DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
FOOD AND DRUG ADMINISTRATION

[21 CFR PART 1]

DRUGS

LABELING AND ADVERTISING; NOTICE OF PROPOSED RULE MAKING

The Kefauver-Harris Drug Amendments of 1962 (Public Law 87-781), among other things, amended section 502(e) of the Federal Food, Drug, and Cosmetic Act (relating to labeling information regarding the names of drug preparations and the ingredients thereof) and established a new section 502 (n) (relating to the content of prescription-drug advertisements). For proper administration of these two new sections of the act, the Commissioner of Food and Drugs, under the authority provided therein (secs. 502 (e), (n), 701 (e), 52 Stat. 1050, 1051, 1055, as amended 70 Stat. 919, 72 Stat. 948, 74 Stat, 399, 76 Stat, 790, 791, 792; 21 U.S.C. 352 (e), (n) and note under sec. 352; 371(e)) and delegated to him by the Secretary of Health, Education, and Welfare (25 F.R. 8625) proposes to amend the regulations previously adopted under section 502(e) of the act (21 CFR 1.105) and to adopt new regulations under section 502 (n), as set forth below.

The proposed amendments will be effected by revoking § 1.105 and by adding to Part 1 new §§ 1.104 and 1.105, reading as follows:

§1.104 Drugs; statement of formula.

(a) The formula information required by section 502 (e) (1) (A)(ii) of the Federal Food, Drug, and Cosmetic act shall appear together, without any intervening written, printed, or graphic matter, except such statements as "Warning-May be habit forming" that are specifically required for certain ingredients by the act or regulations thereunder.

(b) The term "ingredient" applies to any substance present in the drug, whether added to the formulation as a single substance or in admixture with other substances.

(c) The labeling of a drug may be misleading by reason (among other reasons) of:

(1) The order in which the names of ingredients present in the drug appear in the labeling, or the relative prominence otherwise given such names; or

(2) Failure to reveal the proportion of, or other fact with respect to, an ingredient present in such drug, when such proportion or other fact is material in the light of the representation that such ingredient is present in such drug; or (3) The use of a fanciful name for an ingredient employed in such a manner as to imply that the ingredient has some unique effectiveness or composition when, in fact, the ingredient is a common substance, the limitations of which are readily recognized when the ingredient is listed by its established name; or

(4) The failure to state prominently and forthrightly the composition of a drug identified by a fanciful name, in such a way as reasonably to inform the purchaser of its composition, permitting a rational buying choice between the drug and other drugs available for the same use; or

(5) The featuring in the labeling or inert or inactive ingredients; or

(6) Designation of a drug or ingredient by a trade name that, because of similarity in spelling or pronunication, may be confused with the trade name or the established name of a different drug or ingredient.

(d) (1) If the drug is in tablet or capsule form or other unit dosage form, any statement of the quantity of an ingredient contained therein shall express the quantity of such ingredient in each such unit. If the drug is not in unit dosage form, any statement of the quantity of an ingredient contained therein shall express the amount of such ingredient in a specified unit of weight or measure of the drug, or the percentage of such ingredient in such drug. Such statements shall be in terms that are informative to licensed practitioners in the case of a prescription drug, and to the layman in the case of a nonprescription drug.

(2) A statement of the percentage of an ingredient in a drug shall, if the term "percent" is used without qualification, mean percent weight in weight, if the ingredient and the drug are both solids; percent weight in volume at 68° Fahrenheit (20° Centigrade), if the ingredient is a solid and the drug is a liquid; and percent volume in volume at 68° Fahrenheit (20° Centigrade), if both the ingredient and the drug are liquids, except that alcohol shall be stated in terms of percent volume of absolute alcohol at 60° Fahrenheit (15.56° Centigrade).

(e) A derivative or preparation of substance named in section 502(e) of the act is an article derived or prepared from such substance by any method, including actual or theoretical chemical action.

(f) If an ingredient is a derivative or preparation of a substance specifically named in section 502(e) of the act and the established name of such ingredient does not indicate that it is a derivative or preparation of the parent substance named in section 502(e), the labeling shall, in conjunction with the listing of the established name of such ingredient, declare the name of the parent substance from which such ingredient is derived or prepared, and state that such article is a derivative or preparation of such parent substance.

(g) If the labeling of a prescription drug bears a proprietary name or designation for the drug or any ingredient thereof, the established name, if such there be, corresponding to such proprietary name or designation, shall accompany each appearance of such proprietary name or designation. The established name shall appear in immediate conjunction with the proprietary name or designation, without any intervening matter except the words "brand of" or, alternatively, brackets surrounding the established name. The established name shall be printed in letters that are at least half as large as the letters comprising the proprietary name or designation with which it is joined, and the established name shall have a prominence commensurate with the prominence with which such proprietary name or designation appears, taking into account all pertinent factors, including typography, layout, contrast, and other printing features.

