Azzindani/US_Regulation_CFR_20260101 · Datasets at Hugging Face

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

300

GENERAL

Subpart B

Combination Drugs

300.50

Fixed-combination prescription drugs for humans.

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 or antibiotic monograph 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.

regulation

[{"label": "(a)", "text": "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:", "source": null}, {"label": "(1)", "text": "To enhance the safety or effectiveness of the principal active component; and", "source": null}, {"label": "(2)", "text": "To minimize the potential for abuse of the principal active component.", "source": null}, {"label": "(b)", "text": "If a combination drug presently the subject of an approved new-drug application or antibiotic monograph 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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}]

[40 FR 13496, Mar. 27, 1975]

Mar. 27, 1975

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:300:300.50

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

300

GENERAL

Subpart C

Substances Generally Prohibited From Drugs

300.100

Chlorofluorocarbon propellants.

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.

regulation

§ 2.125

[43 FR 11317, Mar. 17, 1978]

Mar. 17, 1978

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:300:300.100

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart A

General Provisions

310.3

Definitions and interpretations.

As used in this part: (a) The term act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). (b) Department means the Department of Health and Human Services. (c) Secretary means the Secretary of Health and Human Services. (d) Commissioner means the Commissioner of Food and Drugs. (e) The term person includes individuals, partnerships, corporations, and associations. (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) New drug substance means any substance that when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance. (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 sponsor means the person or agency who assumes responsibility for an investigation of a new drug, including responsibility for compliance with applicable provisions of the act and regulations. The “sponsor” may be an individual, partnership, corporation, or Government agency and may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new drugs. (k) The phrase related drug(s) includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety, including articles prepared or manufactured by other manufacturers: and any other drug containing a component so related by chemical structure or known pharmacological properties that, in the opinion of experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, it is prudent to assume or ascertain the liability of similar side effects and contraindications. (l) Special packaging as defined in section 2(4) of the Poison Prevention Packaging Act of 1970 means packaging that is designed or constructed to be significantly difficult for children under 5 years of age to open or obtain a toxic or harmful amount of the substance contained therein within a reasonable time and not difficult for normal adults to use properly, but does not mean packaging which all such children cannot open or obtain a toxic or harmful amount within a reasonable time. (m) [Reserved] (n) The term radioactive drug means any substance defined as a drug in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons and includes any nonradioactive reagent kit or nuclide generator which is intended to be used in the preparation of any such substance but does not include drugs such as carbon-containing compounds or potassium-containing salts which contain trace quantities of naturally occurring radionuclides. The term “radioactive drug” includes a “radioactive biological product” as defined in § 600.3(ee) of this chapter.

regulation

[{"label": "(a)", "text": "The term act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).", "source": null}, {"label": "(b)", "text": "Department means the Department of Health and Human Services.", "source": null}, {"label": "(c)", "text": "Secretary means the Secretary of Health and Human Services.", "source": null}, {"label": "(d)", "text": "Commissioner means the Commissioner of Food and Drugs.", "source": null}, {"label": "(e)", "text": "The term person includes individuals, partnerships, corporations, and associations.", "source": null}, {"label": "(f)", "text": "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.", "source": null}, {"label": "(g)", "text": "New drug substance means any substance that when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance.", "source": null}, {"label": "(h)", "text": "The newness of a drug may arise by reason (among other reasons) of:", "source": null}, {"label": "(1)", "text": "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.", "source": null}, {"label": "(2)", "text": "The newness for a drug use of a combination of two or more substances, none of which is a new drug.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(4)", "text": "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.", "source": null}, {"label": "(5)", "text": "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.", "source": null}, {"label": "(i)", "text": "[Reserved]", "source": null}, {"label": "(j)", "text": "The term sponsor means the person or agency who assumes responsibility for an investigation of a new drug, including responsibility for compliance with applicable provisions of the act and regulations. The “sponsor” may be an individual, partnership, corporation, or Government agency and may be a manufacturer, scientific institution, or an investigator regularly and lawfully engaged in the investigation of new drugs.", "source": null}, {"label": "(k)", "text": "The phrase related drug(s) includes other brands, potencies, dosage forms, salts, and esters of the same drug moiety, including articles prepared or manufactured by other manufacturers: and any other drug containing a component so related by chemical structure or known pharmacological properties that, in the opinion of experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, it is prudent to assume or ascertain the liability of similar side effects and contraindications.", "source": null}, {"label": "(l)", "text": "Special packaging as defined in section 2(4) of the Poison Prevention Packaging Act of 1970 means packaging that is designed or constructed to be significantly difficult for children under 5 years of age to open or obtain a toxic or harmful amount of the substance contained therein within a reasonable time and not difficult for normal adults to use properly, but does not mean packaging which all such children cannot open or obtain a toxic or harmful amount within a reasonable time.", "source": null}, {"label": "(m)", "text": "[Reserved]", "source": null}, {"label": "(n)", "text": "The term radioactive drug means any substance defined as a drug in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons and includes any nonradioactive reagent kit or nuclide generator which is intended to be used in the preparation of any such substance but does not include drugs such as carbon-containing compounds or potassium-containing salts which contain trace quantities of naturally occurring radionuclides. The term “radioactive drug” includes a “radioactive biological product” as defined in § 600.3(ee) of this chapter.", "source": null}]

21 U.S.C. 321

§ 600.3

[39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11, 1974; 40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. 22, 1985]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

True

The term act; The term radioactive drug; The term sponsor; New drug substance

5 years

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.3

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart A

General Provisions

310.4

Biologics; products subject to license control.

(a) Except for radioactive biological products intended for human use, a new drug shall not be deemed to be subject to section 505 of the act if it is a drug licensed under the Public Health Service Act of July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or under the animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832 (21 U.S.C. 151 et seq.)). (b) A radioactive biological product (as defined in § 600.3(ee) of this chapter) intended for human use is subject to section 505 of the act. Any license for such a radioactive biological product which is issued under the Public Health Service Act of July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) and which has not been revoked or suspended as of August 25, 1975 shall constitute an approved new drug application in effect under the same terms and conditions as set forth in such license and such portions of the establishment license relating to such product, which include data and information required under part 314 of this chapter for a new drug application. Any such radioactive biological product for which licensure under the Public Health Service Act is pending on August 25, 1975 shall, upon determination that it is acceptable for licensure, be approved as a new drug application in lieu of issuance of a biological product license.

regulation

[{"label": "(a)", "text": "Except for radioactive biological products intended for human use, a new drug shall not be deemed to be subject to section 505 of the act if it is a drug licensed under the Public Health Service Act of July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or under the animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832 (21 U.S.C. 151 et seq.)).", "source": null}, {"label": "(b)", "text": "A radioactive biological product (as defined in § 600.3(ee) of this chapter) intended for human use is subject to section 505 of the act. Any license for such a radioactive biological product which is issued under the Public Health Service Act of July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) and which has not been revoked or suspended as of August 25, 1975 shall constitute an approved new drug application in effect under the same terms and conditions as set forth in such license and such portions of the establishment license relating to such product, which include data and information required under part 314 of this chapter for a new drug application. Any such radioactive biological product for which licensure under the Public Health Service Act is pending on August 25, 1975 shall, upon determination that it is acceptable for licensure, be approved as a new drug application in lieu of issuance of a biological product license.", "source": null}]

42 U.S.C. 201; 21 U.S.C. 151

§ 600.3

[40 FR 31312, July 25, 1975]

July 25, 1975

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.4

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart A

General Provisions

310.6

Applicability of “new drug” or safety or effectiveness findings in drug efficacy study implementation notices and notices of opportunity for hearing to identical, related, and similar drug products.

(a) The Food and Drug Administration's conclusions on the effectiveness of drugs are currently being published in the Federal Register as Drug Efficacy Study Implementation (DESI) Notices and as Notices of Opportunity for Hearing. The specific products listed in these notices include only those that were introduced into the market through the new drug procedures from 1938-62 and were submitted for review by the National Academy of Sciences-National Research Council (NAS-NRC), Drug Efficacy Study Group. Many products which are identical to, related to, or similar to the products listed in these notices have been marketed under different names or by different firms during this same period or since 1962 without going through the new drug procedures or the Academy review. Even though these products are not listed in the notices, they are covered by the new drug applications reviewed and thus are subject to these notices. All persons with an interest in a product that is identical, related, or similar to a drug listed in a drug efficacy notice or a notice of opportunity for a hearing will be given the same opportunity as the applicant to submit data and information, to request a hearing, and to participate in any hearing. It is not feasible for the Food and Drug Administration to list all products which are covered by an NDA and thus subject to each notice. However, it is essential that the findings and conclusions 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 be applied to all identical, related, and similar drug products to which they are reasonably applicable. Any product not in compliance with an applicable drug efficacy notice is in violation of section 505 (new drugs) and/or section 502 (misbranding) of the act. (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. Where the relationships are more subtle and not readily recognized, the purchasing agent may request an opinion by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section. (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 Federal Register that a drug will not be subject to an OTC panel review pursuant to §§ 330.10, 330.11, and 330.5 of this chapter.

regulation

[{"label": "(a)", "text": "The Food and Drug Administration's conclusions on the effectiveness of drugs are currently being published in the Federal Register as Drug Efficacy Study Implementation (DESI) Notices and as Notices of Opportunity for Hearing. The specific products listed in these notices include only those that were introduced into the market through the new drug procedures from 1938-62 and were submitted for review by the National Academy of Sciences-National Research Council (NAS-NRC), Drug Efficacy Study Group. Many products which are identical to, related to, or similar to the products listed in these notices have been marketed under different names or by different firms during this same period or since 1962 without going through the new drug procedures or the Academy review. Even though these products are not listed in the notices, they are covered by the new drug applications reviewed and thus are subject to these notices. All persons with an interest in a product that is identical, related, or ", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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. Where the relationships are more subtle and not readily recognized, the purchasing agent may request an opinion by writing to the Food and Drug Administration at the address shown in paragraph (e) of this section.", "source": null}, {"label": "(e)", "text": "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.", "source": null}, {"label": "(f)", "text": "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 Federal Register that a drug will not be subject to an OTC panel review pursuant to §§ 330.10, 330.11, and 330.5 of this chapter.", "source": null}]

§ 330.10

[39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.6

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart B

Specific Administrative Rulings and Decisions

310.100

New drug status opinions; statement of policy.

(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 Federal Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et al. (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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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 Federal Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et al.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

Pub. L. 87-781

[39 FR 11680, Mar. 29, 1974]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.100

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart B

Specific Administrative Rulings and Decisions

310.101

FD&C Red No. 4; procedure for discontinuing use in new drugs for ingestion; statement of policy.

(a) Section 81.10(d) of this chapter published December 11, 1964 (29 FR 16983), terminated the provisional listing of FD&C Red No. 4 for use in drugs that may be ingested and canceled the effectiveness of certificates for this color additive and mixtures containing it as of June 9, 1965 (§ 81.30(c) of this chapter), insofar as ingested drugs are concerned. On August 19, 1965 (30 FR 10289), FD&C Red No. 4 was restored to provisional listing by amendment to § 81.1(a) of this chapter, which restricted the use of color to the terms of § 81.25 of this chapter. The use of FD&C Red No. 4 or mixtures containing it in the manufacture of ingested drugs (except for limited use as provided in § 81.25 of this chapter) will result in adulteration and may constitute grounds for withdrawing approval of drugs for which a new drug approval is in effect. (b) An approved supplemental new drug application will not be required to provide for discontinuing the use of FD&C Red No. 4 in the manufacture of articles that are the subject of approved new drug applications, provided that the applicant submits to the Food and Drug Administration a written notice of the date on which the change in formulation will be put into effect. (c) It will be the policy of the Food and Drug Administration to take no action against a drug or applicant where a permitted color additive is substituted for FD&C Red No. 4 in the manufacture of a drug prior to receipt of a written notice of approval of a supplemental new drug application, provided that the applicant submits a satisfactory supplemental application meeting all the following conditions: (1) The applicant submits a full list of the components and a full statement of the composition of the drug. (2) The date when the composition of the drug will be changed is stated. (3) The applicant submits data showing that the change in composition does not interfere with any assay or other control procedures used in manufacturing the drug, or that the assay and other control procedures are revised to make them adequate. (4) The data available to establish the stability of the revised formulation are included, and if the data are too limited to support a conclusion that the drug will retain its declared potency for a reasonable marketing period, a commitment from the applicant: (i) To test the stability of marketed batches at reasonable intervals; (ii) To submit the data as they become available; and (iii) To recall from the market any batch found to fall below the approved specifications for the drug. (d) When a supplemental application proposes the change prescribed in paragraph (c) of this section and the applicant informs the Food and Drug Administration that the changes have been put into effect, such notification will be regarded as an agreement by the applicant to an extension of the time for formal action on the supplemental application. (e) Except as provided in paragraph (c) of this section, no provision of this statement of policy shall limit the authority of the Secretary of Health and Human Services or of the Commissioner of Food and Drugs to suspend or withdraw approval of a new-drug application as prescribed by section 505(e) of the act or to initiate any other regulatory proceedings with respect to a drug or applicant under the provisions of the act.

regulation

[{"label": "(a)", "text": "Section 81.10(d) of this chapter published December 11, 1964 (29 FR 16983), terminated the provisional listing of FD&C Red No. 4 for use in drugs that may be ingested and canceled the effectiveness of certificates for this color additive and mixtures containing it as of June 9, 1965 (§ 81.30(c) of this chapter), insofar as ingested drugs are concerned. On August 19, 1965 (30 FR 10289), FD&C Red No. 4 was restored to provisional listing by amendment to § 81.1(a) of this chapter, which restricted the use of color to the terms of § 81.25 of this chapter. The use of FD&C Red No. 4 or mixtures containing it in the manufacture of ingested drugs (except for limited use as provided in § 81.25 of this chapter) will result in adulteration and may constitute grounds for withdrawing approval of drugs for which a new drug approval is in effect.", "source": null}, {"label": "(b)", "text": "An approved supplemental new drug application will not be required to provide for discontinuing the use of FD&C Red No. 4 in the manufacture of articles that are the subject of approved new drug applications, provided that the applicant submits to the Food and Drug Administration a written notice of the date on which the change in formulation will be put into effect.", "source": null}, {"label": "(c)", "text": "It will be the policy of the Food and Drug Administration to take no action against a drug or applicant where a permitted color additive is substituted for FD&C Red No. 4 in the manufacture of a drug prior to receipt of a written notice of approval of a supplemental new drug application, provided that the applicant submits a satisfactory supplemental application meeting all the following conditions:", "source": null}, {"label": "(1)", "text": "The applicant submits a full list of the components and a full statement of the composition of the drug.", "source": null}, {"label": "(2)", "text": "The date when the composition of the drug will be changed is stated.", "source": null}, {"label": "(3)", "text": "The applicant submits data showing that the change in composition does not interfere with any assay or other control procedures used in manufacturing the drug, or that the assay and other control procedures are revised to make them adequate.", "source": null}, {"label": "(4)", "text": "The data available to establish the stability of the revised formulation are included, and if the data are too limited to support a conclusion that the drug will retain its declared potency for a reasonable marketing period, a commitment from the applicant:", "source": null}, {"label": "(i)", "text": "To test the stability of marketed batches at reasonable intervals;", "source": null}, {"label": "(ii)", "text": "To submit the data as they become available; and", "source": null}, {"label": "(iii)", "text": "To recall from the market any batch found to fall below the approved specifications for the drug.", "source": null}, {"label": "(d)", "text": "When a supplemental application proposes the change prescribed in paragraph (c) of this section and the applicant informs the Food and Drug Administration that the changes have been put into effect, such notification will be regarded as an agreement by the applicant to an extension of the time for formal action on the supplemental application.", "source": null}, {"label": "(e)", "text": "Except as provided in paragraph (c) of this section, no provision of this statement of policy shall limit the authority of the Secretary of Health and Human Services or of the Commissioner of Food and Drugs to suspend or withdraw approval of a new-drug application as prescribed by section 505(e) of the act or to initiate any other regulatory proceedings with respect to a drug or applicant under the provisions of the act.", "source": null}]

§ 81.30; § 81.25; § 81.1

[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 15674, Mar. 22, 1977]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.101

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart B

Specific Administrative Rulings and Decisions

310.103

New drug substances intended for hypersensitivity testing.

(a) The Food and Drug Administration is aware of the need in the practice of medicine for the ingredients of a new drug to be available for tests of hypersensitivity to such ingredients and therefore will not object to the shipment of a new drug substance, as defined in § 310.3(g), for such purpose if all of the following conditions are met: (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) “Caution: Federal law prohibits dispensing without a prescription”; 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.)

regulation

[{"label": "(a)", "text": "The Food and Drug Administration is aware of the need in the practice of medicine for the ingredients of a new drug to be available for tests of hypersensitivity to such ingredients and therefore will not object to the shipment of a new drug substance, as defined in § 310.3(g), for such purpose if all of the following conditions are met:", "source": null}, {"label": "(1)", "text": "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.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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:", "source": null}, {"label": "(i)", "text": "“Caution: Federal law prohibits dispensing without a prescription”; and", "source": null}, {"label": "(ii)", "text": "“For use only in patch testing”.", "source": null}, {"label": "(4)", "text": "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.", "source": null}, {"label": "(5)", "text": "The new drug substance is manufactured by the same procedures and meets the same specifications as the component used in the finished dosage form.", "source": null}, {"label": "(6)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.)", "source": null}]

§ 310.3

[39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

2 years

False

True

2 years

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.103

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart C

New Drugs Exempted From Prescription-Dispensing Requirements

310.200

Prescription-exemption procedure.

(a) Duration of prescription requirement. Any drug limited to prescription use under section 503(b)(1)(C) of the act remains so limited until it is exempted as provided in paragraph (b) or (e) of this section. (b) Prescription-exemption procedure for drugs limited by a new drug application. Any drug limited to prescription use under section 503(b)(1)(C) of the act shall be exempted from prescription-dispensing requirements when the Commissioner finds such requirements are not necessary for the protection of the public health by reason of the drug's toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and he finds that the drug is safe and effective for use in self-medication as directed in proposed labeling. A proposal to exempt a drug from the prescription-dispensing requirements of section 503(b)(1)(C) of the act may be initiated by the Commissioner or by any interested person. Any interested person may file a petition seeking such exemption, which petition may be pursuant to part 10 of this chapter, or in the form of a supplement to an approved new drug application. (c) New drug status of drugs exempted from the prescription requirement. A drug exempted from the prescription requirement under the provisions of paragraph (b) of this section is a “new drug” within the meaning of section 201(p) of the act until it has been used to a material extent and for a material time under such conditions except as provided in paragraph (e) of this section. (d) Prescription legend not allowed on exempted drugs. The use of the prescription caution statement quoted in section 503(b) (4) of the act, in the labeling of a drug exempted under the provisions of this section, constitutes misbranding. Any other statement or suggestion in the labeling of a drug exempted under this section, that such drug is limited to prescription use, may constitute misbranding. (e) Prescription-exemption procedure of OTC drug review. A drug limited to prescription use under section 503(b)(1)(C) of the act may also be exempted from prescription-dispensing requirements by the procedure set forth in § 330.13 of this chapter.

regulation

[{"label": "(a)", "text": "Duration of prescription requirement. Any drug limited to prescription use under section 503(b)(1)(C) of the act remains so limited until it is exempted as provided in paragraph (b) or (e) of this section.", "source": null}, {"label": "(b)", "text": "Prescription-exemption procedure for drugs limited by a new drug application. Any drug limited to prescription use under section 503(b)(1)(C) of the act shall be exempted from prescription-dispensing requirements when the Commissioner finds such requirements are not necessary for the protection of the public health by reason of the drug's toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, and he finds that the drug is safe and effective for use in self-medication as directed in proposed labeling. A proposal to exempt a drug from the prescription-dispensing requirements of section 503(b)(1)(C) of the act may be initiated by the Commissioner or by any interested person. Any interested person may file a petition seeking such exemption, which petition may be pursuant to part 10 of this chapter, or in the form of a supplement to an approved new drug application.", "source": null}, {"label": "(c)", "text": "New drug status of drugs exempted from the prescription requirement. A drug exempted from the prescription requirement under the provisions of paragraph (b) of this section is a “new drug” within the meaning of section 201(p) of the act until it has been used to a material extent and for a material time under such conditions except as provided in paragraph (e) of this section.", "source": null}, {"label": "(d)", "text": "Prescription legend not allowed on exempted drugs. The use of the prescription caution statement quoted in section 503(b) (4) of the act, in the labeling of a drug exempted under the provisions of this section, constitutes misbranding. Any other statement or suggestion in the labeling of a drug exempted under this section, that such drug is limited to prescription use, may constitute misbranding.", "source": null}, {"label": "(e)", "text": "Prescription-exemption procedure of OTC drug review. A drug limited to prescription use under section 503(b)(1)(C) of the act may also be exempted from prescription-dispensing requirements by the procedure set forth in § 330.13 of this chapter.", "source": null}]

§ 330.13

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.200

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart C

New Drugs Exempted From Prescription-Dispensing Requirements

310.201

Exemption for certain drugs limited by new-drug applications to prescription sale.

(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) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid) preparations meeting all the following conditions: (i) The N-acetyl-p-aminophenol 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 N-acetyl-p-aminophenol 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 0.325 gram (5 grains) of N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not more than 100 milligrams of N-acetyl-p-aminophenol per milliliter. (v) The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic. (vi) The dosages of N-acetyl-p-aminophenol recommended or suggested in the labeling do not exceed: For adults, 0.65 gram (10 grains) per dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12 years of age, one-half of the maximum adult dose or dosage; for children 3 to 6 years of age, one-fifth of the maximum adult dose or dosage. (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, a clear warning statement against administration of the drug to children under 6 years of age and against use of the drug for a prolonged period, except as such uses may be directed by a physician. (3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-N′-2-thiazolyl-N′-p-methoxybenzyl-ethyl- enediamine hydrochloride) preparations meeting all the following conditions: (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 (N,N-dimethyl-(a-phenyl-O-toloxy) ethylamine dihydrogen citrate), preparations meeting all the following conditions: (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: (a) Clear warning statements against administration of the drug to children under 6 years of age, except as directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness. (b) If the article is offered for temporary relief of the symptoms of colds, a statement that continued administration for such use should not exceed 3 days, except as directed by a physician. (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 dosage form 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 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: (a) Exceeding the recommended dosage. (b) Prolonged use, except as directed by a physician, since persistent or recurring symptoms may indicate a serious disease requiring medical attention. (c) Administration to children under 12 years of age except as directed by a physician. (9) [Reserved] (10) Sodium fluoride preparations meeting all the following conditions: (i) The sodium fluoride is prepared, with other components, in a dosage form suitable for household use as a dentifrice powder, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The sodium fluoride 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 sodium fluoride per gram and is packaged to contain not more than 300 milligrams of sodium fluoride per retail package. (v) The preparation is labeled with adequate directions for use only as a dentifrice by adults and children 6 years of age and over, and includes instructions to rinse the mouth thoroughly after brushing the teeth. (vi) The labeling bears, in juxtaposition with the directions for use, a clear warning statement against use by children under 6 years of age. (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: (a) Use on serious burns or skin conditions or prolonged use, except as directed by a physician. (b) Spraying the preparation in the vicinity of eyes, mouth, nose, or ears. (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)-(14)[Reserved] (15) Sodium monofluorophosphate (Na2PO3F) preparations meeting all the following conditions: (i) The sodium monofluorophosphate is prepared with other components in an aqueous solution suitable for household use as a dentifrice, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act. (ii) The sodium monofluorophosphate 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 60 milligrams of sodium monofluorophosphate per milliliter and is packaged to contain not more than 3.6 grams of sodium monofluorophosphate per retail package. (v) The preparation is labeled with adequate directions for use only as a dentifrice by adults and children 6 years of age and over, and includes instructions to rinse the mouth thoroughly after brushing the teeth. (vi) The labeling bears, in juxtaposition with the directions for use, a clear warning statement against use by children under 6 years of age. (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: (a) Clear warning statements against use of more than 5 doses daily, and against use longer than 4 days unless directed by a physician. (b) A clear warning statement to the effect that frequent use may cause nervousness or sleeplessness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician. (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: (a) Use on serious burns and on infected, deep, and puncture wounds unless directed by a physician. (b) Spraying the preparation near the eyes or other mucous membranes. (c) Inhaling the preparation. (d) Use near open flames. (e) Puncturing the container or throwing the container into fire. (19) Pramoxine hydrochloride (4-N-butoxyphenyl γ-morpholinopropyl ether hydrochloride) preparations meeting all the following conditions: (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 applications of the preparation per day, unless directed by a physician. (vii) The labeling bears, in juxtaposition with the directions for use, clear warning statements against: (a) Prolonged use. (b) Application to large areas of the body. (c) Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician. (d) Use in the eyes or nose. (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: (a) A clear warning statement against administration of the drug to children under 2 years of age, unless directed by a physician. (b) Clear warning statements against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition. (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-n-butoxy-β-piperidonopropiophenone hydrochloride) preparations meeting all the following conditions: (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: (a) By external application to the skin for the temporary relief of pain and itching in sunburn, nonpoisonous insect bites, minor burns, cuts, abrasions, and other minor skin irritations. (b) [Reserved] (c) In the prevention or treatment of other minor conditions in which it is indicated. (vi) The labeling bears, in juxtaposition with the directions for use, clear warning statements against: (a) Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician. (b) Use in case of rectal bleeding, as this may indicate serious disease. (c) Use in the eyes. (d) Prolonged use. (e) Application to large areas of the body. (f) Use for deep or puncture wounds or serious burns. (24) Chlorothen citrate (chloromethapyrilene citrate; N,N-dimethyl-N′-(2-pyridyl)-N ′-(5-chloro-2-thenyl) ethylenediamine citrate) preparations meeting all the following conditions: (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: (a) Clear warning statements against administration of the drug to children under 6 years of age or exceeding the recommended dosage, unless directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness. (b) If the article is offered for the temporary relief of symptoms of colds, a statement that continued administration for such use should not exceed 3 days, unless directed by a physician. (25) [Reserved] (26) Methoxyphenamine hydrochloride (β-(o-methoxyphenyl)-isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)-2-methylamino- propane hydrochloride) preparations meeting all the following conditions: (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: (a) A clear warning statement against administration of the drug to children under 6 years of age, unless directed by a physician. (b) A clear warning statement to the effect that frequent or prolonged use may cause nervousness, restlessness, or drowsiness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician. (c) A clear warning statement against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition. (27) Biphenamine hydrochloride (β-diethylaminoethyl-3-phenyl-2-hydroxy-benzoate 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 meet their professed standards of identity, strength, quality, and purity. (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]

regulation

[{"label": "(a)", "text": "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:", "source": null}, {"label": "(1)", "text": "N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "The N-acetyl-p-aminophenol 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.", "source": null}, {"label": "(ii)", "text": "The N-acetyl-p-aminophenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505 (b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 0.325 gram (5 grains) of N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.", "source": null}, {"label": "(vi)", "text": "The dosages of N-acetyl-p-aminophenol recommended or suggested in the labeling do not exceed: For adults, 0.65 gram (10 grains) per dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12 years of age, one-half of the maximum adult dose or dosage; for children 3 to 6 years of age, one-fifth of the maximum adult dose or dosage.", "source": null}, {"label": "(vii)", "text": "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.", "source": null}, {"label": "(viii)", "text": "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”.", "source": null}, {"label": "(2)", "text": "Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The sodium gentisate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 0.5 gram (7.7 grains) of anhydrous sodium gentisate per dosage unit.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use in minor conditions as a simple analgesic.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "The labeling bears, in juxtaposition with the dosage recommendations, a clear warning statement against administration of the drug to children under 6 years of age and against use of the drug for a prolonged period, except as such uses may be directed by a physician.", "source": null}, {"label": "(3)", "text": "Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-N′-2-thiazolyl-N′-p-methoxybenzyl-ethyl- enediamine hydrochloride) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The isoamylhydrocupreine, zola-amine hydrochloride, and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 0.25 percent of isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "The preparation is labeled with adequate directions for use in the temporary relief of local pain and itching associated with hemorrhoids.", "source": null}, {"label": "(vii)", "text": "The directions provide for the use of not more than two suppositories or two applications of ointment in a 24-hour period.", "source": null}, {"label": "(viii)", "text": "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.", "source": null}, {"label": "(4)", "text": "Phenyltoloxamine dihydrogen citrate (N,N-dimethyl-(a-phenyl-O-toloxy) ethylamine dihydrogen citrate), preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The phenyltoloxamine dihydrogen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 88 milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of phenyltoloxamine) per dosage unit.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "The labeling bears, in juxtaposition with the dosage recommendations:", "source": null}, {"label": "(a)", "text": "Clear warning statements against administration of the drug to children under 6 years of age, except as directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness.", "source": null}, {"label": "(b)", "text": "If the article is offered for temporary relief of the symptoms of colds, a statement that continued administration for such use should not exceed 3 days, except as directed by a physician.", "source": null}, {"label": "(8)", "text": "Dicyclomine hydrochloride (1-cyclohexylhexahydrobenzoic acid. β-diethylaminoethyl ester hydrochloride; diethylaminocarbethoxy-bicyclohexyl hydrochloride) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "The dicyclomine hydrochloride is prepared with suitable antacid and other components, in tablet or other dosage form 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.", "source": null}, {"label": "(ii)", "text": "The dicyclomine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "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.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "The labeling bears, in juxtaposition with the dosage recommendations, clear warning statements against:", "source": null}, {"label": "(a)", "text": "Exceeding the recommended dosage.", "source": null}, {"label": "(b)", "text": "Prolonged use, except as directed by a physician, since persistent or recurring symptoms may indicate a serious disease requiring medical attention.", "source": null}, {"label": "(c)", "text": "Administration to children under 12 years of age except as directed by a physician.", "source": null}, {"label": "(9)", "text": "[Reserved]", "source": null}, {"label": "(10)", "text": "Sodium fluoride preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "The sodium fluoride is prepared, with other components, in a dosage form suitable for household use as a dentifrice powder, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.", "source": null}, {"label": "(ii)", "text": "The sodium fluoride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 5 milligrams of sodium fluoride per gram and is packaged to contain not more than 300 milligrams of sodium fluoride per retail package.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use only as a dentifrice by adults and children 6 years of age and over, and includes instructions to rinse the mouth thoroughly after brushing the teeth.", "source": null}, {"label": "(vi)", "text": "The labeling bears, in juxtaposition with the directions for use, a clear warning statement against use by children under 6 years of age.", "source": null}, {"label": "(11)", "text": "Hexadenol (a mixture of tetracosanes and their oxidation products) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The hexadenol and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 5 percent by weight of hexadenol.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use by external application in the treatment of minor burns and minor skin irritations.", "source": null}, {"label": "(vi)", "text": "The labeling bears, in juxtaposition with the directions for use, clear warning statements against:", "source": null}, {"label": "(a)", "text": "Use on serious burns or skin conditions or prolonged use, except as directed by a physician.", "source": null}, {"label": "(b)", "text": "Spraying the preparation in the vicinity of eyes, mouth, nose, or ears.", "source": null}, {"label": "(12)", "text": "Sulfur dioxide preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The sulfur dioxide and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 5 grams of sulfur dioxide per 100 milliliters of solution.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(15)", "text": "Sodium monofluorophosphate (Na2PO3F) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "The sodium monofluorophosphate is prepared with other components in an aqueous solution suitable for household use as a dentifrice, and containing no drug limited to prescription sale under the provisions of section 503(b)(1) of the act.", "source": null}, {"label": "(ii)", "text": "The sodium monofluorophosphate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 60 milligrams of sodium monofluorophosphate per milliliter and is packaged to contain not more than 3.6 grams of sodium monofluorophosphate per retail package.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use only as a dentifrice by adults and children 6 years of age and over, and includes instructions to rinse the mouth thoroughly after brushing the teeth.", "source": null}, {"label": "(vi)", "text": "The labeling bears, in juxtaposition with the directions for use, a clear warning statement against use by children under 6 years of age.", "source": null}, {"label": "(16)", "text": "Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "The tuaminoheptane sulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iv)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(v)", "text": "The tuaminoheptane sulfate content of the preparation does not exceed 10 milligrams per milliliter.", "source": null}, {"label": "(vi)", "text": "The preparation is labeled with adequate directions for use in the temporary relief of nasal congestion.", "source": null}, {"label": "(vii)", "text": "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.", "source": null}, {"label": "(viii)", "text": "The labeling bears, in juxtaposition with the dosage recommendations:", "source": null}, {"label": "(a)", "text": "Clear warning statements against use of more than 5 doses daily, and against use longer than 4 days unless directed by a physician.", "source": null}, {"label": "(b)", "text": "A clear warning statement to the effect that frequent use may cause nervousness or sleeplessness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician.", "source": null}, {"label": "(17)", "text": "[Reserved]", "source": null}, {"label": "(18)", "text": "Vibesate (a mixture of copolymers of hydroxy-vinyl chlorideacetate, sebacic acid, and modified maleic rosin ester) preparations meeting all the following conditions.", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The vibesate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 13 percent by weight of vibesate.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "The labeling bears in juxtaposition with the directions for use clear warning statements against:", "source": null}, {"label": "(a)", "text": "Use on serious burns and on infected, deep, and puncture wounds unless directed by a physician.", "source": null}, {"label": "(b)", "text": "Spraying the preparation near the eyes or other mucous membranes.", "source": null}, {"label": "(c)", "text": "Inhaling the preparation.", "source": null}, {"label": "(d)", "text": "Use near open flames.", "source": null}, {"label": "(e)", "text": "Puncturing the container or throwing the container into fire.", "source": null}, {"label": "(19)", "text": "Pramoxine hydrochloride (4-N-butoxyphenyl γ-morpholinopropyl ether hydrochloride) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The pramoxine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 1.0 percent of pramoxine hydrochloride.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician.", "source": null}, {"label": "(vii)", "text": "The labeling bears, in juxtaposition with the directions for use, clear warning statements against:", "source": null}, {"label": "(a)", "text": "Prolonged use.", "source": null}, {"label": "(b)", "text": "Application to large areas of the body.", "source": null}, {"label": "(c)", "text": "Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician.", "source": null}, {"label": "(d)", "text": "Use in the eyes or nose.", "source": null}, {"label": "(20)", "text": "Carbetapentane citrate (2-(2-diethylaminoethoxy)-ethyl-1-phenyl- cyclopentyl-1-carboxylate citrate) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The carbetapentane citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, and application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "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.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "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:", "source": null}, {"label": "(a)", "text": "A clear warning statement against administration of the drug to children under 2 years of age, unless directed by a physician.", "source": null}, {"label": "(b)", "text": "Clear warning statements against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition.", "source": null}, {"label": "(21)", "text": "Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The pamabrom and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 50 milligrams of pamabrom per dosage unit.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "The dosages recommended or suggested in the labeling do not exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour period.", "source": null}, {"label": "(22)", "text": "Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-piperidinium methylsulfate) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The diphemanil methylsulfate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 2.0 percent of diphemanil methylsulfate.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "The directions for use recommend or suggest not more than four applications of the preparation per day, unless directed by a physician.", "source": null}, {"label": "(vii)", "text": "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.”", "source": null}, {"label": "(23)", "text": "Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone hydrochloride; 4-n-butoxy-β-piperidonopropiophenone hydrochloride) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The dyclonine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 1.0 percent of dyclonine hydrochloride.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use:", "source": null}, {"label": "(a)", "text": "By external application to the skin for the temporary relief of pain and itching in sunburn, nonpoisonous insect bites, minor burns, cuts, abrasions, and other minor skin irritations.", "source": null}, {"label": "(b)", "text": "[Reserved]", "source": null}, {"label": "(c)", "text": "In the prevention or treatment of other minor conditions in which it is indicated.", "source": null}, {"label": "(vi)", "text": "The labeling bears, in juxtaposition with the directions for use, clear warning statements against:", "source": null}, {"label": "(a)", "text": "Continued use if redness, irritation, swelling, or pain persists or increases, unless directed by a physician.", "source": null}, {"label": "(b)", "text": "Use in case of rectal bleeding, as this may indicate serious disease.", "source": null}, {"label": "(c)", "text": "Use in the eyes.", "source": null}, {"label": "(d)", "text": "Prolonged use.", "source": null}, {"label": "(e)", "text": "Application to large areas of the body.", "source": null}, {"label": "(f)", "text": "Use for deep or puncture wounds or serious burns.", "source": null}, {"label": "(24)", "text": "Chlorothen citrate (chloromethapyrilene citrate; N,N-dimethyl-N′-(2-pyridyl)-N ′-(5-chloro-2-thenyl) ethylenediamine citrate) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The chlorothen citrate and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 25 milligrams of chlorothen citrate per dosage unit.", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "The labeling bears, in juxtaposition with the dosage recommendations:", "source": null}, {"label": "(a)", "text": "Clear warning statements against administration of the drug to children under 6 years of age or exceeding the recommended dosage, unless directed by a physician, and against driving a car or operating machinery while using the drug, since it may cause drowsiness.", "source": null}, {"label": "(b)", "text": "If the article is offered for the temporary relief of symptoms of colds, a statement that continued administration for such use should not exceed 3 days, unless directed by a physician.", "source": null}, {"label": "(25)", "text": "[Reserved]", "source": null}, {"label": "(26)", "text": "Methoxyphenamine hydrochloride (β-(o-methoxyphenyl)-isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)-2-methylamino- propane hydrochloride) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The methoxyphenamine hydrochloride and all other components of the preparation meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 3.5 milligrams of methoxyphenamine hydrochloride per milliliter.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use in the temporary relief of cough due to minor conditions in which it is indicated.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "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:", "source": null}, {"label": "(a)", "text": "A clear warning statement against administration of the drug to children under 6 years of age, unless directed by a physician.", "source": null}, {"label": "(b)", "text": "A clear warning statement to the effect that frequent or prolonged use may cause nervousness, restlessness, or drowsiness, and that individuals with high blood pressure, heart disease, diabetes, or thyroid disease should not use the preparation unless directed by a physician.", "source": null}, {"label": "(c)", "text": "A clear warning statement against use of the drug in the presence of high fever or if cough persists, since persistent cough as well as high fever may indicate the presence of a serious condition.", "source": null}, {"label": "(27)", "text": "Biphenamine hydrochloride (β-diethylaminoethyl-3-phenyl-2-hydroxy-benzoate hydrochloride) preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "The biphenamine hydrochloride meets its professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iii)", "text": "If the preparation is a new drug, an application pursuant to section 505(b) of the act is approved for it.", "source": null}, {"label": "(iv)", "text": "The preparation contains not more than 1 percent of biphenamine hydrochloride.", "source": null}, {"label": "(v)", "text": "The preparation is labeled with adequate directions for use for the temporary relief of itching and scaling due to dandruff.", "source": null}, {"label": "(vi)", "text": "The label bears a conspicuous warning to keep the drug out of the reach of children.", "source": null}, {"label": "(28)", "text": "Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium chloride ophthalmic preparations meeting all the following conditions:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "The tyloxapol, benzalkonium chloride, and other ingredients used to prepare the isotonic aqueous solution meet their professed standards of identity, strength, quality, and purity.", "source": null}, {"label": "(iv)", "text": "An application pursuant to section 505(b) of the act is approved for the drug.", "source": null}, {"label": "(v)", "text": "The preparation contains 0.25 percent of tyloxapol and 0.02 percent of benzalkonium chloride.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(29)", "text": "[Reserved]", "source": null}, {"label": "(b)", "text": "[Reserved]", "source": null}]

[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

1 week; 3 years; 3 days; 6 years; 10 days; 4 days; 1 year; 4 years; 12 years; 2 years

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.201

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart D

Records and Reports

310.303

Continuation of long-term studies, records, and reports on certain drugs for which new drug applications have been approved.

