1999, part 352 was added, effective May 21, 2001. At 65 FR 36319, June 8, 2000, the effective date was delayed until Dec. 31, 2002. At 66 FR 67485, Dec. 31, 2001, the effective date was stayed until further notice.
(a) An over-the-counter sunscreen drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to Chapter I of Title 21 unless otherwise noted.
As used in this part:
(a)
(b)
(1)
(2)
(3)
(c)
(d)
The active ingredient of the product consists of any of the following, within the concentration specified for each ingredient, and the finished product provides a minimum SPF value of not less than 2 as measured by the testing procedures established in subpart D of this part:
(a) Aminobenzoic acid (PABA) up to 15 percent.
(b) Avobenzone up to 3 percent.
(c) Cinoxate up to 3 percent.
(d) [Reserved]
(e) Dioxybenzone up to 3 percent.
(f) Homosalate up to 15 percent.
(g) [Reserved]
(h) Menthyl anthranilate up to 5 percent.
(i) Octocrylene up to 10 percent.
(j) Octyl methoxycinnamate up to 7.5 percent.
(k) Octyl salicylate up to 5 percent.
(l) Oxybenzone up to 6 percent.
(m) Padimate O up to 8 percent.
(n) Phenylbenzimidazole sulfonic acid up to 4 percent.
(o) Sulisobenzone up to 10 percent.
(p) Titanium dioxide up to 25 percent.
(q) Trolamine salicylate up to 12 percent.
(r) Zinc oxide up to 25 percent.
At 67 FR 41823, June 20, 2002, § 352.10 was amended by revising paragraphs (f) through (n), effective Sept. 1, 2002. This amendment could not be incorporated because at 66 FR 67485, Dec. 31, 2001 the effective date was stayed until further notice. For the convenience of the user, the text is set forth as follows:
(f) Ensulizole up to 4 percent.
(g) Homosalate up to 15 percent.
(h) [Reserved]
(i) Meradimate up to 5 percent.
(j) Octinoxate up to 7.5 percent.
(k) Octisalate up to 5 percent.
(l) Octocrylene up to 10 percent.
(m) Oxybenzone up to 6 percent.
(n) Padimate O up to 8 percent.
The SPF of any combination product is measured by the testing procedures established in subpart D of this part.
(a)
(2) Two or more sunscreen active ingredients identified in § 352.10(b), (c), (e), (f), (i) through (l), (o), and (q) may be combined with each other in a single product when used in the concentrations established for each ingredient in § 352.10. The concentration of each active ingredient must be sufficient to contribute a minimum SPF of not less than 2 to the finished product. The finished product must have a minimum SPF of not less than the number of sunscreen active ingredients used in the combination multiplied by 2.
(b)-(c) [Reserved]
At 67 FR 41823, June 20, 2002, § 352.20 was amended by revising paragraphs (a)(1) through (a)(2), effective Sept. 1, 2002. This amendment could not be incorporated because at 66 FR 67485, Dec. 31, 2001 the effective date was stayed until further notice. For the convenience of the user, the text is set forth as follows:
(a)
(2) Two or more sunscreen active ingredients identified in § 352.10(b), (c), (e), (g), (j) through (m), (o), and (q) may be combined with each other in a single product when used in the concentrations established for each ingredient in § 352.10. The concentration of each active ingredient must be sufficient to contribute a minimum SPF of not less than 2 to the finished product. The finished product must have a minimum SPF of not less than the number of sunscreen active ingredients used in the combination multiplied by 2.
In addition to the statement of identity required in § 352.52, the following labeling statements shall be prominently placed on the principal display panel:
(a)
(2)
(b)
(2) “SPF (insert SPF value of the product, as stated in paragraph (a)(1) or (a)(2) of this section, after it has been tested using the water resistant sunscreen product testing procedures in § 352.76).”
(c)
(2) “SPF (insert SPF value of the product, as stated in paragraph (a)(1) or (a)(2) of this section, after it has been tested using the very water resistant sunscreen product testing procedures in § 352.76).”
(a)
(b)
(1)
(ii)
(iii)
(2)
(i)
(ii)
(iii)
(c)
(1)
(ii) “Stop use and ask a doctor if [bullet] rash or irritation develops and lasts”.
(2)
(d)
(1)
(ii) “[bullet] children under 6 months of age: ask a doctor”.
(2)
(3)
(4)
(e)
(i)
(ii)
(iii)
(2)
(f)
(1) The labeling shall meet the requirements of § 201.66(c) of this chapter except that the title, headings, and information described in § 201.66(c)(1), (c)(3), and (c)(7) may be omitted, and the headings, subheadings, and information described in § 201.66(c)(2), (c)(4), (c)(5), and (c)(6) may be presented as follows:-
(i) The active ingredients (§ 201.66(c)(2) of this chapter) shall be listed in alphabetical order.