(h) In the cast of a prescription drug containing two or more active ingredients, if the label bears a proprietary name or designation for such mixture and there is no established name corresponding to such proprietary name or designation, the formula information required on the label by section 502(e) (1) (A)(ii) of the act shall follow immediately after the most prominent display of the proprietary name or designation, without other intervening written, printed, or graphic matter, except such phrase as "Each tablet contains," etc. The size and prominence of this information shall bear a reasonable relationship to the size and prominence of the proprietary name and other prominent features of the label. If the drug is packaged in a container too small to bear the formula information on the main display panel, the formula information required by section 502(e) (1) (A) (ii) of the act may appear elsewhere on the label, even though the proprietary name or designation appears on the main display panel of the label; but side or back-panel placement shall in this case be so arranged and printed as to provide size and prominence of display reasonably related to the size and prominence of the front-panel display.

(i) A drug packaged in a container too small or otherwise unable to accommodate a label with sufficient space to bear the information required for compliance with section 502 (e) (1) (A) (ii) and (B) shall be exempt from compliance with those clauses: Provided, That:

(1) The label bears:

(i) The proprietary name of the drug;

(ii) The established name, if such there be, of the drug;

(iii) An identifying lot or control number; and

(iv) The name of the manufacturer, packer, or distributor of the drug; and

(2) All the information required to appear on the label by the act and the regulations thereunder appears on the carton or other outer container or wrapper if such carton, outer container, or wrapper has sufficient space to bear such information, or such complete label information appears on a leaflet with the package.

§1.105 Prescription-drug advertisements.

(a) The provisions of § 1.104 (a) through (h), inclusive, shall apply to the information presented in an advertisement for a prescription drug concerning the established name and the formula.

(b) A "brief summary" relating to side effects, contraindications, and effectiveness shall be presented in any prescription-drug advertisement that provides any information regarding indications or dosage recommendations. This summary shall fairly show the effectiveness of the drug in the conditions for which it is recommended in the advertisement, together with a showing of those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and any other use or uses for which the drug is commonly prescribed. A fair balance shall be made in presenting the

information on effectiveness and that on side effects and contraindications; such fair balance shall be achieved even if small size of the advertisement limits the total amount of information presented.

(c) An advertisement for a prescripition drug covered by an approved newdrug application must not recommend nor suggest any use that is not in the labeling accepted in the approved new-drug application. The advertisement must present information from the approved new-drug application labeling concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and any other use or uses for which the drug is commonly prescribed.

(d) An advertisement for a prescription drug subject to certification must not recommend nor suggest any use that is not in the labeling covered by the certification or covered by the applicable certification regulations or regulations providing for exemption from certification. The advertisement must present information from such labeling covered by the certification, or the applicable certification regulations or regulations providing for exemption from certification, concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and any other use or uses from which the drug is commonly prescribed.

(e) In the case of a prescription drug not subject to the new-drug provisions or the certification provisions, an advertisement may recommend use of the drug only for those purposes for which the article is generally recognized as safe and effective by medical experts or for those purposes for which the article is generally recognized as safe by medical experts and for which there exists substantial evidence, consisting of adequate and well controlled investigations, including clinical investigations, by medical experts, on the basis of which it can fairly and responsibly be concluded that the drug is effective for such purposes. The advertisement must present information concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and for any other use or uses for which the drug is commonly prescribed.

(f) The information in an advertisement for a prescription drug concerning side effects and contraindications must be presented in close association with the information concerning effectiveness and must have the same degree of prominence as the information concerning effectiveness, taking into account all pertinent factors, including typography, layout, contrast, and other printing features.

(g) (1) No advertisement concerning a prescription drug may be disseminated without prior approval by the Food and Drug Administration if use of the drug may cause fatalities or serious damage and the sponsor of the drug has been notified by the Food and Drug Administration by certified mail that advertisements for the drug must be approved before dissemination. After information concerning the possibility that the drug may cause fatalities or serious damage has been widely publicized in medical literature, the Food and Drug Administration may notify the sponsor of the drug by mail that prior approval of avertisements for the drug is no longer necessary. Dissemination of an advertisement not in compliance with this paragraph shall be deemed to be an act that causes a drug to be misbranded under section 502 (n) of the act.