(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.

regulation

[{"label": "(a)", "text": "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 s", "source": null}, {"label": "(b)", "text": "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.", "source": null}]

§ 310.304.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, 1977]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.303

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart D

Records and Reports

310.304

Drugs that are subjects of approved new drug applications and that require special studies, records, and reports.

Listed below are the new drugs and requirements referred to in § 310.303: (a) [Reserved] (b) Methadone. Methadone may be used as an analgesic in severe pain, for the detoxification of narcotic addicts, and as an oral substitute for heroin or other morphine-like drugs, in the maintenance treatment of narcotic addicts, pursuant to the conditions established in § 291.505. Further data and information are required to establish the safety and effectiveness of methadone under a variety of conditions during widespread and long-term use. In view of the tremendous public health and social problems associated with the use of heroin, the demonstrated usefulness of methadone in treatment, the lack of a safe and effective alternative drug or treatment modality, the need for additional safety and effectiveness data on methadone for narcotic addict treatment and the danger to health that could be created by uncontrolled distribution and use of methadone for narcotic addict treatment, the Commissioner of Food and Drugs finds that it is not in the public interest either to withhold the drug from the market until it has been proved safe and effective under all conditions of use for narcotic addict treatment or to grant full approval for unrestricted distribution, prescription, dispensing, or administration of methadone for this use. The Commissioner therefore concludes that it is essential to the public interest to prescribe detailed conditions for safe and effective use of methadone for narcotic addict treatment, utilizing the IND and NDA control mechanisms and the authority granted under the Comprehensive Drug Abuse Prevention and Control Act of 1970, to assure that the required additional information for assessing the safety and effectiveness of methadone is obtained, to maintain close control over the safe distribution, administration, and dispensing of the drug, and to detail responsibilities for such control. The conditions established in § 291.505 constitute a determination of the appropriate methods of professional practice in the medical treatment of the narcotic addiction of various classes of narcotic addicts with respect to the use of methadone, pursuant to section 4 of the Comprehensive Drug Abuse Prevention and Control Act of 1970.

regulation

[{"label": "(a)", "text": "[Reserved]", "source": null}, {"label": "(b)", "text": "Methadone. Methadone may be used as an analgesic in severe pain, for the detoxification of narcotic addicts, and as an oral substitute for heroin or other morphine-like drugs, in the maintenance treatment of narcotic addicts, pursuant to the conditions established in § 291.505. Further data and information are required to establish the safety and effectiveness of methadone under a variety of conditions during widespread and long-term use. In view of the tremendous public health and social problems associated with the use of heroin, the demonstrated usefulness of methadone in treatment, the lack of a safe and effective alternative drug or treatment modality, the need for additional safety and effectiveness data on methadone for narcotic addict treatment and the danger to health that could be created by uncontrolled distribution and use of methadone for narcotic addict treatment, the Commissioner of Food and Drugs finds that it is not in the public interest either to withhold the drug fr", "source": null}]

§ 310.303; § 291.505.; § 291.505

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 9546, Mar. 5, 1976; 41 FR 28263, July 9, 1976; 42 FR 46710, Sept. 16, 1977]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.304

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart D

Records and Reports

310.305

Records and reports concerning adverse drug experiences on marketed prescription drugs for human use without approved new drug applications.

(a) Scope. FDA is requiring manufacturers, packers, and distributors of marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application to establish and maintain records and make reports to FDA of: (1) All serious, unexpected adverse drug experiences associated with the use of their drug products; (2) Any significant increase in the frequency of a serious, expected adverse drug experience; and (3) Any significant increase in the frequency of therapeutic failure (lack of effect). These reports will enable FDA to protect the public health by helping to monitor the safety of marketed drug products and to ensure that these drug products are not adulterated or misbranded. (b) Definitions. The following definitions of terms apply to this section: (1) FDA means the Food and Drug Administration. (2) Adverse drug experience means any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: an adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose, whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action. (3) Unexpected means an adverse drug experience that is not listed in the current labeling for the drug product and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents. (4) Serious means an adverse drug experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose. (5) Increased frequency means an increase in the rate of occurrence of a particular adverse drug experience, e.g., an increased number of reports of a particular adverse drug experience after appropriate adjustment for drug exposure. (c) Reporting requirements—15-day “Alert reports.” (1)(i) Any person whose name appears on the label of a marketed prescription drug product as its manufacturer, packer, or distributor shall report to FDA each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible but in any case within 15 working days of initial receipt of the information. Each report shall be accompanied by a copy of the current labeling for the drug product. (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) Each person identified in paragraph (c)(1) of this section shall submit one copy of each report 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. (3) Each person identified in paragraph (c)(1) of this section shall promptly investigate all serious, unexpected adverse drug experiences that are the subject of these 15-day Alert reports and shall submit followup reports within 15 working days of receipt of new information or as requested by FDA. If additional information is not obtainable, a followup report may be required that describes briefly the steps taken to seek additional information and the reasons why it could not be obtained. (4) Each person identified in paragraph (c)(1) of this section shall review periodically (at least once each year) the frequency of reports of adverse drug experiences that are both serious and expected and reports of therapeutic failure (lack of effect), received or otherwise obtained, and report any significant increase in frequency as soon as possible but in any case within 15 working days of determining that a significant increase in frequency exists. Reports of a significant increase in frequency are required to be submitted in narrative form (including the time period on which the increased frequency is based, the method of analysis, and the interpretation of the results), rather than using Form FDA-1639. (5) In order to avoid unnecessary duplication in the submission of, and followup to, reports required in this section, including reports required by paragraph (c)(4) of this section, a packer's or distributor's obligations may be met by submission of all reports of serious adverse drug experiences to the manufacturer of the drug product. If a packer or distributor elects to submit these adverse drug experience reports to the manufacturer rather than to FDA, it shall submit each report to the manufacturer within 3 working days of its receipt by the packer or distributor, and the manufacturer shall then comply with the requirements of this section even if its name does not appear on the label of the drug product. Under this circumstance, the packer or distributor shall maintain a record of this action which shall include: (i) A copy of each drug experience report. (ii) Date the report was received by the packer or distributor. (iii) Date the report was submitted to the manufacturer. (iv) Name and address of the manufacturer. (6) 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.” (d) Reporting form. (1) Except as provided in paragraph (d)(3) of this section, each person identified in paragraph (c)(1) of this section shall submit each report of a serious and unexpected adverse drug experience on a Form FDA-1639 (Adverse Reaction Report). (2) Each completed Form FDA-1639 should pertain only to an individual patient. (3) Instead of using Form FDA-1639, a manufacturer, packer, or distributor may use a computer-generated FDA-1639 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 Form FDA-1639, and (ii) The format is agreed to in advance by the Division of Epidemiology and Surveillance (HFD-730). (4) Single copies of Form FDA-1639 may be obtained from the Division of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the PHS Forms and Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857. (e) Patient privacy. Manufacturers, packers, and distributors should not include in reports under this section the names and addresses of individual patients; instead, the manufacturer, packer, and distributor should assign a unique code number to each report, preferably not more than eight characters in length. The manufacturer, packer, and distributor should include the name of the reporter from whom the information was received. Names of patients, individual reporters, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter. (f) Recordkeeping. (1) Each manufacturer, packer, and distributor shall maintain for a period of 10 years records of all adverse drug experiences required under this section to be reported or reviewed periodically for a significant increase in frequency, including raw data and any correspondence relating to the adverse drug experiences, and the records required to be maintained under paragraph (c)(5) of this section. (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) Disclaimer. A report or information submitted by a manufacturer, packer, or distributor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the manufacturer, packer, or distributor, or by FDA, that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. The manufacturer, packer, or distributor need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0210)

regulation

[{"label": "(a)", "text": "Scope. FDA is requiring manufacturers, packers, and distributors of marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application to establish and maintain records and make reports to FDA of:", "source": null}, {"label": "(1)", "text": "All serious, unexpected adverse drug experiences associated with the use of their drug products;", "source": null}, {"label": "(2)", "text": "Any significant increase in the frequency of a serious, expected adverse drug experience; and", "source": null}, {"label": "(3)", "text": "Any significant increase in the frequency of therapeutic failure (lack of effect).", "source": null}, {"label": "(b)", "text": "Definitions. The following definitions of terms apply to this section:", "source": null}, {"label": "(1)", "text": "FDA means the Food and Drug Administration.", "source": null}, {"label": "(2)", "text": "Adverse drug experience means any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: an adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose, whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action.", "source": null}, {"label": "(3)", "text": "Unexpected means an adverse drug experience that is not listed in the current labeling for the drug product and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular accidents.", "source": null}, {"label": "(4)", "text": "Serious means an adverse drug experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose.", "source": null}, {"label": "(5)", "text": "Increased frequency means an increase in the rate of occurrence of a particular adverse drug experience, e.g., an increased number of reports of a particular adverse drug experience after appropriate adjustment for drug exposure.", "source": null}, {"label": "(c)", "text": "Reporting requirements—15-day “Alert reports.” (1)(i) Any person whose name appears on the label of a marketed prescription drug product as its manufacturer, packer, or distributor shall report to FDA each adverse drug experience received or otherwise obtained that is both serious and unexpected as soon as possible but in any case within 15 working days of initial receipt of the information. Each report shall be accompanied by a copy of the current labeling for the drug product.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(2)", "text": "Each person identified in paragraph (c)(1) of this section shall submit one copy of each report 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.", "source": null}, {"label": "(3)", "text": "Each person identified in paragraph (c)(1) of this section shall promptly investigate all serious, unexpected adverse drug experiences that are the subject of these 15-day Alert reports and shall submit followup reports within 15 working days of receipt of new information or as requested by FDA. If additional information is not obtainable, a followup report may be required that describes briefly the steps taken to seek additional information and the reasons why it could not be obtained.", "source": null}, {"label": "(4)", "text": "Each person identified in paragraph (c)(1) of this section shall review periodically (at least once each year) the frequency of reports of adverse drug experiences that are both serious and expected and reports of therapeutic failure (lack of effect), received or otherwise obtained, and report any significant increase in frequency as soon as possible but in any case within 15 working days of determining that a significant increase in frequency exists. Reports of a significant increase in frequency are required to be submitted in narrative form (including the time period on which the increased frequency is based, the method of analysis, and the interpretation of the results), rather than using Form FDA-1639.", "source": null}, {"label": "(5)", "text": "In order to avoid unnecessary duplication in the submission of, and followup to, reports required in this section, including reports required by paragraph (c)(4) of this section, a packer's or distributor's obligations may be met by submission of all reports of serious adverse drug experiences to the manufacturer of the drug product. If a packer or distributor elects to submit these adverse drug experience reports to the manufacturer rather than to FDA, it shall submit each report to the manufacturer within 3 working days of its receipt by the packer or distributor, and the manufacturer shall then comply with the requirements of this section even if its name does not appear on the label of the drug product. Under this circumstance, the packer or distributor shall maintain a record of this action which shall include:", "source": null}, {"label": "(i)", "text": "A copy of each drug experience report.", "source": null}, {"label": "(ii)", "text": "Date the report was received by the packer or distributor.", "source": null}, {"label": "(iii)", "text": "Date the report was submitted to the manufacturer.", "source": null}, {"label": "(iv)", "text": "Name and address of the manufacturer.", "source": null}, {"label": "(6)", "text": "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.”", "source": null}, {"label": "(d)", "text": "Reporting form. (1) Except as provided in paragraph (d)(3) of this section, each person identified in paragraph (c)(1) of this section shall submit each report of a serious and unexpected adverse drug experience on a Form FDA-1639 (Adverse Reaction Report).", "source": null}, {"label": "(2)", "text": "Each completed Form FDA-1639 should pertain only to an individual patient.", "source": null}, {"label": "(3)", "text": "Instead of using Form FDA-1639, a manufacturer, packer, or distributor may use a computer-generated FDA-1639 or other alternative format (e.g., a computer-generated tape or tabular listing) provided that:", "source": null}, {"label": "(i)", "text": "The content of the alternative format is equivalent in all elements of information to those specified in Form FDA-1639, and", "source": null}, {"label": "(ii)", "text": "The format is agreed to in advance by the Division of Epidemiology and Surveillance (HFD-730).", "source": null}, {"label": "(4)", "text": "Single copies of Form FDA-1639 may be obtained from the Division of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the PHS Forms and Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD 20857.", "source": null}, {"label": "(e)", "text": "Patient privacy. Manufacturers, packers, and distributors should not include in reports under this section the names and addresses of individual patients; instead, the manufacturer, packer, and distributor should assign a unique code number to each report, preferably not more than eight characters in length. The manufacturer, packer, and distributor should include the name of the reporter from whom the information was received. Names of patients, individual reporters, health care professionals, hospitals, and geographical identifiers in adverse drug experience reports are not releasable to the public under FDA's public information regulations in part 20 of this chapter.", "source": null}, {"label": "(f)", "text": "Recordkeeping. (1) Each manufacturer, packer, and distributor shall maintain for a period of 10 years records of all adverse drug experiences required under this section to be reported or reviewed periodically for a significant increase in frequency, including raw data and any correspondence relating to the adverse drug experiences, and the records required to be maintained under paragraph (c)(5) of this section.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(g)", "text": "Disclaimer. A report or information submitted by a manufacturer, packer, or distributor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the manufacturer, packer, or distributor, or by FDA, that the report or information constitutes an admission that the drug caused or contributed to an adverse effect. The manufacturer, packer, or distributor need not admit, and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect.", "source": null}]

§ 211.198

[51 FR 24779, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1993]

July 3, 1986

(Revised as of April 1, 1996)

False

True

Adverse drug experience; Increased frequency

10 years

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.305

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.500

Digoxin products for oral use; conditions for marketing.

(a) Studies have shown evidence of clinically significant differences in bio-availability in different batches of certain marketed digoxin products for oral use from single manufacturers as well as in batches of these products produced by different manufacturers. These differences were observed despite the fact that the products met compendial specifications. Other studies have shown that there is a sufficient correlation between bioavailabil-ity in vivo and the dissolution rate of digoxin tablets in vitro to make the dissolution test an important addition to the compendial standards. Because of the potential for serious risk to cardiac patients using digoxin products which may vary in bioavailability, the Commissioner of Food and Drugs has determined that immediate action must be taken to assure the uniformity of all digoxin products for oral use. The Commissioner is of the opinion that digoxin products for oral use are new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act for which approved new drug applications are required. The Commissioner has determined that, because of questions raised regarding the bioavailability of digoxin products for oral use, there is sufficient evidence to invoke the authority under section 505(j) of the act to fully investigate this question and to facilitate a determination of whether there is a ground for withdrawal of approval of the drug product under section 505(e) of the act. Marketing of these products may be continued only under the following conditions: (1) Digoxin products for oral use, other than tablets: Any person marketing digoxin products for oral use, other than tablets, shall submit to the Food and Drug Administration on or before February 21, 1974, an abbreviated new drug application for these products. Any such drug product then on the market which is not the subject of an application submitted for the drug product shall be subject to regulatory procedures under section 505 of the act. In addition to the information specified in § 314.50 of this chapter, the application shall contain: (i) A full list of the articles used as components of the digoxin product, specifications for components, detailed identification and analytical procedures used to assure that the components meet established specifications of identity, strength, quality, and purity and a complete description of the manufacturing process. (ii) The source of the digoxin used in the formulation including the name and address of the supplier. (iii) A statement that stability studies will be conducted to establish a suitable expiration date for the digoxin product in the form in which it is distributed. (iv) A statement that the product label will contain a suitable expiration date. In the absence of any stability test data, this expiration date shall be no longer than one year after the batch is manufactured. If the expiration date is greater than one year, supporting stability data shall be included in the application. (v) Labeling that is in compliance with all requirements of the act and regulations promulgated thereunder, the pertinent parts of which are as indicated in paragraph (e) of this section. (vi) A statement that the applicant will initiate recall of all stocks of the drug product outstanding when so requested by the Food and Drug Administration. (vii) A statement that the applicant intends to conduct in vivo bioavailability tests and that the applicant, under the records and reports provisions of section 505(k) of the act, will: (a) Within 30 days after the submission of the application, submit to the Food and Drug Administration the protocol which the applicant proposes to follow in conducting these in vivo bioavailability tests. The protocol shall contain all of the essential elements set forth in paragraph (d) of this section. The tests shall not be initiated prior to receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed and either approved or its deficiencies delineated. (b) Within 180 days after receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed, submit to the Food and Drug Administration the results of the in vivo bioavailability tests. (2) Digoxin tablets: Any person marketing digoxin tablets, in addition to complying with all of the requirements of paragraph (a)(1) of this section, shall include in their abbreviated new drug application: (i) A statement that the applicant will establish procedures to test each lot of digoxin tablets prior to releasing the batch for distribution to assure that the batch meets all of The United States Pharmacopeia (USP XVIII) requirements for digoxin tablets including, but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin. (ii) A statement that finished product specifications shall be established to include provisions to assure that the range of average one-hour dissolution values among batches of digoxin tablets does not exceed 20 percent. (3) Before releasing for distribution any batch of digoxin tablets manufactured after January 22, 1974, the manufacturer shall: (i) Test a sample of the batch to assure that the batch meets all of the requirements of The United States Pharmacopeia (USP XVIII) including but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin. (ii) Submit a sample of the batch to the Food and Drug Administration according to the procedures set forth in paragraph (g) of this section. Results of tests conducted on the batch by or for the manufacturer and the batch production record shall accompany the sample. (iii) Withhold the batch from distribution until he is notified by the Food and Drug Administration that the sample was tested and found to meet all of the requirements in The United States Pharmacopeia (USP XVIII) for potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin. (iv) Submit a sample of each batch of digoxin tablets as provided for in paragraph (a)(3)(ii) of this section until he is notified by the Food and Drug Administration that he is released from the certification program. This notification will be made on the basis of sample test results, inspectional findings regarding compliance with current good manufacturing practice, and compliance with all other requirements of this section and any other directives issued by the Food and Drug Administration as a condition for release from the certification program. (4) Any manufacturer who has distributed any batch of digoxin tablets which does not meet the compendial requirement for dissolution, when tested by the method in The United States Pharmacopeia (USP XVIII), shall initiate recall of the subject batch when so requested by the Food and Drug Administration. (b) Failure of an applicant to submit the protocol and/or the results of the in vivo bioavailability tests showing adequate evidence of the product's bioavailability within the times specified in paragraph (a)(1)(vii) of this section and/or to comply with all of the certification requirements of paragraph (a)(3) of this section shall be justification for withdrawal of approval of the application under section 505(e) of the act. (c) Any product reformulation or change in manufacturing process will require the submission of a supplement to the approved abbreviated new drug application containing adequate data to demonstrate the bioavailability of the reformulated product. Food and Drug Administration approval of the supplement is required before the reformulated product is marketed. The Food and Drug Administration recommends that, where digoxin tablets are reformulated, manufacturers reformulate their product to achieve dissolution of 70 to 90 percent at one hour when tested by all three methods (i.e., the USP method, and the “paddle-water” and “paddle-acid” methods) described in paragraph (h) of this section. (d) The protocol for the in vivo bioavailability tests required in paragraphs (a) and (c) of this section shall employ a three-way crossover design using the digoxin test product; a reference digoxin tablet supplied, on request, by the Food and Drug Administration; and bulk digoxin USP in an oral solution. Appropriate venous blood and urinary samples are to be collected and analyzed. The method shall be capable of detecting the difference between the reference tablet and the reference oral solution. Bioavailability of the test product shall be demonstrated if a mean absorption of at least 75 percent of the combined mean of the two reference standards is observed. Assistance in developing a protocol for a particular dosage formulation may be obtained by contacting the Food and Drug Administration, Center for Drug Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD 20857. (e) Parts of the digoxin product labeling indicated below shall be as follows: Digoxin Labeling Guidelines (adult and pediatric) description Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific and powerful effects on the myocardium. These drugs are found in a number of plants. The term “digitalis” is used to designate the whole group. Typically, the glycosides are composed of three portions: a steroid nucleus, a lactone ring, and a sugar (hence “glycosides”). (This section should include a chemical and physical description of digoxin and the same quantitative ingredient information as that required on the label.) Action The digitalis glycosides have qualitatively the same therapeutic effects on the heart. They (1) increase the force of myocardial contraction, (2) increase the refractory period of the atrioventricular (A-V) node, and (3) to a lesser degree, affect the sinoatrial (S-A) node and conduction system via the parasympathetic and sympathetic nervous systems. Gastrointestinal absorption of digoxin is a passive process. About 50-75 percent of digoxin in tablet form is absorbed. Digoxin is only 20-25 percent bound to plasma proteins and is predominantly excreted by the kidneys unmetabolized unless there is significant renal failure. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass, presumably because of tissue binding. In subjects with normal renal function, digoxin is excreted exponentially with an average half-life of 36 hours, resulting in the loss of 35-40 percent of the body stores daily. Serum levels and pharmacokinetics are essentially unchanged by massive weight loss, suggesting that lean body mass should be used in dosage calculations. The peak blood level from oral dosing with tablets occurs 1-3 hours after administration. The onset of therapeutic action of digoxin after oral tablets is 1-2 hours, with the peak therapeutic effect occurring 6-8 hours after dosing. indications 1. Congestive heart failure, all degrees, is the primary indication. The increased cardiac output due to digoxin results in diuresis and general amelioration of the disturbances characteristic of right (venous congestion, edema) and left (dyspnea, orthopnea, cardiac asthma) heart failure. Digoxin, generally, is most effective in “low output” failure and less effective in “high output” (bronchopulmonary insufficiency, infection, hyperthyroidism) heart failure. Digoxin should be continued after heart failure is abolished unless some known precipitating factor is corrected. 2. Atrial fibrillation, especially when the ventricular rate is elevated. Digoxin rapidly reduces ventricular rates and eliminates the pulse deficit. Palpitation, precordial distress or weakness are relieved and any concomitant congestive failure ameliorated. Digoxin should be continued in doses necessary to maintain the desired ventricular rate and other clinical effects. 3. Atrial flutter. Digoxin slows the heart and regular sinus rhythm may appear. Frequently the flutter is converted to atrial fibrillation with a slow ventricular rate. Stopping digoxin at this point may be followed by restoration of sinus rhythm, especially if the flutter was of the paroxysmal type. It is preferable, however, to continue digoxin if failure ensues or if atrial flutter is a frequent occurrence. 4. Paroxysmal atrial tachycardia. Oral digoxin may be used, especially if the condition is resistant to lesser measures. Depending on the urgency, a more rapid acting parenteral preparation may be preferable to initiate digitalization, although if heart failure has ensued or paroxysms recur frequently, digoxin should be maintained by oral administration. Digoxin is not indicated in sinus tachycardia unless due to heart failure. 5. Cardiogenic shock. The drug is often employed, especially when the condition is accompanied by pulmonary edema. Digoxin seems to affect adversely shock due to septicemia from gram negative bacteria. contraindications The presence of toxic effects (See ADVERSE REACTIONS section) induced by any digitalis preparation is a contraindication to all of the gylcosides. Allergy, though rare, does occur. It may not extend to all preparations, and another may be tried. Ventricular fibrillation. Warnings Digitalis alone or with other drugs has been promoted for use in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs in the treatment of obesity is dangerous. Many of the arrhythmias for which digoxin is advised closely resemble those reflecting digoxin intoxication. If the possibility of digoxin intoxication cannot be excluded, cardiac glycosides should be temporarily withheld if permitted by the clinical situation. The patient with congestive heart failure may complain of nausea and vomiting. These symptoms may also be indications on digoxin intoxication. A clinical determination of the cause of these symptoms must be attempted before further drug administration. Patients with renal insufficiency require smaller than usual doses of digoxin. See ACTION section for mechanism. precautions Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Care must be taken to avoid digoxin toxicity if digoxin is used to help the arrhythmia. Digoxin is not indicated for the treatment of ventricular tachycardia unless congestive heart failure supervenes after a protracted episode not itself due to digoxin. Potassium depletion sensitizes the myocardium to digoxin, and toxicity may develop even with the usual dosage. Hypokalemia may also alter the rate of onset and intensity of the positive inotropic effect of digoxin. Therefore, it is desirable to maintain normal serum potassium levels in patients being treated with digoxin. Potassium wastage may result from diuretic or corticosteriod therapy, hemodialysis, and from suction of gastrointestinal secretions. It may accompany malnutrition, diarrhea, prolonged vomiting, old age, and long-standing congestive heart failure. In general, rapid changes in serum potassium or other electrolytes are to be avoided, and intravenous treatment with potassium should be reserved only for special circumstances as described below (see TREATMENT OF ARRHYTHMIAS PRODUCED BY OVERDOSAGES section). Patients with acute myocardial infarction, severe pulmonary disease, or far advanced heart failure may be more sensitive to digoxin and more prone to disturbances of rhythm. Calcium affects contractility and excitability of the heart in a manner similar to that of digoxin. Calcium may produce serious arrhythmias in digitalized patients. In myxedema the digoxin requirements are less because excretion rate is decreased and blood levels are significantly higher. In incomplete A-V block, especially in patients subject to Stokes-Adams attacks, advanced or complete heart block may develop if digoxin is given. Heart failure in these patients can usually be controlled by other measures and by increasing the heart rate. Patients with chronic constructive pericarditis may respond unfavorably to digoxin. Patients with idiopathic hypertrophic subaortic stenosis must be managed extremely carefully. Unless cardiac failure is severe, it is doubtful whether digoxin should be employed. Renal insufficiency delays the excretion of digoxin, and dosage must be adjusted accordingly in patients with renal disease. Note: This applies also to potassium administration should it become necessary. Electrical conversion of arrhythmias may require reduction of digoxin dosage. adverse reactions Gynecomastia, uncommon. Overdosage or toxic effects. Gastrointestinal: Anorexia, nausea, vomiting, diarrhea are the most common early symptoms of overdosages in the adult (but rarely conspicuous in infants). Uncontrolled heart failure may also produce such symptoms. Central nervous system: Visual disturbances (blurred vision, yellow vision), headache, weakness, apathy. Cardiac disturbances (arrhythmias): Ventricular premature beats are the most common, except in infants and young children. Paroxysmal and nonparoxysmal nodal rhythms, atrioventricular (interference) disassociation and paroxysmal atrial tachycardia (PAT) with block are also common arrhythmias due to digoxin overdosage. Conduction disturbances: Excessive slowing of the pulse is a clinical sign of digoxin overdosage. Atrioventricular block of increasing degree may proceed to complete heart block. Note: The electrocardiogram is fundamental in determining the presence and nature of these cardiac toxic disturbances. Digoxin may also induce other changes (as of the ST segment), but these provide no measure of the degree of digitalization. treatment of arrhythmias produced by overdosages Digoxin should be discontinued until all signs of toxicity are abolished. Discontinuation may be all that is necessary if toxic manifestations are not severe and appear after the time for peak effect of the drug. Potassium salts are commonly used. Potassium chloride in divided oral doses totaling 4-6 grams for adults (see PEDIATRIC INFORMATION section for pediatric dosage) may be given provided renal function is adequate. When correction of the arrhythmia is urgent and the serum potassium level is low or normal, potassium should be administered intravenously in a solution of 5 percent dextrose in water. A total of 40-100 milliequivalents (30 milliequivalents per 500 milliliters) is given at the rate of 20 milliequivalents per hour unless limited by pain due to local irritation. Additional amounts may be given if the arrhythmia is uncontrolled and the potassium well tolerated. Continuous electrocardiographic monitoring should be performed to watch for any evidence of potassium toxicity, e.g., peaking of T waves, and to observe the effect on the arrhythmia so that the infusion may be promptly stopped when the desired effect is achieved. Caution: Potassium should not be used and may be dangerous for severe or complete heart block due to digoxin and not related to any tachycardia. Other agents that have been approved for the treatment of digoxin intoxication include procainamide, lidocaine, and propranolol. dosage and administration Oral digoxin is administered slowly or rapidly as required until the desired therapeutic effect is obtained without symptoms of overdosage. The amount can be predicted approximately from the lean body mass of the patient with allowances made for excretion during the time taken to induce digitalization. Subsequent maintenance dosage is also determined tentatively by the amount necessary to sustain the desired therapeutic effect. Recommended dosages are practical average figures that may require considerable modification as dictated by individual sensitivity or associated conditions. Diminished renal function is the most important factor requiring modification of recommended or average doses. (See WARNINGS and PRECAUTIONS sections.) The average amount of digoxin that patients must accumulate to be digitalized with digoxin tablets is 1.0-1.5 milligrams. Digitalization may be accomplished by any of several approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount accumulated. In previously undigitalized patients, a single loading dose of 0.5-0.75 milligram orally usually produces a detectable effect in 1-2 hours that becomes maximal in 6-8 hours. Additional doses of 0.25-0.5 milligram may be given cautiously at 6-8 hour intervals to full digitalization. In previously undigitalized patients, institution of daily maintenance therapy (0.125-0.5 milligram, see next paragraph) without a loading dose results in development of a steady-state plateau concentrations in about 7 days in patients with normal renal function. The average daily oral maintenance dose is 0.125-0.5 milligram, usually 0.25 milligram. In the elderly patient, 0.125-0.25 milligram should be considered the average maintenance dose. In patients with renal impairment, digoxin excretion is impaired and serum half-life is prolonged (see ACTION section). Digitalizing and maintenance doses are lower than those recommended for patients with normal renal functions. Signs of digoxin toxicity develop sooner in patients with renal impairment, and it takes longer for toxic signs and symptoms to disappear. Because of the prolonged half-life, a longer period of time is required to achieve an initial or new steady-state plateau in patients with renal impairment than in patients with normal renal function. It cannot be overemphasized that the values given are averages and substantial individual variation can be expected. (If pediatric dosage is available, the labeling sections above should be expanded to include the following information.) pediatric information warnings Newborn infants display considerable variability in their tolerance to digoxin, depending on their degree of maturity. Premature and immature infants are particularly sensitive, and dosage must be reduced and digitalization should be even more individualized and cautiously approached than in more mature infants. Impaired renal function must also be carefully taken into consideration. Congestive heart failure accompanying acute glomerulonephritis requires extreme care in digitalization. A relatively low total dose administered in divided doses and concomitant use of antihypertensive drugs has been recommended. ECG monitoring is essential. Digoxin should be discontinued as soon as possible. Patients with idiopathic hypertrophic subaortic stenosis must be managed extremely carefully. Unless cardiac failure is severe, it is doubtful whether digoxin should be employed. Patients with rheumatic carditis, especially when severe, are unusually sensitive to digoxin and prone to disturbances of rhythm. If heart failure develops, digitalization may be initiated with relatively low doses; then it can be cautiously increased until a beneficial effect is obtained. If a therapeutic trial does not result in improvement, the drug should be considered ineffective and be discontinued. Note: Digitalis glycosides are an important cause of accidental poisoning in children. precautions Dosage must be carefully titrated and differences in the bioavailability of parenteral preparations, elixirs, and tablets should be taken into account when switching patients from one preparation to another. Electrocardiographic monitoring may be necessary to avoid intoxication. Premonitory signs of toxicity in the newborn are undue slowing of the sinus rate, sinoatrial arrest, and prolongation of PR interval. adverse reactions Toxic signs differ from the adult in a number of respects. Cardiac arrhythmias are the more reliable and frequent signs of toxicity. Vomiting and diarrhea, neurologic and visual disturbances are rare as initial signs. Premature ventricular systoles are rarely seen; nodal and atrial systoles are more frequent. Atrial arrhythmias, atrial ectopic rhythms, and paroxysmal atrial tachycardia with A-V block particularly are more common manifestations of toxicity in children. Ventricular arrhythmias are rare. treatment of arrhythmias produced by overdosages (See adult section for other recommendations for the treatment of arrhythmias produced by overdosages and for additional recommendations and cautions regarding the use of potassium.) Potassium preparations may be given orally in divided doses totaling 1-1.5 milliequivalents/kilogram (1 gram K contains 13.4 milliequivalents). When correction of the arrhythmia is urgent, approximately 0.5 milliequivalents/kilogram of potassium per hour may be given, with careful electrocardiographic monitoring, as a solution of 20 milliequivalents or less per 500 milliliters in 5 percent dextrose in water. The total dose should generally not exceed 2 milliequivalents of potassium/kilogram. dosage and administration Digitalization must be individualized. Generally, premature and immature infants are particularly sensitive, requiring reduced dosage that must be determined by careful titration. Oral Dosage. Beyond the immediate newborn period, children require proportionally greater doses than adults on the basis of body weight or surface area. The recommended oral digitalizing dosages in children with normal renal function are: Newborn infants (normal), up to 1 month, require 40-60 micrograms/kilogram. Infants, 1 month to 2 years, require approximately 60-80 micrograms/kilogram. Children 2 years to 10 years, require 40-60 micrograms/kilogram. Children, over 10 years of age, require adult dosages in proportion to their body weight. Maintenance therapy is 20-30 percent of the digitalizing dose administered each day. Long term use of digoxin is indicated in almost all infants who have been digitalized for acute congestive heart failure unless the cause is transient. Many favor maintaining digoxin until at least 2 years of age in all infants with paroxysmal atrial tachycardia or in those who show either definite or latent failure. Many children with severe inoperable congenital defects need digoxin throughout childhood and often for life. (f) Abbreviated new drug applications shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857. (g) All samples of digoxin tablets required by paragraph (a)(3) of this section to be submitted to the Food and Drug Administration shall be handled as follows: (1) The sample shall consist of 6 subsamples of 1000 tablets each collected at random from throughout the manufacturing run. Each of the 6 subsamples shall be identified with the name of the product, the labeled potency, the date of manufacture, the batch number, and the name and address of the manufacturer. (2) The sample together with the batch production record and results of all tests conducted by or for the manufacturer to determine the product's identity, strength, quality, and purity, content uniformity and dissolution shall be submitted to the Department of Health and Human Services, Public Health Service, FDA National Center for Drug Analysis, 1114 Market St., St. Louis, MO 63101. The outer wrapper shall be identified “SAMPLE—DIGOXIN CERTIFICATION.” (h) The Food and Drug Administration is aware of data with two in vitro methods, in addition to that described in The United States Pharmacopeia (USP XVIII), developed to measure digoxin tablets dissolution. These two methods, the so-called “paddle-water” and “paddle-acid” methods, are described below and are identical with the exception of the nature of the dissolution medium used in the procedures (i.e., distilled or deionized water vs. dilute hydrochloric acid (0.6 percent volume/volume)). The dissolution apparatus used in these two methods differs significantly from the apparatus described in the method in the compendium. The Food and Drug Administration is aware that the three methods (i.e., USP, “paddle-water,” and “paddle-acid”) show significant differences in dissolution in comparative tests on some formulations. Definitive bioavailability data to compare the relative value of each of these methods to predict bioavailability of the few formulations where the methods show significant differences in dissolution rate are not now available. Manufacturers who conduct research utilizing the “paddle-water” and “paddle-acid” methods, particularly in comparison with the method in The United States Pharmacopeia, shall submit any data obtained using these methods to the Food and Drug Administration pursuant to section 505(k) of the act. (1) Dissolution apparatus. (Note: Throughout this procedure use scrupulously clean glassware, which previously has been rinsed with dilute hydrochloric acid, distilled or deionized water, then with alcohol, and carefully dried. Take precautions to prevent contamination from airborne, fluorescent particles and from metal and rubber surfaces.) The apparatus consists of a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No. 26220 or equivalent), a motor, and a polytetrafluoroethylene stirring blade (Sargent S-76637, Size B, 3 inch length; or equivalent) on a glass stirring shaft (Sargent 5-76636, 14.5 inch length; or equivalent). The water bath may be of any convenient size that permits keeping the water temperature uniformly at 37° C. ±0.5° C. throughout the test. The vessel is spherical, and is provided with three ports at the top, one of which is centered. The lower half of the vessel is 65 millimeters in inside radius and the vessel's nominal capacity is 1000 milliliters. The glass stirring shaft from the motor is placed in the center port, and one of the outer ports may be used for insertion of a thermometer. Samples may be removed for analysis through the other port. The motor is fitted with a speed-regulating device that allows the motor speed to be held at 50 rpm ±2 rpm. The motor is suspended above the vessel in such a way that it may be raised or lowered to position the stirring blade. The glass stirring shaft is 10 millimeters in diameter and about 37 centimeters in length. It must run true on the motor axis without perceptible wobble. The polytetrafluoroethylene stirring blade is 4 millimeters thick and forms a section of a circle, whose diameter is 83 millimeters and which is subtended by parallel chords of 42 and 77 millimeters. The blade is positioned horizontally, with the 42-millimeter edge down, 2.5 centimeters ±0.2 centimeter above the lowest inner surface of the vessel. (2) Reagents—(i) Dissolution medium. For “paddle-water,” use distilled or deionized water. For “paddle-acid,” use dilute hydrochloric acid (0.6 percent volume/volume). Use the same batch of dissolution medium throughout the test. (ii) Standard solutions. Accurately weigh approximately 25 milligrams of The United States Pharmacopeia Digoxin Reference Standard, dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter volumetric flask and add 95 percent ethanol to volume and mix. Dilute 10.0 milliliters of this first solution to 100.0 milliliters with 95 percent ethanol and mix for the second solution. Just prior to use, individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of the second solution with dissolution medium to 50.0 milliliters. These solutions are equivalent to 20, 40, 60, 80, and 100 percent of dissolution, respectively, for a 0.25 milligram digoxin tablet. (iii) Extraction solvent. Prepare a solvent containing 6 volumes of chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol, analytical reagent grade. (iv) Ascorbic acid-methanol solution. Prepare a solution containing 2 milligrams of ascorbic acid, analytical reagent grade, per 1 milliliter of methanol, absolute, analytical reagent grade. (v) Hydrochloric acid, concentrated reagent grade. (vi) Hydrogen peroxide-methanol solution. On the day of use, dilute 2.0 milliliters of recently assayed 30 percent hydrogen peroxide, reagent grade, with methanol, absolute, analytical reagent grade to 100.0 milliliters. Store in a refrigerator. Just prior to use, dilute 2.0 milliliters of this solution with methanol to 100.0 milliliters. (3) Procedure—(i) Dissolution. Place 500 milliliters of dissolution medium in the vessel, immerse it in the constant-temperature bath set at 37°C.±0.5°C., and allow the dissolution medium to assume the temperature of the bath. Position the shaft so that there is a distance of 2.5 centimeters ±0.2 centimeter between the midpoint of the bottom of the blade and the bottom of the vessel. With the stirrer operating at a speed of 50 rpm±2 rpm, place 1 tablet into the flask. After 60 minutes, accurately timed, withdraw 25 milliliters, using a glass syringe connected to a glass sampling tube, of solution from a point midway between the stirring shaft and the wall of the vessel, and approximately midway in depth. Filter the solution promptly after withdrawal, using a suitable membrane filter of not greater than 0.8 micron porosity (Millipore AAWP 025 00, or equivalent), mounted in a suitable holder (Millipore Swinnex SX00 025 00, or equivalent), discarding the first 100 milliliters of filtrate. This is the test solution. Repeat the dissolution procedure on 5 additional tablets. (ii) Extraction. Transfer 10.0 milliliters of each of the six filtrates, 10.0 milliliters of each of the five standard solutions, and 10.0 milliliters of dissolution medium, to provide a blank, in separate 60-milliliter separators. Extract each solution with two 10-milliliter portions of extraction solvent. Combine the extracts of each solution in separate, glass-stoppered, 50-milliliter conical flasks, and evaporate on a steam bath with the aid of a stream of nitrogen to dryness, rinsing the sides of the flasks with extraction solvent. Take care to ensure that all traces of solvent are removed, but avoid prolonged heating. For convenience the residues may be stored in a vacuum desiccator overnight. (iii) Measurement of fluorescence. Begin with the standard solutions, and keep all flasks in the same sequence throughout, so that the elapsed time from addition of reagents to reading of fluorescence is the same for each. Carry the test solutions, standard solutions, and the blank through the determination in one group. Add the following three reagents in as rapid a sequence as possible, swirling after each addition, treating 1 flask at a time, in the order named: 1.0 milliliter of ascorbic acid-methanol solution, 3.0 milliliters of concentrated hydrochloric acid, and 1.0 milliliter of hydrogen peroxide-methanol solution. Insert the stoppers in the flasks, and after 2 hours, measure the fluorescence at about 485 millimicrons, using excitation at about 372 millimicrons. In order to provide a check on the stability of the fluorometer, reread one or more standard solutions. Correct each reading for the blank and plot a standard curve of fluorescence versus precentage dissolution. Determine the percentage dissolution of digoxin in the test solutions by reading from the standard graph. (iv) Digoxin tablets formulated so that the quantity of digoxin dissolved at one hour, when tested by the method in The United States Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed amount of digoxin and so that the quantity of digoxin dissolved at 15 minutes is greater than 90 percent of the assayed amount of digoxin are new drugs which may be marketed only with an approved full new drug application as provided for in § 314.50 of this chapter. The application shall include, but not be limited to, clinical studies establishing significantly greater bioavailability than digoxin tablets meeting compendial requirements and dosage recommendations based on clinical studies establishing the safe and effective use of the bioavailable digoxin product. Marketing of these digoxin products will be allowed only under a proprietary or trade name, established name, and labeling which differs from that used for digoxin tablets that meet all of the requirements in The United States Pharmacopeia (USP XVIII) and that are formulated so that either (a) the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin. New drug applications for these digoxin products shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Drug Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, MD 20857.