(ii) The heading and the indication required by § 201.66(c)(4) may be limited to: “Use [in bold type] helps prevent sunburn.”
(iii) The “external use only” warning in § 201.66(c)(5)(i) of this chapter may be omitted.
(iv) The subheadings in § 201.66(c)(5)(iii) through (c)(5)(vii) of this chapter may be omitted, provided the information after the heading “Warnings” states: “Keep out of eyes.” and “Stop use if skin rash occurs.”
(v) The warning in § 201.66(c)(5)(x) of this chapter may be limited to the following: “Keep out of reach of children.”
(vi) For a lipstick, the warnings “Keep out of eyes” in § 352.52(f)(1)(iv) and “Keep out of reach of children” in § 352.52(f)(1)(v) and the directions in § 352.52(d) may be omitted.
(2) The labeling shall be printed in accordance with the requirements of § 201.66(d) of this chapter except that any requirements related to § 201.66(c)(1), (c)(3), and (c)(7), and the horizontal barlines and hairlines described in § 201.66(d)(8), may be omitted.
Statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable.
(a)
(b)
(1) In addition, the labeling of the product may contain any of the “other allowable statements” that are identified in the applicable monographs.
(2) For permitted combinations containing a sunscreen and a skin protectant identified in § 352.20(b).
(c)
(d)
(a)
(b)
(2) Preparation A and preparation B are heated separately to 77 to 82 °C, with constant stirring, until the contents of each part are solubilized. Add preparation A slowly to preparation B while stirring. Continue stirring until the emulsion formed is cooled to room temperature (15 to 30 °C). Add sufficient purified water to obtain 100 grams of standard sunscreen preparation.
(c)
(1)
(2)
(3)
(4)
(5)
A solar simulator used for determining the SPF of a sunscreen drug product should be filtered so that it provides a continuous emission spectrum from 290 to 400 nanometers similar to sunlight at sea level from the sun at a zenith angle of 10° it has less than 1 percent of its total energy output contributed by nonsolar wavelengths shorter than 290 nanometers; and it has not more than 5 percent of its total energy output contributed by wavelengths longer than 400 nanometers. In addition, a solar simulator should have no significant time-related fluctuations in radiation emissions after an appropriate warmup time, and it should have good beam uniformity (within 10 percent) in the exposure plane. To ensure that the solar simulator delivers the appropriate spectrum of UV radiation, it must be measured periodically with an accurately-calibrated spectroradiometer system or equivalent instrument.
(a)
(2) A medical history shall be obtained from all subjects with emphasis on the effects of sunlight on their skin. Ascertain the general health of the individual, the individual's skin type (I, II, or III), whether the individual is taking medication (topical or systemic) that is known to produce abnormal sunlight responses, and whether the individual is subject to any abnormal responses to sunlight, such as a phototoxic or photoallergic response.
(b)
(c)
(d)
(2)
(e)
(f)
(g)
(h)
(i)
(a)(1) The following erythema action spectrum shall be used to calculate the erythema effective exposure of a solar simulator:
V
V
V
(2) The data contained in this action spectrum are to be used as spectral weighting factors to calculate the erythema effective exposure of a solar simulator as follows:
(b)
(c)
SPF value =the ratio of erythema effective exposure (Joules per square meter) (MED(PS)) to the erythema effective exposure (Joules per square meter) (MED(US)).
(d)
The general testing procedures in § 352.72 shall be used as part of the following tests, except where modified in this section. An indoor fresh water pool, whirlpool, and/or jacuzzi maintained at 23 to 32 °C shall be used in these testing procedures. Fresh water is clean drinking water that meets the standards in 40 CFR part 141. The pool and air temperature and the relative humidity shall be recorded.
(a)
(1) Apply sunscreen product (followed by the waiting period after application of the sunscreen product indicated on the product labeling).
(2) 20 minutes moderate activity in water.
(3) 20-minute rest period (do not towel test sites).
(4) 20 minutes moderate activity in water.
(5) Conclude water test (air dry test sites without toweling).
(6) Begin solar simulator exposure to test site areas as described in § 352.73.
(b)
(1) Apply sunscreen product (followed by the waiting period after application of the sunscreen product indicated on the product labeling).
(2) 20 minutes moderate activity in water.
(3) 20-minute rest period (do not towel test sites).
(4) 20 minutes moderate activity in water.
(5) 20-minute rest period (do not towel test sites).
(6) 20 minutes moderate activity in water.
(7) 20-minute rest period (do not towel test sites).
(8) 20 minutes moderate activity in water.
(9) Conclude water test (air dry test sites without toweling).
(10) Begin solar simulator exposure to test site areas as described in § 352.73.
