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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)

Glycyrrhiza (licorice)
Homatropine methylbromide
Hydrangea, powdered extract (extract of hy-

drangea)
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

(v) Keratolytic drug products.

Precipitated sulfur Sublimed sulfur

(vi) Local anesthetic drug products.

Diperodon
Phenacaine hydrochloride

(vii) Other drug products.

Collinsonia extract
Escherichia coli vaccines
Lappa extract
Leptandra extract
Live yeast cell derivative
Mullein

(viii) Protectant drug products.

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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)(25) 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

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 ipe

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.

(25) June 19, 1996, for products subject to paragraph (a)(6)(iv)(C) of this section.

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(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

[55 FR 46919, Nov. 7, 1990)

EDITORIAL NOTE: For FEDERAL REGISTER CItations affecting $310.545, see the List of CFR Sections Affected in the Finding Aids section of this volume.

EFFECTIVE DATE NOTES: 1. At 60 FR 42436, Aug. 16, 1995, in $310.545, paragraph (a)(15)(11) was stayed for topical otic drug products for the drying of water-clogged ears.

2. At 61 FR 9571, Mar. 8, 1996, in $310.545 in paragraph (a)(6)(11)(B), the entry for “l-desoxyephedrine (topical)" was stayed until further notice.

proved 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 pror ted 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.

(59 FR 43252, Aug. 22, 1994)

$310.547 Drug products containing

quinine offered over-the-counter (OTC) for the treatment and/or prevention of malaria.

$310.546 Drug products containing ac

tive ingredients offered over-thecounter (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 ap

(a) Quinine and quinine salts have been used OTC for the treatment and/or prevention of malaria, a serious and potentially life-threatening disease. Quinine is no longer the drug of choice for the treatment and/or prevention of most types of malaria. In addition, there are serious and complicating aspects of the disease itself and some potentially serious and life-threatening risks associated with the use of quinine at doses employed for the treatment of malaria. There is a lack of adequate data to establish general recognition of the safety of quinine drug products for OTC use in the treatment and/or prevention of malaria. Therefore, quinine or quinine salts cannot be safely and effectively used for the treatment and/ or prevention of malaria except under the care and supervision of a doctor.

(b) Any OTC drug product containing quinine or quinine salts that is labeled, represented, or promoted for the treatment and/or prevention of malaria is regarded as a new drug within the meaning of section 201(p) of the act, for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter

vestigational new drug in a clinical in

vestigation. 312.41 Comment and advice on an IND. 312.42 Clinical holds and requests for modi

fication. 312.44 Termination. 312.45 Inactive status. 312.47 Meetings. 312.48 Dispute resolution.

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 malaria 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 April 20, 1998, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

Subpart D-Responsibilities of Sponsors

and Investigators

[63 FR 13528, Mar. 20, 1998)

312.50 General responsibilities of sponsors. 312.52 Transfer of obligations to a contract

research organization. 312.53 Selecting investigators and monitors. 312.54 Emergency research under $50.24 of

this chapter. 312.55 Informing investigators. 312.56 Review of ongoing investigations. 312.57 Recordkeeping and record retention. 312.58 Inspection of sponsor's records and

reports. 312.59 Disposition of unused supply of inves

tigational drug. 312.60 General responsibilities of investiga

tors. 312.61 Control of the investigational drug. 312.62 Investigator recordkeeping and

record retention. 312.64 Investigator reports. 312.66 Assurance of IRB review. 312.68 Inspection of investigator's records

and reports. 312.69 Handling of controlled substances. 312.70 Disqualification of a clinical inves

tigator.

EFFECTIVE DATE NOTE: At 63 FR 13528, Mar. 20, 1998, $310.547 was added to subpart E, effective Apr. 20, 1998.

PART 312-INVESTIGATIONAL NEW

DRUG APPLICATION

Subpart A-General Provisions

Sec. 312.1 Scope. 312.2 Applicability. 312.3 Definitions and interpretations. 312.6 Labeling of an investigational new

drug. 312.7 Promotion and charging for investiga

tional drugs. 312.10 Waivers.

Subpart E-Drugs Intended to Treat Life

threatening and Severely-debilitating Illnesses

Subpart B-Investigational New Drug

Application (IND)

312.20 Requirement for an IND. 312.21 Phases of an investigation. 312.22 General principles of the IND submis

sion. 312.23 IND content and format. 312.30 Protocol amendments. 312.31 Information amendments. 312.32 IND safety reports. 312.33 Annual reports. 312.34 Treatment use of an investigational

new drug. 312.35 Submissions for treatment use. 312.36 Emergency use of an investigational

new drug. 312.38 Withdrawal of an IND.

312.80 Purpose. 312.81 Scope. 312.82 Early consultation. 312.83 Treatment protocols. 312.84 Risk-benefit analysis in review of

marketing applications for drugs to treat life-threatening and severely-debilitating

illnesses. 312.85 Phase 4 studies. 312.86 Focused FDA regulatory research. 312.87 Active monitoring of conduct and

evaluation of clinical trials. 312.88 Safeguards for patient safety.

Subpart F-Miscellaneous

312.110 Import and export requirements. 312.120 Foreign clinical studies not con

ducted under an IND. 312.130 Availability for public disclosure of

data and information in an IND. 312.140 Address for correspondence. 312.145 Guidelines.

Subpart c-Administrative Actions

312.40 General requirements for use of an in

Subpart G-Drugs for Investigational Use in

Laboratory Research Animals or in
Vitro Tests

312.160 Drugs for investigational use in lab

oratory research animals or in vitro tests.

AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 371; 42 U.S.C. 262.

SOURCE: 52 FR 8831, Mar. 19, 1987, unless otherwise noted.

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.

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.

(6) A clinical investigation involving an exception from informed consent under $50.24 of this chapter is not exempt from the requirements of this part.

(c) Bioavailability studies. The applicability of this part to in vivo bioavailability studies in humans is subject to the provisions of 8320.31.

$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.)).

(h) 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

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