regulation

[{"label": "(a)", "text": "Studies have shown evidence of clinically significant differences in bio-availability in different batches of certain marketed digoxin products for oral use from single manufacturers as well as in batches of these products produced by different manufacturers. These differences were observed despite the fact that the products met compendial specifications. Other studies have shown that there is a sufficient correlation between bioavailabil-ity in vivo and the dissolution rate of digoxin tablets in vitro to make the dissolution test an important addition to the compendial standards. Because of the potential for serious risk to cardiac patients using digoxin products which may vary in bioavailability, the Commissioner of Food and Drugs has determined that immediate action must be taken to assure the uniformity of all digoxin products for oral use. The Commissioner is of the opinion that digoxin products for oral use are new drugs within the meaning of section 201(p) of the Federal Food, D", "source": null}, {"label": "(1)", "text": "Digoxin products for oral use, other than tablets: Any person marketing digoxin products for oral use, other than tablets, shall submit to the Food and Drug Administration on or before February 21, 1974, an abbreviated new drug application for these products. Any such drug product then on the market which is not the subject of an application submitted for the drug product shall be subject to regulatory procedures under section 505 of the act. In addition to the information specified in § 314.50 of this chapter, the application shall contain:", "source": null}, {"label": "(i)", "text": "A full list of the articles used as components of the digoxin product, specifications for components, detailed identification and analytical procedures used to assure that the components meet established specifications of identity, strength, quality, and purity and a complete description of the manufacturing process.", "source": null}, {"label": "(ii)", "text": "The source of the digoxin used in the formulation including the name and address of the supplier.", "source": null}, {"label": "(iii)", "text": "A statement that stability studies will be conducted to establish a suitable expiration date for the digoxin product in the form in which it is distributed.", "source": null}, {"label": "(iv)", "text": "A statement that the product label will contain a suitable expiration date. In the absence of any stability test data, this expiration date shall be no longer than one year after the batch is manufactured. If the expiration date is greater than one year, supporting stability data shall be included in the application.", "source": null}, {"label": "(v)", "text": "Labeling that is in compliance with all requirements of the act and regulations promulgated thereunder, the pertinent parts of which are as indicated in paragraph (e) of this section.", "source": null}, {"label": "(vi)", "text": "A statement that the applicant will initiate recall of all stocks of the drug product outstanding when so requested by the Food and Drug Administration.", "source": null}, {"label": "(vii)", "text": "A statement that the applicant intends to conduct in vivo bioavailability tests and that the applicant, under the records and reports provisions of section 505(k) of the act, will:", "source": null}, {"label": "(a)", "text": "Within 30 days after the submission of the application, submit to the Food and Drug Administration the protocol which the applicant proposes to follow in conducting these in vivo bioavailability tests. The protocol shall contain all of the essential elements set forth in paragraph (d) of this section. The tests shall not be initiated prior to receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed and either approved or its deficiencies delineated.", "source": null}, {"label": "(b)", "text": "Within 180 days after receiving notification from the Food and Drug Administration that the bioavailability protocol has been reviewed, submit to the Food and Drug Administration the results of the in vivo bioavailability tests.", "source": null}, {"label": "(2)", "text": "Digoxin tablets: Any person marketing digoxin tablets, in addition to complying with all of the requirements of paragraph (a)(1) of this section, shall include in their abbreviated new drug application:", "source": null}, {"label": "(i)", "text": "A statement that the applicant will establish procedures to test each lot of digoxin tablets prior to releasing the batch for distribution to assure that the batch meets all of The United States Pharmacopeia (USP XVIII) requirements for digoxin tablets including, but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.", "source": null}, {"label": "(ii)", "text": "A statement that finished product specifications shall be established to include provisions to assure that the range of average one-hour dissolution values among batches of digoxin tablets does not exceed 20 percent.", "source": null}, {"label": "(3)", "text": "Before releasing for distribution any batch of digoxin tablets manufactured after January 22, 1974, the manufacturer shall:", "source": null}, {"label": "(i)", "text": "Test a sample of the batch to assure that the batch meets all of the requirements of The United States Pharmacopeia (USP XVIII) including but not limited to, potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.", "source": null}, {"label": "(ii)", "text": "Submit a sample of the batch to the Food and Drug Administration according to the procedures set forth in paragraph (g) of this section. Results of tests conducted on the batch by or for the manufacturer and the batch production record shall accompany the sample.", "source": null}, {"label": "(iii)", "text": "Withhold the batch from distribution until he is notified by the Food and Drug Administration that the sample was tested and found to meet all of the requirements in The United States Pharmacopeia (USP XVIII) for potency, content uniformity, and dissolution and either (a) that the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) that the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin.", "source": null}, {"label": "(iv)", "text": "Submit a sample of each batch of digoxin tablets as provided for in paragraph (a)(3)(ii) of this section until he is notified by the Food and Drug Administration that he is released from the certification program. This notification will be made on the basis of sample test results, inspectional findings regarding compliance with current good manufacturing practice, and compliance with all other requirements of this section and any other directives issued by the Food and Drug Administration as a condition for release from the certification program.", "source": null}, {"label": "(4)", "text": "Any manufacturer who has distributed any batch of digoxin tablets which does not meet the compendial requirement for dissolution, when tested by the method in The United States Pharmacopeia (USP XVIII), shall initiate recall of the subject batch when so requested by the Food and Drug Administration.", "source": null}, {"label": "(b)", "text": "Failure of an applicant to submit the protocol and/or the results of the in vivo bioavailability tests showing adequate evidence of the product's bioavailability within the times specified in paragraph (a)(1)(vii) of this section and/or to comply with all of the certification requirements of paragraph (a)(3) of this section shall be justification for withdrawal of approval of the application under section 505(e) of the act.", "source": null}, {"label": "(c)", "text": "Any product reformulation or change in manufacturing process will require the submission of a supplement to the approved abbreviated new drug application containing adequate data to demonstrate the bioavailability of the reformulated product. Food and Drug Administration approval of the supplement is required before the reformulated product is marketed. The Food and Drug Administration recommends that, where digoxin tablets are reformulated, manufacturers reformulate their product to achieve dissolution of 70 to 90 percent at one hour when tested by all three methods (i.e., the USP method, and the “paddle-water” and “paddle-acid” methods) described in paragraph (h) of this section.", "source": null}, {"label": "(d)", "text": "The protocol for the in vivo bioavailability tests required in paragraphs (a) and (c) of this section shall employ a three-way crossover design using the digoxin test product; a reference digoxin tablet supplied, on request, by the Food and Drug Administration; and bulk digoxin USP in an oral solution. Appropriate venous blood and urinary samples are to be collected and analyzed. The method shall be capable of detecting the difference between the reference tablet and the reference oral solution. Bioavailability of the test product shall be demonstrated if a mean absorption of at least 75 percent of the combined mean of the two reference standards is observed. Assistance in developing a protocol for a particular dosage formulation may be obtained by contacting the Food and Drug Administration, Center for Drug Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD 20857.", "source": null}, {"label": "(e)", "text": "Parts of the digoxin product labeling indicated below shall be as follows:", "source": null}, {"label": "(f)", "text": "Abbreviated new drug applications shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857.", "source": null}, {"label": "(g)", "text": "All samples of digoxin tablets required by paragraph (a)(3) of this section to be submitted to the Food and Drug Administration shall be handled as follows:", "source": null}, {"label": "(1)", "text": "The sample shall consist of 6 subsamples of 1000 tablets each collected at random from throughout the manufacturing run. Each of the 6 subsamples shall be identified with the name of the product, the labeled potency, the date of manufacture, the batch number, and the name and address of the manufacturer.", "source": null}, {"label": "(2)", "text": "The sample together with the batch production record and results of all tests conducted by or for the manufacturer to determine the product's identity, strength, quality, and purity, content uniformity and dissolution shall be submitted to the Department of Health and Human Services, Public Health Service, FDA National Center for Drug Analysis, 1114 Market St., St. Louis, MO 63101. The outer wrapper shall be identified “SAMPLE—DIGOXIN CERTIFICATION.”", "source": null}, {"label": "(h)", "text": "The Food and Drug Administration is aware of data with two in vitro methods, in addition to that described in The United States Pharmacopeia (USP XVIII), developed to measure digoxin tablets dissolution. These two methods, the so-called “paddle-water” and “paddle-acid” methods, are described below and are identical with the exception of the nature of the dissolution medium used in the procedures (i.e., distilled or deionized water vs. dilute hydrochloric acid (0.6 percent volume/volume)). The dissolution apparatus used in these two methods differs significantly from the apparatus described in the method in the compendium. The Food and Drug Administration is aware that the three methods (i.e., USP, “paddle-water,” and “paddle-acid”) show significant differences in dissolution in comparative tests on some formulations. Definitive bioavailability data to compare the relative value of each of these methods to predict bioavailability of the few formulations where the methods show significan", "source": null}, {"label": "(1)", "text": "Dissolution apparatus.", "source": null}, {"label": "(2)", "text": "Reagents—(i) Dissolution medium. For “paddle-water,” use distilled or deionized water. For “paddle-acid,” use dilute hydrochloric acid (0.6 percent volume/volume). Use the same batch of dissolution medium throughout the test.", "source": null}, {"label": "(ii)", "text": "Standard solutions. Accurately weigh approximately 25 milligrams of The United States Pharmacopeia Digoxin Reference Standard, dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter volumetric flask and add 95 percent ethanol to volume and mix. Dilute 10.0 milliliters of this first solution to 100.0 milliliters with 95 percent ethanol and mix for the second solution. Just prior to use, individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of the second solution with dissolution medium to 50.0 milliliters. These solutions are equivalent to 20, 40, 60, 80, and 100 percent of dissolution, respectively, for a 0.25 milligram digoxin tablet.", "source": null}, {"label": "(iii)", "text": "Extraction solvent. Prepare a solvent containing 6 volumes of chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol, analytical reagent grade.", "source": null}, {"label": "(iv)", "text": "Ascorbic acid-methanol solution. Prepare a solution containing 2 milligrams of ascorbic acid, analytical reagent grade, per 1 milliliter of methanol, absolute, analytical reagent grade.", "source": null}, {"label": "(v)", "text": "Hydrochloric acid, concentrated reagent grade.", "source": null}, {"label": "(vi)", "text": "Hydrogen peroxide-methanol solution. On the day of use, dilute 2.0 milliliters of recently assayed 30 percent hydrogen peroxide, reagent grade, with methanol, absolute, analytical reagent grade to 100.0 milliliters. Store in a refrigerator. Just prior to use, dilute 2.0 milliliters of this solution with methanol to 100.0 milliliters.", "source": null}, {"label": "(3)", "text": "Procedure—(i) Dissolution. Place 500 milliliters of dissolution medium in the vessel, immerse it in the constant-temperature bath set at 37°C.±0.5°C., and allow the dissolution medium to assume the temperature of the bath. Position the shaft so that there is a distance of 2.5 centimeters ±0.2 centimeter between the midpoint of the bottom of the blade and the bottom of the vessel. With the stirrer operating at a speed of 50 rpm±2 rpm, place 1 tablet into the flask. After 60 minutes, accurately timed, withdraw 25 milliliters, using a glass syringe connected to a glass sampling tube, of solution from a point midway between the stirring shaft and the wall of the vessel, and approximately midway in depth. Filter the solution promptly after withdrawal, using a suitable membrane filter of not greater than 0.8 micron porosity (Millipore AAWP 025 00, or equivalent), mounted in a suitable holder (Millipore Swinnex SX00 025 00, or equivalent), discarding the first 100 milliliters of filtrate. Thi", "source": null}, {"label": "(ii)", "text": "Extraction. Transfer 10.0 milliliters of each of the six filtrates, 10.0 milliliters of each of the five standard solutions, and 10.0 milliliters of dissolution medium, to provide a blank, in separate 60-milliliter separators. Extract each solution with two 10-milliliter portions of extraction solvent. Combine the extracts of each solution in separate, glass-stoppered, 50-milliliter conical flasks, and evaporate on a steam bath with the aid of a stream of nitrogen to dryness, rinsing the sides of the flasks with extraction solvent. Take care to ensure that all traces of solvent are removed, but avoid prolonged heating. For convenience the residues may be stored in a vacuum desiccator overnight.", "source": null}, {"label": "(iii)", "text": "Measurement of fluorescence. Begin with the standard solutions, and keep all flasks in the same sequence throughout, so that the elapsed time from addition of reagents to reading of fluorescence is the same for each. Carry the test solutions, standard solutions, and the blank through the determination in one group. Add the following three reagents in as rapid a sequence as possible, swirling after each addition, treating 1 flask at a time, in the order named: 1.0 milliliter of ascorbic acid-methanol solution, 3.0 milliliters of concentrated hydrochloric acid, and 1.0 milliliter of hydrogen peroxide-methanol solution. Insert the stoppers in the flasks, and after 2 hours, measure the fluorescence at about 485 millimicrons, using excitation at about 372 millimicrons. In order to provide a check on the stability of the fluorometer, reread one or more standard solutions. Correct each reading for the blank and plot a standard curve of fluorescence versus precentage dissolution. Determine the", "source": null}, {"label": "(iv)", "text": "Digoxin tablets formulated so that the quantity of digoxin dissolved at one hour, when tested by the method in The United States Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed amount of digoxin and so that the quantity of digoxin dissolved at 15 minutes is greater than 90 percent of the assayed amount of digoxin are new drugs which may be marketed only with an approved full new drug application as provided for in § 314.50 of this chapter. The application shall include, but not be limited to, clinical studies establishing significantly greater bioavailability than digoxin tablets meeting compendial requirements and dosage recommendations based on clinical studies establishing the safe and effective use of the bioavailable digoxin product. Marketing of these digoxin products will be allowed only under a proprietary or trade name, established name, and labeling which differs from that used for digoxin tablets that meet all of the requirements in The United States Phar", "source": null}]

§ 314.50

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 43137, Sept. 30, 1976; 41 FR 49482, Nov. 3, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

8 hour; 36 hours; 2 hours; 180 days; 1 month; 30 days; 10 years; 7 days; 2 years; 8 hours; 3 hours

False

True

180 days; at least 2 year; within 180 day; within 30 day; 30 days

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.500

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.501

Patient package inserts for oral contraceptives.

(a) Requirement for a patient package insert. The safe and effective use of oral contraceptive drug products requires that patients be fully informed of the benefits and the risks involved in their use. An oral contraceptive drug product that does not comply with the requirements of this section is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act. Each dispenser of an oral contraceptive drug product shall provide a patient package insert to each patient (or to an agent of the patient) to whom the product is dispensed, except that the dispenser may provide the insert to the parent or legal guardian of a legally incompetent patient (or to the agent of either). The patient package insert is required to be placed in or accompany each package dispensed to the patient. (b) Distribution requirements. (1) For oral contraceptive drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient. (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) Contents of patient package insert. A patient package insert for an oral contraceptive drug product is required to contain the following: (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 and risks from the use of oral contraceptives. (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) Other indications. The patient package insert may identify indications in addition to contraception that are identified in the professional labeling for the drug product. (e) Labeling guidance texts. The Food and Drug Administration issues informal labeling guidance texts under § 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of this section. A request for a copy of the guidance texts should be directed to the Center for Drug Evaluation and Research, Division of Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. (f) Requirement to supplement approved application. Holders of approved applications for oral contraceptive drug products that are subject to the requirements of this section are required to submit supplements under § 314.70(c) of this chapter to provide for the labeling required by this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.

regulation

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(1) For oral contraceptive drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(c)", "text": "Contents of patient package insert. A patient package insert for an oral contraceptive drug product is required to contain the following:", "source": null}, {"label": "(1)", "text": "The name of the drug.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "A statement comparing the effectiveness of oral contraceptives to other methods of contraception.", "source": null}, {"label": "(4)", "text": "A boxed warning concerning the increased risks associated with cigarette smoking and oral contraceptive use.", "source": null}, {"label": "(5)", "text": "A discussion of the contraindications to use, including information that the patient should provide to the prescriber before taking the drug.", "source": null}, {"label": "(6)", "text": "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.", "source": null}, {"label": "(7)", "text": "A warning regarding the most serious side effects of oral contraceptives.", "source": null}, {"label": "(8)", "text": "A statement of other serious adverse reactions and potential safety hazards that may result from the use of oral contraceptives.", "source": null}, {"label": "(9)", "text": "A statement concerning common, but less serious side effects which may help the patient evaluate the benefits and risks from the use of oral contraceptives.", "source": null}, {"label": "(10)", "text": "Information on precautions the patients should observe while taking oral contraceptives, including the following:", "source": null}, {"label": "(i)", "text": "A statement of risks to the mother and unborn child from the use of oral contraceptives before or during early pregnancy;", "source": null}, {"label": "(ii)", "text": "A statement concerning excretion of the drug in human milk and associated risks to the nursing infant;", "source": null}, {"label": "(iii)", "text": "A statement about laboratory tests which may be affected by oral contraceptives; and", "source": null}, {"label": "(iv)", "text": "A statement that identifies activities and drugs, foods, or other substances the patient should avoid because of their interactions with oral contraceptives.", "source": null}, {"label": "(11)", "text": "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.", "source": null}, {"label": "(12)", "text": "A statement of the possible benefits associated with oral contraceptive use.", "source": null}, {"label": "(13)", "text": "The following information about the drug product and the patient package insert:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(d)", "text": "Other indications. The patient package insert may identify indications in addition to contraception that are identified in the professional labeling for the drug product.", "source": null}, {"label": "(e)", "text": "Labeling guidance texts. The Food and Drug Administration issues informal labeling guidance texts under § 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of this section. A request for a copy of the guidance texts should be directed to the Center for Drug Evaluation and Research, Division of Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.", "source": null}, {"label": "(f)", "text": "Requirement to supplement approved application. Holders of approved applications for oral contraceptive drug products that are subject to the requirements of this section are required to submit supplements under § 314.70(c) of this chapter to provide for the labeling required by this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.", "source": null}]

§ 10.90; § 314.70

[54 FR 22587, May 25, 1989]

May 25, 1989

(Revised as of April 1, 1996)

False

30 days

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.501

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.502

Intrauterine devices for human use for the purpose of contraception.

(a) New drug status of certain intrauterine devices for human use for the purpose of contraception. (1) The Food and Drug Administration has become aware of the increased clinical use for the purpose of contraception of intrauterine devices (IUD's) that incorporate heavy metals, drugs, or other active substances. The amount of local irritation caused by such active materials has been reported as being correlated, in animal studies, to the efficacy of such devices in achieving their contraceptive effect. Several investigators have reported different pregnancy rates which appear to be dependent on the type of metal used and/or the amount of exposed surface of the metal. Drugs have been incorporated with otherwise inert intrauterine devices to increase the contraceptive effect, decrease adverse reactions, or provide increased medical acceptability. (2) Intrauterine devices used for the purpose of contraception and incorporating heavy metals, drugs, or other active substances to increase the contraceptive effect, to decrease adverse reactions, or to provide increased medical acceptability, are not generally recognized as safe and effective for contraception and are new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. A completed and signed “Investigational New Drug Application” set forth in part 312 of this chapter) must therefore be submitted to cover clinical investigations to obtain evidence that such preparations are safe and effective for this use. An approved new drug application is required for the marketing of such articles. (b) Labeling of intrauterine contraceptive devices considered new drugs (drug IUD's). The intrauterine contraceptive device is a popular method of contraception used by several million women in the United States. Although this method of contraception is generally safe and effective, certain complications and side effects may result from its use. A Food and Drug Administration review of the labeling of intrauterine contraceptive devices currently marketed in the United States reveals that information necessary for the safe and effective use of these products is not uniformly available to either the practitioner or the patient. Based on the review of the labeling and on the recommendations of the Ad Hoc Obstetric-Gynecology Advisory Committee, the Commissioner has concluded that in the interest of safe and effective use, and prevention of misleading labeling, there is a need to establish uniform physician and patient labeling for such drugs. (1) Labeling accompanying each drug IUD and directed to the physician shall be substantially as follows, adjusted where appropriate to the requirements of a particular drug IUD. Description (To be supplied by manufacturer) Description shall include the following information: 1. Proprietary or established name of the IUD. 2. Major ingredients or composition. 3. Model. 4. Physical dimensions (size and shape). 5. Description of components in package or system. 6. A statement that the product is sterile. 7. Other characteristics. Mode of Action or Principles of IUD Design (To be supplied by the manufacturer) The manufacturer shall include information on the mode of action or principles of the IUD's design. At a minimum, the statement should provide that IUD's seem to interfere in some manner with nidation in the endometrium, probably through foreign body reaction in the uterus. Indications and Usage The labeling may include indications and usages other than those stated below, provided that an approved new drug application is in effect. (Name of drug IUD) is indicated for contraception. Contraindications IUD's should not be inserted when the following conditions exist: 1. Pregnancy or suspicion of pregnancy. 2. Abnormalities of the uterus resulting in distortion of the uterine cavity. 3. Acute pelvic inflammatory disease or a history of repeated pelvic inflammatory disease. 4. Post partum endometritis or infected abortion in the past 3 months. 5. Known or suspected uterine or cervical malignancy including unresolved, abnormal “Pap” smear. 6. Genital bleeding of unknown etiology. 7. Untreated acute cervicitis until infection is controlled. 8. Copper-containing IUD's should not be inserted in presence of diagnosed Wilson's Disease. 9. Known allergy to copper. (For copper-containing IUD's.) Warnings 1. Pregnancy— a. Long-term effects.—Long-term effects on the offspring when pregnancy occurs with (name of drug IUD) in place are unknown. b. Septic abortion. Reports have indicated an increased incidence of septic abortion associated in some instances with septicemia, septic shock, and death in patients becoming pregnant with an IUD in place. Most of these reports have been associated with the mid-trimester of pregnacy. In some cases, the initial symptoms have been insidious and not easily recognized. If pregnancy should occur with an IUD in place, the IUD should be removed if the string is visible or, if removal proves to be or would be difficult, termination of the pregnancy should be considered and offered the patient as an option bearing in mind that the risks associated with an elective abortion increase with gestational age. c. Continuation of pregnancy. If the patient chooses to continue the pregnancy, she must be warned of the increased risk of spontaneous abortion and of the increased risk of sepsis, including death if the pregnancy continues with the IUD in place. The patient must be closely observed and she must be advised to report all abnormal symptoms, such as flu-like syndrome, fever, abdominal cramping and pain, bleeding, or vaginal discharge immediately because generalized symptoms of septicemia may be insidious. 2. Ectopic pregnancy. a. A pregnancy that occurs with an IUD in place is more likely to be ectopic than a pregnancy occurring without an IUD in place. Accordingly, patients who become pregnant while using the IUD should be carefully evaluated for the possibility of an ectopic pregnancy. b. Special attention should be directed to patients with delayed menses, slight metrorrhagia and/or unilateral pelvic pain and to those patients who wish to terminate a pregnancy because of IUD failure to determine whether ectopic pregnancy has occurred. 3. Pelvic infection. Pelvic infection may occur with the IUD in place and at times result in the development of tubo-ovarian abscesses or general peritonitis. Appropriate aerobic and anaerobic bacteriologocal studies should be done and antibiotic therapy initiated. If the infection does not show a marked clinical improvement within 24 to 48 hours, the IUD should be removed and the continuing treatment reassessed based upon the results of culture and sensitivity tests. 4. Embedment. Partial penetration or lodging of the IUD in the edometrium can result in difficult removals. 5. Perforation. Partial or total perforation of the uterine wall or cervix may occur with the use of IUD's. The possibility of perforation must be kept in mind during insertion and at the time of any subsequent examination. If perforation occurs, the IUD should be removed. Adhesions, foreign body reactions, and intestinal obstruction may result if an IUD is left in the peritioneal cavity. 6. Congenital anomalies. Systemically administered sex steroids, including progestational agents, have been associated with an increased risk of congenital anomalies. It is not known whether such anomalies could occur when pregnancy is continued with a progesterone-containing IUD in place. Precautions 1. Patient counseling. Prior to insertion the physician, nurse, or other trained health professional must provide the patient with the Patient Brochure. The patient should be given the opportunity to read the brochure and discuss fully any questions she may have concerning the IUD as well as other methods of contraception. 2. Patient evaluation and clinical considerations. a. A complete medical history should be obtained to determine conditions that might influence the selection of an IUD. Physical examination should include a pelvic examination, “Pap” smear, gonorrhea culture and, if indicated, appropriate tests for other forms of venereal disease. b. The uterus should be carefully sounded prior to insertion to determine the degree of patency of the endocervical canal and the internal os, and the direction and depth of the uterine cavity. In occasional cases, severe cervical stenosis may be encountered. Do not use excessive force to overcome this resistance. c. The uterus should sound to a depth of 6 to 8 centimeters (cm). Insertion of an IUD into a uterine cavity measuring less than 6.5 cm by sounding may increase the incidence of expulsion, bleeding, and pain. d. The possibility of insertion in the presence of an existing undetermined pregnancy is reduced if insertion is performed during or shortly following a menstrual period. The IUD should not be inserted post partum or postabortion until involution of the uterus is completed. The incidence of perforation and expulsion is greater if involution is not completed. e. IUD's should be used with caution in those patients who have an anemia or a history of menorrhagia or hypermenorrhea. Patients experiencing menorrhagia and/or metrorrhagia following IUD insertion may be at risk for the development of hypochromic microcytic anemia. Also, IUD's should be used with caution in patients receiving anticoagulants or having a coagulopathy. f. Syncope, bradycardia or other neurovascular episodes may occur during insertion or removal of IUD's especially in patients with a previous disposition to these conditions. g. Patients with valvular or congenital heart disease are more prone to develop subacute bacterial endocarditis than patients who do not have valvular or congenital heart disease. Use of an IUD in these patients may represent a potential source of septic emboli. h. Use of an IUD in those patients with acute cervicitis should be postponed until proper treatment has cleared up the infection. i. Since an IUD may be expelled or displaced, patients should be reexamined and evaluated shortly after the first postinsertion menses, but definitely within 3 months after insertion. Thereafter annual examination with appropriate medical and laboratory examination should be carried out. The IUD should be replaced every ---- years (information to be supplied by manufacturer). j. The patient should be told that some bleeding and cramps may occur during the first few weeks after insertion, but if her symptoms continue or are severe she should report them to her physician. She should be instructed on how to check after each menstrual period to make certain that the thread still protrudes from the cervix, and she should be cautioned that there is no contraceptive protection if the IUD is expelled. She should be cautioned not to pull on the thread and displace the IUD. If partial expulsion occurs, removal is indicated and a new IUD may be inserted. The patient should be told to return in ---- years for replacement of the IUD. k. The use of medical diathermy (shortwave and microwave) in patients with metal-containing IUD's may cause heat injury to the surrounding tissue. Therefore, medical diathermy to the abdominal and sacral areas should not be used. l. Copper-containing IUD's—A copper induced urticarial allergic skin reaction may develop in women wearing a copper-containing IUD. If symptoms of such an allergic response occur, the patient should be instructed to tell the consulting physician that a copper-bearing device is being worn. Adverse Reactions These adverse reactions are not listed in any order of frequency or severity. Reported adverse reactions include: endometritis, spontaneous abortion, septic abortion, septicemia, perforation of the uterus and cervix, embedment, fragmentation of the IUD, pelvic infection, vaginitis, leukorrhea, cervical erosion, pregnancy, ectopic pregnancy, difficult removal, complete or partial expulsion of the IUD, intermenstrual spotting, prolongation of menstrual flow, anemia, pain and cramping, dysmenorrhea backaches, dyspareunia, neurovascular episodes including bradycardia, and syncope secondary to insertion. Perforation into the abdomen has been followed by abdominal adhesions, intestinal penetration, intestinal obstruction, and cystic masses in the pelvis For copper-containing IUD's the following adverse reaction should also be added: urticarial allergic skin reaction. Directions for Use (To be supplied by manufacturer) Directions for use shall include the following: 1. Insertion technique. 2. Requirements for replacement and removal (including information on whether the IUD should be replaced periodically and, if so, how often). Clincial Studies Different event rates have been recorded with the use of different IUD's. Inasmuch as these rates are usually derived from separate studies conducted by different investigators in several population groups, they cannot be compared with precision. Furthermore, event rates tend to be lower as clinical experience is expanded, possibly due to retention in the clinical study of those patients who accept the treatment regimen and do not discontinue due to adverse reactions or pregnancy. In clincial trials conducted by (name of sponsor) with the (name of drug IUD), use effectiveness was determined as follows for parous and nulliparous women, as tabulated by the life table method. (Rates are expressed as events per 100 women through 12 and 24 months of use.) This experience is based on (number) women/months of use, including (number) women who completed 12 months of use and (number) women who completed 24 months of use. 12 mo Parous Nulliparous 24 mo Parous Nulliparous Pregnancy Expulsion Medical removal Continuation rate (2) Labeling, in sufficient quantities to be available to patients who express interest in IUD's, shall accompany each drug IUD (packaged separately from the sterile packaging), be made available to the patient, and contain the following information: Patient Information This brochure provides information on the use of intrauterine contraceptive devices (IUD's). There are other birth control methods that may be suitable. Before deciding which type of birth control method to use, you should read this brochure and have the opportunity to discuss fully with your doctor any questions you may have about the IUD and other methods of contraception. Preinsertion Information what you should know about the iud IUD's are small articles of various sizes and shapes which are inserted into the uterus (womb). The purpose of the IUD is to prevent pregnancy. How the IUD prevents pregnancy is not completely understood. Several theories have been suggested. IUD's seem to interfere in some manner with the implantation of the fertilized egg in the lining of the uterine cavity. The IUD does not prevent ovulation. The effectiveness of the IUD is measured by the pregnancy rate of women who use it and the rate of adverse reactions and side effects requiring removal of the IUD. Use-Effectiveness Different pregnancy and adverse reaction rates have been reported with the use of different IUD's. Because these rates are usually derived from separate studies conducted by different investigators in several population groups, they cannot be compared with precision. In clinical trials with (name of drug IUD), ——— patients completed ——— cycles or months in use. The incdience of unplanned pregnancies was ——— per 100 woman years or ——— women out of 100 became pregnant in a year while using an IUD. The incidence of adverse reactions requiring medical removal of the IUD is ——— per 100 woman years or ——— women out of 100 discontinued using the IUD for medical reasons. What You Should Tell Your Doctor Before you have an IUD inserted, you should tell your doctor if you have ever had, or suspect you have ever had, any of the following conditions which might make the IUD unsuitable as a method of contraception for you: Abnormalities of the uterus (womb). Allergy to copper. Anemia. Bleeding between periods. Cancer of the uterus (womb) or cervix. Fainting attacks. Heart disease. Heart murmur. Heavy menstrual flow. Infection of the uterus (womb) or cervix. Pelvic infection (plus in fallopian tubes). Prior IUD use. Prior uterine surgery. Recent abortion or miscarriage. Recent pregnancy. Severe mentstrual cramps. Suspected or possible pregnancy. Suspicious or abnormal “Pap” smear. Unexplained genital bleeding. Vaginal discharge or infection. Venereal disease. Wilson's disease. Adverse Reactions The following adverse reactions and side effects have been reported and may occur after the IUD is inserted: Anemia. Backache. Blood poisoning (septicemia). Bowel obstruction. Cervical infection. Complete or partial expulsion. Cysts on ovaries and tubes. Delayed menstruation. Difficult removal. Embedment. Fainting at the time of insertion or removal. Fragmentation of the IUD. Intermenstrual spotting. Internal abdominal adhesions. Pain and cramps. Painful intercourse. Pelvic infection. Perforation of the uterus (womb) or cervix. Pregnancy outside the uterus (womb) (tubal or ovarian). Prolonged or heavy menstrual flow. Septic abortion (infected miscarriage) followed in some cases by blood poisoning (septicemia) which can lead to death. Spontaneous abortion (miscarriage). Vaginal discharge and infection. If you decide on the IUD as your method of birth control, read the following information and instructions carefully. Please keep this brochure so that you may refer to it. If you have any questions, consult your doctor. Postinsertion Information description (To be supplied by manufacturer) Description shall include the following information: 1. Proprietary or established name of the drug IUD. 2. Model. 3. Physical dimensions (size and shape). 4. Composition (metal or plastic). 5. Color and number of the tail or threads. 6. Other characteristics. Directions for Use 1. Checking your IUD. A tail or thread is attached to the IUD so you can check to see if it is still in place since the IUD can come out of the uterus (womb) without your knowing it. This occurs most often during or right after a menstrual period. Follow these steps to make sure your IUD is in place: a. Wash your hands. b. Assume the squatting postion or seat yourself on the toilet. c. Insert the index or middle finger high in vagina and locate the cervix (mouth of the uterus (womb)). The cervix feels firm like the tip of your nose. d. Feel for the tail or thread of the IUD, which should be in the cervix high in your vagina. e. If your can feel the tail or thread it is likely that the IUD is in place and working. You should not pull on the tail or thread. This may displace the IUD. f. After each menstrual period, you should check to make sure the tail or thread is in place in the cervix. You may check for the tail or thread more often if you wish. g. If you think the IUD has come out or has been displaced (e.g., you cannot feel the tail or thread or you can feel the IUD itself), use another birth control method, such as contraceptive vaginal foam, cream, or jelly, or condoms (rubbers), until you can be checked. (These alternative methods are not as effective as the IUD.) Call your doctor for an examination. h. You should return to see your doctor as soon as possible after your next menstrual period, after insertion of your IUD, but no later than 3 months after insertion. This will allow the doctor to make sure that the IUD is in the correct position. i. After your first checkup, you should be checked at least once a year by your doctor. 2. Continuation and removal. While you are wearing the IUD, you may use tampons and take douches, if this is your usual practice. With some IUD's, you may wear the IUD until you wish to become pregnant. With other IUD's it is necessary that they be replaced every year or so in order for you to continue being protected against pregnancy. Check with your doctor concerning this. You should return to your doctor if you wish to have the IUD removed. Side Effects The following may occur during or after the IUD is inserted: 1. Some bleeding occurs following insertion in most women. Because of this, your doctor may choose to insert your IUD during or at the end of your menstrual period. This also reduces the possibility that you are pregnant at the time of IUD insertion. 2. Bleeding between menstrual periods, usually in the form of spotting, may occur during the first 2 or 3 months after insertion. The first few menstrual periods after the insertion may be heavier and longer. If these conditions continue for longer than 2 or 3 months, consult your doctor. 3. Pain, usually in the form of uterine cramps or low backache, may occur at the time of insertion and last for a few days. Simple pain medication usually relieves the cramping. 4. Fainting may occur at the time of insertion or removal of an IUD. This passes quickly and is not usually serious. 5. The IUD may be expelled during the first two or three menstrual cycles following insertion. Expulsion increases the risk of an unplanned pregnancy. Although not as effective as the IUD, the use of a second contraceptive method, such as a contraceptive vaginal foam, cream, or jelly, or condoms (rubbers) is recommended. Warnings 1. Call your doctor for any of the following reasons: a. Severe or prolonged bleeding. If the flow is heavier and lasts much longer than your usual menstrual flow, you may need to have the IUD removed to prevent the development of anemia. b. Pelvic pain and cramps. This could mean an infection has developed requiring treatment. c. Exposure to venereal disease (VD). If exposure to venereal disease is suspected, report for examination and treatment promptly. Failure to do so could result in serious pelvic infection because use of an IUD in itself does not prevent venereal disease. d. Tail or thread disappearance. If you cannot feel the tail or thread coming through the cervix, it is possible that the IUD has been expelled or displaced or that perforation has occurred. If any of these has occurred, you are no longer protected from becoming pregnant. Use another birth control method, such as contraceptive vaginal foam, cream, or jelly, or condoms (rubbers), until you can be checked. (These alternative methods are not as effective as the IUD.) 2. Do not undergo medical diathermy (including shortwave or microwave) treatments to the abdomen or lower back areas if you are wearing a metal IUD. These treatments may cause heat injury to the surrounding tissues. Special Warning About Pregnancy With an IUD in Place Some women become pregnant while using an IUD. If you miss your menstrual period, or if you have a scanty flow during your period, or if you supect that you might be pregnant, see your doctor right away. Serious complication of sepsis (severe infection), septic abortion (infected miscarriage), and death have occurred when a pregnancy continues with an IUD in place. Most of the occurrences of these serious complications have been reported in the middle third of pregnancy. If your doctor confirms that you are pregnant, he should remove the IUD if the tail is visible. Removal of an IUD in pregnancy decreases the likelihood of serious complications. If removal of your IUD proves to be difficult, you and your doctor should discuss at that time the question of continuing the pregnancy in view of the serious complications that may occur. In reaching a decision as to whether or not to have an abortion, it should be remembered that the risks associated with terminating a pregnancy increase with the length of time you are pregnant. (3) Any drug IUD that is not labeled as required by this section and that is either introduced or delivered for introduction into interstate commerce, or held for sale after shipment in interstate commerce after November 7, 1977, is misbranded pursuant to section 502 of the act. However, a drug IUD in the possession of an independent wholesaler, a retailer, or a licensed practitioner before November 7, 1977, is not misbranded if labeling required by paragraph (b)(2) of this section is furnished to such independent wholesalers, retailers, or licensed practitioners in sufficient quantities to accompany each device in their possession. (4) The holder of an approved new drug application for such device, as described in paragraph (a)(2) of this section, shall submit a supplement to his application to provide for the labeling described in paragraphs (b) (1) and (2) of this section. The supplement shall be submitted before November 7, 1977, under the provisions of § 314.70 of this chapter. The labeling may be put into use without advance approval by the Food and Drug Administration. (c) Applicability. Paragraphs (a) and (b) of this section do not apply to the following intrauterine contraceptive devices, which are subject to the requirements of § 801.427 of this chapter: (1) Intrauterine devices fabricated solely from inactive materials, e.g., inactive plastics or metals. (2) Intrauterine devices with substances added to improve the physical characteristics if such substances do not contribute to contraception through chemical action on or within the body and are not dependent upon being metabolized for the achievement of the contraceptive purpose. (3) Intrauterine devices that contain a component, such as barium, added exclusively for the purpose of visualization by x-ray.