The formulation or mode of administration of certain products may require modification of the testing procedures in this subpart. In addition, alternative methods (including automated or in vitro procedures) employing the same basic procedures as those described in this subpart may be used. Any proposed modification or alternative procedure shall be submitted as a petition in accord with § 10.30 of this chapter. The petition should contain data to support the modification or data demonstrating that an alternative procedure provides results of equivalent accuracy. All information submitted will be subject to the disclosure rules in part 20 of this chapter.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter anticaries drug product in a form suitable for topical administration to the teeth is generally recognized as safe and effective and is not misbranded if it meets each condition in this part and each general condition established in § 330.1 of this chapter.
(b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this part:
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k)
(l)
(m)
The active ingredient of the product consists of any of the following when used in the concentration and dosage form established for each ingredient:
(a)
(2)
(3)
(ii) An aqueous solution of acidulated phosphate fluoride derived from sodium fluoride acidulated with a mixture of sodium phosphate, dibasic, and phosphoric acid to a pH of 3.5 and which yields an effective fluoride ion concentration of 0.01 percent.
(iii) Sodium fluoride 0.02 percent aqueous solution with a pH of approximately 7.
(iv) Sodium fluoride 0.05 percent aqueous solution with a pH of approximately 7.
(v) Sodium fluoride concentrate containing adequate directions for mixing with water before using to result in a 0.02-percent or 0.05-percent aqueous solution with a pH of approximately 7.
(b)
(2)
(c)
(ii) Stannous fluoride 0.351 to 0.474 percent with an available fluoride ion concentration ≥ 290 ppm for products containing the abrasive calcium pyrophosphate.
(2)
(3)
(a)
(1)
(2)
(3)
(b)
(a)
(b)
(c)
(1)
(2)
(d)
(1)
(ii)
(iii)
(2)
(ii)
(3)
(ii)
(4)
(5)
(e)
(1)
(2)
(f)
(2)
In addition to the statement of identity required in § 355.50, the following statement shall be prominently placed on the principal display panel: “IMPORTANT: Read directions for proper use.”
(a) The labeling for anticaries fluoride treatment rinses identified in § 355.10(a)(3) and (c)(3) that are specially formulated so they may be swallowed (fluoride supplements) and are provided to health professionals (but not to the general public) may contain the following additional dosage information: Children 3 to under 14 years of age: As a supplement in areas where the water supply is nonfluoridated (less than 0.3 parts per million (ppm)), clean the teeth with a toothpaste and rinse with 5 milliliters (mL) of 0.02 percent or 10 mL of 0.01 percent fluoride ion rinse daily, then swallow. When the water supply contains 0.3 to 0.7 ppm fluoride ion, reduce the dose to 2.5 mL of 0.02 percent or 5 mL of 0.01 percent fluoride ion rinse daily.
(b) The labeling for products marketed to health to health professionals in package sizes larger than those specified in § 355.20 shall include the statements: “For Professional Office Use Only” and “This product is not intended for home or unsupervised consumer use.”
(a) A fluoride dentifrice drug product shall meet the biological test requirements for animal caries reduction and one of the following tests: Enamel solubility reduction or fluoride enamel uptake. The testing procedures for these biological tests are labeled
(b) The United States Pharmacopeia fluoride dentifrice reference standards along with reference standard stability profiles (total fluoride, available fluoride ion, pH, and specific gravity) required to be used in the biological tests are available to any purchaser upon written request to the United States Pharmacopeial Convention, Inc., 1260 Twinbrook Parkway, Rockville, MD 20852.
(c) Alternative testing procedures may be used. Any proposed modification or alternative testing procedures shall be submitted as a petition in accord with § 10.30 of this chapter. The petition should contain data to support the modification or data demonstrating that an alternative testing procedure provides results of equivalent accuracy. All information submitted will be subjected to the disclosure rules in part 20 of this chapter.
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter anthelmintic drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this subpart and each general condition established in § 330.1.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
The active ingredient of the product is pyrantel pamoate when used within the dosage limits established in § 357.150(d)(1).
(a)
(b)
(c)
(1) “Abdominal cramps, nausea, vomiting, diarrhea, headache, or dizziness sometimes occur after taking this drug. If any of these conditions persist consult a doctor.”
(2) “If you are pregnant or have liver disease, do not take this product unless directed by a doctor.”
(d)
(1) Adults, children 12 years of age and over, and children 2 years to under 12 years of age: Oral dosage is a single dose of 5 milligrams of pyrantel base per pound, or 11 milligrams per kilogram, of body weight not to exceed 1 gram. Dosing information should be converted to easily understood directions for the consumer using the following dosage schedule:
(2) “Read package insert carefully before taking this medication. Take only according to directions and do not exceed the recommended dosage unless directed by a doctor. Medication should only be taken on time as a single dose; do not repeat treatment unless directed by a doctor. When one individual in a household has pinworms, the entire household should be treated unless otherwise advised. See Warnings. If any worms other than pinworms are present before or after treatment, consult a doctor. If any symptoms or pinworms are still present after treatment, consult a doctor.
(3) “This product can be taken any time of day, with or without meals. It may be taken alone or with milk or fruit juice. Use of a laxative is not necessary prior to, during, or after medication.”
(e)
The labeling of the product contains a consumer package insert which includes the following information:
(a) A discussion of the symptoms suggestive of pinworm infestation, including a statement that pinworms must be visually identified before taking this medication.
(b) A detailed description of how to find and identify the pinworm.
(c) A commentary on the life cycle of the pinworm.
(d) A commentary on the ways in which pinworms may be spread from person to person and hygienic procedures to follow to avoid such spreading.
(e) The appropriate labeling information contained in § 357.150
The labeling provided to health professionals (but not to the general public) may contain an additional indication: “For the treatment of common roundworm infestation.”
(a) An over-the-counter cholecystokinetic drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart in addition to each of the general conditions established in § 330.1.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
The active ingredient of the product consists of any of the following when used within the specified concentration and dosage form established for each ingredient:
(a) 50-percent aqueous emulsion of corn oil.
(b) Hydrogenated soybean oil in a suitable, water-dispersible powder. The hydrogenated soybean oil is food-grade, partially hydrogenated with a melting point of 41 to 43.5 °C, an iodine value of 65 to 69, and a fatty acid composition as follows:
(a)
(b)
(c)
(d)
(1) “Take only when instructed by a doctor:”
(2)
(i) “Shake well before using.”
(ii) Oral dosage is 60 milliliters 20 minutes before diagnostic gallbladder x-ray or as directed by a doctor.
(3)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
The labeling provided to health professionals (but not to the general public) may contain the following information for ingredients identified in § 357.210:
(a) An over-the-counter deodorant drug product for internal use in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each condition in this subpart and each general condition established in § 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
(a)
(b)
(c)
(d)
The active ingredient of the product consists of either of the following when used within the dosage limits established for each ingredient in § 357.850(d):
(a) Bismuth subgallate.
(b) Chlorophyllin copper complex.
(a)
(b)
(1)
(2)
(ii) “An aid to reduce fecal odor due to incontinence.”
(c)
(ii) The warning required by § 330.1(g) of this chapter concerning overdose is not required on products containing
(2) [Reserved]
(d)
(1)
(2)
21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
(a) An over-the-counter wart remover drug product in a form suitable for topical application is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each of the general conditions established in § 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
(a)
(b)
(c)
The product consists of any of the following active ingredients within the specified concentration and in the dosage form established for each ingredient.
(a) Salicylic acid 12 to 40 percent in a plaster vehicle.
(b) Salicylic acid 5 to 17 percent in a collodion-like vehicle.
(c) Salicylic acid 15 percent in a karaya gum, glycol plaster vehicle.
(a)
(b)
(1) “For the removal of common warts. The common wart is easily recognized by the rough ‘cauliflower-like’ appearance of the surface.”
(2) “For the removal of plantar warts on the bottom of the foot. The plantar wart is recognized by its location only on the bottom of the foot, its tenderness, and the interruption of the footprint pattern.”
(c)
(1)
(ii) “Do not use this product on irritated skin, on any area that is infected or reddened, if you are a diabetic, or if you have poor blood circulation.”
(iii) “If discomfort persists, see your doctor.”
(iv) “Do not use on moles, birthmarks, warts with hair growing from them, genital warts, or warts on the face or mucous membranes.”
(2)
(ii) “Keep away from fire or flame.”
(3)
(4)
(ii) “Avoid inhaling vapors.”
(d)
(1)
(2)
(3)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
(f) The phrase “or podiatrist” may be used in addition to the word “doctor” in any of the labeling statements in this section when a product is labeled with the indication identified in § 358.150(b)(2).
(a) An over-the-counter corn and callus remover drug product in a form suitable for topical application is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each of the general conditions established in § 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
(a)
(b)
(c)
The product consists of any of the following active ingredients within the specified concentrations and in the dosage form established for each ingredient.
(a) Salicylic acid 12 to 40 percent in a plaster vehicle.
(b) Salicylic acid 12 to 17.6 percent in a collodion-like vehicle.
(a)
(b)
(1) “For the removal of corns and calluses.”
(2) In addition to the information identified in paragraph (b)(1) of this section, the labeling of the product may contain the following statement: “Relieves pain by removing corns and calluses.”
(c)
(1)
(ii) “Do not use this product on irritated skin, on any area that is infected or reddened, if you are a diabetic, or if you have poor blood circulation.”