regulation

[{"label": "(a)", "text": "New drug status of certain intrauterine devices for human use for the purpose of contraception. (1) The Food and Drug Administration has become aware of the increased clinical use for the purpose of contraception of intrauterine devices (IUD's) that incorporate heavy metals, drugs, or other active substances. The amount of local irritation caused by such active materials has been reported as being correlated, in animal studies, to the efficacy of such devices in achieving their contraceptive effect. Several investigators have reported different pregnancy rates which appear to be dependent on the type of metal used and/or the amount of exposed surface of the metal. Drugs have been incorporated with otherwise inert intrauterine devices to increase the contraceptive effect, decrease adverse reactions, or provide increased medical acceptability.", "source": null}, {"label": "(2)", "text": "Intrauterine devices used for the purpose of contraception and incorporating heavy metals, drugs, or other active substances to increase the contraceptive effect, to decrease adverse reactions, or to provide increased medical acceptability, are not generally recognized as safe and effective for contraception and are new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. A completed and signed “Investigational New Drug Application” set forth in part 312 of this chapter) must therefore be submitted to cover clinical investigations to obtain evidence that such preparations are safe and effective for this use. An approved new drug application is required for the marketing of such articles.", "source": null}, {"label": "(b)", "text": "Labeling of intrauterine contraceptive devices considered new drugs (drug IUD's). The intrauterine contraceptive device is a popular method of contraception used by several million women in the United States. Although this method of contraception is generally safe and effective, certain complications and side effects may result from its use. A Food and Drug Administration review of the labeling of intrauterine contraceptive devices currently marketed in the United States reveals that information necessary for the safe and effective use of these products is not uniformly available to either the practitioner or the patient. Based on the review of the labeling and on the recommendations of the Ad Hoc Obstetric-Gynecology Advisory Committee, the Commissioner has concluded that in the interest of safe and effective use, and prevention of misleading labeling, there is a need to establish uniform physician and patient labeling for such drugs.", "source": null}, {"label": "(1)", "text": "Labeling accompanying each drug IUD and directed to the physician shall be substantially as follows, adjusted where appropriate to the requirements of a particular drug IUD.", "source": null}, {"label": "(2)", "text": "Labeling, in sufficient quantities to be available to patients who express interest in IUD's, shall accompany each drug IUD (packaged separately from the sterile packaging), be made available to the patient, and contain the following information:", "source": null}, {"label": "(3)", "text": "Any drug IUD that is not labeled as required by this section and that is either introduced or delivered for introduction into interstate commerce, or held for sale after shipment in interstate commerce after November 7, 1977, is misbranded pursuant to section 502 of the act. However, a drug IUD in the possession of an independent wholesaler, a retailer, or a licensed practitioner before November 7, 1977, is not misbranded if labeling required by paragraph (b)(2) of this section is furnished to such independent wholesalers, retailers, or licensed practitioners in sufficient quantities to accompany each device in their possession.", "source": null}, {"label": "(4)", "text": "The holder of an approved new drug application for such device, as described in paragraph (a)(2) of this section, shall submit a supplement to his application to provide for the labeling described in paragraphs (b) (1) and (2) of this section. The supplement shall be submitted before November 7, 1977, under the provisions of § 314.70 of this chapter. The labeling may be put into use without advance approval by the Food and Drug Administration.", "source": null}, {"label": "(c)", "text": "Applicability. Paragraphs (a) and (b) of this section do not apply to the following intrauterine contraceptive devices, which are subject to the requirements of § 801.427 of this chapter:", "source": null}, {"label": "(1)", "text": "Intrauterine devices fabricated solely from inactive materials, e.g., inactive plastics or metals.", "source": null}, {"label": "(2)", "text": "Intrauterine devices with substances added to improve the physical characteristics if such substances do not contribute to contraception through chemical action on or within the body and are not dependent upon being metabolized for the achievement of the contraceptive purpose.", "source": null}, {"label": "(3)", "text": "Intrauterine devices that contain a component, such as barium, added exclusively for the purpose of visualization by x-ray.", "source": null}]

§ 801.427; § 314.70

[42 FR 23777, May 10, 1977; 42 FR 25854, May 20, 1977; 42 FR 35155, July 8, 1977; 55 FR 11578, Mar. 29. 1990]

May 10, 1977

(Revised as of April 1, 1996)

True

[{"title": "", "headers": [{"text": "12 mo", "level": "1"}, {"text": "Parous", "level": "2"}, {"text": "Nulliparous", "level": "2"}, {"text": "24 mo", "level": "1"}, {"text": "Parous", "level": "2"}, {"text": "Nulliparous", "level": "2"}], "rows": [[{"text": "Pregnancy", "indent": "01"}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}], [{"text": "Expulsion", "indent": "01"}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}], [{"text": "Medical removal", "indent": "01"}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}], [{"text": "Continuation rate", "indent": "01"}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}, {"text": "", "indent": null}]], "cdef": "s15,7,7,7,7", "cols": "5", "opts": "L2"}]

False

24 months; 48 hours; 12 months; 3 months

False

True

within 3 month; 3 months

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.502

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.503

Requirements regarding certain radioactive drugs.

(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 by the Public Health Service in the case of biologics. Continued distribution under the investigational exemption when the drugs are intended for established uses will not be permitted. (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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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 by the Public Health Service in the case of biologics. Continued distribution under the investigational exemption when the drugs are intended for established uses will not be permitted.", "source": null}, {"label": "(c)", "text": "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:", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(e)", "text": "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.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(4)", "text": "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.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(g)", "text": "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:", "source": null}, {"label": "(1)", "text": "The research project title;", "source": null}, {"label": "(2)", "text": "A brief description of the purpose of the project;", "source": null}, {"label": "(3)", "text": "The name of the investigator responsible;", "source": null}, {"label": "(4)", "text": "The name and license number of the institution holding the specific license under 10 CFR 35.11 (or equivalent regulation of an Agreement State);", "source": null}, {"label": "(5)", "text": "The name and maximum amount per subject of the radionuclide used;", "source": null}, {"label": "(6)", "text": "The number of subjects involved; and", "source": null}, {"label": "(7)", "text": "The date on which the administration of the radioactive drugs is expected to be completed.", "source": null}, {"label": "(h)", "text": "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.", "source": null}]

10 CFR 35.11

[39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

Mar. 29, 1974

(Revised as of April 1, 1996)

True

[{"title": "", "headers": [{"text": "Isotope", "level": "1"}, {"text": "Chemical form", "level": "1"}, {"text": "Use", "level": "1"}], "rows": [[{"text": "Chromium 51", "indent": "01"}, {"text": "Chromate", "indent": null}, {"text": "Spleen scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Placenta localization.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Red blood cell labeling and survival studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Labeled human serum albumin", "indent": null}, {"text": "Gastrointestinal protein loss studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Placenta localization.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Labeled red blood cells", "indent": null}, {"text": "Do.", "indent": null}], [{"text": "Cobalt 58 or Cobalt 60", "indent": "01"}, {"text": "Labeled cyanocobalamin", "indent": null}, {"text": "Intestinal absorption studies.", "indent": null}], [{"text": "Gold 198", "indent": "01"}, {"text": "Colloidal", "indent": null}, {"text": "Liver scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Intracavitary treatment of pleural effusions and/or ascites.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Interstitial treatment of cancer.", "indent": null}], [{"text": "Iodine 131", "indent": "01"}, {"text": "Iodide", "indent": null}, {"text": "Diagnosis of thyroid functions.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Thyroid scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Treatment of hyperthyroidism and/or cardiac dysfunction.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Treatment of thyroid carcinoma.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Iodinated human serum albumin", "indent": null}, {"text": "Blood volume determinations.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Cisternography.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Brain tumor localization.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Placenta localization.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Cardiac scans for determination of pericardial effusions.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Rose Bengal", "indent": null}, {"text": "Liver function studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Liver scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Iodopyracet, sodium iodohippurate, sodium diatrizoate, diatrizoate methylglucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate", "indent": null}, {"text": "Kidney function studies and kidney scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Labeled fats and/or fatty acids", "indent": null}, {"text": "Fat absorption studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Cholografin", "indent": null}, {"text": "Cardiac scans for determination of pericardial effusions.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Macroaggregated iodinated human serum albumin", "indent": null}, {"text": "Lung scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Colloidal microaggregated human serum albumin", "indent": null}, {"text": "Liver scans.", "indent": null}], [{"text": "Iodine 125", "indent": "01"}, {"text": "Iodide", "indent": null}, {"text": "Diagnosis of thyroid function.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Iodinated human serum albumin", "indent": null}, {"text": "Blood volume determinations.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Rose Bengal", "indent": null}, {"text": "Liver function studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Iodopyracet, sodium iodohippurate, sodium diatrizoate, diatrizoate methyl-glucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate", "indent": null}, {"text": "Kidney function studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Labeled fats and/or fatty acids", "indent": null}, {"text": "Fat absorption studies.", "indent": null}], [{"text": "Iron 59", "indent": "01"}, {"text": "Chloride, citrate and/or sulfate", "indent": null}, {"text": "Iron turnover studies.", "indent": null}], [{"text": "Krypton 85", "indent": "01"}, {"text": "Gas", "indent": null}, {"text": "Diagnosis of cardiac abnormalities.", "indent": null}], [{"text": "Mercury 197", "indent": "01"}, {"text": "Chlormerodrin", "indent": null}, {"text": "Kidney scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Brain scans.", "indent": null}], [{"text": "Mercury 203 1", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Kidney scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Brain scans.", "indent": null}], [{"text": "Phosphorus 32", "indent": "01"}, {"text": "Soluble phosphate", "indent": null}, {"text": "Treatment of polycythemia vera.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Treatment of leukemia and bone metastasis.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Colloidal chromic phosphate", "indent": null}, {"text": "Intracavitary treatment of pleural effusions and/or ascites.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Interstitial treatment of cancer.", "indent": null}], [{"text": "Potassium 42", "indent": "01"}, {"text": "Chloride", "indent": null}, {"text": "Potassium space studies.", "indent": null}], [{"text": "Selenium 75", "indent": "01"}, {"text": "Labeled methionine", "indent": null}, {"text": "Pancreas scans.", "indent": null}], [{"text": "Strontium 85", "indent": "01"}, {"text": "Nitrate or chloride", "indent": null}, {"text": "Bone scans on patients with diagnosed cancer.", "indent": null}], [{"text": "Technetium 99m", "indent": "01"}, {"text": "Pertechnetate", "indent": null}, {"text": "Brain scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Thyroid scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Sulfur colloid", "indent": null}, {"text": "Liver and spleen scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Pertechnetate", "indent": null}, {"text": "Placenta localization.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Blood pool scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Salivary gland scans.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Diethylenetri-amine pentaacetic acid (DTPA)", "indent": null}, {"text": "Kidney scans.", "indent": null}], [{"text": "Xenon 133", "indent": "01"}, {"text": "Gas", "indent": null}, {"text": "Diagnosis of cardia abnormalities. Cerebral bloodflow studies. Pulmonary function studies. Muscle bloodflow studies.", "indent": null}]], "cdef": "xs42,r40,r40", "cols": "3", "opts": "L2"}, {"title": "", "headers": [{"text": "Isotope", "level": "1"}, {"text": "Chemical form", "level": "1"}, {"text": "Use", "level": "1"}], "rows": [[{"text": "Fluorine 18", "indent": "01"}, {"text": "Fluoride", "indent": null}, {"text": "Bone imaging.", "indent": null}], [{"text": "Indium-113m", "indent": "01"}, {"text": "Diethylenetriamine pentaacetic acid (DTPA)", "indent": null}, {"text": "Brain imaging; kidney imaging.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Chloride", "indent": null}, {"text": "Placenta imaging; blood pool imaging.", "indent": null}], [{"text": "Technetium 99m", "indent": "01"}, {"text": "Human serum albumin microspheres", "indent": null}, {"text": "Lung imaging.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Diethylenetriamine pentaacetic acid (Sn)", "indent": null}, {"text": "Kidney imaging; kidney function studies.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "......do", "indent": null}, {"text": "Brain imaging.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Polyphosphates", "indent": null}, {"text": "Bone imaging.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Technetated aggregated albumin (human)", "indent": null}, {"text": "Lung imaging.", "indent": null}], [{"text": "Do", "indent": "01"}, {"text": "Disodium etidronate", "indent": null}, {"text": "Bone imaging.", "indent": null}]], "cdef": "xs42,r40,r40", "cols": "3", "opts": "L2"}]

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.503

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.504

Amphetamines (amphetamine, dextroamphetamine, and their salts and levamfetamine and its salts) for human use.

(a) Amphetamine and dextroamphetamine and their salts. (1) Pursuant to the drug efficacy requirements of the Federal Food, Drug, and Cosmetic Act, the National Academy of Sciences-National Research Council, Drug Efficacy Study Group, has evaluated certain dosage forms of amphetamines and other sympathomimetic stimulant drugs intended for use in the treatment of obesity and for other uses. The Academy found that such drugs as a class have been shown to have a generally short-term anorectic action. They further commented that clinical opinion on the contribution of the sympathomimetic stimulants in a weight reduction program varies widely, the anorectic effect of these drugs often plateaus or diminishes after a few weeks, most studies of them are for short periods, no available evidence shows that use of anorectic alters the natural history of obesity, some evidence indicates that anorectic effects may be strongly influenced by the suggestibility of the patient, and reservations exist about the adequacy of the controls in some of the clinical studies. Their significant potential for drug abuse was also cited. (2) In addition to those dosage forms that were reviewed for efficacy by the Academy, other dosage forms of amphetamine drugs are on the market that were not cleared through the new drug procedures. While certain amphetamines were marketed prior to enactment of the Federal Food, Drug, and Cosmetic Act in 1938, some of the conditions of use subsequently prescribed, recommended, or suggested in their labeling (for example, for the treatment of obesity) differ from uses claimed for the amphetamines before said enactment. Such uses have not been cleared through the effectiveness provisions of the Drug Amendments of 1962 (Pub. L. 87-781 which amended the Federal Food, Drug, and Cosmetic Act). These drugs are very extensively used in the treatment of obesity. The extent of use for such purposes as narcolepsy and minimal brain dysfunction in children is believed to be minor as compared with the total usage of these drugs. Because of their stimulant effect on the central nervous system, they have a potential for misuse by those to whom they are available through a physician's prescription, and their abuse by those who obtain them through illicit channels is well documented. Production data indicate that amphetamines have been produced and prescribed in quantities greatly in excess of demonstrated medical needs. (3) Pursuant to a notice published in the Federal Register of August 8, 1970 (35 FR 12652), which required the submission of new drug applications as a condition for continued marketing of amphetamines, 106 new drug applications for amphetamines or amphetamine-containing drug products were received. The data submitted in those applications, and data obtained from other sources concerning anorectic drugs, generally supported the efficacy of anorectic drugs. (b) On the basis of currently available evidence derived from short-term studies, the Commissioner concludes that single drug entity oral dosage forms of amphetamine or dextroamphetamine are effective in the management of exogenous obesity as a short-term (a few weeks) adjunct in a regimen of weight reduction, based on caloric restrictions, for patients in whom obesity is refractory to other measures. For purposes of this regulation, a mixture of dextroamphetamine and amphetamine is ordinarily regarded as a single drug entity. (c) The Food and Drug Administration is not aware of data providing substantial evidence of the effectiveness of levamfetamine and its salts and regards these preparations as new drugs requiring approved full new drug applications. (d) In view of the well-documented history of abuse of parenteral amphetamines, the severe risk of drug dependence, and the availability of safer alternative parenteral drugs which are equally effective for recognized non-anorectic indications, the Food and Drug Administration regards parenteral amphetamines as lacking evidence of safety. (e) Any combination drug containing amphetamine or dextroamphetamine is regarded as a new drug requiring an approved full new drug application as a condition for marketing. Data in new drug applications are required to fulfill the criteria set forth in § 300.50 of this chapter governing fixed combination prescription drugs for humans. (f) New drug applications have been received from persons marketing orally administered single entity amphetamine or dextroamphetamine dosage forms. Any other person who intends to market such drug is required to submit to the Food and Drug Administration an abbreviated application under § 314.55 of this chapter. (g) The labeling conditions for single entity oral dosage forms of amphetamine and dextroamphetamine and their salts are as follows: (1) The label shall bear the statement “Caution: Federal law prohibits dispensing without prescription”. (2) The drug shall be labeled to comply with all requirements of the act and regulations. The labeling shall bear adequate information for safe and effective use of the drug. The indications for use are: Narcolepsy. Minimal brain dysfunction in children (hyperkinetic behavior disorders), as an aid to general management. Management of exogenous obesity as short-term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction, for patients in whom obesity is refractory to other measures. (3) Complete labeling guidelines are available from the Food and Drug Administration. (h) Regulatory proceedings will be initiated with regard to any such drug within the jurisdiction of the act which is not in accord with this regulation.

regulation

[{"label": "(a)", "text": "Amphetamine and dextroamphetamine and their salts. (1) Pursuant to the drug efficacy requirements of the Federal Food, Drug, and Cosmetic Act, the National Academy of Sciences-National Research Council, Drug Efficacy Study Group, has evaluated certain dosage forms of amphetamines and other sympathomimetic stimulant drugs intended for use in the treatment of obesity and for other uses. The Academy found that such drugs as a class have been shown to have a generally short-term anorectic action. They further commented that clinical opinion on the contribution of the sympathomimetic stimulants in a weight reduction program varies widely, the anorectic effect of these drugs often plateaus or diminishes after a few weeks, most studies of them are for short periods, no available evidence shows that use of anorectic alters the natural history of obesity, some evidence indicates that anorectic effects may be strongly influenced by the suggestibility of the patient, and reservations exist about ", "source": null}, {"label": "(2)", "text": "In addition to those dosage forms that were reviewed for efficacy by the Academy, other dosage forms of amphetamine drugs are on the market that were not cleared through the new drug procedures. While certain amphetamines were marketed prior to enactment of the Federal Food, Drug, and Cosmetic Act in 1938, some of the conditions of use subsequently prescribed, recommended, or suggested in their labeling (for example, for the treatment of obesity) differ from uses claimed for the amphetamines before said enactment. Such uses have not been cleared through the effectiveness provisions of the Drug Amendments of 1962 (Pub. L. 87-781 which amended the Federal Food, Drug, and Cosmetic Act). These drugs are very extensively used in the treatment of obesity. The extent of use for such purposes as narcolepsy and minimal brain dysfunction in children is believed to be minor as compared with the total usage of these drugs. Because of their stimulant effect on the central nervous system, they have ", "source": null}, {"label": "(3)", "text": "Pursuant to a notice published in the Federal Register of August 8, 1970 (35 FR 12652), which required the submission of new drug applications as a condition for continued marketing of amphetamines, 106 new drug applications for amphetamines or amphetamine-containing drug products were received. The data submitted in those applications, and data obtained from other sources concerning anorectic drugs, generally supported the efficacy of anorectic drugs.", "source": null}, {"label": "(b)", "text": "On the basis of currently available evidence derived from short-term studies, the Commissioner concludes that single drug entity oral dosage forms of amphetamine or dextroamphetamine are effective in the management of exogenous obesity as a short-term (a few weeks) adjunct in a regimen of weight reduction, based on caloric restrictions, for patients in whom obesity is refractory to other measures. For purposes of this regulation, a mixture of dextroamphetamine and amphetamine is ordinarily regarded as a single drug entity.", "source": null}, {"label": "(c)", "text": "The Food and Drug Administration is not aware of data providing substantial evidence of the effectiveness of levamfetamine and its salts and regards these preparations as new drugs requiring approved full new drug applications.", "source": null}, {"label": "(d)", "text": "In view of the well-documented history of abuse of parenteral amphetamines, the severe risk of drug dependence, and the availability of safer alternative parenteral drugs which are equally effective for recognized non-anorectic indications, the Food and Drug Administration regards parenteral amphetamines as lacking evidence of safety.", "source": null}, {"label": "(e)", "text": "Any combination drug containing amphetamine or dextroamphetamine is regarded as a new drug requiring an approved full new drug application as a condition for marketing. Data in new drug applications are required to fulfill the criteria set forth in § 300.50 of this chapter governing fixed combination prescription drugs for humans.", "source": null}, {"label": "(f)", "text": "New drug applications have been received from persons marketing orally administered single entity amphetamine or dextroamphetamine dosage forms. Any other person who intends to market such drug is required to submit to the Food and Drug Administration an abbreviated application under § 314.55 of this chapter.", "source": null}, {"label": "(g)", "text": "The labeling conditions for single entity oral dosage forms of amphetamine and dextroamphetamine and their salts are as follows:", "source": null}, {"label": "(1)", "text": "The label shall bear the statement “Caution: Federal law prohibits dispensing without prescription”.", "source": null}, {"label": "(2)", "text": "The drug shall be labeled to comply with all requirements of the act and regulations. The labeling shall bear adequate information for safe and effective use of the drug. The indications for use are:", "source": null}, {"label": "(3)", "text": "Complete labeling guidelines are available from the Food and Drug Administration.", "source": null}, {"label": "(h)", "text": "Regulatory proceedings will be initiated with regard to any such drug within the jurisdiction of the act which is not in accord with this regulation.", "source": null}]

Pub. L. 87-781

§ 314.55; § 300.50

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 10885, Mar. 15, 1976; 55 FR 11578, Mar. 29, 1990]

Mar. 29, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.504

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.506

Use of vinyl chloride as an ingredient, including propellant, of aerosol drug products.

(a) Vinyl chloride has been used as a propellant in aerosol drug preparations. Evidence indicates that vinyl chloride inhalation can result in acute toxicity manifested by dizziness, headache, disorientation, and unconsciousness where inhaled at high concentrations. Cardiac effects, bone changes, and degenerative changes in the brain, liver, and kidneys have been reported in animals. Studies also demonstrate carcinogenic effects in animals as a result of inhalation exposure to vinyl chloride. Recently, vinyl chloride has been linked to liver disease, including liver cancer, in workers engaged in the polymerization of vinyl chloride. (b) The Commissioner finds that there is a lack of general recognition by qualified experts of the safety or effectiveness of aerosol drug preparations containing vinyl chloride as an ingredient, including propellant. Therefore, any such product containing vinyl chloride is a new drug and a new drug application approved under section 505 of the Federal Food, Drug, and Cosmetic Act is required for marketing. (c) Clinical investigations designed to obtain evidence that any aerosol drug preparation containing vinyl chloride as an ingredient, including propellant, 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 within the jurisdiction of the act which is not in accord with this regulation is subject to regulatory action.

regulation

[{"label": "(a)", "text": "Vinyl chloride has been used as a propellant in aerosol drug preparations. Evidence indicates that vinyl chloride inhalation can result in acute toxicity manifested by dizziness, headache, disorientation, and unconsciousness where inhaled at high concentrations. Cardiac effects, bone changes, and degenerative changes in the brain, liver, and kidneys have been reported in animals. Studies also demonstrate carcinogenic effects in animals as a result of inhalation exposure to vinyl chloride. Recently, vinyl chloride has been linked to liver disease, including liver cancer, in workers engaged in the polymerization of vinyl chloride.", "source": null}, {"label": "(b)", "text": "The Commissioner finds that there is a lack of general recognition by qualified experts of the safety or effectiveness of aerosol drug preparations containing vinyl chloride as an ingredient, including propellant. Therefore, any such product containing vinyl chloride is a new drug and a new drug application approved under section 505 of the Federal Food, Drug, and Cosmetic Act is required for marketing.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any aerosol drug preparation containing vinyl chloride as an ingredient, including propellant, 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.", "source": null}, {"label": "(d)", "text": "Any such drug within the jurisdiction of the act which is not in accord with this regulation is subject to regulatory action.", "source": null}]

[39 FR 30830, Aug. 26, 1974, as amended at 55 FR 11578, Mar. 29, 1990]

Aug. 26, 1974

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.506

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.507

Aerosol drug products for human use containing 1,1,1-trichloroethane.

(a) Trichloroethane has been used in aerosol drug products as a solvent for the active ingredients and to reduce the vapor pressure of the propellants. It is potentially toxic to the cardiovascular system, i.e., can sensitize the heart to epinephrine. At a sufficiently large concentration, it is a potent anesthetic agent. Deaths associated with aerosol decongestant products intended to be inhaled and containing trichloroethane have been reported. Most of the deaths resulted from abuse or gross misuse of the preparations. (b) The Food and Drug Administration finds that there is a lack of general recognition by qualified experts of the safety or effectiveness of trichloroethane in aerosol drug products intended for inhalation either directly or indirectly. Any aerosol drug product containing trichloroethane and labeled, represented, or advertised for use by inhalation is a new drug and subject to regulatory proceedings unless it is the subject of a new drug application approved pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act. (c) Clinical investigations designed to obtain evidence that any aerosol drug product containing trichloroethane and labeled, represented, or advertised for use by inhalation either directly or indirectly is safe and effective for the purposes intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter. (d) Regulatory proceedings will be initiated with regard to any such drug within the jurisdiction of the act which is not in accord with this regulation on January 16, 1978.

regulation

[{"label": "(a)", "text": "Trichloroethane has been used in aerosol drug products as a solvent for the active ingredients and to reduce the vapor pressure of the propellants. It is potentially toxic to the cardiovascular system, i.e., can sensitize the heart to epinephrine. At a sufficiently large concentration, it is a potent anesthetic agent. Deaths associated with aerosol decongestant products intended to be inhaled and containing trichloroethane have been reported. Most of the deaths resulted from abuse or gross misuse of the preparations.", "source": null}, {"label": "(b)", "text": "The Food and Drug Administration finds that there is a lack of general recognition by qualified experts of the safety or effectiveness of trichloroethane in aerosol drug products intended for inhalation either directly or indirectly. Any aerosol drug product containing trichloroethane and labeled, represented, or advertised for use by inhalation is a new drug and subject to regulatory proceedings unless it is the subject of a new drug application approved pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any aerosol drug product containing trichloroethane and labeled, represented, or advertised for use by inhalation either directly or indirectly is safe and effective for the purposes intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.", "source": null}, {"label": "(d)", "text": "Regulatory proceedings will be initiated with regard to any such drug within the jurisdiction of the act which is not in accord with this regulation on January 16, 1978.", "source": null}]

[42 FR 63387, Dec. 16, 1977, as amended at 55 FR 11578, Mar. 29, 1990]

Dec. 16, 1977

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.507

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.508

Use of certain halogenated salicylanilides as an inactive ingredient in drug products.

(a) 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)) have been used as active or inactive ingredients in a number of over-the-counter (OTC) drug products, largely antibacterial soaps, for antimicrobial, preservative, and other purposes. These halogenated salicylanilides are potent photosensitizers and can cause disabling skin disorders. In some instances the photosensitization may persist for prolonged periods as a severe reaction without further exposure to these chemicals. Safer alternative antimicrobial agents are available. (b) These halogenated salicylanilides are not generally recognized as safe and effective for use as active or inactive ingredients in any drug products. Therefore, any drug product containing such a halogenated salicylanilide as an ingredient at any level for any purpose is 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 pursuant to 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 containing a halogenated salicylanilide as an ingredient at any level for any purpose 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 initially introduced into interstate commerce after December 1, 1975, that is not in compliance with this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "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)) have been used as active or inactive ingredients in a number of over-the-counter (OTC) drug products, largely antibacterial soaps, for antimicrobial, preservative, and other purposes. These halogenated salicylanilides are potent photosensitizers and can cause disabling skin disorders. In some instances the photosensitization may persist for prolonged periods as a severe reaction without further exposure to these chemicals. Safer alternative antimicrobial agents are available.", "source": null}, {"label": "(b)", "text": "These halogenated salicylanilides are not generally recognized as safe and effective for use as active or inactive ingredients in any drug products. Therefore, any drug product containing such a halogenated salicylanilide as an ingredient at any level for any purpose is 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 pursuant to section 505 of the act and part 314 of this chapter is required for marketing.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any drug product containing a halogenated salicylanilide as an ingredient at any level for any purpose 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.", "source": null}, {"label": "(d)", "text": "Any such drug product initially introduced into interstate commerce after December 1, 1975, that is not in compliance with this section is subject to regulatory action.", "source": null}]

[40 FR 50530, Oct. 30, 1975, as amended at 55 FR 11578, Mar. 29, 1990]

Oct. 30, 1975

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.508

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.509

Parenteral drug products in plastic containers.

(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 Federal Food, Drug, and Cosmetic Act, and requires an approved new drug application as a condition for marketing. A “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) It is common medical practice to add various drugs to containers of large volume parenteral drug products for single administration to the patient, although in many cases the safety and effectiveness of that practice has not been demonstrated. Accordingly the Commissioner of Food and Drugs concludes that reports of a full investigation of the compatibility of the immediate container of certain large volume parenteral drugs with certain other drugs that may be added regularly to the parenteral delivery system is necessary under section 505(k) of the act to determine whether there is ground for requiring revision of the labeling to provide for safer use of the large volume parenteral drug products or ground for withdrawing approval, under section 505(e) of the act, of any of the approved new drug applications for the products. 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) Each holder of an approved new drug application (NDA) for a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic container shall submit the following to the Food and Drug Administration: (1) The protocol that the NDA holder proposes to follow in conducting compatibility studies for its large volume parenteral drug product and each additive drug listed in paragraph (d) of this section, on or before April 16, 1979. (2) A status report of the ongoing studies 9 months after the applicant has received written acceptance of the protocol from the Food and Drug Administration. (3) The final report at the completion of the compatibility studies within 24 months following acceptance of the protocol by the Food and Drug Administration. (d) Reports of compatibility studies with each of the following drugs shall be submitted under paragraph (c) of this section for each large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container, unless a waiver is granted under paragraph (e) of this section for a specific drug product: Aminophylline Amphotericin Ampicillin Calcium gluconate Carbenicillin Cephalosporins Chloramphenicol Chloramphenicol sodium succinate Clindamycin phosphate Cyclophosphamide Cytarabine Diphenhydramine Erythromicins Fluorouracil Gentamicin Heparin Hydrocortisone sodium succinate Insulin Isoproterenol Kanamycin Levarterenol Lidocaine Lincomycin Magnesium sulfate Metaraminol Methicillin Methotrexate Methyldopa Oxacillin Oxytocin Penicillin G Potassium chloride Sodium bicarbonate Sodium chloride Tetracyclines Vitamins (single-entity and multiple vitamin products) (e) The required submission of a report of a compatibility study of a large volume parenteral drug product packaged in plastic and any additive drug listed in paragraph (d) of this section may be waived upon a showing that the report is unnecessary or techniques are not available for conducting a compatibility study that would produce meaningful data. A request for a waiver shall be submitted to the Director of the Division of Surgical-Dental Drug Products (HFD-160), Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, 5600 Fishers Lane, Rockville, MD 20857. (f) Until the results of the 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. (g) After February 13, 1979, the Food and Drug Administration shall approve a new drug application for a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container if all of the following conditions are met: (1) The application is otherwise approvable. (2) The application contains the results of studies to determine the compatibility of the large volume parenteral drug product's plastic container with drugs that may be added regularly to the parenteral delivery system. (h) After February 13, 1979, the Food and Drug Administration shall approve a new drug application for a drug product intended to be added to a parenteral delivery system that includes a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container if all of the following conditions are met: (1) The application is otherwise approvable. (2) The application contains the results of studies to determine the compatibility of the additive drug product with the plastic immediate container of marketed large volume parenteral drug products for intravenous use in humans. (i) Holders of new drug applications for large volume parenteral drug products that are subject to this section and who must submit supplements under § 314.70(c)(2) of this chapter to provide for the labeling required under paragraph (f) of this section may put the labeling into use without advance approval by the Food and Drug Administration. (j) 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).

regulation

[{"label": "(a)", "text": "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 Federal Food, Drug, and Cosmetic Act, and requires an approved new drug application as a condition for marketing. A “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.", "source": null}, {"label": "(b)", "text": "It is common medical practice to add various drugs to containers of large volume parenteral drug products for single administration to the patient, although in many cases the safety and effectiveness of that practice has not been demonstrated. Accordingly the Commissioner of Food and Drugs concludes that reports of a full investigation of the compatibility of the immediate container of certain large volume parenteral drugs with certain other drugs that may be added regularly to the parenteral delivery system is necessary under section 505(k) of the act to determine whether there is ground for requiring revision of the labeling to provide for safer use of the large volume parenteral drug products or ground for withdrawing approval, under section 505(e) of the act, of any of the approved new drug applications for the products. 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 wit", "source": null}, {"label": "(c)", "text": "Each holder of an approved new drug application (NDA) for a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic container shall submit the following to the Food and Drug Administration:", "source": null}, {"label": "(1)", "text": "The protocol that the NDA holder proposes to follow in conducting compatibility studies for its large volume parenteral drug product and each additive drug listed in paragraph (d) of this section, on or before April 16, 1979.", "source": null}, {"label": "(2)", "text": "A status report of the ongoing studies 9 months after the applicant has received written acceptance of the protocol from the Food and Drug Administration.", "source": null}, {"label": "(3)", "text": "The final report at the completion of the compatibility studies within 24 months following acceptance of the protocol by the Food and Drug Administration.", "source": null}, {"label": "(d)", "text": "Reports of compatibility studies with each of the following drugs shall be submitted under paragraph (c) of this section for each large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container, unless a waiver is granted under paragraph (e) of this section for a specific drug product:", "source": null}, {"label": "(e)", "text": "The required submission of a report of a compatibility study of a large volume parenteral drug product packaged in plastic and any additive drug listed in paragraph (d) of this section may be waived upon a showing that the report is unnecessary or techniques are not available for conducting a compatibility study that would produce meaningful data. A request for a waiver shall be submitted to the Director of the Division of Surgical-Dental Drug Products (HFD-160), Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health and Human Services, 5600 Fishers Lane, Rockville, MD 20857.", "source": null}, {"label": "(f)", "text": "Until the results of the 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:", "source": null}, {"label": "(1)", "text": "A statement that additives may be incompatible.", "source": null}, {"label": "(2)", "text": "A statement that, if additive drugs are introduced into the parenteral system, aseptic techniques should be used and the solution should be thoroughly mixed.", "source": null}, {"label": "(3)", "text": "A statement that a solution containing an additive drug should not be stored.", "source": null}, {"label": "(g)", "text": "After February 13, 1979, the Food and Drug Administration shall approve a new drug application for a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container if all of the following conditions are met:", "source": null}, {"label": "(1)", "text": "The application is otherwise approvable.", "source": null}, {"label": "(2)", "text": "The application contains the results of studies to determine the compatibility of the large volume parenteral drug product's plastic container with drugs that may be added regularly to the parenteral delivery system.", "source": null}, {"label": "(h)", "text": "After February 13, 1979, the Food and Drug Administration shall approve a new drug application for a drug product intended to be added to a parenteral delivery system that includes a large volume parenteral drug product for intravenous use in humans that is packaged in a plastic immediate container if all of the following conditions are met:", "source": null}, {"label": "(1)", "text": "The application is otherwise approvable.", "source": null}, {"label": "(2)", "text": "The application contains the results of studies to determine the compatibility of the additive drug product with the plastic immediate container of marketed large volume parenteral drug products for intravenous use in humans.", "source": null}, {"label": "(i)", "text": "Holders of new drug applications for large volume parenteral drug products that are subject to this section and who must submit supplements under § 314.70(c)(2) of this chapter to provide for the labeling required under paragraph (f) of this section may put the labeling into use without advance approval by the Food and Drug Administration.", "source": null}, {"label": "(j)", "text": "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).", "source": null}]

42 U.S.C. 201

§ 314.70

[43 FR 58562, Dec. 15, 1978, as amended at 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

Dec. 15, 1978

(Revised as of April 1, 1996)

False

24 months; 9 months

False

True

9 months; within 24 month

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.509

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.510

Use of aerosol drug products containing zirconium.

(a) Aerosol products containing zirconium have been used in over-the-counter drug products as antiperspirants. Based upon the lack of toxicological data adequate to establish a safe level for use and the adverse benefit-to-risk ratio, such aerosol products containing zirconium cannot be considered generally recognized as safe for use in drug products. The benefit from using aerosol drug products containing zirconium is insignificant when compared to the risk. Safer alternative antiperspirant products are available. (b) Any aerosol drug product containing zirconium is 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 pursuant to section 505 of the act and part 314 of this chapter is required for marketing. (c) Clinical investigations designed to obtain evidence that any aerosol drug product containing zirconium is safe 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 introduced in interstate commerce after September 15, 1977 that is not in compliance with this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "Aerosol products containing zirconium have been used in over-the-counter drug products as antiperspirants. Based upon the lack of toxicological data adequate to establish a safe level for use and the adverse benefit-to-risk ratio, such aerosol products containing zirconium cannot be considered generally recognized as safe for use in drug products. The benefit from using aerosol drug products containing zirconium is insignificant when compared to the risk. Safer alternative antiperspirant products are available.", "source": null}, {"label": "(b)", "text": "Any aerosol drug product containing zirconium is 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 pursuant to section 505 of the act and part 314 of this chapter is required for marketing.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any aerosol drug product containing zirconium is safe 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.", "source": null}, {"label": "(d)", "text": "Any such drug product introduced in interstate commerce after September 15, 1977 that is not in compliance with this section is subject to regulatory action.", "source": null}]

[42 FR 41376, Aug. 16, 1977, as amended at 55 FR 11579, Mar. 29, 1990]

Aug. 16, 1977

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.510

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.513

Chloroform, use as an ingredient (active or inactive) in drug products.

(a) Chloroform has been used as an ingredient in drug products, such as cough preparations, liniments, and toothpastes. Although considered safe for many years, recent information has become available associating chloroform with carcinogenic effects in animals. Studies conducted by the National Cancer Institute have demonstrated that the oral administration of chloroform to mice and rats induced hepatocellular carcinomas (liver cancer) in mice and renal tumors in male rats. (b) Any drug product containing chloroform as an ingredient is a new drug within the meaning of section 201(p) of the act and misbranded and is subject to regulatory action under sections 301, 502, and 505 of the act. Any drug product containing chloroform in residual amounts from its use as a processing solvent during manufacture, or as a byproduct from the synthesis of an ingredient, is not, for the purpose of this section, considered to contain chloroform as an ingredient. (c) Any holder of an approved new drug application for a drug product containing chloroform as an ingredient shall submit to the Food and Drug Administration on or before July 29, 1976 a supplemental application providing for a revised formulation removing chloroform as an ingredient. (1) The supplemental application shall contain: (i) A full list of articles used as components and a full statement of the composition of the drug product. (ii) The date that the composition of the drug product will be changed. (iii) Data showing that the change in composition does not interfere with any assay or other control procedures used in manufacturing the drug product, or that the assay and other control procedures are revised to make them adequate. (iv) Data available to establish the stability of the revised formulation and, if the data are too limited to support a conclusion that the drug will retain its declared potency for a reasonable marketing period, a commitment from the applicant: (a) To test the stability of marketed batches at reasonable intervals; (b) To submit the data as they become available; and (c) To recall from the market any batch found to fall outside the approved specifications for the drug. (v) Copies of the label and all other labeling to be used for the drug product (a total of 12 copies if in final printed form, 4 copies if in draft form). (2) If such drug product now contains more than one percent chloroform, the revised formulation containing no chloroform shall not be marketed before the receipt of written notice of approval of the supplemental application by the Food and Drug Administration. (3) If such drug product now contains one percent or less chloroform, the revised formulation containing no chloroform may be marketed, subject to the conditions of § 314.70(c) of this chapter, after submission of the supplemental application but prior to the receipt of written notice of its approval by the Food and Drug Administration. (d) Any sponsor of a “Investigational New Drug Application” (IND) for a drug product containing chloroform as an ingredient shall amend the IND on or before July 29, 1976 to revise the formulation removing chloroform as an ingredient. (e) The Commissioner will initiate action to withdraw approval of an application or terminate an IND in accordance with the applicable provisions of section 505 of the act and parts 312 and 314 of this chapter upon failure of a holder of an approved new drug application or sponsor of an IND to comply with the provisions of paragraph (c) or (d) of this section.

regulation

[{"label": "(a)", "text": "Chloroform has been used as an ingredient in drug products, such as cough preparations, liniments, and toothpastes. Although considered safe for many years, recent information has become available associating chloroform with carcinogenic effects in animals. Studies conducted by the National Cancer Institute have demonstrated that the oral administration of chloroform to mice and rats induced hepatocellular carcinomas (liver cancer) in mice and renal tumors in male rats.", "source": null}, {"label": "(b)", "text": "Any drug product containing chloroform as an ingredient is a new drug within the meaning of section 201(p) of the act and misbranded and is subject to regulatory action under sections 301, 502, and 505 of the act. Any drug product containing chloroform in residual amounts from its use as a processing solvent during manufacture, or as a byproduct from the synthesis of an ingredient, is not, for the purpose of this section, considered to contain chloroform as an ingredient.", "source": null}, {"label": "(c)", "text": "Any holder of an approved new drug application for a drug product containing chloroform as an ingredient shall submit to the Food and Drug Administration on or before July 29, 1976 a supplemental application providing for a revised formulation removing chloroform as an ingredient.", "source": null}, {"label": "(1)", "text": "The supplemental application shall contain:", "source": null}, {"label": "(i)", "text": "A full list of articles used as components and a full statement of the composition of the drug product.", "source": null}, {"label": "(ii)", "text": "The date that the composition of the drug product will be changed.", "source": null}, {"label": "(iii)", "text": "Data showing that the change in composition does not interfere with any assay or other control procedures used in manufacturing the drug product, or that the assay and other control procedures are revised to make them adequate.", "source": null}, {"label": "(iv)", "text": "Data available to establish the stability of the revised formulation and, if the data are too limited to support a conclusion that the drug will retain its declared potency for a reasonable marketing period, a commitment from the applicant:", "source": null}, {"label": "(a)", "text": "To test the stability of marketed batches at reasonable intervals;", "source": null}, {"label": "(b)", "text": "To submit the data as they become available; and", "source": null}, {"label": "(c)", "text": "To recall from the market any batch found to fall outside the approved specifications for the drug.", "source": null}, {"label": "(v)", "text": "Copies of the label and all other labeling to be used for the drug product (a total of 12 copies if in final printed form, 4 copies if in draft form).", "source": null}, {"label": "(2)", "text": "If such drug product now contains more than one percent chloroform, the revised formulation containing no chloroform shall not be marketed before the receipt of written notice of approval of the supplemental application by the Food and Drug Administration.", "source": null}, {"label": "(3)", "text": "If such drug product now contains one percent or less chloroform, the revised formulation containing no chloroform may be marketed, subject to the conditions of § 314.70(c) of this chapter, after submission of the supplemental application but prior to the receipt of written notice of its approval by the Food and Drug Administration.", "source": null}, {"label": "(d)", "text": "Any sponsor of a “Investigational New Drug Application” (IND) for a drug product containing chloroform as an ingredient shall amend the IND on or before July 29, 1976 to revise the formulation removing chloroform as an ingredient.", "source": null}, {"label": "(e)", "text": "The Commissioner will initiate action to withdraw approval of an application or terminate an IND in accordance with the applicable provisions of section 505 of the act and parts 312 and 314 of this chapter upon failure of a holder of an approved new drug application or sponsor of an IND to comply with the provisions of paragraph (c) or (d) of this section.", "source": null}]

§ 314.70

[41 FR 26845, June 29, 1976, as amended at 55 FR 11579, Mar. 29, 1990]

June 29, 1976

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.513

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.515

Patient package inserts for estrogens.

(a) Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed of the benefits and risks involved in the use of these drugs. Accordingly, except as provided in paragraph (e) of this section, each estrogen drug product restricted to prescription distribution, including products containing estrogens in fixed combinations with other drugs, shall be dispensed to patients with a patient package insert containing information concerning the drug's benefits and risks. An estrogen drug product that does not comply with the requirements of this section is misbranded under section 502(a) of the Federal Food, Drug, and Cosmetic Act. (b) Distribution requirements. (1) For estrogen drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient. (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 thereafter, as long as the therapy continues. (c) Patient package insert contents. A patient package insert for an estrogen drug product is required to contain the following information: (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) Guidance language. The Food and Drug Administration issues informal labeling guidance texts under § 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of paragraph (c) of this section. Requests for a copy of the guidance text should be directed to the Center for Drug Evaluation and Research, Division of Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. (e) Exemptions. This section does not apply to estrogen-progestogen oral contraceptives. Labeling requirements for these products are set forth in § 310.501. (f) Requirement to supplement approved application. Holders of approved applications for estrogen drug products that are subject to the requirements of this section must submit supplements under § 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.

regulation

[{"label": "(a)", "text": "Requirement for a patient package insert. FDA concludes that the safe and effective use of drug products containing estrogens requires that patients be fully informed of the benefits and risks involved in the use of these drugs. Accordingly, except as provided in paragraph (e) of this section, each estrogen drug product restricted to prescription distribution, including products containing estrogens in fixed combinations with other drugs, shall be dispensed to patients with a patient package insert containing information concerning the drug's benefits and risks. An estrogen drug product that does not comply with the requirements of this section is misbranded under section 502(a) of the Federal Food, Drug, and Cosmetic Act.", "source": null}, {"label": "(b)", "text": "Distribution requirements. (1) For estrogen drug products, the manufacturer and distributor shall provide a patient package insert in or with each package of the drug product that the manufacturer or distributor intends to be dispensed to a patient.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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 thereafter, as long as the therapy continues.", "source": null}, {"label": "(c)", "text": "Patient package insert contents. A patient package insert for an estrogen drug product is required to contain the following information:", "source": null}, {"label": "(1)", "text": "The name of the drug.", "source": null}, {"label": "(2)", "text": "The name and place of business of the manufacturer, packer, or distributor.", "source": null}, {"label": "(3)", "text": "A statement regarding the benefits and proper uses of estrogens.", "source": null}, {"label": "(4)", "text": "The contraindications to use, i.e., when estrogens should not be used.", "source": null}, {"label": "(5)", "text": "A description of the most serious risks associated with the use of estrogens.", "source": null}, {"label": "(6)", "text": "A brief summary of other side effects of estrogens.", "source": null}, {"label": "(7)", "text": "Instructions on how a patient may reduce the risks of estrogen use.", "source": null}, {"label": "(8)", "text": "The date, identified as such, of the most recent revision of the patient package insert.", "source": null}, {"label": "(d)", "text": "Guidance language. The Food and Drug Administration issues informal labeling guidance texts under § 10.90(b)(9) of this chapter to provide assistance in meeting the requirements of paragraph (c) of this section. Requests for a copy of the guidance text should be directed to the Center for Drug Evaluation and Research, Division of Metabolism and Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.", "source": null}, {"label": "(e)", "text": "Exemptions. This section does not apply to estrogen-progestogen oral contraceptives. Labeling requirements for these products are set forth in § 310.501.", "source": null}, {"label": "(f)", "text": "Requirement to supplement approved application. Holders of approved applications for estrogen drug products that are subject to the requirements of this section must submit supplements under § 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section. Such labeling may be put into use without advance approval by the Food and Drug Administration.", "source": null}]

§ 310.501.; § 10.90; § 314.70

[55 FR 18723, May 4, 1990]

May 4, 1990

(Revised as of April 1, 1996)

False

30 days

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.515

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.516

Progestational drug products; labeling directed to the patient.

(a) The Commissioner of Food and Drugs concludes that the safe and effective use of any progestational drug product requires that patients be informed that there is an increased risk of birth defects in children whose mothers have taken this drug during the first 4 months of pregnancy. Accordingly, except as provided by paragraph (d) of this section, any progestational drug product that is the subject of a new drug application approved either before or after October 9, 1962 and all identical, related, or similar drug products as defined in § 310.6, whether or not the subject of an approved new drug application, shall be dispensed to patients with labeling in lay language containing such a warning. The patient labeling shall be provided as a separate printed leaflet independent of any additional materials. (b) The patient labeling shall specifically include the following: (1) Name of the drug. (2) Name and place of business of the manufacturer, packer, or distributor. (3) A warning that there is an increased risk of birth defects in children whose mothers take this drug during the first 4 months of pregnancy. (4) A brief discussion of the nature of the risks of birth defects resulting from the use of these drugs during the first 4 months of pregnancy. (5) A brief statement that these drugs are no longer considered safe as a test for pregnancy. (6) A statement that the patient should inform her physician as soon as possible if she discovers that she was pregnant when she took the drug. (c) The patient labeling shall be printed in accordance with the following specifications: (1) The minimum letter size shall be one-sixteenth of an inch in height. (2) Letter heights pertain to the lower-case letter “o” or its equivalent that shall meet the minumim height standard. (3) Type used shall conform to the minimum letter height. The body copy shall contain 1-point leading, noncondensed type, and shall not contain any light-face type or small capital letters. (d) This section does not apply to a progestogen-containing product intended for contraception, which shall be labeled according to the requirements of § 310.501. (e)(1) Patient labeling for each progestational drug product shall be provided in or with each package intended to be dispensed to the patient. Patient labeling for drug products 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 first administration of the drug and every 30 days thereafter, as long as the therapy continues. (2) In the case of progestational drug products in bulk packages intended for multiple dispensing, a sufficient number of patient-labeling pieces shall be included in or shall accompany each bulk package to assure that one can be included with each package dispensed to every patient. Each bulk package shall be labeled with instructions to the dispenser to include one patient-labeling piece with each package dispensed to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient-labeling pieces to the dispenser. (3) In the case of progestational drug products for injection, each package shall include a sufficient number of patient-labeling pieces for the volume of the vial, and instructions to the practitioner administering the drug to give one patient-labeling piece to each premenopausal woman, except those in whom childbearing is impossible, receiving the drug. (4) This section does not apply to oral dosage forms labeled solely for the treatment of advanced cancer. (5) Any progestational drug product, except as noted in paragraphs (d) and (e)(4) of this section, that is not labeled as required by this section and is either introduced or delivered for introduction into interstate commerce, or held for sale after shipment in interstate commerce, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act. However, a progestational drug product in the possession of a wholesaler or retailer before December 12, 1978, is not misbranded if adequate numbers of copies of the patient labeling are furnished to the wholesaler or retailer to permit any retail purchaser after that date to obtain such labeling with the product. The requirement that any progestational drug product be dispensed with patient labeling, as applied to physicians who dispense or administer the drug, will not be effective for supplies in their possession on the effective date, but will apply only to supplies received thereafter. (f) The Food and Drug Administration has available guideline patient labeling for progestational drug products that includes information responsive to all items specified in paragraph (b) of this section. This labeling was published in a separate notice appearing in the Federal Register of January 12, 1989. Any person may rely on this labeling as complying with paragraph (b) of this section. (g) Holders of approved new drug applications for progestational drug products that are subject to the requirements of this section shall submit supplements under § 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section.

regulation

[{"label": "(a)", "text": "The Commissioner of Food and Drugs concludes that the safe and effective use of any progestational drug product requires that patients be informed that there is an increased risk of birth defects in children whose mothers have taken this drug during the first 4 months of pregnancy. Accordingly, except as provided by paragraph (d) of this section, any progestational drug product that is the subject of a new drug application approved either before or after October 9, 1962 and all identical, related, or similar drug products as defined in § 310.6, whether or not the subject of an approved new drug application, shall be dispensed to patients with labeling in lay language containing such a warning. The patient labeling shall be provided as a separate printed leaflet independent of any additional materials.", "source": null}, {"label": "(b)", "text": "The patient labeling shall specifically include the following:", "source": null}, {"label": "(1)", "text": "Name of the drug.", "source": null}, {"label": "(2)", "text": "Name and place of business of the manufacturer, packer, or distributor.", "source": null}, {"label": "(3)", "text": "A warning that there is an increased risk of birth defects in children whose mothers take this drug during the first 4 months of pregnancy.", "source": null}, {"label": "(4)", "text": "A brief discussion of the nature of the risks of birth defects resulting from the use of these drugs during the first 4 months of pregnancy.", "source": null}, {"label": "(5)", "text": "A brief statement that these drugs are no longer considered safe as a test for pregnancy.", "source": null}, {"label": "(6)", "text": "A statement that the patient should inform her physician as soon as possible if she discovers that she was pregnant when she took the drug.", "source": null}, {"label": "(c)", "text": "The patient labeling shall be printed in accordance with the following specifications:", "source": null}, {"label": "(1)", "text": "The minimum letter size shall be one-sixteenth of an inch in height.", "source": null}, {"label": "(2)", "text": "Letter heights pertain to the lower-case letter “o” or its equivalent that shall meet the minumim height standard.", "source": null}, {"label": "(3)", "text": "Type used shall conform to the minimum letter height. The body copy shall contain 1-point leading, noncondensed type, and shall not contain any light-face type or small capital letters.", "source": null}, {"label": "(d)", "text": "This section does not apply to a progestogen-containing product intended for contraception, which shall be labeled according to the requirements of § 310.501.", "source": null}, {"label": "(2)", "text": "In the case of progestational drug products in bulk packages intended for multiple dispensing, a sufficient number of patient-labeling pieces shall be included in or shall accompany each bulk package to assure that one can be included with each package dispensed to every patient. Each bulk package shall be labeled with instructions to the dispenser to include one patient-labeling piece with each package dispensed to the patient. This section does not preclude the manufacturer or labeler from distributing additional patient-labeling pieces to the dispenser.", "source": null}, {"label": "(3)", "text": "In the case of progestational drug products for injection, each package shall include a sufficient number of patient-labeling pieces for the volume of the vial, and instructions to the practitioner administering the drug to give one patient-labeling piece to each premenopausal woman, except those in whom childbearing is impossible, receiving the drug.", "source": null}, {"label": "(4)", "text": "This section does not apply to oral dosage forms labeled solely for the treatment of advanced cancer.", "source": null}, {"label": "(5)", "text": "Any progestational drug product, except as noted in paragraphs (d) and (e)(4) of this section, that is not labeled as required by this section and is either introduced or delivered for introduction into interstate commerce, or held for sale after shipment in interstate commerce, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act. However, a progestational drug product in the possession of a wholesaler or retailer before December 12, 1978, is not misbranded if adequate numbers of copies of the patient labeling are furnished to the wholesaler or retailer to permit any retail purchaser after that date to obtain such labeling with the product. The requirement that any progestational drug product be dispensed with patient labeling, as applied to physicians who dispense or administer the drug, will not be effective for supplies in their possession on the effective date, but will apply only to supplies received thereafter.", "source": null}, {"label": "(f)", "text": "The Food and Drug Administration has available guideline patient labeling for progestational drug products that includes information responsive to all items specified in paragraph (b) of this section. This labeling was published in a separate notice appearing in the Federal Register of January 12, 1989. Any person may rely on this labeling as complying with paragraph (b) of this section.", "source": null}, {"label": "(g)", "text": "Holders of approved new drug applications for progestational drug products that are subject to the requirements of this section shall submit supplements under § 314.70(c) of this chapter to provide for the labeling required by paragraph (a) of this section.", "source": null}]

§ 310.501.; § 310.6; § 314.70

[43 FR 47181, Oct. 13, 1978, as amended at 46 FR 53657, Oct. 30, 1981; 54 FR 1163, Jan. 12, 1989]

Oct. 13, 1978

(Revised as of April 1, 1996)

False

30 days; 4 months

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.516

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.517

Labeling for oral hypoglycemic drugs of the sulfonylurea class.

(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 (Diabetes, 19 (supp. 2): 747-830, 1970). 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 21/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of (name of drug) and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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:", "source": null}]

[49 FR 14331, Apr. 11, 1984]

Apr. 11, 1984

(Revised as of April 1, 1996)

False

8 years

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.517

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.519

Drug products marketed as over-the-counter (OTC) daytime sedatives.

(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 evidence presently available, there are no ingredients that can be generally recognized as safe and effective for use as OTC daytime sedatives. (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.

regulation

[{"label": "(a)", "text": "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 evidence presently available, there are no ingredients that can be generally recognized as safe and effective for use as OTC daytime sedatives.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at 55 FR 11579, Mar. 29, 1990]

June 22, 1979

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.519

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.525

Sweet spirits of nitre drug products.

(a) Historically, sweet spirits of nitre has been present as an ingredient in over-the-counter (OTC) drug products for various uses. Based upon the lack of adequate data to establish effectiveness for any use and the adverse benefit-to-risk ratio, sweet spirits of nitre drug products cannot be considered generally recognized as safe and effective. The benefit from using sweet spirits of nitre for any use is insignificant when compared to the risk. (b) Any drug product containing sweet spirits of nitre is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act and is a new drug within the meaning of section 201(p) of 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. (c) Clinical investigations designed to obtain evidence that any drug product containing sweet spirits of nitre for any 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) Any drug product containing sweet spirits of nitre in interstate commerce after June 27, 1980, that is not in compliance with this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "Historically, sweet spirits of nitre has been present as an ingredient in over-the-counter (OTC) drug products for various uses. Based upon the lack of adequate data to establish effectiveness for any use and the adverse benefit-to-risk ratio, sweet spirits of nitre drug products cannot be considered generally recognized as safe and effective. The benefit from using sweet spirits of nitre for any use is insignificant when compared to the risk.", "source": null}, {"label": "(b)", "text": "Any drug product containing sweet spirits of nitre is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act and is a new drug within the meaning of section 201(p) of 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.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any drug product containing sweet spirits of nitre for any 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.", "source": null}, {"label": "(d)", "text": "Any drug product containing sweet spirits of nitre in interstate commerce after June 27, 1980, that is not in compliance with this section is subject to regulatory action.", "source": null}]

[45 FR 43401, June 27, 1980, as amended at 55 FR 11579, Mar. 29, 1990]

June 27, 1980

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.525

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.526

Camphorated oil drug products.

(a) Historically, camphorated oil (also known as camphor liniment), a solution of 20 percent camphor in cottonseed oil, has been marketed as an over-the-counter (OTC) drug product for various uses, primarily as a topical counterirritant or liniment. A large number of accidental ingestions of camphorated oil, often mistaken for castor oil, cod liver oil, mineral oil, olive oil, cough medicine, or other drug products, have been reported and toxicity has often resulted, primarily in infants and young children. Because of the potential hazard for poisoning to occur, the benefit from using any drug product containing camphor in oil or from using any camphor-containing drug product that is labeled as “camphorated oil” or “camphor liniment,” or any similar name such as “camphor oil” or “camphorated liniment,” for any use, is insignificant when compared to the risk. Based upon the adverse benefit-to-risk ratio, camphorated oil, any drug product containing camphor in oil, or any other drug product containing camphor that is represented, suggested, or purported to be camphorated oil, such as a product labeled “camphor liniment,” “camphor oil,” “camphorated liniment,” or any similar name, cannot be considered generally recognized as safe. (b) Any camphorated oil drug product, any drug product containing camphor in oil, or any other drug product containing camphor that is represented, suggested or purported to be camphorated oil, e.g., “camphor liniment,” “camphor oil,” “camphorated liniment,” is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act and is a new drug within the meaning of section 201(p) of 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. (c) Clinical investigations designed to obtain evidence that any camphorated oil drug product, any drug product containing camphor in oil, or any other drug product containing camphor that is represented, suggested, or purported to be camphorated oil, e.g., “camphor liniment,” “camphor oil,” “camphorated liniment,” is safe 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 September 21, 1982 that is not in compliance with this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "Historically, camphorated oil (also known as camphor liniment), a solution of 20 percent camphor in cottonseed oil, has been marketed as an over-the-counter (OTC) drug product for various uses, primarily as a topical counterirritant or liniment. A large number of accidental ingestions of camphorated oil, often mistaken for castor oil, cod liver oil, mineral oil, olive oil, cough medicine, or other drug products, have been reported and toxicity has often resulted, primarily in infants and young children. Because of the potential hazard for poisoning to occur, the benefit from using any drug product containing camphor in oil or from using any camphor-containing drug product that is labeled as “camphorated oil” or “camphor liniment,” or any similar name such as “camphor oil” or “camphorated liniment,” for any use, is insignificant when compared to the risk. Based upon the adverse benefit-to-risk ratio, camphorated oil, any drug product containing camphor in oil, or any other drug product ", "source": null}, {"label": "(b)", "text": "Any camphorated oil drug product, any drug product containing camphor in oil, or any other drug product containing camphor that is represented, suggested or purported to be camphorated oil, e.g., “camphor liniment,” “camphor oil,” “camphorated liniment,” is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act and is a new drug within the meaning of section 201(p) of 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.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any camphorated oil drug product, any drug product containing camphor in oil, or any other drug product containing camphor that is represented, suggested, or purported to be camphorated oil, e.g., “camphor liniment,” “camphor oil,” “camphorated liniment,” is safe 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.", "source": null}, {"label": "(d)", "text": "Any such drug product in interstate commerce after September 21, 1982 that is not in compliance with this section is subject to regulatory action.", "source": null}]

[47 FR 41720, Sept. 21, 1982, as amended at 55 FR 11579, Mar. 29, 1990]

Sept. 21, 1982

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.526

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.527

Drug products containing active ingredients offered over-the-counter (OTC) for external use as hair growers or for hair loss prevention.

(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.

regulation

[{"label": "(a)", "text": "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 pr", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[54 FR 28777, July 7, 1989]

July 7, 1989

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.527

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.528

Drug products containing active ingredients offered over-the-counter (OTC) for use as an aphrodisiac.

(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 are powerful hormones when administered internally and are not safe for use except under the supervision of a physician. There is a lack of adequate data to establish general recognition of the safety and effectiveness of any of these ingredients, or any other ingredient, for OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use are either false, misleading, or unsupported by scientific data. The following claims are examples of some that have been made for aphrodisiac drug products for OTC use: “acts as an aphrodisiac;” “arouses or increases sexual desire and improves sexual performance;” “helps restore sexual vigor, potency, and performance;” “improves performance, staying power, and sexual potency;” and “builds virility and sexual potency.” Based on evidence currently available, any OTC drug product containing ingredients for use as an aphrodisiac cannot be generally recognized as safe and effective. (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.

regulation

[{"label": "(a)", "text": "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 are powerful hormones when administered internally and are not safe for use except under the supervision of a physician. There is a lack of adequate data to establish general recognition of the safety and effectiveness of any of these ingredients, or any other ingredient, for OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use are either false, misleading, or unsupported by scientific data. The following claims are exa", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[54 FR 28786, July 7, 1989]

July 7, 1989

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.528

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.529

Drug products containing active ingredients offered over-the-counter (OTC) for oral use as insect repellents.

(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 this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "Any such drug product in interstate commerce after December 17, 1985, that is not in compliance with this section is subject to regulatory action.", "source": null}]

[40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990]

June 17, 1985

(Revised as of April 1, 1996)

False

24 hours

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.529

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.530

Topically applied hormone-containing drug products for over-the-counter (OTC) human use.

(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.

regulation

[{"label": "(a)", "text": "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, ", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}, {"label": "(e)", "text": "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.", "source": null}]

[58 FR 47610, Sept. 9, 1993]

Sept. 9, 1993

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.530

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.531

Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of boils.

(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 these purposes. These “drawing salves” contained various ingredients. Based on evidence currently available, any OTC drug product offered for the treatment of boils cannot be considered generally recognized as safe and effective. (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.

regulation

[{"label": "(a)", "text": "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 these purposes. These “drawing salves” contained various ingredients. Based on evidence currently available, any OTC drug product offered for the treatment of boils cannot be considered generally recognized as safe and effective.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}, {"label": "(e)", "text": "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.", "source": null}, {"label": "(f)", "text": "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.", "source": null}]

[58 FR 60336, Nov. 15, 1993]

Nov. 15, 1993

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.531

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.532

Drug products containing active ingredients offered over-the-counter (OTC) to relieve the symptoms of benign prostatic hypertrophy.

(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.

regulation

[{"label": "(a)", "text": "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 ", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[55 FR 6930, Feb. 27, 1990]

Feb. 27, 1990

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.532

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.533

Drug products containing active ingredients offered over-the-counter (OTC) for human use as an anticholinergic in cough-cold drug products.

(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 (d, dl hyoscyamine) and scopolamine (l- hyoscine), are probably safe for oral use at dosages that have been used in marketed cough-cold products (0.2 milligram) but there are inadequate data to establish general recognition of the effectiveness of these ingredients as an anticholinergic for cough-cold use. Belladonna alkaloids for inhalation use, as contained in Atropa belladonna and Datura stramonium, are neither safe nor effective as an OTC anticholinergic. There are inadequate safety and effectiveness data to establish general recognition of the safety and/or effectiveness or any of these ingredients, or any other ingredient, for OTC use as an anticholinergic in cough-cold drug products. (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.

regulation

[{"label": "(a)", "text": "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 (d, dl hyoscyamine) and scopolamine (l- hyoscine), are probably safe for oral use at dosages that have been used in marketed cough-cold products (0.2 milligram) but there are inadequate data to establish general recognition of the effectiveness of thes", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990]

Nov. 8, 1985

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.533

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.534

Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents.

(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 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 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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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 marketing. In the absence of an approved new drug application, such product is also misbranded under section 502 of the act.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990]

July 18, 1986

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.534

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.536

Drug products containing active ingredients offered over-the-counter (OTC) for use as a nailbiting or thumbsucking deterrent.

(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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[58 FR 46754, Sept. 2, 1993]

Sept. 2, 1993

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.536

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.537

Drug products containing active ingredients offered over-the-counter (OTC) for oral administration for the treatment of fever blisters and cold sores.

(a) l-lysine (lysine, lysine hydrochloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been present in orally administered OTC drug products to treat fever blisters and cold sores. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other orally administered ingredients for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores. Based on evidence currently available, any OTC drug product for oral administration containing ingredients offered for use in treating or relieving the symptoms or discomfort of fever blisters and cold sores cannot be generally recognized as safe and effective. (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, represented, or promoted for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores 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 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.

regulation

[{"label": "(a)", "text": "l-lysine (lysine, lysine hydrochloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been present in orally administered OTC drug products to treat fever blisters and cold sores. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these or any other orally administered ingredients for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores. Based on evidence currently available, any OTC drug product for oral administration containing ingredients offered for use in treating or relieving the symptoms or discomfort of fever blisters and cold sores cannot be generally recognized as safe and effective.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "Clinical investigations designed to obtain evidence that any drug product for oral administration labeled, represented, or promoted for OTC use to treat or relieve the symptoms or discomfort of fever blisters and cold sores 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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[57 FR 29173, June 30, 1992]

June 30, 1992

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.537

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.538

Drug products containing active ingredients offered over-the-counter (OTC) for use for ingrown toenail relief.