(iii) “If discomfort persists, see your doctor or podiatrist.”
(2)
(ii) “Keep away from fire or flame.”
(3)
(4)
(ii) “Avoid inhaling vapors.”
(d)
(1)
(2)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
(a) An over-the-counter pediculicide drug product in a form suitable for topical application is generally recognized as safe and effective and is not misbranded if it meets each condition in this subpart and each general condition established in § 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
The active ingredients of the product consist of the combination of pyrethrum extract (providing a concentration of pyrethrins of 0.17 to 0.33 percent) with piperonyl butoxide (2 to 4 percent) in a nonaerosol dosage formulation.
(a)
(b)
(c)
(1) “Use with caution on persons allergic to ragweed.”
(2) “For external use only. Do not use near the eyes or permit contact with mucous membranes, such as inside the nose, mouth, or vagina, as irritation may occur. Keep out of eyes when rinsing hair. Adults and children: Close eyes tightly and do not open eyes until product is rinsed out. Also, protect children's eyes with washcloth, towel or other suitable material, or by a similar method. If product gets into the eyes, immediately flush with water.”
(3) “If skin irritation or infection is present or develops, discontinue use and consult a doctor. Consult a doctor if infestation of eyebrows or eyelashes occurs.”
(4) The word “physician” may be substituted for the word “doctor” in any of the warning statements in this paragraph.
(d)
(1)
(2)
(3)
(e)
(1) “
(2) “
(3) “
(a) An over-the-counter dandruff, seborrheic dermatitis, or psoriasis drug product in a form suitable for topical application is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this subpart and each general condition established in § 330.1 of this chapter.
(b) References in this subpart to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted.
As used in this subpart:
(a)
(b)
(c)
(d)
(e) Selenium sulfide, micronized. Selenium sulfide that has been finely ground and that has a median particle size of approximately 5 micrometers (μm), with not more than 0.1 percent of the particles greater than 15 μm and not more than 0.1 percent of the particles less than 0.5 μm.
The active ingredient of the product consists of any of the following within the specified concentration established for each ingredient:
(a)
(2) Pyrithione zinc, 0.3 to 2 percent when formulated to be applied and then washed off after brief exposure.
(3) Pyrithione zinc, 0.1 to 0.25 percent when formulated to be applied and left on the skin or scalp.
(4) Salicylic acid, 1.8 to 3 percent.
(5) Selenium sulfide, 1 percent.
(6) Selenium sulfide, micronized, 0.6 percent.
(7) Sulfur, 2 to 5 percent.
(b)
(2) Pyrithione zinc, 0.95 to 2 percent when formulated to be applied and then washed off after brief exposure.
(3) Pyrithione zinc, 0.1 to 0.25 percent when formulated to be applied and left on the skin or scalp.
(4) Salicylic acid, 1.8 to 3 percent.
(5) Selenium sulfide, 1 percent.
(c)
(2) Salicylic acid, 1.8 to 3 percent.
Salicylic acid identified in § 358.710(a) (4) may be combined with sulfur identified in § 358.710(a)(6) provided each ingredient is present within the established concentration and the product is labeled for the control of dandruff.
(a)
(1) “Dandruff (insert product form)” or “antidandruff (insert product form)”.
(2) “Seborrheic dermatitis (insert product form)”.
(3) “Psoriasis (insert product form)”.
(b)
(1) (“For relief of” or “Controls”) “the symptoms of” (select one or more of the following, as appropriate: “dandruff,” “seborrheic dermatitis,” and/or “psoriasis.”)
(2) The following terms or phrases may be used in place of or in addition to the words “For the relief of” or “Controls” in the indications in paragraph (b)(1) of this section: “fights,” “reduces,” “helps eliminate,” “helps stop,” “controls recurrence of,” “fights recurrence of,” “helps prevent recurrence of,” “reduces recurrence of,” “helps eliminate recurrence of,” “helps stop recurrence of.”
(3) The following terms may be used in place of the words “the symptoms of” in the indications in paragraph (b)(1) of this section: (“skin” and/or “scalp,” as appropriate) (select one or more of the following: “itching,” “irritation,” “redness,” “flaking,” “scaling,”) “associated with.”
(c)
(1)
(ii) “Avoid contact with the eyes. If contact occurs, rinse eyes thoroughly with water.”
(iii) “If condition worsens or does not improve after regular use of this product as directed, consult a doctor.”
(2)
(ii) “Do not use for prolonged periods without consulting a doctor.”
(3)
(4)
(5)
(d)
(1)
(2)
(3)
(e) The word “physician” may be substituted for the word “doctor” in any of the labeling statements in this section.