(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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[58 FR 47605, Sept. 9, 1993]

Sept. 9, 1993

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.538

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.540

Drug products containing active ingredients offered over-the-counter (OTC) for use as stomach acidifiers.

(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 compliance with this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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 compliance with this section is subject to regulatory action.", "source": null}]

[53 FR 31271, Aug. 17, 1988]

Aug. 17, 1988

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.540

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.541

Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hypophosphatemia.

(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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[55 FR 19858, May 11, 1990]

May 11, 1990

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.541

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.542

Over-the-counter (OTC) drug products containing active ingredients offered for use in the treatment of hyperphosphatemia.

(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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[55 FR 19858, May 11, 1990]

May 11, 1990

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.542

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.543

Drug products containing active ingredients offered over-the-counter (OTC) for human use in exocrine pancreatic insufficiency.

(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, the safe and effective use of these enzymes for treating exocrine pancreatic insufficiency cannot be regulated adequately by an OTC drug monograph. Information on the product's formulation, manufacture, quality control procedures, and final formulation effectiveness testing are necessary in an approved application to ensure that a company has the ability to manufacture a proper bioactive formulation. In addition, continuous physician monitoring of patients who take these drug products is a collateral measure necessary to the safe and effective use of these enzymes, causing such products to be available by prescription only. (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.

regulation

[{"label": "(a)", "text": "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, the safe and effective use of these enzymes for treating exocrine pancreatic insufficiency cannot be regulated adequately by an OTC drug monograph. Information on the product's formulation, manufacture, quality control procedures, and final formulation effectiveness testing are necessary in an approved application to ensure that a co", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}, {"label": "(e)", "text": "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.", "source": null}]

[60 FR 20165, Apr. 24, 1995]

Apr. 24, 1995

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.543

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.544

Drug products containing active ingredients offered over-the-counter (OTC) for use as a smoking deterrent.

(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 Lobelia inflata herb), menthol, methyl salicylate, povidone-silver nitrate, quinine ascorbate, silver acetate, silver nitrate, and thymol have been present as ingredients in such drug products. 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 as a smoking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a smoking deterrent cannot be generally recognized as safe and effective. (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 initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. After December 1, 1993, any such OTC drug product containing lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata herb), povidone-silver nitrate, silver acetate, or any other ingredients initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

regulation

[{"label": "(a)", "text": "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 Lobelia inflata herb), menthol, methyl salicylate, povidone-silver nitrate, quinine ascorbate, silver acetate, silver nitrate, and thymol have been present as ingredients in such drug products. 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 as a smoking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a smoking deterrent cannot be generally recognized as safe and effective.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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 initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action. After December 1, 1993, any such OTC drug product containing lobeline (in the form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata herb), povidone-silver nitrate, silver acetate, or any other ingredients initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.", "source": null}]

[58 FR 31241, June 1, 1993]

June 1, 1993

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.544

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.545

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses.

(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) Topical acne drug products. Alcloxa Alkyl isoquinolinium bromide Aluminum chlorohydrex Aluminum hydroxide Benzocaine Benzoic acid Boric acid Calcium polysulfide Calcium thiosulfate Camphor Chloroxylenol Cloxyquin Coal tar Dibenzothiophene Estrone Magnesium aluminum silicate Magnesium sulfate Phenol Phenolate sodium Phenyl salicylate Povidone-iodine Pyrilamine maleate Resorcinol (as single ingredient) Resorcinol monoacetate (as single ingredient) Salicylic acid (over 2 up to 5 percent) Sodium borate Sodium thiosulfate Tetracaine hydrochloride Thymol Vitamin E Zinc oxide Zinc stearate Zinc sulfide (2) Anticaries drug products—(i) Approved as of May 7, 1991. Hydrogen fluoride Sodium carbonate Sodium monofluorophosphate (6 percent rinse) Sodium phosphate (ii) Approved as of October 7, 1996. Calcium sucrose phosphate Dicalcium phosphate dihydrate Disodium hydrogen phosphate1 1 These ingredients are nonmonograph except when used to prepare acidulated phosphate fluoride treatment rinses identified in § 355.10(a)(3) of this chapter. Phosphoric acid1 Sodium dihydrogen phosphate Sodium dihydrogen phosphate monohydrate Sodium phosphate, dibasic anhydrous reagent1 (3) Antidiarrheal drug products. Aluminum hydroxide Atropine sulfate Calcium carbonate Carboxymethylcellulose sodium Glycine Homatropine methylbromide Hyoscyamine sulfate Lactobacillus acidophilus Lactobacillus bulgaricus Opium, powdered Opium tincture Paregoric Phenyl salicylate Scopolamine hydrobromide Zinc phenolsulfonate (4) Antiperspirant drug products. Alum, potassium Aluminum bromohydrate Aluminum chloride (alcoholic solutions) Aluminum chloride (aqueous solution) (aerosol only) Aluminum sulfate Aluminum sulfate, buffered (aerosol only) Sodium aluminum chlorohydroxy lactate (5) [Reserved] (6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug products—(i) Antihistamine drug products—(A) Ingredients. Methapyrilene hydrochloride Methapyrilene fumarate Thenyldiamine hydrochloride (B) Ingredients. Phenyltoloxamine dihydrogen citrate Methapyrilene hydrochloride Methapyrilene fumarate Thenyldiamine hydrochloride (ii) Nasal decongestant drug products—(A) Approved as of May 7, 1991. Allyl isothiocyanate Camphor (lozenge) Creosote, beechwood (oral) Eucalyptol (lozenge) Eucalyptol (mouthwash) Eucalyptus oil (lozenge) Eucalyptus oil (mouthwash) Menthol (mouthwash) Peppermint oil (mouthwash) Thenyldiamine hydrochloride Thymol Thymol (lozenge) Thymol (mouthwash) Turpentine oil (B) Approved as of August 23, 1995. Bornyl acetate (topical) Cedar leaf oil (topical) Creosote, beechwood (topical) l-desoxyephedrine (topical) Ephedrine (oral) Ephedrine hydrochloride (oral) Ephedrine sulfate (oral) Racephedrine hydrochloride (oral/topical) (iii) Expectorant drug products. Ammonium chloride Antimony potassium tartrate Beechwood creosote Benzoin preparations (compound tincture of benzoin, tincture of benzoin) Camphor Chloroform Eucalyptol/eucalyptus oil Horehound Iodides (calcium iodide anyhydrous, hydroidic acid syrup, iodized lime, potassium iodide) Ipecac Ipecac fluidextract Ipecac syrup Menthol/peppermint oil Pine tar preparations (extract white pine compound, pine tar, syrup of pine tar, compound white pine syrup, white pine) Potassium guaiacolsulfonate Sodium citrate Squill preparations (squill, squill extract) Terpin hydrate preparations (terpin hydrate, terpin hydrate elixir) Tolu preparations (tolu, tolu balsam, tolu balsam tincture) Turpentine oil (spirits of turpentine) (iv) Bronchodilator drug products—(A) Approved as of October 2, 1987. Aminophylline Belladonna alkaloids Euphorbia pilulifera Metaproterenol sulfate Methoxyphenamine hydrochloride Pseudoephedrine hydrochloride Pseudoephedrine sulfate Theophylline, anhydrous Theophylline calcium salicylate Theophylline sodium glycinate (B) Approved as of January 29, 1996. Any combination drug product containing theophylline (e.g., theophylline and ephedrine, or theophylline and ephedrine and phenobarbital). (7) Dandruff/seborrheic dermatitis/psoriasis drug products. Alkyl isoquinolinium bromide Allantoin Benzalkonium chloride Benzethonium chloride Boric acid Calcium undecylenate Captan Chloroxylenol Colloidal oatmeal Cresol, saponated Ethohexadiol Eucalyptol Juniper tar Lauryl isoquinolinium bromide Menthol Mercury oleate Methylbenzethonium chloride Methyl salicylate Phenol Phenolate sodium Pine tar Povidone-iodine Resorcinol Sodium borate Sodium salicylate Thymol Undecylenic acid (8) Digestive aid drug products—(i) Approved as of May 7, 1991. Bismuth sodium tartrate Calcium carbonate Cellulase Dehydrocholic acid Dihydroxyaluminum sodium carbonate Duodenal substance Garlic, dehydrated Glutamic acid hydrochloride Hemicellulase Homatropine methylbromide Magnesium hydroxide Magnesium trisilicate Ox bile extract Pancreatin Pancrelipase Papain Peppermint oil Pepsin Sodium bicarbonate Sodium citrate Sorbitol (ii) Approved as of November 10, 1993. Alcohol Aluminum hydroxide Amylase Anise seed Aromatic powder Asafetida Aspergillus oryza enzymes (except lactase enzyme derived from Aspergillus oryzae) Bacillus acidophilus Bean Belladonna alkaloids Belladonna leaves, powdered extract Betaine hydrochloride Bismuth subcarbonate Bismuth subgallate Black radish powder Blessed thistle (cnicus benedictus) Buckthorn Calcium gluconate Capsicum Capsicum, fluid extract of Carbon Cascara sagrada extract Catechu, tincture Catnip Chamomile flowers Charcoal, wood Chloroform Cinnamon oil Cinnamon tincture Citrus pectin Diastase Diastase malt Dog grass Elecampane Ether Fennel acid Galega Ginger Glycine Hydrastis canadensis (golden seal) Hectorite Horsetail Huckleberry Hydrastis fluid extract Hydrochloric acid Iodine Iron ox bile Johnswort Juniper Kaolin, colloidal Knotgrass Lactic acid Lactose Lavender compound, tincture of Linden Lipase Lysine hydrochloride Mannitol Mycozyme Myrrh, fluid extract of Nettle Nickel-pectin Nux vomica extract Orthophosphoric acid Papaya, natural Pectin Peppermint Peppermint spirit Phenacetin Potassium bicarbonate Potassium carbonate Protease Prolase Rhubarb fluid extract Senna Sodium chloride Sodium salicylate Stem bromelain Strawberry Strychnine Tannic acid Trillium Woodruff (iii) Charcoal, activated (9) [Reserved] (10) External analgesic drug products—(i) Analgesic and anesthetic drug products. Aspirin Chloral hydrate Chlorobutanol Cyclomethycaine sulfate Eugenol Hexylresorcinol Methapyrilene hydrochloride Salicylamide Thymol (ii) Counterirritant drug products. Chloral hydrate Eucalyptus oil (iii) Male genital desensitizer drug products. Benzyl alcohol Camphorated metacresol Ephedrine hydrochloride (iv) Diaper rash drug products. Any ingredient(s) labeled with claims or directions for use in the treatment and/or prevention of diaper rash. (v) Fever blister and cold sore treatment drug products. Allyl isothiocyanate Aspirin Bismuth sodium tartrate Camphor (exceeding 3 percent) Capsaicin Capsicum Capsicum oleoresin Chloral hydrate Chlorobutanol Cyclomethycaine sulfate Eucalyptus oil Eugenol Glycol salicylate Hexylresorcinol Histamine dihydrochloride Menthol (exceeding 1 percent) Methapyrilene hydrochloride Methyl nicotinate Methyl salicylate Pectin Salicylamide Strong ammonia solution Tannic acid Thymol Tripelennamine hydrochloride Trolamine salicylate Turpentine oil Zinc sulfate (vi) Insect bite and sting drug products. Alcohol Alcohol, ethoxylated alkyl Benzalkonium chloride Calamine Ergot fluidextract Ferric chloride Panthenol Peppermint oil Pyrilamine maleate Sodium borate Trolamine salicylate Turpentine oil Zinc oxide Zirconium oxide (vii) Poison ivy, poison oak, and poison sumac drug products. Alcohol Aspirin Benzethonium chloride Benzocaine (0.5 to 1.25 percent) Bithionol Calamine Cetalkonium chloride Chloral hydrate Chlorobutanol Chlorpheniramine maleate Creosote, beechwood Cyclomethycaine sulfate Dexpanthenol Diperodon hydrochloride Eucalyptus oil Eugenol Glycerin Glycol salicylate Hectorite Hexylresorcinol Hydrogen peroxide Impatiens biflora tincture Iron oxide Isopropyl alcohol Lanolin Lead acetate Merbromin Mercuric chloride Methapyrilene hydrochloride Panthenol Parethoxycaine hydrochloride Phenyltoloxamine dihydrogen citrate Povidone-vinylacetate copolymers Pyrilamine maleate Salicylamide Salicylic acid Simethicone Sulfur Tannic acid Thymol Trolamine salicylate Turpentine oil Zirconium oxide Zyloxin (11) [Reserved] (12) Laxative drug products—(i) Bulk laxatives. Agar Carrageenan (degraded) Carrageenan (native) Guar gun (ii) Saline laxative. Tartaric acid (iii) Stool softener. Poloxamer 188 (iv) Stimulant laxatives. Aloin Bile salts/acids Calcium pantothenate Calomel Colocynth Elaterin resin Frangula Gamboge Ipomea Jalap Ox bile Podophyllum resin Prune concentrate dehydrate Prune powder Rhubarb, Chinese Sodium Oleate (13) [Reserved] (14) Oral health care drug products (nonantimicrobial). Antipyrine Camphor Cresol Dibucaine Dibucaine hydrochloride Eucalyptol Lidocaine Lidocaine hydrochloride Methly salicylate Myrrh tincture Pyrilamine maleate Sorbitol Sugars Tetracaine Tetracaine hydrochloride Thymol (15) Topical otic drug products for the prevention of swimmer's ear and for the drying of water-clogged ears—(i) Approved as of May 7, 1991. Acetic acid (ii) Approved as of August 15, 1995. Glycerin and anhydrous glycerin Isopropyl alcohol (16) Poison treatment drug products. Ipecac fluidextract Ipecac tincture Zinc sulfate (17) Skin bleaching drug products. Mercury, ammoniated (18) Skin protectant drug products. (i) Ingredients. Allantoin (wound healing claims only) Sulfur Tannic acid Zinc acetate (wound healing claims only) (ii) Astringent drug products. Acetone Alcohol Alum, ammonium Alum, potassium Aluminum chlorhydroxy complex Aromatics Benzalkonium chloride Benzethonium chloride Benzocaine Benzoic acid Boric acid Calcium acetate Camphor gum Clove oil Colloidal oatmeal Cresol Cupric sulfate Eucalyptus oil Eugenol Ferric subsulfate (Monsel's Solution) Honey Isopropyl alcohol Menthol Methyl salicylate Oxyquinoline sulfate P-t-butyl-m-cresol Peppermint oil Phenol Polyoxeythylene laurate Potassium ferrocyanide Sage oil Silver nitrate Sodium borate Sodium diacetate Talc Tannic acid glycerite Thymol Topical starch Zinc chloride Zinc oxide Zinc phenolsulfonate Zinc stearate Zinc sulfate (iii) Diaper rash drug products. Aluminum hydroxide Cocoa butter Cysteine hydrochloride Glycerin Protein hydrolysate Racemethionine Sulfur Tannic acid Zinc acetate Zinc carbonate (iv) Fever blister and cold sore treatment drug products. Bismuth subnitrate Boric acid Pyridoxine hydrochloride Sulfur Tannic acid Topical starch Trolamine Zinc sulfate (v) Insect bite and sting drug products. Alcohol Alcohol, ethoxylated alkyl Ammonia solution, strong Ammonium hydroxide Benzalkonium chloride Camphor Ergot fluidextract Ferric chloride Menthol Peppermint oil Phenol Pyrilamine maleate Sodium borate Trolamine Turpentine oil Zirconium oxide (vi) Poison ivy, poison oak, and poison sumac drug products. Alcohol Anion and cation exchange resins buffered Benzethonium chloride Benzocaine Benzyl alcohol Bismuth subnitrate Bithionol Boric acid Camphor Cetalkonium chloride Chloral hydrate Chlorpheniramine maleate Creosote Diperodon hydrochloride Diphenhydramine hydrochloride Eucalyptus oil Ferric chloride Glycerin Hectorite Hydrogen peroxide Impatiens biflora tincture Iron oxide Isopropyl alcohol Lanolin Lead acetate Lidocaine Menthol Merbromin Mercuric chloride Panthenol Parethoxycaine hydrochloride Phenol Phenyltoloxamine dihydrogen citrate Povidone-vinylacetate copolymers Salicylic acid Simethicone Tannic acid Topical starch Trolamine Turpentine oil Zirconium oxide Zyloxin (19) [Reserved] (20) Weight control drug products. Alcohol Alfalfa Alginic acid Anise oil Arginine Ascorbic acid Bearberry Biotin Bone marrow, red Buchu Buchu, potassium extract Caffeine Caffeine citrate Calcium Calcium carbonate Calcium caseinate Calcium lactate Calcium pantothenate Carboxymethylcellulose sodium Carrageenan Cholecalcierol Choline Chondrus Citric acid Cnicus benedictus Copper Copper gluconate Corn oil Corn syrup Corn silk, potassium extract Cupric sulfate Cyanocobalamin (vitamin B12) Cystine Dextrose Docusate sodium Ergocalciferol Ferric ammonium citrate Ferric pyrophosphate Ferrous fumarate Ferrous gluconate Ferrous sulfate (iron) Flax seed Folic acid Fructose Guar gum Histidine Hydrastis canadensis Inositol Iodine Isoleucine Juniper, potassium extract Karaya gum Kelp Lactose Lecithin Leucine Liver concentrate Lysine Lysine hydrochloride Magnesium Magnesium oxide Malt Maltodextrin Manganese citrate Mannitol Methionine Methylcellulose Mono- and di-glycerides Niacinamide Organic vegetables Pancreatin Pantothenic acid Papain Papaya enzymes Pepsin Phenacetin Phenylalanine Phosphorus Phytolacca Pineapple enzymes Plantago seed Potassium citrate Pyridoxine hydrochloride (vitamin B6) Riboflavin Rice polishings Saccharin Sea minerals Sesame seed Sodium Sodium bicarbonate Sodium caseinate Sodium chloride (salt) Soybean protein Soy meal Sucrose Thiamine hydrochloride (vitamin B1) Thiamine mononitrate (vitamin B1 mononitrate) Threonine Tricalcium phosphate Tryptophan Tyrosine Uva ursi, potassium extract Valine Vegetable Vitamin A Vitamin A acetate Vitamin A palmitate Vitamin E Wheat germ Xanthan gum Yeast (21) Ophthalmic drug products. (i) Ophthalmic anesthetic drug products. Antipyrine Piperocaine hydrochloride (ii) Ophthalmic anti-infective drug products. Boric acid Mild silver protein Yellow mercuric oxide (iii) Ophthalmic astringent drug products. Infusion of rose petals (iv) Ophthalmic demulcent drug products. Polyethylene glycol 6000 (v) Ophthalmic vasoconstrictor drug products. Phenylephrine hydrochloride (less than 0.08 percent) (22) Topical antifungal drug products. (i) Diaper rash drug products. Any ingredient(s) labeled with claims or directions for use in the treatment and/or prevention of diaper rash. (ii) Ingredients. Alcloxa Alum, potassium Aluminum sulfate Amyltricresols, secondary Basic fuchsin Benzethonium chloride Benzoic acid Benzoxiquine Boric acid Camphor Candicidin Chlorothymol Coal tar Dichlorophen Menthol Methylparaben Oxyquinoline Oxyquinoline sulfate Phenol Phenolate sodium Phenyl salicylate Propionic acid Propylparaben Resorcinol Salicylic acid Sodium borate Sodium caprylate Sodium propionate Sulfur Tannic acid Thymol Tolindate Triacetin Zinc caprylate Zinc propionate (iii) Any ingredient(s) labeled with claims or directions for use on the scalp or on the nails. (iv) Ingredients. Camphorated metacresol Chloroxylenol m-cresol Nystatin (23) Internal analgesic drug products. Aminobenzoic acid Antipyrine Aspirin, aluminum Calcium salicylate Codeine Codeine phosphate Codeine sulfate Iodoantipyrine Lysine aspirin Methapyrilene fumarate Phenacetin Pheniramine maleate Pyrilamine maleate Quinine Salsalate Sodium aminobenzoate (24) Orally administered menstrual drug products. Alcohol Alfalfa leaves Aloes Asclepias tuberosa Asparagus Barosma Bearberry (extract of uva ursi) Bearberry fluidextract (extract of bearberry) Blessed thistle (cnicus benedictus) Buchu powdered extract (extract of buchu) Calcium lactate Calcium pantothenate Capsicum oleoresin Cascara fluidextract, aromatic (extract of cascara) Chlorprophenpyridamine maleate Cimicifuga racemosa Codeine Collinsonia (extract stone root) Corn silk Couch grass Dog grass extract Ethyl nitrite Ferric chloride Ferrous sulfate Gentiana lutea (gentian) Glycyrrhiza (licorice) Homatropine methylbromide Hydrangea, powdered extract (extract of hydrangea) Hydrastis canadensis (golden seal) Hyoscyamine sulfate Juniper oil (oil of juniper) Magnesium sulfate Methapyrilene hydrochloride Methenamine Methylene blue Natural estrogenic hormone Niacinamide Nutmeg oil (oil of nutmeg) Oil of erigeron Parsley Peppermint spirit Pepsin, essence Phenacetin Phenindamine tartrate Phenyl salicylate Piscidia erythrina Pipsissewa Potassium acetate Potassium nitrate Riboflavin Saw palmetto Senecio aureus Sodium benzoate Sodium nitrate Sucrose Sulferated oils of turpentine Taraxacum officinale Theobromine sodium salicylate Theophylline Thiamine hydrochloride Triticum Turpentine, venice (venice turpertine) Urea (25) Pediculicide drug products—(i) Approved as of November 10, 1993. Benzocaine Benzyl alcohol Benzyl benzoate Chlorophenothane (dichlorodiphenyl trichloroethane) Coconut oil soap, aqueous Copper oleate Docusate sodium Formic acid Isobornyl thiocyanoacetate Picrotoxin Propylene glycol Sabadilla alkaloids Sulfur, sublimed Thiocyanoacetate (ii) Approved as of June 14, 1994. The combination of pyrethrum extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol dosage formulation. (26) Anorectal druq products—(i) Anticholinergic drug products. Atropine Belladonna extract (ii) Antiseptic drug products. Boric acid Boroglycerin Hydrastis Phenol Resorcinol Sodium salicylic acid phenolate (iii) Astringent drug products. Tannic acid (iv) Counterirritant drug products. Camphor (greater than 3 to 11 percent) Hydrastis Menthol (1.25 to 16 percent) Turpentine oil (rectified) (6 to 50 percent) (v) Keratolytic drug products. Precipitated sulfur Sublimed sulfur (vi) Local anesthetic drug products. Diperodon Phenacaine hydrochloride (vii) Other druq products. Collinsonia extract Escherichia coli vaccines Lappa extract Leptandra extract Live yeast cell derivative Mullein (viii) Protectant druq products. Bismuth oxide Bismuth subcarbonate Bismuth subgallate Bismuth subnitrate Lanolin alcohols (ix) Vasoconstrictor druq products. Epinephrine undecylenate (x) Wound healinq druq products. Cholecalciferol Cod liver oil Live yeast cell derivative Peruvian balsam Shark liver oil Vitamin A (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)(24) 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)(9) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv), (a)(14) through (a)(15)(i), and (a)(16) through (a)(18)(i) 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 that contain menthol as an antipruritic in combination with the antidandruff ingredient coal tar identified in § 358.710(a)(1) of this chapter. (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 paragraph (a)(18)(ii) of this section, except products that contain ferric subsulfate. (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.

regulation

[{"label": "(a)", "text": "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:", "source": null}, {"label": "(1)", "text": "Topical acne drug products.", "source": null}, {"label": "(2)", "text": "Anticaries drug products—(i) Approved as of May 7, 1991.", "source": null}, {"label": "(ii)", "text": "Approved as of October 7, 1996.", "source": null}, {"label": "(3)", "text": "Antidiarrheal drug products.", "source": null}, {"label": "(4)", "text": "Antiperspirant drug products.", "source": null}, {"label": "(5)", "text": "[Reserved]", "source": null}, {"label": "(6)", "text": "Cold, cough, allergy, bronchodilator, and antiasthmatic drug products—(i) Antihistamine drug products—(A) Ingredients.", "source": null}, {"label": "(B)", "text": "Ingredients.", "source": null}, {"label": "(ii)", "text": "Nasal decongestant drug products—(A) Approved as of May 7, 1991.", "source": null}, {"label": "(B)", "text": "Approved as of August 23, 1995.", "source": null}, {"label": "(iii)", "text": "Expectorant drug products.", "source": null}, {"label": "(iv)", "text": "Bronchodilator drug products—(A) Approved as of October 2, 1987.", "source": null}, {"label": "(B)", "text": "Approved as of January 29, 1996. Any combination drug product containing theophylline (e.g., theophylline and ephedrine, or theophylline and ephedrine and phenobarbital).", "source": null}, {"label": "(7)", "text": "Dandruff/seborrheic dermatitis/psoriasis drug products.", "source": null}, {"label": "(8)", "text": "Digestive aid drug products—(i) Approved as of May 7, 1991.", "source": null}, {"label": "(ii)", "text": "Approved as of November 10, 1993.", "source": null}, {"label": "(iii)", "text": "Charcoal, activated", "source": null}, {"label": "(9)", "text": "[Reserved]", "source": null}, {"label": "(10)", "text": "External analgesic drug products—(i) Analgesic and anesthetic drug products.", "source": null}, {"label": "(ii)", "text": "Counterirritant drug products.", "source": null}, {"label": "(iii)", "text": "Male genital desensitizer drug products.", "source": null}, {"label": "(iv)", "text": "Diaper rash drug products.", "source": null}, {"label": "(v)", "text": "Fever blister and cold sore treatment drug products.", "source": null}, {"label": "(vi)", "text": "Insect bite and sting drug products.", "source": null}, {"label": "(vii)", "text": "Poison ivy, poison oak, and poison sumac drug products.", "source": null}, {"label": "(11)", "text": "[Reserved]", "source": null}, {"label": "(12)", "text": "Laxative drug products—(i) Bulk laxatives.", "source": null}, {"label": "(ii)", "text": "Saline laxative.", "source": null}, {"label": "(iii)", "text": "Stool softener.", "source": null}, {"label": "(iv)", "text": "Stimulant laxatives.", "source": null}, {"label": "(13)", "text": "[Reserved]", "source": null}, {"label": "(14)", "text": "Oral health care drug products (nonantimicrobial).", "source": null}, {"label": "(15)", "text": "Topical otic drug products for the prevention of swimmer's ear and for the drying of water-clogged ears—(i) Approved as of May 7, 1991.", "source": null}, {"label": "(ii)", "text": "Approved as of August 15, 1995.", "source": null}, {"label": "(16)", "text": "Poison treatment drug products.", "source": null}, {"label": "(17)", "text": "Skin bleaching drug products.", "source": null}, {"label": "(18)", "text": "Skin protectant drug products. (i) Ingredients.", "source": null}, {"label": "(ii)", "text": "Astringent drug products.", "source": null}, {"label": "(iii)", "text": "Diaper rash drug products.", "source": null}, {"label": "(iv)", "text": "Fever blister and cold sore treatment drug products.", "source": null}, {"label": "(v)", "text": "Insect bite and sting drug products.", "source": null}, {"label": "(vi)", "text": "Poison ivy, poison oak, and poison sumac drug products.", "source": null}, {"label": "(19)", "text": "[Reserved]", "source": null}, {"label": "(20)", "text": "Weight control drug products.", "source": null}, {"label": "(21)", "text": "Ophthalmic drug products.", "source": null}, {"label": "(i)", "text": "Ophthalmic anesthetic drug products.", "source": null}, {"label": "(ii)", "text": "Ophthalmic anti-infective drug products.", "source": null}, {"label": "(iii)", "text": "Ophthalmic astringent drug products.", "source": null}, {"label": "(iv)", "text": "Ophthalmic demulcent drug products.", "source": null}, {"label": "(v)", "text": "Ophthalmic vasoconstrictor drug products.", "source": null}, {"label": "(22)", "text": "Topical antifungal drug products.", "source": null}, {"label": "(i)", "text": "Diaper rash drug products. Any ingredient(s) labeled with claims or directions for use in the treatment and/or prevention of diaper rash.", "source": null}, {"label": "(ii)", "text": "Ingredients.", "source": null}, {"label": "(iii)", "text": "Any ingredient(s) labeled with claims or directions for use on the scalp or on the nails.", "source": null}, {"label": "(iv)", "text": "Ingredients.", "source": null}, {"label": "(23)", "text": "Internal analgesic drug products.", "source": null}, {"label": "(24)", "text": "Orally administered menstrual drug products.", "source": null}, {"label": "(25)", "text": "Pediculicide drug products—(i) Approved as of November 10, 1993.", "source": null}, {"label": "(ii)", "text": "Approved as of June 14, 1994. The combination of pyrethrum extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol dosage formulation.", "source": null}, {"label": "(26)", "text": "Anorectal druq products—(i) Anticholinergic drug products.", "source": null}, {"label": "(ii)", "text": "Antiseptic drug products.", "source": null}, {"label": "(iii)", "text": "Astringent drug products.", "source": null}, {"label": "(iv)", "text": "Counterirritant drug products.", "source": null}, {"label": "(v)", "text": "Keratolytic drug products.", "source": null}, {"label": "(vi)", "text": "Local anesthetic drug products.", "source": null}, {"label": "(vii)", "text": "Other druq products.", "source": null}, {"label": "(viii)", "text": "Protectant druq products.", "source": null}, {"label": "(ix)", "text": "Vasoconstrictor druq products.", "source": null}, {"label": "(x)", "text": "Wound healinq druq products.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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)(24) of this section.", "source": null}, {"label": "(1)", "text": "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)(9) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv), (a)(14) through (a)(15)(i), and (a)(16) through (a)(18)(i) of this section.", "source": null}, {"label": "(2)", "text": "February 10, 1992, for products subject to paragraph (a)(20) of this section.", "source": null}, {"label": "(3)", "text": "December 4, 1992, for products subject to paragraph (a)(7) of this section that contain menthol as an antipruritic in combination with the antidandruff ingredient coal tar identified in § 358.710(a)(1) of this chapter.", "source": null}, {"label": "(4)", "text": "February 28, 1990, for products subject to paragraph (a)(6)(iii) of this section, except those that contain ipecac.", "source": null}, {"label": "(5)", "text": "September 14, 1993, for products subject to paragraph (a)(6)(iii) of this section that contain ipecac.", "source": null}, {"label": "(6)", "text": "December 9, 1993, for products subject to paragraph (a)(6)(i)(B) of this section.", "source": null}, {"label": "(7)", "text": "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).", "source": null}, {"label": "(8)", "text": "June 18, 1993, for products subject to paragraph (a)(21) of this section that contain ophthalmic anti-infective ingredients.", "source": null}, {"label": "(9)", "text": "June 18, 1993, for products subject to paragraph (a)(10)(iv) of this section.", "source": null}, {"label": "(10)", "text": "June 18, 1993, for products subject to paragraph (a)(22)(i) of this section.", "source": null}, {"label": "(11)", "text": "November 10, 1993, for products subject to paragraph (a)(18)(ii) of this section, except products that contain ferric subsulfate.", "source": null}, {"label": "(12)", "text": "March 2, 1994, for products subject to paragraph (a)(22)(iii) of this section.", "source": null}, {"label": "(13)", "text": "August 5, 1991, for products subject to paragraphs (a)(26) of this section, except for those that contain live yeast cell derivative.", "source": null}, {"label": "(14)", "text": "September 2, 1994, for products subject to paragraph (a)(26)(vii) and (a)(26)(x) of this section that contain live yeast cell derivative.", "source": null}, {"label": "(15)", "text": "September 23, 1994, for products subject to paragraph (a)(22)(iv) of this section.", "source": null}, {"label": "(16)", "text": "June 14, 1994, for products subject to paragraph (a)(25)(ii) of this section.", "source": null}, {"label": "(17)", "text": "[Reserved]", "source": null}, {"label": "(18)", "text": "August 15, 1995, for products subject to paragraph (a)(15)(ii) of this section.", "source": null}, {"label": "(19)", "text": "October 2, 1987, for products subject to paragraph (a)(6)(iv)(A) of this section.", "source": null}, {"label": "(20)", "text": "January 29, 1996, for products subject to paragraph (a)(6)(iv)(B) of this section.", "source": null}, {"label": "(21)", "text": "April 21, 1994, for products subject to paragraph (a)(8)(iii) of this section.", "source": null}, {"label": "(22)", "text": "April 21, 1993, for products subject to paragraph (a)(18)(ii) of this section that contain ferric subsulfate.", "source": null}, {"label": "(23)", "text": "August 23, 1995, for products subject to paragraph (a)(6)(ii)(B) of this section.", "source": null}, {"label": "(24)", "text": "October 7, 1996, for products subject to paragraph (a)(2)(ii) of this section.", "source": null}, {"label": "(d)", "text": "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)(23) of this section.", "source": null}, {"label": "(1)", "text": "May 7, 1991, for products subject to paragraphs (a)(1) 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), and (a)(14) through (a)(18)(i) of this section.* * * * *", "source": null}]

§ 358.710; § 355.10

[55 FR 46919, Nov. 7, 1990]

Nov. 7, 1990

(Revised as of April 1, 1996)

Editorial Note: For Federal Register citations affecting § 310.545, see the List of CFR Sections Affected in the Finding Aids section of this volume.

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.545

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

Pt. 310

NEW DRUGS

Subpart E

Requirements for Specific New Drugs or Devices

310.546

Drug products containing active ingredients offered over-the-counter (OTC) for the treatment and/or prevention of nocturnal leg muscle cramps.

(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.

regulation

[{"label": "(a)", "text": "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 ", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

[59 FR 43252, Aug. 22, 1994]

Aug. 22, 1994

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:Pt._310:310.546

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A

General Provisions

312.1

Scope.

(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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.", "source": null}]

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.1

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A

General Provisions

312.2

Applicability.

(a) Applicability. Except as provided in this section, this part applies to all clinical investigations of products that are subject to section 505 or 507 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)). (b) Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all the following apply: (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 (a) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and (b) it is shipped in compliance with § 312.160. (ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (a) blood grouping serum; (b) reagent red blood cells; and (c) anti-human globulin. (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. (c) Bioavailability studies. The applicability of this part to in vivo bioavailability studies in humans is subject to the provisions of § 320.31. (d) Unlabeled indication. This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug or antibiotic drug product approved under part 314 or of a licensed biological product. (e) Guidance. FDA may, on its own initiative, issue guidance on the applicability of this part to particular investigational uses of drugs. On request, FDA will advise on the applicability of this part to a planned clinical investigation.

regulation

[{"label": "(a)", "text": "Applicability. Except as provided in this section, this part applies to all clinical investigations of products that are subject to section 505 or 507 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).", "source": null}, {"label": "(b)", "text": "Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all the following apply:", "source": null}, {"label": "(i)", "text": "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;", "source": null}, {"label": "(ii)", "text": "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;", "source": null}, {"label": "(iii)", "text": "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;", "source": null}, {"label": "(iv)", "text": "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", "source": null}, {"label": "(v)", "text": "The investigation is conducted in compliance with the requirements of § 312.7.", "source": null}, {"label": "(ii)", "text": "In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (a) blood grouping serum; (b) reagent red blood cells; and (c) anti-human globulin.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(4)", "text": "FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.", "source": null}, {"label": "(5)", "text": "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.", "source": null}, {"label": "(c)", "text": "Bioavailability studies. The applicability of this part to in vivo bioavailability studies in humans is subject to the provisions of § 320.31.", "source": null}, {"label": "(d)", "text": "Unlabeled indication. This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug or antibiotic drug product approved under part 314 or of a licensed biological product.", "source": null}, {"label": "(e)", "text": "Guidance. FDA may, on its own initiative, issue guidance on the applicability of this part to particular investigational uses of drugs. On request, FDA will advise on the applicability of this part to a planned clinical investigation.", "source": null}]

42 U.S.C. 201

§ 312.7.; § 312.160.; § 320.31.

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.2

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A

General Provisions

312.3

Definitions and interpretations.

(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: Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)). Clinical investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. Contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration. FDA means the Food and Drug Administration. IND means an investigational new drug application. For purposes of this part, “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” Investigational new drug means a new drug, antibiotic drug, or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms “investigational drug” and “investigational new drug” are deemed to be synonymous for purposes of this part. Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. “Subinvestigator” includes any other individual member of that team. Marketing application means an application for a new drug submitted under section 505(b) of the Act, a request to provide for certification of an antibiotic submitted under section 507 of the Act, or a product license application for a biological product submitted under the Public Health Service Act. Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators. Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor. Subject means a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease.

regulation

[{"label": "(a)", "text": "The definitions and interpretations of terms contained in section 201 of the Act apply to those terms when used in this part:", "source": null}, {"label": "(b)", "text": "The following definitions of terms also apply to this part:", "source": null}]

21 U.S.C. 301

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.3

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A

General Provisions

312.6

Labeling of an investigational new drug.

(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.

regulation

[{"label": "(a)", "text": "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.”", "source": null}, {"label": "(b)", "text": "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.", "source": null}]

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.6

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A

General Provisions

312.7

Promotion and charging for investigational drugs.

(a) Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution. (b) Commercial distribution of an investigational new drug. A sponsor or investigator shall not commercially distribute or test market an investigational new drug. (c) Prolonging an investigation. A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application. (d) Charging for and commercialization of investigational drugs—(1) Clinical trials under an IND. Charging for an investigational drug in a clinical trial under an IND is not permitted without the prior written approval of FDA. In requesting such approval, the sponsor shall provide a full written explanation of why charging is necessary in order for the sponsor to undertake or continue the clinical trial, e.g., why distribution of the drug to test subjects should not be considered part of the normal cost of doing business. (2) Treatment protocol or treatment IND. A sponsor or investigator may charge for an investigational drug for a treatment use under a treatment protocol or treatment IND provided: (i) There is adequate enrollment in the ongoing clinical investigations under the authorized IND; (ii) charging does not constitute commercial marketing of a new drug for which a marketing application has not been approved; (iii) the drug is not being commercially promoted or advertised; and (iv) the sponsor of the drug is actively pursuing marketing approval with due diligence. FDA must be notified in writing in advance of commencing any such charges, in an information amendment submitted under § 312.31. Authorization for charging goes into effect automatically 30 days after receipt by FDA of the information amendment, unless the sponsor is notified to the contrary. (3) Noncommercialization of investigational drug. Under this section, the sponsor may not commercialize an investigational drug by charging a price larger than that necessary to recover costs of manufacture, research, development, and handling of the investigational drug. (4) Withdrawal of authorization. Authorization to charge for an investigational drug under this section may be withdrawn by FDA if the agency finds that the conditions underlying the authorization are no longer satisfied. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.", "source": null}, {"label": "(b)", "text": "Commercial distribution of an investigational new drug. A sponsor or investigator shall not commercially distribute or test market an investigational new drug.", "source": null}, {"label": "(c)", "text": "Prolonging an investigation. A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.", "source": null}, {"label": "(d)", "text": "Charging for and commercialization of investigational drugs—(1) Clinical trials under an IND. Charging for an investigational drug in a clinical trial under an IND is not permitted without the prior written approval of FDA. In requesting such approval, the sponsor shall provide a full written explanation of why charging is necessary in order for the sponsor to undertake or continue the clinical trial, e.g., why distribution of the drug to test subjects should not be considered part of the normal cost of doing business.", "source": null}, {"label": "(2)", "text": "Treatment protocol or treatment IND. A sponsor or investigator may charge for an investigational drug for a treatment use under a treatment protocol or treatment IND provided: (i) There is adequate enrollment in the ongoing clinical investigations under the authorized IND; (ii) charging does not constitute commercial marketing of a new drug for which a marketing application has not been approved; (iii) the drug is not being commercially promoted or advertised; and (iv) the sponsor of the drug is actively pursuing marketing approval with due diligence. FDA must be notified in writing in advance of commencing any such charges, in an information amendment submitted under § 312.31. Authorization for charging goes into effect automatically 30 days after receipt by FDA of the information amendment, unless the sponsor is notified to the contrary.", "source": null}, {"label": "(3)", "text": "Noncommercialization of investigational drug. Under this section, the sponsor may not commercialize an investigational drug by charging a price larger than that necessary to recover costs of manufacture, research, development, and handling of the investigational drug.", "source": null}, {"label": "(4)", "text": "Withdrawal of authorization. Authorization to charge for an investigational drug under this section may be withdrawn by FDA if the agency finds that the conditions underlying the authorization are no longer satisfied.", "source": null}]

§ 312.31.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

30 days

False

True

30 days

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.7

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A

General Provisions

312.10

Waivers.

(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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "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:", "source": null}, {"label": "(1)", "text": "An explanation why the sponsor's compliance with the requirement is unnecessary or cannot be achieved;", "source": null}, {"label": "(2)", "text": "A description of an alternative submission or course of action that satisfies the purpose of the requirement; or", "source": null}, {"label": "(3)", "text": "Other information justifying a waiver.", "source": null}, {"label": "(b)", "text": "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:", "source": null}, {"label": "(1)", "text": "The sponsor's compliance with the requirement is unnecessary for the agency to evaluate the application, or compliance cannot be achieved;", "source": null}, {"label": "(2)", "text": "The sponsor's proposed alternative satisfies the requirement; or", "source": null}, {"label": "(3)", "text": "The applicant's submission otherwise justifies a waiver.", "source": null}]

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.10

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.20

Requirement for an IND.

(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.

regulation

[{"label": "(a)", "text": "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).", "source": null}, {"label": "(b)", "text": "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.", "source": null}]

§ 312.2; § 312.40.

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.20

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.21

Phases of an investigation.

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) Phase 1. (1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80. (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) Phase 2. Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects. (c) Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.

regulation

[{"label": "(a)", "text": "Phase 1. (1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(b)", "text": "Phase 2. Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.", "source": null}, {"label": "(c)", "text": "Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.", "source": null}]

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.21

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.22

General principles of the IND submission.

(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 manufacturer's IND or marketing application is ordinarily required to submit all technical information supporting the IND, unless such information may be referenced from the scientific literature.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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 manufacturer's IND or marketing application is ordinarily re", "source": null}]

§ 312.23

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.22

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.23

IND content and format.

(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) Cover sheet (Form FDA-1571). A cover sheet for the application containing the following: (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) A table of contents. (3) Introductory statement and general investigational plan. (i) A brief introductory statement giving the name of the drug and all active ingredients, the drug's pharmacological class, the structural formula of the drug (if known), the formulation of the dosage form(s) to be used, the route of administration, and the broad objectives and planned duration of the proposed clinical investigation(s). (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: (a) The rationale for the drug or the research study; (b) the indication(s) to be studied; (c) the general approach to be followed in evaluating the drug; (d) the kinds of clinical trials to be conducted in the first year following the submission (if plans are not developed for the entire year, the sponsor should so indicate); (e) the estimated number of patients to be given the drug in those studies; and (f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs. (4) [Reserved] (5) Investigator's brochure. If required under § 312.55, a copy of the investigator's brochure, containing the following information: (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) Protocols. (i) A protocol for each planned study. (Protocols for studies not submitted initially in the IND should be submitted in accordance with § 312.30(a).) In general, protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the investigation—an estimate of the number of patients to be involved, a description of safety exclusions, and a description of the dosing plan including duration, dose, or method to be used in determining dose—and should specify in detail only those elements of the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries. Modifications of the experimental design of Phase 1 studies that do not affect critical safety assessments are required to be reported to FDA only in the annual report. (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: (a) A statement of the objectives and purpose of the study. (b) The name and address and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator, and the name of each subinvestigator (e.g., research fellow, resident) working under the supervision of the investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board. (c) The criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied. (d) A description of the design of the study, including the kind of control group to be used, if any, and a description of methods to be used to minimize bias on the part of subjects, investigators, and analysts. (e) The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration of individual patient exposure to the drug. (f) A description of the observations and measurements to be made to fulfill the objectives of the study. (g) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk. (7) Chemistry, manufacturing, and control information. (i) As appropriate for the particular investigations covered by the IND, a section describing the composition, manufacture, and control of the drug substance and the drug product. Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available. FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process. (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: (a) Drug substance. A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy relevant requirements in this paragraph. (b) Drug product. A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy certain requirements in this paragraph. (c) A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial. (d) Labeling. A copy of all labels and labeling to be provided to each investigator. (e) Environmental analysis requirements. A claim for categorical exclusion under § 25.24 or an environmental assessment under § 25.31. (8) Pharmacology and toxicology information. Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations. Guidelines are available from FDA that describe ways in which these requirements may be met. Such information is required to include the identification and qualifications of the individuals who evaluated the results of such studies and concluded that it is reasonably safe to begin the proposed investigations and a statement of where the investigations were conducted and where the records are available for inspection. As drug development proceeds, the sponsor is required to submit informational amendments, as appropriate, with additional information pertinent to safety. (i) Pharmacology and drug disposition. A section describing the pharmacological effects and mechanism(s) of action of the drug in animals, and information on the absorption, distribution, metabolism, and excretion of the drug, if known. (ii) Toxicology. (a) An integrated summary of the toxicological effects of the drug in animals and in vitro. Depending on the nature of the drug and the phase of the investigation, the description is to include the results of acute, subacute, and chronic toxicity tests; tests of the drug's effects on reproduction and the developing fetus; any special toxicity test related to the drug's particular mode of administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology); and any in vitro studies intended to evaluate drug toxicity. (b) For each toxicology study that is intended primarily to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review. (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) Previous human experience with the investigational drug. A summary of previous human experience known to the applicant, if any, with the investigational drug. The information is required to include the following: (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) Additional information. In certain applications, as described below, information on special topics may be needed. Such information shall be submitted in this section as follows: (i) Drug dependence and abuse potential. If the drug is a psychotropic substance or otherwise has abuse potential, a section describing relevant clinical studies and experience and studies in test animals. (ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations. (iii) Other information. A brief statement of any other information that would aid evaluation of the proposed clinical investigations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug. (11) Relevant information. If requested by FDA, any other relevant information needed for review of the application. (b) Information previously submitted. The sponsor ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously must identify the file by name, reference number, volume, and page number where the information can be found. A reference to information submitted to the agency by a person other than the sponsor is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information. (c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor shall also submit a copy of each original literature publication for which an English translation is submitted. (d) Number of copies. The sponsor shall submit an original and two copies of all submissions to the IND file, including the original submission and all amendments and reports. (e) Numbering of IND submissions. Each submission relating to an IND is required to be numbered serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chronologically in sequence. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

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A cover sheet for the application containing the following:", "source": null}, {"label": "(i)", "text": "The name, address, and telephone number of the sponsor, the date of the application, and the name of the investigational new drug.", "source": null}, {"label": "(ii)", "text": "Identification of the phase or phases of the clinical investigation to be conducted.", "source": null}, {"label": "(iii)", "text": "A commitment not to begin clinical investigations until an IND covering the investigations is in effect.", "source": null}, {"label": "(iv)", "text": "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.", "source": null}, {"label": "(v)", "text": "A commitment to conduct the investigation in accordance with all other applicable regulatory requirements.", "source": null}, {"label": "(vi)", "text": "The name and title of the person responsible for monitoring the conduct and progress of the clinical investigations.", "source": null}, {"label": "(vii)", "text": "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.", "source": null}, {"label": "(viii)", "text": "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.", "source": null}, {"label": "(ix)", "text": "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.", "source": null}, {"label": "(2)", "text": "A table of contents.", "source": null}, {"label": "(3)", "text": "Introductory statement and general investigational plan. (i) A brief introductory statement giving the name of the drug and all active ingredients, the drug's pharmacological class, the structural formula of the drug (if known), the formulation of the dosage form(s) to be used, the route of administration, and the broad objectives and planned duration of the proposed clinical investigation(s).", "source": null}, {"label": "(ii)", "text": "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).", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(iv)", "text": "A brief description of the overall plan for investigating the drug product for the following year. The plan should include the following: (a) The rationale for the drug or the research study; (b) the indication(s) to be studied; (c) the general approach to be followed in evaluating the drug; (d) the kinds of clinical trials to be conducted in the first year following the submission (if plans are not developed for the entire year, the sponsor should so indicate); (e) the estimated number of patients to be given the drug in those studies; and (f) any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs.", "source": null}, {"label": "(4)", "text": "[Reserved]", "source": null}, {"label": "(5)", "text": "Investigator's brochure. If required under § 312.55, a copy of the investigator's brochure, containing the following information:", "source": null}, {"label": "(i)", "text": "A brief description of the drug substance and the formulation, including the structural formula, if known.", "source": null}, {"label": "(ii)", "text": "A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans.", "source": null}, {"label": "(iii)", "text": "A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans.", "source": null}, {"label": "(iv)", "text": "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.)", "source": null}, {"label": "(v)", "text": "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.", "source": null}, {"label": "(6)", "text": "Protocols. (i) A protocol for each planned study. (Protocols for studies not submitted initially in the IND should be submitted in accordance with § 312.30(a).) In general, protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the investigation—an estimate of the number of patients to be involved, a description of safety exclusions, and a description of the dosing plan including duration, dose, or method to be used in determining dose—and should specify in detail only those elements of the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries. Modifications of the experimental design of Phase 1 studies that do not affect critical safety assessments are required to be reported to FDA only in the annual report.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "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:", "source": null}, {"label": "(a)", "text": "A statement of the objectives and purpose of the study.", "source": null}, {"label": "(b)", "text": "The name and address and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator, and the name of each subinvestigator (e.g., research fellow, resident) working under the supervision of the investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board.", "source": null}, {"label": "(c)", "text": "The criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied.", "source": null}, {"label": "(d)", "text": "A description of the design of the study, including the kind of control group to be used, if any, and a description of methods to be used to minimize bias on the part of subjects, investigators, and analysts.", "source": null}, {"label": "(e)", "text": "The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration of individual patient exposure to the drug.", "source": null}, {"label": "(f)", "text": "A description of the observations and measurements to be made to fulfill the objectives of the study.", "source": null}, {"label": "(g)", "text": "A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk.", "source": null}, {"label": "(7)", "text": "Chemistry, manufacturing, and control information. (i) As appropriate for the particular investigations covered by the IND, a section describing the composition, manufacture, and control of the drug substance and the drug product. Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available. FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final spe", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(iv)", "text": "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:", "source": null}, {"label": "(a)", "text": "Drug substance. A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy relevant requirements in this paragraph.", "source": null}, {"label": "(b)", "text": "Drug product. A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy certain requirements ", "source": null}, {"label": "(c)", "text": "A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial.", "source": null}, {"label": "(d)", "text": "Labeling. A copy of all labels and labeling to be provided to each investigator.", "source": null}, {"label": "(e)", "text": "Environmental analysis requirements. A claim for categorical exclusion under § 25.24 or an environmental assessment under § 25.31.", "source": null}, {"label": "(8)", "text": "Pharmacology and toxicology information. Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations. Guidelines are available from FDA that describe ways in which these requirements may be met. Such information is required to include the identification and qualifications of the individuals who evaluated the results of such studies and concluded that it is reasonably safe to begin the proposed investigations and a statement of where the investigations were conducted and where the records are available for inspection. As drug development proceeds, the sponsor is required to submit informational amendments, as appropriate, with additional information pertinent to sa", "source": null}, {"label": "(i)", "text": "Pharmacology and drug disposition. A section describing the pharmacological effects and mechanism(s) of action of the drug in animals, and information on the absorption, distribution, metabolism, and excretion of the drug, if known.", "source": null}, {"label": "(ii)", "text": "Toxicology. (a) An integrated summary of the toxicological effects of the drug in animals and in vitro. Depending on the nature of the drug and the phase of the investigation, the description is to include the results of acute, subacute, and chronic toxicity tests; tests of the drug's effects on reproduction and the developing fetus; any special toxicity test related to the drug's particular mode of administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology); and any in vitro studies intended to evaluate drug toxicity.", "source": null}, {"label": "(b)", "text": "For each toxicology study that is intended primarily to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review.", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(9)", "text": "Previous human experience with the investigational drug. A summary of previous human experience known to the applicant, if any, with the investigational drug. The information is required to include the following:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "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).", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(10)", "text": "Additional information. In certain applications, as described below, information on special topics may be needed. Such information shall be submitted in this section as follows:", "source": null}, {"label": "(i)", "text": "Drug dependence and abuse potential. If the drug is a psychotropic substance or otherwise has abuse potential, a section describing relevant clinical studies and experience and studies in test animals.", "source": null}, {"label": "(ii)", "text": "Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations.", "source": null}, {"label": "(iii)", "text": "Other information. A brief statement of any other information that would aid evaluation of the proposed clinical investigations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug.", "source": null}, {"label": "(11)", "text": "Relevant information. If requested by FDA, any other relevant information needed for review of the application.", "source": null}, {"label": "(b)", "text": "Information previously submitted. The sponsor ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously must identify the file by name, reference number, volume, and page number where the information can be found. A reference to information submitted to the agency by a person other than the sponsor is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information.", "source": null}, {"label": "(c)", "text": "Material in a foreign language. The sponsor shall submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor shall also submit a copy of each original literature publication for which an English translation is submitted.", "source": null}, {"label": "(d)", "text": "Number of copies. The sponsor shall submit an original and two copies of all submissions to the IND file, including the original submission and all amendments and reports.", "source": null}, {"label": "(e)", "text": "Numbering of IND submissions. Each submission relating to an IND is required to be numbered serially using a single, three-digit serial number. The initial IND is required to be numbered 000; each subsequent submission (e.g., amendment, report, or correspondence) is required to be numbered chronologically in sequence.", "source": null}]

§ 25.24; § 312.30; § 25.31.; § 312.55; § 312.32

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, 1988]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.23

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.30

Protocol amendments.

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. (a) New protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol already contained in the IND, the sponsor shall submit to FDA a protocol amendment containing the protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has submitted the protocol to FDA for its review; and (2) the protocol has been approved by the Institutional Review Board (IRB) with responsibility for review and approval of the study in accordance with the requirements of part 56. The sponsor may comply with these two conditions in either order. (b) Changes in a protocol. (1) A sponsor shall submit a protocol amendment describing any change in a Phase 1 protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Examples of changes requiring an amendment under this paragraph include: (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: (a) The sponsor has submitted the change to FDA for its review; and (b) The change has been approved by the IRB with responsibility for review and approval of the study. The sponsor may comply with these two conditions in either order. (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) New investigator. A sponsor shall submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol, except that a protocol amendment is not required when a licensed practitioner is added in the case of a treatment protocol under § 312.34. Once the investigator is added to the study, the investigational drug may be shipped to the investigator and the investigator may begin participating in the study. The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added. (d) Content and format. A protocol amendment is required to be prominently identified as such (i.e., “Protocol Amendment: New Protocol”, “Protocol Amendment: Change in Protocol”, or “Protocol Amendment: New Investigator”), and to contain the following: (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)(b). (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) When submitted. A sponsor shall submit a protocol amendment for a new protocol or a change in protocol before its implementation. Protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. When several submissions of new protocols or protocol changes are anticipated during a short period, the sponsor is encouraged, to the extent feasible, to include these all in a single submission. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "New protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol already contained in the IND, the sponsor shall submit to FDA a protocol amendment containing the protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has submitted the protocol to FDA for its review; and (2) the protocol has been approved by the Institutional Review Board (IRB) with responsibility for review and approval of the study in accordance with the requirements of part 56. The sponsor may comply with these two conditions in either order.", "source": null}, {"label": "(b)", "text": "Changes in a protocol. (1) A sponsor shall submit a protocol amendment describing any change in a Phase 1 protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Examples of changes requiring an amendment under this paragraph include:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "Any significant change in the design of a protocol (such as the addition or dropping of a control group).", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(a)", "text": "The sponsor has submitted the change to FDA for its review; and", "source": null}, {"label": "(b)", "text": "The change has been approved by the IRB with responsibility for review and approval of the study. The sponsor may comply with these two conditions in either order.", "source": null}, {"label": "(ii)", "text": "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).", "source": null}, {"label": "(c)", "text": "New investigator. A sponsor shall submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol, except that a protocol amendment is not required when a licensed practitioner is added in the case of a treatment protocol under § 312.34. Once the investigator is added to the study, the investigational drug may be shipped to the investigator and the investigator may begin participating in the study. The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added.", "source": null}, {"label": "(d)", "text": "Content and format. A protocol amendment is required to be prominently identified as such (i.e., “Protocol Amendment: New Protocol”, “Protocol Amendment: Change in Protocol”, or “Protocol Amendment: New Investigator”), and to contain the following:", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "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)(b).", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "If the sponsor desires FDA to comment on the submission, a request for such comment and the specific questions FDA's response should address.", "source": null}, {"label": "(e)", "text": "When submitted. A sponsor shall submit a protocol amendment for a new protocol or a change in protocol before its implementation. Protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. When several submissions of new protocols or protocol changes are anticipated during a short period, the sponsor is encouraged, to the extent feasible, to include these all in a single submission.", "source": null}]

§ 56.104; § 312.23; § 312.34.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, 1988]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

30 days

False

True

within 30 day

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.30

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.31

Information amendments.

(a) Requirement for information amendment. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring an information amendment include: (1) New toxicology, chemistry, or other technical information; or (2) A report regarding the discontinuance of a clinical investigation. (b) Content and format of an information amendment. An information amendment is required to bear prominent identification of its contents (e.g., “Information Amendment: Chemistry, Manufacturing, and Control”, “Information Amendment: Pharmacology-Toxicology”, “Information Amendment: Clinical”), and to contain the following: (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) When submitted. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not more than every 30 days. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Requirement for information amendment. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring an information amendment include:", "source": null}, {"label": "(1)", "text": "New toxicology, chemistry, or other technical information; or", "source": null}, {"label": "(2)", "text": "A report regarding the discontinuance of a clinical investigation.", "source": null}, {"label": "(b)", "text": "Content and format of an information amendment. An information amendment is required to bear prominent identification of its contents (e.g., “Information Amendment: Chemistry, Manufacturing, and Control”, “Information Amendment: Pharmacology-Toxicology”, “Information Amendment: Clinical”), and to contain the following:", "source": null}, {"label": "(1)", "text": "A statement of the nature and purpose of the amendment.", "source": null}, {"label": "(2)", "text": "An organized submission of the data in a format appropriate for scientific review.", "source": null}, {"label": "(3)", "text": "If the sponsor desires FDA to comment on an information amendment, a request for such comment.", "source": null}, {"label": "(c)", "text": "When submitted. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not more than every 30 days.", "source": null}]

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, 1988]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

30 days

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.31

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.32

IND safety reports.

(a) Definitions. The following definitions of terms apply to this section: Associated with the use of the drug means that there is a reasonable possibility that the experience may have been caused by the drug. Serious adverse experience means any experience that suggests a significant hazard, contraindication, side effect, or precaution. With respect to human clinical experience, a serious adverse drug experience includes any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose. With respect to results obtained from tests in laboratory animals, a serious adverse drug experience includes any experience suggesting a significant risk for human subjects, including any finding of mutagenicity, teratogenicity, or carcinogenicity. Unexpected adverse experience means any adverse experience that is not identified in nature, severity, or frequency in the current investigator brochure; or, if an investigator brochure is not required, that is not identified in nature, severity, or freuquency in the risk information described in the general investigational plan or elsewhere in the current application, as amended. (b) Review of safety information. The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from clinical investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers. (c) IND safety reports. (1) Written reports. (i) The sponsor shall notify FDA and all participating investigators in a written IND safety report of any adverse experience associated with use of the drug that is both serious and unexpected. Such notification shall be made as soon as possible and in no event later than 10 working days after the sponsor's initial receipt of the information. Each written notification shall bear prominent identification of its contents, i.e., “IND Safety Report.” Each written notification to FDA shall be transmitted to the FDA division of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which has responsibility for review of the IND. (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) Telephone report. The sponsor shall also notify FDA by telephone of any unexpected fatal or life-threatening experience associated with use of the drug in the clinical studies conducted under the IND no later than 3 working days after receipt of the information. Each telephone call to FDA shall be transmitted to the FDA division of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which has responsibility for review of the IND. For purposes of this section, life-threatening means that the patient was, in the view of the investigator, at immediate (emphasis added) risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused death. For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life-threatening even though drug-induced hepatitis can be fatal. (3) Reporting format or frequency. FDA may request a sponsor to submit IND safety reports in a format or at a frequency different than that required under this paragraph. The sponsor may also propose and adopt a different reporting format or frequency if the change is agreed to in advance by the director of the division in the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is responsible for review of the IND. (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) Followup. (1) The sponsor shall promptly investigate all safety information received by it. (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 experience not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor shall report such experience in a safety report as soon as possible after the determination is made, but in no event longer than 10-working days. (4) Results of a sponsor's investigation of other safety information shall be submitted, as appropriate, in an information amendment or annual report. (e) Disclaimer. A safety report or other information submitted by a sponsor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse experience. A sponsor need not admit, and may deny, that the report or information submitted by the sponsor constitutes an admission that the drug caused or contributed to an adverse experience. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Definitions. The following definitions of terms apply to this section:", "source": null}, {"label": "(b)", "text": "Review of safety information. The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from clinical investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers.", "source": null}, {"label": "(c)", "text": "IND safety reports. (1) Written reports. (i) The sponsor shall notify FDA and all participating investigators in a written IND safety report of any adverse experience associated with use of the drug that is both serious and unexpected. Such notification shall be made as soon as possible and in no event later than 10 working days after the sponsor's initial receipt of the information. Each written notification shall bear prominent identification of its contents, i.e., “IND Safety Report.” Each written notification to FDA shall be transmitted to the FDA division of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which has responsibility for review of the IND.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(2)", "text": "Telephone report. The sponsor shall also notify FDA by telephone of any unexpected fatal or life-threatening experience associated with use of the drug in the clinical studies conducted under the IND no later than 3 working days after receipt of the information. Each telephone call to FDA shall be transmitted to the FDA division of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which has responsibility for review of the IND. For purposes of this section, life-threatening means that the patient was, in the view of the investigator, at immediate (emphasis added) risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused death. For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life-threatening even though drug-induced hepatitis can be fatal.", "source": null}, {"label": "(3)", "text": "Reporting format or frequency. FDA may request a sponsor to submit IND safety reports in a format or at a frequency different than that required under this paragraph. The sponsor may also propose and adopt a different reporting format or frequency if the change is agreed to in advance by the director of the division in the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is responsible for review of the IND.", "source": null}, {"label": "(4)", "text": "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.", "source": null}, {"label": "(d)", "text": "Followup. (1) The sponsor shall promptly investigate all safety information received by it.", "source": null}, {"label": "(2)", "text": "Followup information to a safety report shall be submitted as soon as the relevant information is available.", "source": null}, {"label": "(3)", "text": "If the results of a sponsor's investigation show that an adverse experience not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor shall report such experience in a safety report as soon as possible after the determination is made, but in no event longer than 10-working days.", "source": null}, {"label": "(4)", "text": "Results of a sponsor's investigation of other safety information shall be submitted, as appropriate, in an information amendment or annual report.", "source": null}, {"label": "(e)", "text": "Disclaimer. A safety report or other information submitted by a sponsor under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse experience. A sponsor need not admit, and may deny, that the report or information submitted by the sponsor constitutes an admission that the drug caused or contributed to an adverse experience.", "source": null}]

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, 1990]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.32

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.33

Annual reports.

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) Individual study information. A brief summary of the status of each study in progress and each study completed during the previous year. The summary is required to include the following information for each study: (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, 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) Summary information. Information obtained during the previous year's clinical and nonclinical investigations, including: (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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Individual study information. A brief summary of the status of each study in progress and each study completed during the previous year. The summary is required to include the following information for each study:", "source": null}, {"label": "(1)", "text": "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.", "source": null}, {"label": "(2)", "text": "The total number of subjects initially planned for inclusion in the study, the number entered into the study to date, the number whose participation in the study was completed as planned, and the number who dropped out of the study for any reason.", "source": null}, {"label": "(3)", "text": "If the study has been completed, or if interim results are known, a brief description of any available study results.", "source": null}, {"label": "(b)", "text": "Summary information. Information obtained during the previous year's clinical and nonclinical investigations, including:", "source": null}, {"label": "(1)", "text": "A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.", "source": null}, {"label": "(2)", "text": "A summary of all IND safety reports submitted during the past year.", "source": null}, {"label": "(3)", "text": "A list of subjects who died during participation in the investigation, with the cause of death for each subject.", "source": null}, {"label": "(4)", "text": "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.", "source": null}, {"label": "(5)", "text": "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.", "source": null}, {"label": "(6)", "text": "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.", "source": null}, {"label": "(7)", "text": "A summary of any significant manufacturing or microbiological changes made during the past year.", "source": null}, {"label": "(c)", "text": "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).", "source": null}, {"label": "(d)", "text": "If the investigator brochure has been revised, a description of the revision and a copy of the new brochure.", "source": null}, {"label": "(e)", "text": "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.", "source": null}, {"label": "(f)", "text": "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.", "source": null}, {"label": "(g)", "text": "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.", "source": null}]

§ 312.23

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

1 year; 60 days

False

True

within 60 day

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.33

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.34

Treatment use of an investigational new drug.

(a) General. A drug that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available. During the clinical investigation of the drug, it may be appropriate to use the drug in the treatment of patients not in the clinical trials, in accordance with a treatment protocol or treatment IND. The purpose of this section is to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before general marketing begins, and to obtain additional data on the drug's safety and effectiveness. In the case of a serious disease, a drug ordinarily may be made available for treatment use under this section during Phase 3 investigations or after all clinical trials have been completed; however, in appropriate circumstances, a drug may be made available for treatment use during Phase 2. In the case of an immediately life-threatening disease, a drug may be made available for treatment use under this section earlier than Phase 3, but ordinarily not earlier than Phase 2. For purposes of this section, the “treatment use” of a drug includes the use of a drug for diagnostic purposes. If a protocol for an investigational drug meets the criteria of this section, the protocol is to be submitted as a treatment protocol under the provisions of this section. (b) Criteria. (1) FDA shall permit an investigational drug to be used for a treatment use under a treatment protocol or treatment IND if: (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) Serious disease. For a drug intended to treat a serious disease, the Commissioner may deny a request for treatment use under a treatment protocol or treatment IND if there is insufficient evidence of safety and effectiveness to support such use. (3) Immediately life-threatening disease. (i) For a drug intended to treat an immediately life-threatening disease, the Commissioner may deny a request for treatment use of an investigational drug under a treatment protocol or treatment IND if the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug: (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) Safeguards. Treatment use of an investigational drug is conditioned on the sponsor and investigators complying with the safeguards of the IND process, including the regulations governing informed consent (21 CFR part 50) and institutional review boards (21 CFR part 56) and the applicable provisions of part 312, including distribution of the drug through qualified experts, maintenance of adequate manufacturing facilities, and submission of IND safety reports. (d) Clinical hold. FDA may place on clinical hold a proposed or ongoing treatment protocol or treatment IND in accordance with § 312.42.

regulation

[{"label": "(a)", "text": "General. A drug that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug or other therapy is available. During the clinical investigation of the drug, it may be appropriate to use the drug in the treatment of patients not in the clinical trials, in accordance with a treatment protocol or treatment IND. The purpose of this section is to facilitate the availability of promising new drugs to desperately ill patients as early in the drug development process as possible, before general marketing begins, and to obtain additional data on the drug's safety and effectiveness. In the case of a serious disease, a drug ordinarily may be made available for treatment use under this section during Phase 3 investigations or after all clinical trials have been completed; however, in appropriate circumstances, a drug may be made available for treatment use dur", "source": null}, {"label": "(b)", "text": "Criteria. (1) FDA shall permit an investigational drug to be used for a treatment use under a treatment protocol or treatment IND if:", "source": null}, {"label": "(i)", "text": "The drug is intended to treat a serious or immediately life-threatening disease;", "source": null}, {"label": "(ii)", "text": "There is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population;", "source": null}, {"label": "(iii)", "text": "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", "source": null}, {"label": "(iv)", "text": "The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence.", "source": null}, {"label": "(2)", "text": "Serious disease. For a drug intended to treat a serious disease, the Commissioner may deny a request for treatment use under a treatment protocol or treatment IND if there is insufficient evidence of safety and effectiveness to support such use.", "source": null}, {"label": "(3)", "text": "Immediately life-threatening disease. (i) For a drug intended to treat an immediately life-threatening disease, the Commissioner may deny a request for treatment use of an investigational drug under a treatment protocol or treatment IND if the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the drug:", "source": null}, {"label": "(A)", "text": "May be effective for its intended use in its intended patient population; or", "source": null}, {"label": "(B)", "text": "Would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(c)", "text": "Safeguards. Treatment use of an investigational drug is conditioned on the sponsor and investigators complying with the safeguards of the IND process, including the regulations governing informed consent (21 CFR part 50) and institutional review boards (21 CFR part 56) and the applicable provisions of part 312, including distribution of the drug through qualified experts, maintenance of adequate manufacturing facilities, and submission of IND safety reports.", "source": null}, {"label": "(d)", "text": "Clinical hold. FDA may place on clinical hold a proposed or ongoing treatment protocol or treatment IND in accordance with § 312.42.", "source": null}]

21 CFR part 50; § 312.42.; 21 CFR part 56

[52 FR 19476, May 22, 1987, as amended at 57 FR 13248, Apr. 15, 1992]

May 22, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.34

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.35

Submissions for treatment use.

(a) Treatment protocol submitted by IND sponsor. Any sponsor of a clinical investigation of a drug who intends to sponsor a treatment use for the drug shall submit to FDA a treatment protocol under § 312.34 if the sponsor believes the criteria of § 312.34 are satisfied. If a protocol is not submitted under § 312.34, but FDA believes that the protocol should have been submitted under this section, FDA may deem the protocol to be submitted under § 312.34. A treatment use under a treatment protocol may begin 30 days after FDA receives the protocol or on earlier notification by FDA that the treatment use described in the protocol may begin. (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) Treatment IND submitted by licensed practitioner. (1) If a licensed medical practitioner wants to obtain an investigational drug subject to a controlled clinical trial for a treatment use, the practitioner should first attempt to obtain the drug from the sponsor of the controlled trial under a treatment protocol. If the sponsor of the controlled clinical investigation of the drug will not establish a treatment protocol for the drug under paragraph (a) of this section, the licensed medical practitioner may seek to obtain the drug from the sponsor and submit a treatment IND to FDA requesting authorization to use the investigational drug for treatment use. A treatment use under a treatment IND may begin 30 days after FDA receives the IND or on earlier notification by FDA that the treatment use under the IND may begin. A treatment IND is required to contain the following: (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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Treatment protocol submitted by IND sponsor. Any sponsor of a clinical investigation of a drug who intends to sponsor a treatment use for the drug shall submit to FDA a treatment protocol under § 312.34 if the sponsor believes the criteria of § 312.34 are satisfied. If a protocol is not submitted under § 312.34, but FDA believes that the protocol should have been submitted under this section, FDA may deem the protocol to be submitted under § 312.34. A treatment use under a treatment protocol may begin 30 days after FDA receives the protocol or on earlier notification by FDA that the treatment use described in the protocol may begin.", "source": null}, {"label": "(1)", "text": "A treatment protocol is required to contain the following:", "source": null}, {"label": "(i)", "text": "The intended use of the drug.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "A brief description of the criteria for patient selection.", "source": null}, {"label": "(iv)", "text": "The method of administration of the drug and the dosages.", "source": null}, {"label": "(v)", "text": "A description of clinical procedures, laboratory tests, or other measures to monitor the effects of the drug and to minimize risk.", "source": null}, {"label": "(2)", "text": "A treatment protocol is to be supported by the following:", "source": null}, {"label": "(i)", "text": "Informational brochure for supplying to each treating physician.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "A commitment by the sponsor to assure compliance of all participating investigators with the informed consent requirements of 21 CFR part 50.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(b)", "text": "Treatment IND submitted by licensed practitioner. (1) If a licensed medical practitioner wants to obtain an investigational drug subject to a controlled clinical trial for a treatment use, the practitioner should first attempt to obtain the drug from the sponsor of the controlled trial under a treatment protocol. If the sponsor of the controlled clinical investigation of the drug will not establish a treatment protocol for the drug under paragraph (a) of this section, the licensed medical practitioner may seek to obtain the drug from the sponsor and submit a treatment IND to FDA requesting authorization to use the investigational drug for treatment use. A treatment use under a treatment IND may begin 30 days after FDA receives the IND or on earlier notification by FDA that the treatment use under the IND may begin. A treatment IND is required to contain the following:", "source": null}, {"label": "(i)", "text": "A cover sheet (Form FDA 1571) meeting § 312.23(g)(1).", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "A statement of the steps taken by the practitioner to obtain the drug under a treatment protocol from the drug sponsor.", "source": null}, {"label": "(iv)", "text": "A treatment protocol containing the same information listed in paragraph (a)(1) of this section.", "source": null}, {"label": "(v)", "text": "A statement of the practitioner's qualifications to use the investigational drug for the intended treatment use.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "Agreement to report to FDA safety information in accordance with § 312.32.", "source": null}, {"label": "(2)", "text": "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.", "source": null}]

§ 312.34.; § 312.23; § 312.34; § 312.32.; 21 CFR part 50; § 312.23.

[52 FR 19477, May 22, 1987, as amended at 57 FR 13249, Apr. 15, 1992]

May 22, 1987

(Revised as of April 1, 1996)

False

30 days

False

True

30 days

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.35

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.36

Emergency use of an investigational new drug.