21 U.S.C. 321, 351, 352, 353, 355, 371; 42 U.S.C. 262.
(a) Radioactive drugs (as defined in § 310.3(n) of this chapter) are generally recognized as safe and effective when administered, under the conditions set forth in paragraph (b) of this section, to human research subjects during the course of a research project intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry, but not intended for immediate therapeutic, diagnostic, or similar purposes or to determine the safety and effectiveness of the drug in humans for such purposes (i.e., to carry out a clinical trial). Certain basic research studies, e.g., studies to determine whether a drug localizes in a particular organ or fluid space and to describe the kinetics of that localization, may have eventual therapeutic or diagnostic implications, but the initial studies are considered to be basic research within the meaning of this section.
(b) The conditions under which use of radioactive drugs for research are considered safe and effective are:
(1)
(i) The pharmacological dose is within the limits set forth in paragraph (b)(2) of this section;
(ii) The radiation dose is within the limits set forth in paragraph (b)(3) of this section;
(iii) The radiation exposure is justified by the quality of the study being undertaken and the importance of the information it seeks to obtain;
(iv) The study meets the other requirements set forth in paragraph (d) of this section regarding qualifications of the investigator, proper licensure for handling radioactive materials, selection and consent of research subjects, quality of radioactive drugs used, research protocol design, reporting of adverse reactions, and approval by an appropriate Institutional Review Committee; and
(v) The use of the radioactive drug in human subjects has the approval of the Radioactive Drug Research Committee.
(2)
(3)
(i) Under no circumstances may the radiation dose to an adult research subject from a single study or cumulatively from a number of studies conducted within 1 year be generally recognized as safe if such dose exceeds the following:
(ii) For a research subject under 18 years of age at his last birthday, the radiation dose shall not exceed 10 percent of that set forth in paragraph (b)(3)(i) of this section.
(iii) All radioactive material included in the drug either as essential material or as a significant contaminant or impurity shall be included when determining the total radiation doses and dose commitments. Radiation doses from x-ray procedures that are part of the research study (i.e., would not have occurred but for the study) shall also be included. The possibility of followup studies shall be considered for inclusion in the dose calculations.
(iv) Numerical definitions of dose shall be based on an absorbed fraction method of radiation absorbed dose calculation, such as the system set forth by the Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine, or the system set forth by the International Commission on Radiological Protection.
(c) A Radioactive Drug Research Committee, in order to comply with paragraph (b)(1) of this section, shall be composed, shall function, and shall obtain and maintain approval of the Food and Drug Administration in conformity with the following:
(1)
(2)
(3)
1. Title of the research project.
2. Brief description of the purpose of the research project.
3. Name of the investigator responsible.
4. Pharmacological dose:
a. Active ingredients.
b. Maximum amount administered per subject.
5. Name of the radionuclide(s) used, including any present, as significant contaminants or impurities.
6. Radiation absorbed dose. Provide the maximum dose commitement to the whole body and each organ specified in 21 CFR 361.1(b)(3)(i) that was received by a representative subject and the calculations or references that were used to estimate these maximum dose commitments. The report shall include the dose contribution of both the administered radionuclide(s) and any X-ray procedures associated with the study. If the study elicits data on the uptake or excretion of the radioactive drug pertinent to the estimation of dose commitment, report the mean value and range of values. For each subject provide:
(a) Age, sex, and approximate weight.
(b) Total activity of each radionuclide administered for each radioactive drug used in the study. Report each X-ray procedure used in conjunction with the study.
(c) If the subject has participated in other radioactive drug research studies, report the name of the radioactive drug used in these other studies, the date of administration, and the total activity of each radionuclide administered. If any X-ray procedures were used, identify the X-ray procedure(s) and include an estimate of the absorbed radiation doses.
(d) If more than one administration of a radioactive drug per subject, cumulative radiation dose and dose commitment, expressed as whole body, active blood-forming organs, lens of the eye, gonads, and other organ doses from the administered radionuclides.
7. A claim of confidentiality, if any.
(4)
(5)
(d) In making the determination required in paragraph (b)(1) of this section, a Radioactive Drug Research Committee shall consider the following requirements and assure that each is met:
(1)
(i) The investigator provide absorbed dose calculations based on biologic distribution data available from published literature or from other valid studies.
(ii) The investigator provide for an acceptable method of radioassay of the radioactive drug prior to its use to assure that the dose calculations actually reflect the administered dose.
(iii) The radioactive drug chosen for the study has that combination of half-life, types of radiations, radiation energy, metabolism, chemical properties, etc., which results in the lowest dose to the whole body or specific organs with which it is possible to obtain the necessary information.
(iv) The investigator utilize adequate and appropriate instrumentation for the detection and measurement of the specific radionuclide.
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(e) The results of any research conducted pursuant to this section as part of the evaluation of a drug pursuant to part 312 of this chapter shall be included in the submissions required under part 312 of this chapter.