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 § 312.34. In such a case, FDA may authorize shipment of the drug for a specified use in advance of submission of an IND. A request for such authorization may be transmitted to FDA by telephone or other rapid communication means. For investigational biological drugs, the request should be directed to the Division of Biological Investigational New Drugs (HFB-230), Center for Biologics Evaluation and Research, 8800 Rockville Pike, Bethesda, MD 20892, 301-443-4864. For all other investigational drugs, the request for authorization should be directed to the Document Management and Reporting Branch (HFD-53), Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, MD 20857, 301-443-4320. After normal working hours, eastern standard time, the request should be directed to the FDA Division of Emergency and Epidemiological Operations, 202-857-8400. Except in extraordinary circumstances, such authorization will be conditioned on the sponsor making an appropriate IND submission as soon as practicable after receiving the authorization. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

§ 312.34.; § 312.23

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, 1990]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.36

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart B

Investigational New Drug Application (IND)

312.38

Withdrawal of an IND.

(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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "At any time a sponsor may withdraw an effective IND without prejudice.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}]

§ 312.59.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.38

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.40

General requirements for use of an investigational new drug in a clinical investigation.

(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.

regulation

[{"label": "(a)", "text": "An investigational new drug may be used in a clinical investigation if the following conditions are met:", "source": null}, {"label": "(1)", "text": "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", "source": null}, {"label": "(2)", "text": "Each participating investigator conducts his or her investigation in compliance with the requirements of this part and parts 50 and 56.", "source": null}, {"label": "(b)", "text": "An IND goes into effect:", "source": null}, {"label": "(1)", "text": "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", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(c)", "text": "A sponsor may ship an investigational new drug to investigators named in the IND:", "source": null}, {"label": "(1)", "text": "Thirty days after FDA receives the IND; or", "source": null}, {"label": "(2)", "text": "On earlier FDA authorization to ship the drug.", "source": null}, {"label": "(d)", "text": "An investigator may not administer an investigational new drug to human subjects until the IND goes into effect under paragraph (b) of this section.", "source": null}]

§ 312.42

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.40

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.41

Comment and advice on an IND.

(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 investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application. (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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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 investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application.", "source": null}, {"label": "(c)", "text": "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.", "source": null}]

§ 312.42

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.41

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.42

Clinical holds and requests for modification.

(a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety. (b) Grounds for imposition of clinical hold—(1) Clinical hold of a Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that: (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. (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that: (i) Any of the conditions in paragraph (b)(1)(i) through (iv) 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) Proposed use. FDA may place a proposed treatment IND or treatment protocol on clinical hold if it is determined that: (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) to make the specified determination under § 312.34(b). (ii) Ongoing use. FDA may place an ongoing treatment protocol or treatment IND on clinical hold if it is determined that: (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: (1) May be effective for its intended use in its intended population; or (2) Would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury. (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) Clinical hold of any study that is not designed to be adequate and well-controlled. FDA may place a proposed or ongoing investigation that is not designed to be adequate and well-controlled on clinical hold if it finds that: (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. (c) Discussion of deficiency. Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of clinical hold FDA will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the clinical hold order. (d) Imposition of clinical hold. The clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order will identify the studies under the IND to which the hold applies, and will briefly explain the basis for the action. The clinical hold order will be made by or on behalf of the Division Director with responsibility for review of the IND. As soon as possible, and no more than 30 days after imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold. (e) Resumption of clinical investigations. If, by the terms of the clinical hold order, resumption of the affected investigation is permitted without prior notification by FDA once a stated correction or modification is made, the investigation may proceed as soon as the correction or modification is made. In all other cases, an investigation may only resume after the Division Director (or the Director's designee) with responsibility for review of the IND has notified the sponsor that the investigation may proceed. In these cases resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfied the agency that the investigation(s) can proceed. Resumption of a study may be authorized by telephone or other means of rapid communication. (f) Appeal. If the sponsor disagrees with the reasons cited for the clinical hold, the sponsor may request reconsideration of the decision in accordance with § 312.48. (g) Conversion of IND on clinical hold to inactive status. If all investigations covered by an IND remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under § 312.45.

regulation

[{"label": "(a)", "text": "General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety.", "source": null}, {"label": "(b)", "text": "Grounds for imposition of clinical hold—(1) Clinical hold of a Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that:", "source": null}, {"label": "(i)", "text": "Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury;", "source": null}, {"label": "(ii)", "text": "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;", "source": null}, {"label": "(iii)", "text": "The investigator brochure is misleading, erroneous, or materially incomplete; or", "source": null}, {"label": "(iv)", "text": "The IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.", "source": null}, {"label": "(2)", "text": "Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that:", "source": null}, {"label": "(i)", "text": "Any of the conditions in paragraph (b)(1)(i) through (iv) of this section apply; or", "source": null}, {"label": "(ii)", "text": "The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.", "source": null}, {"label": "(3)", "text": "Clinical hold of a treatment IND or treatment protocol.", "source": null}, {"label": "(i)", "text": "Proposed use. FDA may place a proposed treatment IND or treatment protocol on clinical hold if it is determined that:", "source": null}, {"label": "(A)", "text": "The pertinent criteria in § 312.34(b) for permitting the treatment use to begin are not satisfied; or", "source": null}, {"label": "(B)", "text": "The treatment protocol or treatment IND does not contain the information required under § 312.35 (a) or (b) to make the specified determination under § 312.34(b).", "source": null}, {"label": "(ii)", "text": "Ongoing use. FDA may place an ongoing treatment protocol or treatment IND on clinical hold if it is determined that:", "source": null}, {"label": "(A)", "text": "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;", "source": null}, {"label": "(B)", "text": "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:", "source": null}, {"label": "(C)", "text": "The sponsor of the controlled clinical trial is not pursuing marketing approval with due diligence;", "source": null}, {"label": "(D)", "text": "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", "source": null}, {"label": "(E)", "text": "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:", "source": null}, {"label": "(1)", "text": "May be effective for its intended use in its intended population; or", "source": null}, {"label": "(2)", "text": "Would not expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury.", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(4)", "text": "Clinical hold of any study that is not designed to be adequate and well-controlled. FDA may place a proposed or ongoing investigation that is not designed to be adequate and well-controlled on clinical hold if it finds that:", "source": null}, {"label": "(i)", "text": "Any of the conditions in paragraph (b)(1) or (b)(2) of this section apply; or", "source": null}, {"label": "(ii)", "text": "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", "source": null}, {"label": "(iii)", "text": "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", "source": null}, {"label": "(iv)", "text": "The drug has been studied in one or more adequate and well-controlled investigations that strongly suggest lack of effectiveness; or", "source": null}, {"label": "(v)", "text": "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", "source": null}, {"label": "(vi)", "text": "The drug has received marketing approval for the same indication in the same patient population; or", "source": null}, {"label": "(vii)", "text": "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", "source": null}, {"label": "(viii)", "text": "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.", "source": null}, {"label": "(c)", "text": "Discussion of deficiency. Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of clinical hold FDA will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the clinical hold order.", "source": null}, {"label": "(d)", "text": "Imposition of clinical hold. The clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order will identify the studies under the IND to which the hold applies, and will briefly explain the basis for the action. The clinical hold order will be made by or on behalf of the Division Director with responsibility for review of the IND. As soon as possible, and no more than 30 days after imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold.", "source": null}, {"label": "(e)", "text": "Resumption of clinical investigations. If, by the terms of the clinical hold order, resumption of the affected investigation is permitted without prior notification by FDA once a stated correction or modification is made, the investigation may proceed as soon as the correction or modification is made. In all other cases, an investigation may only resume after the Division Director (or the Director's designee) with responsibility for review of the IND has notified the sponsor that the investigation may proceed. In these cases resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfied the agency that the investigation(s) can proceed. Resumption of a study may be authorized by telephone or other means of rapid communication.", "source": null}, {"label": "(f)", "text": "Appeal. If the sponsor disagrees with the reasons cited for the clinical hold, the sponsor may request reconsideration of the decision in accordance with § 312.48.", "source": null}, {"label": "(g)", "text": "Conversion of IND on clinical hold to inactive status. If all investigations covered by an IND remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under § 312.45.", "source": null}]

§ 312.35; § 312.45.; § 312.23; § 312.34; § 312.48.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19477, May 22, 1987; 57 FR 13249, Apr. 15, 1992]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

1 year; 30 days

False

True

30 days

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.42

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.44

Termination.

(a) General. This section describes the procedures under which FDA may terminate an IND. If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in paragraph (d) of this section, a termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section after first attempting to resolve differences informally or, when appropriate, through the clinical hold procedures described in § 312.42. (b) Grounds for termination—(1) Phase 1. FDA may propose to terminate an IND during Phase 1 if it finds that: (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) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that: (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) Opportunity for sponsor response. (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. (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) Immediate termination of IND. Notwithstanding paragraphs (a) through (c) of this section, if at any time FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the agency shall immediately, by written notice to the sponsor from the Director of the Center for Drug Evaluation and Research or the Director of the Center for Biologics Evaluation and Research, terminate the IND. An IND so terminated is subject to reinstatement by the Director on the basis of additional submissions that eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an opportunity for a regulatory hearing under part 16 on the question of whether the IND should be reinstated. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "General. This section describes the procedures under which FDA may terminate an IND. If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in paragraph (d) of this section, a termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section after first attempting to resolve differences informally or, when appropriate, through the clinical hold procedures described in § 312.42.", "source": null}, {"label": "(b)", "text": "Grounds for termination—(1) Phase 1. FDA may propose to terminate an IND during Phase 1 if it finds that:", "source": null}, {"label": "(i)", "text": "Human subjects would be exposed to an unreasonable and significant risk of illness or unjury.", "source": null}, {"label": "(ii)", "text": "The IND does not contain sufficient information required under § 312.23 to assess the safety to subjects of the clinical investigations.", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(iv)", "text": "The clinical investigations are being conducted in a manner substantially different than that described in the protocols submitted in the IND.", "source": null}, {"label": "(v)", "text": "The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation or permitted by § 312.7.", "source": null}, {"label": "(vi)", "text": "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.", "source": null}, {"label": "(vii)", "text": "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.", "source": null}, {"label": "(viii)", "text": "The sponsor fails to submit an accurate annual report of the investigations in accordance with § 312.33.", "source": null}, {"label": "(ix)", "text": "The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.", "source": null}, {"label": "(x)", "text": "The IND has remained on inactive status for 5 years or more.", "source": null}, {"label": "(xi)", "text": "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).", "source": null}, {"label": "(2)", "text": "Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that:", "source": null}, {"label": "(i)", "text": "Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi) of this section apply; or", "source": null}, {"label": "(ii)", "text": "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", "source": null}, {"label": "(iii)", "text": "There is convincing evidence that the drug is not effective for the purpose for which it is being investigated.", "source": null}, {"label": "(3)", "text": "FDA may propose to terminate a treatment IND if it finds that:", "source": null}, {"label": "(i)", "text": "Any of the conditions in paragraphs (b)(1)(i) through (x) of this section apply; or", "source": null}, {"label": "(ii)", "text": "Any of the conditions in § 312.42(b)(3) apply.", "source": null}, {"label": "(c)", "text": "Opportunity for sponsor response. (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in writing, and invite correction or explanation within a period of 30 days.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(d)", "text": "Immediate termination of IND. Notwithstanding paragraphs (a) through (c) of this section, if at any time FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the agency shall immediately, by written notice to the sponsor from the Director of the Center for Drug Evaluation and Research or the Director of the Center for Biologics Evaluation and Research, terminate the IND. An IND so terminated is subject to reinstatement by the Director on the basis of additional submissions that eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an opportunity for a regulatory hearing under part 16 on the question of whether the IND should be reinstated.", "source": null}]

§ 312.23; § 312.7.; § 312.42; § 312.42.; § 312.32; § 312.33.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, 1990; 57 FR 13249, Apr. 15, 1992]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

30 days; 5 years; 10 days

False

True

within 10 day

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.44

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.45

Inactive status.

(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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}, {"label": "(e)", "text": "An IND that remains on inactive status for 5 years or more may be terminated under § 312.44.", "source": null}]

§ 312.30; § 312.44.; § 312.130.; § 312.42; § 312.59.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

2 years; 30 days; 1 year; 5 years

False

True

30 days

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.45

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.47

Meetings.

(a) General. Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA's resources permit. The general principle underlying the conduct of such meetings is that there should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation. These meetings shall be conducted and documented in accordance with part 10. (b) “End-of-Phase 2” meetings and meetings held before submission of a marketing application. At specific times during the drug investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful expenditures of time and money and thus in speeding the drug development and evaluation process. In particular, FDA has found that meetings at the end of Phase 2 of an investigation (end-of-Phase 2 meetings) are of considerable assistance in planning later studies and that meetings held near completion of Phase 3 and before submission of a marketing application (“pre-NDA” meetings) are helpful in developing methods of presentation and submission of data in the marketing application that facilitate review and allow timely FDA response. (1) End-of-Phase 2 meetings—(i) Purpose. The purpose of an end-of-Phase 2 meeting is to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols, and to identify any additional information necessary to support a marketing application for the uses under investigation. (ii) Eligibility for meeting. While the end-of-Phase 2 meeting is designed primarily for IND's involving new molecular entities or major new uses of marketed drugs, a sponsor of any IND may request and obtain an end-of-Phase 2 meeting. (iii) Timing. To be most useful to the sponsor, end-of-Phase 2 meetings should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to Phase 3. (iv) Advance information. At least 1 month in advance of an end-of-Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, and, if available, tentative labeling for the drug. The recommended contents of such a submission are described more fully in FDA Staff Manual Guide 4850.7 that is publicly available under FDA's public information regulations in Part 20. (v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are to be made with the division in FDA's Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is responsible for review of the IND. The meeting will be scheduled by FDA at a time convenient to both FDA and the sponsor. Both the sponsor and FDA may bring consultants to the meeting. The meeting should be directed primarily at establishing agreement between FDA and the sponsor of the overall plan for Phase 3 and the objectives and design of particular studies. The adequacy of technical information to support Phase 3 studies and/or a marketing application may also be discussed. Agreements reached at the meeting on these matters will be recorded in minutes of the conference that will be taken by FDA in accordance with § 10.65 and provided to the sponsor. The minutes along with any other written material provided to the sponsor will serve as a permanent record of any agreements reached. Barring a significant scientific development that requires otherwise, studies conducted in accordance with the agreement shall be presumed to be sufficient in objective and design for the purpose of obtaining marketing approval for the drug. (2) “Pre-NDA” meetings. FDA has found that delays associated with the initial review of a marketing application may be reduced by exchanges of information about a proposed marketing application. The primary purpose of this kind of exchange is to uncover any major unresolved problems, to identify those studies that the sponsor is relying on as adequate and well-controlled to establish the drug's effectiveness, to acquaint FDA reviewers with the general information to be submitted in the marketing application (including technical information), to discuss appropriate methods for statistical analysis of the data, and to discuss the best approach to the presentation and formatting of data in the marketing application. Arrangements for such a meeting are to be initiated by the sponsor with the division responsible for review of the IND. To permit FDA to provide the sponsor with the most useful advice on preparing a marketing application, the sponsor should submit to FDA's reviewing division at least 1 month in advance of the meeting the following information: (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) Any other information for discussion at the meeting. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "General. Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA's resources permit. The general principle underlying the conduct of such meetings is that there should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation. These meetings shall be conducted and documented in accordance with part 10.", "source": null}, {"label": "(b)", "text": "“End-of-Phase 2” meetings and meetings held before submission of a marketing application. At specific times during the drug investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful expenditures of time and money and thus in speeding the drug development and evaluation process. In particular, FDA has found that meetings at the end of Phase 2 of an investigation (end-of-Phase 2 meetings) are of considerable assistance in planning later studies and that meetings held near completion of Phase 3 and before submission of a marketing application (“pre-NDA” meetings) are helpful in developing methods of presentation and submission of data in the marketing application that facilitate review and allow timely FDA response.", "source": null}, {"label": "(1)", "text": "End-of-Phase 2 meetings—(i) Purpose. The purpose of an end-of-Phase 2 meeting is to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols, and to identify any additional information necessary to support a marketing application for the uses under investigation.", "source": null}, {"label": "(ii)", "text": "Eligibility for meeting. While the end-of-Phase 2 meeting is designed primarily for IND's involving new molecular entities or major new uses of marketed drugs, a sponsor of any IND may request and obtain an end-of-Phase 2 meeting.", "source": null}, {"label": "(iii)", "text": "Timing. To be most useful to the sponsor, end-of-Phase 2 meetings should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to Phase 3.", "source": null}, {"label": "(iv)", "text": "Advance information. At least 1 month in advance of an end-of-Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, and, if available, tentative labeling for the drug. The recommended contents of such a submission are described more fully in FDA Staff Manual Guide 4850.7 that is publicly available under FDA's public information regulations in Part 20.", "source": null}, {"label": "(v)", "text": "Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are to be made with the division in FDA's Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research which is responsible for review of the IND. The meeting will be scheduled by FDA at a time convenient to both FDA and the sponsor. Both the sponsor and FDA may bring consultants to the meeting. The meeting should be directed primarily at establishing agreement between FDA and the sponsor of the overall plan for Phase 3 and the objectives and design of particular studies. The adequacy of technical information to support Phase 3 studies and/or a marketing application may also be discussed. Agreements reached at the meeting on these matters will be recorded in minutes of the conference that will be taken by FDA in accordance with § 10.65 and provided to the sponsor. The minutes along with any other written material provided to the sponsor will serve as a permanent record of any agreements reache", "source": null}, {"label": "(2)", "text": "“Pre-NDA” meetings. FDA has found that delays associated with the initial review of a marketing application may be reduced by exchanges of information about a proposed marketing application. The primary purpose of this kind of exchange is to uncover any major unresolved problems, to identify those studies that the sponsor is relying on as adequate and well-controlled to establish the drug's effectiveness, to acquaint FDA reviewers with the general information to be submitted in the marketing application (including technical information), to discuss appropriate methods for statistical analysis of the data, and to discuss the best approach to the presentation and formatting of data in the marketing application. Arrangements for such a meeting are to be initiated by the sponsor with the division responsible for review of the IND. To permit FDA to provide the sponsor with the most useful advice on preparing a marketing application, the sponsor should submit to FDA's reviewing division at l", "source": null}, {"label": "(i)", "text": "A brief summary of the clinical studies to be submitted in the application.", "source": null}, {"label": "(ii)", "text": "A proposed format for organizing the submission, including methods for presenting the data.", "source": null}, {"label": "(iii)", "text": "Any other information for discussion at the meeting.", "source": null}]

§ 10.65

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, 1990]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

1 month

False

True

at least 1 month

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.47

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart C

Administrative Actions

312.48

Dispute resolution.

(a) General. The Food and Drug Administration is committed to resolving differences between sponsors and FDA reviewing divisions with respect to requirements for IND's as quickly and amicably as possible through the cooperative exchange of information and views. (b) Administrative and procedural issues. When administrative or procedural disputes arise, the sponsor should first attempt to resolve the matter with the division in FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research which is responsible for review of the IND, beginning with the consumer safety officer assigned to the application. If the dispute is not resolved, the sponsor may raise the matter with the person designated as ombudsman, whose function shall be to investigate what has happened and to facilitate a timely and equitable resolution. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings and obtaining timely replies to inquiries. Further details on this procedure are contained in FDA Staff Manual Guide 4820.7 that is publicly available under FDA's public information regulations in part 20. (c) Scientific and medical disputes. (1) When scientific or medical disputes arise during the drug investigation process, sponsors should discuss the matter directly with the responsible reviewing officials. If necessary, sponsors may request a meeting with the appropriate reviewing officials and management representatives in order to seek a resolution. Requests for such meetings shall be directed to the director of the division in FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research which is responsible for review of the IND. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times. (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.

regulation

[{"label": "(a)", "text": "General. The Food and Drug Administration is committed to resolving differences between sponsors and FDA reviewing divisions with respect to requirements for IND's as quickly and amicably as possible through the cooperative exchange of information and views.", "source": null}, {"label": "(b)", "text": "Administrative and procedural issues. When administrative or procedural disputes arise, the sponsor should first attempt to resolve the matter with the division in FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research which is responsible for review of the IND, beginning with the consumer safety officer assigned to the application. If the dispute is not resolved, the sponsor may raise the matter with the person designated as ombudsman, whose function shall be to investigate what has happened and to facilitate a timely and equitable resolution. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings and obtaining timely replies to inquiries. Further details on this procedure are contained in FDA Staff Manual Guide 4820.7 that is publicly available under FDA's public information regulations in part 20.", "source": null}, {"label": "(c)", "text": "Scientific and medical disputes. (1) When scientific or medical disputes arise during the drug investigation process, sponsors should discuss the matter directly with the responsible reviewing officials. If necessary, sponsors may request a meeting with the appropriate reviewing officials and management representatives in order to seek a resolution. Requests for such meetings shall be directed to the director of the division in FDA's Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research which is responsible for review of the IND. FDA will make every attempt to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}]

§ 312.47

[52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.48

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.50

General responsibilities of sponsors.

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.

regulation

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.50

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.52

Transfer of obligations to a contract research organization.

(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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}]

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.52

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.53

Selecting investigators and monitors.

(a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug. (b) Control of drug. A sponsor shall ship investigational new drugs only to investigators participating in the investigation. (c) Obtaining information from the investigator. Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: (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: (a) Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, or welfare of subjects; (b) Will comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements in this part; (c) Will personally conduct or supervise the described investigation(s); (d) Will inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent and institutional review board review and approval are met; (e) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with § 312.64; (f) Has read and understands the information in the investigator's brochure, including the potential risks and side effects of the drug; and (g) Will ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments. (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) Curriculum vitae. A curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation. (3) Clinical protocol. (i) For Phase 1 investigations, a general outline of the planned investigation including the estimated duration of the study and the maximum number of subjects that will be involved. (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. (d) Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the progress of the investigation. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.", "source": null}, {"label": "(b)", "text": "Control of drug. A sponsor shall ship investigational new drugs only to investigators participating in the investigation.", "source": null}, {"label": "(c)", "text": "Obtaining information from the investigator. Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following:", "source": null}, {"label": "(1)", "text": "A signed investigator statement (Form FDA-1572) containing:", "source": null}, {"label": "(i)", "text": "The name and address of the investigator;", "source": null}, {"label": "(ii)", "text": "The name and code number, if any, of the protocol(s) in the IND identifying the study(ies) to be conducted by the investigator;", "source": null}, {"label": "(iii)", "text": "The name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be conducted;", "source": null}, {"label": "(iv)", "text": "The name and address of any clinical laboratory facilities to be used in the study;", "source": null}, {"label": "(v)", "text": "The name and address of the IRB that is responsible for review and approval of the study(ies);", "source": null}, {"label": "(vi)", "text": "A commitment by the investigator that he or she:", "source": null}, {"label": "(a)", "text": "Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, or welfare of subjects;", "source": null}, {"label": "(b)", "text": "Will comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements in this part;", "source": null}, {"label": "(c)", "text": "Will personally conduct or supervise the described investigation(s);", "source": null}, {"label": "(d)", "text": "Will inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent and institutional review board review and approval are met;", "source": null}, {"label": "(e)", "text": "Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with § 312.64;", "source": null}, {"label": "(f)", "text": "Has read and understands the information in the investigator's brochure, including the potential risks and side effects of the drug; and", "source": null}, {"label": "(g)", "text": "Will ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.", "source": null}, {"label": "(vii)", "text": "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.", "source": null}, {"label": "(viii)", "text": "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).", "source": null}, {"label": "(2)", "text": "Curriculum vitae. A curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation.", "source": null}, {"label": "(3)", "text": "Clinical protocol. (i) For Phase 1 investigations, a general outline of the planned investigation including the estimated duration of the study and the maximum number of subjects that will be involved.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(d)", "text": "Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the progress of the investigation.", "source": null}]

§ 312.64

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.53

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.55

Informing investigators.

(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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "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).", "source": null}, {"label": "(b)", "text": "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.", "source": null}]

§ 312.32.; § 312.23

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.55

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.56

Review of ongoing investigations.

(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 safety and effectiveness of the drug as it is obtained from the investigator. The sponsors shall make such reports to FDA regarding information relevant to the safety of the drug as are required under § 312.32. The sponsor shall make annual reports on the progress of the investigation in accordance with § 312.33. (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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "The sponsor shall monitor the progress of all clinical investigations being conducted under its IND.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "The sponsor shall review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator. The sponsors shall make such reports to FDA regarding information relevant to the safety of the drug as are required under § 312.32. The sponsor shall make annual reports on the progress of the investigation in accordance with § 312.33.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

§ 312.33.; § 312.59; § 312.32.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.56

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.57

Recordkeeping and record retention.

(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 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. (c) 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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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.", "source": null}, {"label": "(c)", "text": "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.", "source": null}]

§ 320.63; § 320.38.; § 320.38

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 58 FR 25926, Apr. 28, 1993]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

2 years

False

True

2 years

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.57

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.58

Inspection of sponsor's records and reports.

(a) FDA inspection. A sponsor 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 any records and reports relating to a clinical investigation conducted under this part. Upon written request by FDA, the sponsor shall submit the records or reports (or copies of them) to FDA. The sponsor shall discontinue shipments of the drug to any investigator who has failed to maintain or make available records or reports of the investigation as required by this part. (b) Controlled substances. If an investigational new drug is a substance listed in any schedule of the Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery, receipt, and disposition of the drug, which are required to be kept under this part or other applicable parts of this chapter shall, upon the request of a properly authorized employee of the Drug Enforcement Administration of the U.S. Department of Justice, be made available by the investigator or sponsor to whom the request is made, for inspection and copying. In addition, the sponsor shall assure that adequate precautions are taken, 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.

regulation

[{"label": "(a)", "text": "FDA inspection. A sponsor 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 any records and reports relating to a clinical investigation conducted under this part. Upon written request by FDA, the sponsor shall submit the records or reports (or copies of them) to FDA. The sponsor shall discontinue shipments of the drug to any investigator who has failed to maintain or make available records or reports of the investigation as required by this part.", "source": null}, {"label": "(b)", "text": "Controlled substances. If an investigational new drug is a substance listed in any schedule of the Controlled Substances Act (21 U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery, receipt, and disposition of the drug, which are required to be kept under this part or other applicable parts of this chapter shall, upon the request of a properly authorized employee of the Drug Enforcement Administration of the U.S. Department of Justice, be made available by the investigator or sponsor to whom the request is made, for inspection and copying. In addition, the sponsor shall assure that adequate precautions are taken, 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.", "source": null}]

21 U.S.C. 801

21 CFR part 1308

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.58

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.59

Disposition of unused supply of investigational drug.

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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

§ 312.57.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.59

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.60

General responsibilities of investigators.

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, obtain the informed consent of each human subject to whom the drug is administered, except as provided in § 50.23. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56.

regulation

§ 50.23.

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.60

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.61

Control of the investigational drug.

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.

regulation

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.61

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.62

Investigator recordkeeping and record retention.

(a) Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under § 312.59. (b) Case histories. An investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated with the investigational drug or employed as a control in the investigation. (c) Record retention. An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under § 312.59.", "source": null}, {"label": "(b)", "text": "Case histories. An investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated with the investigational drug or employed as a control in the investigation.", "source": null}, {"label": "(c)", "text": "Record retention. An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.", "source": null}]

§ 312.59.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

2 years

False

True

2 years

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.62

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.64

Investigator reports.

(a) Progress reports. The investigator shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required under § 312.33 to submit annual reports to FDA on the progress of the clinical investigations. (b) Safety reports. An investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately. (c) Final report. An investigator shall provide the sponsor with an adequate report shortly after completion of the investigator's participation in the investigation. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Progress reports. The investigator shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required under § 312.33 to submit annual reports to FDA on the progress of the clinical investigations.", "source": null}, {"label": "(b)", "text": "Safety reports. An investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately.", "source": null}, {"label": "(c)", "text": "Final report. An investigator shall provide the sponsor with an adequate report shortly after completion of the investigator's participation in the investigation.", "source": null}]

§ 312.33

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.64

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.66

Assurance of IRB review.

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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.66

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.68

Inspection of investigator's records and reports.

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.

regulation

§ 312.62.

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.68

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.69

Handling of controlled substances.

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.

regulation

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.69

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart D

Responsibilities of Sponsors and Investigators

312.70

Disqualification of a clinical investigator.

(a) If FDA has information indicating that an investigator has repeatedly or deliberately failed to comply with the requirements of this part, Part 50, or part 56, or has submitted 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, or has deliberately or repeatedly submitted false information to the sponsor in any required report, the Commissioner will notify the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the investigator is not entitled to receive investigational drugs. The notification will provide a statement of basis for such determination. (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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "If FDA has information indicating that an investigator has repeatedly or deliberately failed to comply with the requirements of this part, Part 50, or part 56, or has submitted 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.", "source": null}, {"label": "(b)", "text": "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, or has deliberately or repeatedly submitted false information to the sponsor in any required report, the Commissioner will notify the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the investigator is not entitled to receive investigational drugs. The notification will provide a statement of basis for such determination.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}, {"label": "(e)", "text": "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.", "source": null}, {"label": "(f)", "text": "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.", "source": null}]

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, 1990]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.70

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.80

Purpose.

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.

regulation

§ 314.105

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.80

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.81

Scope.

This section applies to new drug, antibiotic, 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.

regulation

[{"label": "(a)", "text": "For purposes of this section, the term “life-threatening” means:", "source": null}, {"label": "(1)", "text": "Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and", "source": null}, {"label": "(2)", "text": "Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival.", "source": null}, {"label": "(b)", "text": "For purposes of this section, the term “severely debilitating” means diseases or conditions that cause major irreversible morbidity.", "source": null}, {"label": "(c)", "text": "Sponsors are encouraged to consult with FDA on the applicability of these procedures to specific products.", "source": null}]

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.81

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.82

Early consultation.

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) Pre-investigational new drug (IND) meetings. Prior to the submission of the initial IND, the sponsor may request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of animal studies needed to initiate human testing. The meeting may also provide an opportunity for discussing the scope and design of phase 1 testing, and the best approach for presentation and formatting of data in the IND. (b) End-of-phase 1 meetings. When data from phase 1 clinical testing are available, the sponsor may again request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of phase 2 controlled clinical trials, with the goal that such testing will be adequate to provide sufficient data on the drug's safety and effectiveness to support a decision on its approvability for marketing. The procedures outlined in § 312.47(b)(1) with respect to end-of-phase 2 conferences, including documentation of agreements reached, would also be used for end-of-phase 1 meetings.

regulation

[{"label": "(a)", "text": "Pre-investigational new drug (IND) meetings. Prior to the submission of the initial IND, the sponsor may request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of animal studies needed to initiate human testing. The meeting may also provide an opportunity for discussing the scope and design of phase 1 testing, and the best approach for presentation and formatting of data in the IND.", "source": null}, {"label": "(b)", "text": "End-of-phase 1 meetings. When data from phase 1 clinical testing are available, the sponsor may again request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of phase 2 controlled clinical trials, with the goal that such testing will be adequate to provide sufficient data on the drug's safety and effectiveness to support a decision on its approvability for marketing. The procedures outlined in § 312.47(b)(1) with respect to end-of-phase 2 conferences, including documentation of agreements reached, would also be used for end-of-phase 1 meetings.", "source": null}]

§ 312.47

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.82

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.83

Treatment protocols.

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)).

regulation

§ 312.34; § 312.42

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.83

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.84

Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses.

(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 standing advisory committee of the application's filing and its availability for review. (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.

regulation

[{"label": "(a)", "text": "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.", "source": null}, {"label": "(b)", "text": "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 standing advisory committee of the application's filing and its availability for review.", "source": null}, {"label": "(c)", "text": "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.", "source": null}, {"label": "(d)", "text": "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.", "source": null}]

§ 312.80; § 314.101; § 312.82; § 314.120

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.84

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.85

Phase 4 studies.

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.

regulation

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.85

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.86

Focused FDA regulatory research.

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.

regulation

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.86

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.87

Active monitoring of conduct and evaluation of clinical trials.

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.

regulation

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.87

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart E

Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses

312.88

Safeguards for patient safety.

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).

regulation

§ 314.50; § 312.32; § 312.23; § 314.80

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.88

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart F

Miscellaneous

312.110

Import and export requirements.

(a) Imports. An investigational new drug offered for import into the United States complies with the requirements of this part if it is subject to an IND that is in effect for it under § 312.40 and: (1) The consignee in the United States is the sponsor of the IND; (2) the consignee is a qualified investigator named in the IND; or (3) the consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the investigational drug, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the investigational drug. (b) Exports. An investigational new drug intended for export from the United States complies with the requirements of this part as follows: (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 an antibiotic drug product shipped in accordance with the provisions of section 801(d) of the act. (5) This paragraph does not apply to the export of new drugs (including biological products) approved for export under section 802 of the act or section 351(h)(1)(A) of the Public Health Service Act. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Imports. An investigational new drug offered for import into the United States complies with the requirements of this part if it is subject to an IND that is in effect for it under § 312.40 and: (1) The consignee in the United States is the sponsor of the IND; (2) the consignee is a qualified investigator named in the IND; or (3) the consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the investigational drug, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the investigational drug.", "source": null}, {"label": "(b)", "text": "Exports. An investigational new drug intended for export from the United States complies with the requirements of this part as follows:", "source": null}, {"label": "(1)", "text": "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", "source": null}, {"label": "(2)", "text": "If FDA authorizes shipment of the drug for use in a clinical investigation. Authorization may be obtained as follows:", "source": null}, {"label": "(i)", "text": "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.", "source": null}, {"label": "(ii)", "text": "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.", "source": null}, {"label": "(iii)", "text": "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.", "source": null}, {"label": "(3)", "text": "This paragraph applies only where the drug is to be used for the purpose of clinical investigation.", "source": null}, {"label": "(4)", "text": "This paragraph does not apply to the export of an antibiotic drug product shipped in accordance with the provisions of section 801(d) of the act.", "source": null}, {"label": "(5)", "text": "This paragraph does not apply to the export of new drugs (including biological products) approved for export under section 802 of the act or section 351(h)(1)(A) of the Public Health Service Act.", "source": null}]

§ 312.40

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.110

21

Food and Drugs

I

Food and Drug Administration, Department of Health and Human Services (Continued)

D

DRUGS FOR HUMAN USE

312

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart F

Miscellaneous

312.120

Foreign clinical studies not conducted under an IND.

(a) Introduction. This section describes the criteria for acceptance by FDA of foreign clinical studies not conducted under an IND. In general, FDA accepts such studies provided they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community. Studies meeting these criteria may be utilized to support clinical investigations in the United States and/or marketing approval. Marketing approval of a new drug or antibiotic drug based solely on foreign clinical data is governed by § 314.106. (b) Data submissions. A sponsor who wishes to rely on a foreign clinical study to support an IND or to support an application for marketing approval shall submit to FDA the following information: (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) Conformance with ethical principles. (1) Foreign clinical research is required to have been conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” (see paragraph (c)(4) of this section) or the laws and regulations of the country in which the research was conducted, whichever represents the greater protection of the individual. (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: Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects Introduction 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. I. Basic Principles 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 by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society. 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. II. Medical Research Combined with Professional Care (Clinical Research) 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. III. Non-Therapeutic Biomedical Research Involving Human Subjects (Non-Clinical Biomedical Research) 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. (Collection of information requirements approved by the Office of Management and Budget under control number 0910-0014)

regulation

[{"label": "(a)", "text": "Introduction. This section describes the criteria for acceptance by FDA of foreign clinical studies not conducted under an IND. In general, FDA accepts such studies provided they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community. Studies meeting these criteria may be utilized to support clinical investigations in the United States and/or marketing approval. Marketing approval of a new drug or antibiotic drug based solely on foreign clinical data is governed by § 314.106.", "source": null}, {"label": "(b)", "text": "Data submissions. A sponsor who wishes to rely on a foreign clinical study to support an IND or to support an application for marketing approval shall submit to FDA the following information:", "source": null}, {"label": "(1)", "text": "A description of the investigator's qualifications;", "source": null}, {"label": "(2)", "text": "A description of the research facilities;", "source": null}, {"label": "(3)", "text": "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;", "source": null}, {"label": "(4)", "text": "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", "source": null}, {"label": "(5)", "text": "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.", "source": null}, {"label": "(c)", "text": "Conformance with ethical principles. (1) Foreign clinical research is required to have been conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” (see paragraph (c)(4) of this section) or the laws and regulations of the country in which the research was conducted, whichever represents the greater protection of the individual.", "source": null}, {"label": "(2)", "text": "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.", "source": null}, {"label": "(3)", "text": "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.", "source": null}, {"label": "(4)", "text": "The “Declaration of Helsinki” states as follows:", "source": null}]

§ 314.126.; § 314.106.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 56 FR 22113, May 14, 1991]

Mar. 19, 1987

(Revised as of April 1, 1996)

False

CFR

1996

CFR-1996-title21-vol5.xml

https://www.govinfo.gov/bulkdata/CFR/1996/title-21

cfr:1996:21:312:312.120