(f) A radioactive drug prepared, packaged, distributed, and primarily intended for use in accordance with the requirements of this section shall be exempt from section 502(f)(1) of the act and §§ 201.5 and 201.100 of this chapter if the packaging, label, and labeling are in compliance with Federal, State, and local law regarding radioactive materials and if the label of the immediate container and shielded container, if any, either separate from or as part of any label and labeling required for radioactive materials by the Nuclear Regulatory Commission or by State or local radiological health authorities bear the following:
(1) The statement “Rx only”;
(2) The statement “To be administered in compliance with the requirements of Federal regulations regarding radioactive drugs for research use (21 CFR 361.1)”;
(3) The established name of the drug, if any;
(4) The established name and quantity of each active ingredient;
(5) The name and half-life of the radionuclide, total quantity of radioactivity in the drug product's immediate container, and amount of radioactivity per unit volume or unit mass at a designated referenced time;
(6) The route of administration, if it is for the other than oral use;
(7) The net quantity of contents;
(8) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug;
(9) The name and address of the manufacturer, packer, or distributor;
(10) The expiration date, if any;
(11) If the drug is intended for parenteral use, a statement as to whether the contents are sterile;
(12) If the drug is for other than oral use, the names of all inactive ingredients, except that:
(i) Trace amounts of harmless substances added solely for individual product identification need not be named.
(ii) If the drug is intended for parenteral use, the quantity or proportion of all inactive ingredients, except that ingredients added to adjust pH or to make the drug isotonic may be declared by name and a statement of their effect; if the vehicle is water for injection, it need not be named.
21 U.S.C. 321, 331, 351, 352, 353, 355, 371.
The warning and caution statements suggested in subparts B and C of this part, for inclusion in the label or labeling of drugs and devices subject to section 502(d) and (f)(2) and other relevant provisions of the Federal Food, Drug, and Cosmetic Act are issued for the purpose of assisting industry in preparing proper labeling for these articles for over-the-counter sale and in meeting the legal requirements of the act that the label or labeling of drugs and devices bear adequate warnings, in such manner and form as are necessary for the protection of users. Only section 502(d) of the act requires use of the specific language included in these suggested warning and caution statements. These suggested warning or caution statements are illustrative of those that may be necessary or desirable. It is the responsibility of the manufacturer, packer, shipper, or distributor in interstate commerce to see that such statements are adequate for compliance with the provisions of the law. Omission of any article from this suggested list does not relieve drugs and devices subject to provisions of the act from bearing adequate warning or caution statements where such statements are necessary or desirable for the protection of the user.
(a) As used in this part, the term
(b) The terms
(c) Official compendia are defined in section 201(j) of the act.
Drugs exempted from prescription-dispensing requirements under section 503(b)(1)(C) of the act are subject to the labeling requirements prescribed in § 310.201(a) of this chapter. Although, for convenience, warning and caution statements for a number of the drugs named in § 310.201 of this chapter (cross-referenced in the text of this part) are included in subpart B of this part, the inclusion of such drugs in §§ 369.20, 369.21, 369.22 in no way affects the requirements for compliance with § 310.201(a) of this chapter, or the provisions of an effective application pursuant to section 505(b) of the act.
The warning and caution statements included in subpart B of this part in no
Any drug included in the official compendia defined by the act shall bear such warning or caution statement as may be required by such compendia, and no statement in subpart B or subpart C of this part is intended to alter, modify, or permit the omission of any such statement required by such compendia.
The mention in any warning or caution statement included in subparts A, B, and C of this part, of a disease condition does not imply a finding on the part of the Food and Drug Administration that any drug or device is efficacious in such condition; nor is any drug or device bearing labeling referring to such disease condition precluded from regulatory action under the applicable provisions of the act if such claim is considered to be misbranding.
Section 369.20 includes under certain items, but not all medicines, the statement: “Keep this and all medicines out of children's reach. In case of overdose, get medical help or contact a Poison Control Center right away,” or “Keep out of reach of children.” However, in view of the possibility of accidental ingestion of drugs, it is not only suggested but is recommended that one of these statements be used on the label of all drug products.
Necessary warning statements should appear in the labeling prominently and conspicuously as compared to other words, statements, designs, and devices, and in bold type on clearly contrasting background, in order to comply with the provisions of section 502(c) and (f)(2) of the act. The warning statements should be placed in the labeling in juxtaposition with the directions for use and, in any case, should appear on the label when there is sufficient label space in addition to mandatory label information.
The reference to drowsiness is not required on preparations for the promotion of sleep or on preparations that are shown not to produce drowsiness.
Do not apply to broken skin. If a rash develops, discontinue use.
The reference to wounds and burns is not required on preparations intended solely for diaper rash.
In the case of scopolamine or scopolamine aminoxide preparations indicated for insomnia, the portion of the above warning that reads “children under 6 years of age” should read instead “children under 12 years of age”.
Mercury preparations should have added to the “frequent use” statement, the words “and serious mercury poisoning”.
Phenolphthalein preparations should bear, in addition to the general warning, the following statement:
See also Mineral Oil Laxatives.
Avoid swallowing.
This warning is not required on articles containing not more than 0.5 milligram of cobalt as a cobalt salt per dosage unit and which recommend administration of not more than 0.5 milligram per dose and not more than 2 milligrams per 24-hour period.
If offered for use in arthritis or rheumatism, in juxtaposition therewith, the statement:
See also “Salicylates” in this section for additional warnings for preparations containing methyl salicylate.
See also Creosote * * * Douche for additional warning.
See also Dispensers Pressurized by Gaseous Propellants * * * for additional warnings to be included for products under pressure.
“Do not use more than the recommended dosage. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.”
Boric acid offered for use in the preparation of ophthalmic solutions should bear the statement: Prepare solution by boiling in water. Store in a sterile container. Prepare sufficient for one day's use and discard unused portion.
“Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away;” or “Keep out of reach of children.”
If the article is an aspirin preparation, it should bear the first of the above two warning statements. In either case, the above information should appear on the label.
One of the two immediately preceding caution statements is required on the label of all aspirin tablets, but such a statement is not required on the labels of other salicylates clearly offered for administration to adults only.
If offered for use in arthritis or rheumatism, in juxtaposition therewith, the statement:
“Do not use otherwise than as directed. Keep out of reach of children to avoid accidental poisoning. If swallowed, get medical help or contact a Poison Control Center right away.”
If the preparation is a counter-irritant or rubefacient the statement:
If offered for use in arthritis or rheumatism, in juxtaposition therewith, the statement:
For temporary use only until a dentist can be consulted.
“Keep out of reach of children; avoid inhaling. If swallowed, get medical help or contact a Poison Control Center right away.”
If offered for use in arthritis, or rheumatism, in juxtaposition therewith, the statement:
If offered for symptoms of colds, the statement:
“Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.”
The warnings herein shall appear prominently and conspicuously, but in no case may the letters be less than
If the label of any package is too small to accommodate the warnings, the Commissioner may establish by regulation an acceptable alternative method, e.g., a type size smaller than
In the case of products packaged in glass containers, the word “break” may be substituted for the word “puncture.”
The words “Avoid spraying in eyes” may be deleted from the warning in the case of a product not expelled as a spray, or that is intended to be used in the eyes.
In addition to the above warning, the label of a drug packaged in a self-pressurized container in which the propellant consists in whole or in part of a halocarbon or hydrocarbon shall bear the following warning:
The warning is not required for the following products:
(a) Products expelled in the form of a foam or cream, which contain less than ten percent propellant in the container;
(b) Products in a container with a physical barrier that prevents escape of the propellant at the time of use;
(c) Products of a net quantity of contents of less than 2 ozs. that are designed to release a measured amount of product with each valve actuation;
(d) Products of a net quantity of contents of less than
Ipecac syrup packaged for over-the-counter sale must bear statements to the following effect, in a prominent and conspicuous manner:
The following statement (boxed and in red letters):
“For emergency use to cause vomiting in poisoning. Before using, call physician, the Poison Control Center, or hospital emergency room immediately for advice.”
The following warning: Warning—Keep out of reach of children. Do not use in unconscious persons. Ordinarily, this drug should not be used if strychnine, corrosives such as alkalies (lye) and strong acids, or petroleum distillates such as kerosene, gasoline, coal oil, fuel oil, paint thinner, or cleaning fluid have been ingested.
“Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.”
If offered for use in arthritis or rheumatism, in juxtaposition therewith, the statement:
For
A list of CFR titles, subtitles, chapters, subchapters and parts and an alphabetical list of agencies publishing in the CFR are included in the CFR Index and Finding Aids volume to the Code of Federal Regulations which is published separately and revised annually.
Material Approved for Incorporation by Reference
Table of CFR Titles and Chapters
Alphabetical List of Agencies Appearing in the CFR
List of CFR Sections Affected
The Director of the Federal Register has approved under 5 U.S.C. 552(a) and 1 CFR Part 51 the incorporation by reference of the following publications. This list contains only those incorporations by reference effective as of the revision date of this volume. Incorporations by reference found within a regulation are effective upon the effective date of that regulation. For more information on incorporation by reference, see the preliminary pages of this volume.
All changes in this volume of the Code of Federal Regulations which were made by documents published in the
For the period before January 1, 2001, see the “List of Sections Affected, 1949-1963, 1964-1972, 1973-1985, and 1986-2000,” published in 11 separate volumes.