(2) Any other advertisement may be submitted to the Food and Drug Administration prior to publication for comment. If the advertiser is notified that the submitted advertisement is not in violation and, at some subsequent time, the Food and Drug Administration changes its opinion, the advertiser will be so notified and will be given a reasonable time for correction before any regulatory action is taken under this section. Notification to the advertiser that a proposed advertisement is or is not considered to be in violation shall be in written form. (h) An advertisement issued or caused to be issued by the manufacturer, packer, or distributor of the drug promoted by the advertisement and which is not in compliance with section 502(n) of the act and the applicable regulations thereunder shall cause all stocks of such drug in possession of the person responsible for issuing or causing the issuance of the advertisement, and all stocks of the drug distributed by such person and still in the channels of commerce, to be misbranded under section 502(n) of the act.

(i) Brochures, mailing pieces, detailing pieces, file cards, bulletins, price lists, catalogs, house organs, literature reprints, and similar pieces of printed matter concerning a drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor, including reference publications for use by medical prac

titioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug, are regarded as labeling not subject to section 502(n) of the act but subject to the "full disclosure" requirements of § 1.106 (b) or (c).

The Commissioner of Food and Drugs hereby offers an opportunity to all interested persons to submit their views in writing with reference to this proposal to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington 25, D.C., within 45 days from the date of publication of this notice in the Federal Register. Views and comments should be submitted in triplicate. Dated: February 8, 1963.

GEO. P. LARRICK, Commissioner of Food and Drugs.

[F.R. Doc. 63-1570; Filed, Feb. 13, 1963; 8:45 a.m.]

[21 CFR PART 130]

NEW DRUGS

PROPOSED REVISION OF REGULATIONS

The Commissioner Food and Drugs, in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (secs. 503 (b) (1) (3), 505, 701 (a), 52 Stat. 1052, 1053, 1055, as amended 65 Stat. 648, 76 Stat. 781, 782, 783, 784, 785, 788; 21 U.S.C. 353 (B) (1) (3), 355, 371(a)) and under the authority delegated to him by the Secretary of Health, Education, and Welfare (25 F.R. 8625), proposes to revise Part 130-New Drugs, to read as set forth below, and hereby invites all interested persons to submit views and comments regarding the proposed revision. Such views and comments should be submitted in writing to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., within 45 days from the date of publication of this notice in the Federal Register.

PART 130-NEW DRUGS

Subpart A-Procedural and Interpretative Regulations

Definitions and interpretations.

Biologics; products subject to license control.

New drugs for investigational use; exemptions from section 505 (a).
Applications.

Reasons for refusing to file applications.

Comment on applications.

Withdrawal of applications without prejudice.

Supplemental applications.

Sec.

130.1

130.2

130.3

130.4 130.5

130.6

130.7

Amended applications.

130.8

130.9

130.10

130.11

130.12

130.13

130.14

130.15

130.16

130.17

Hearing examiner.

130.18

130.19

130.20

130.21 130.22

Notification of applicant of approval of application.

Insufficient information in application.

Refusal to approve the application.

Records and reports concerning experience on new drugs.

Contents of notice of hearing.

Failure to file an appearance.

Appearance of respondent.

Prehearing and other conferences.

Submission of documentary evidence in advance.

Excerpts from documentary evidence.

Submission and receipt of evidence.

Transcript of the testimony.

Tentative order.

130.23

Oral and written arguments.

130.24

130.25

Exceptions to the tentative order.

130.26

Issuance of final order.

130.27

130.26

Withdrawal of approval of an application.

Revocation of order refusing to approve application, or suspending or withdrawing

Confidentiality of information contained in new-drug applications.

Notice of withdrawal of approval of application.

Subpart B-Drugs Exempted From Prescription-Dispensing Requirements

130.101 Prescription-exemption procedure.

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

AUTHORITY: §§ 130.1 to 130.102 issued under secs. 503, 505, 701, 52 Stat. 1051, 1052, 1055, as amended; 21 U.S.C. 353, 355, 371.

CROSS REFERENCES: For other regulations in this chapter concerning new drugs, see also §§ 1.106, 3.45, 3.511, 3.512, and 121.7.

SUBPART A-PROCEDURAL AND INTERPRETATIVE REGULATIONS

§ 130.1 Definitions and interpretations.

(a) As used in this part, the term "act" means the Federal Food, Drug, and Cosmetic Act approved June 25, 1938 (52 Stat. 1040 et seq., as amended; 21 U.S.C. 301-392).

(b) "Department" means the Department of Health, Education, and Welfare. (c) "Secretary" means the Secretary of Health, Education, and Welfare. (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 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 use 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.

§ 130.2 Biologics; products subject to license control.

A new drug shall not be deemd 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-toxin law of March 4, 1913 (37 Stat. 832; 21 U.S.C. 151 et seq.)

§ 130.3 New drugs for investigational use; exemptions from section 505(a). [Regulations under this section were published in the FEDERAL REGISTER of January 8, 1963 (28 F.R. 179) and no changes in this section are proposed.] § 130.4 Applications.

(a) Applications to be filed under the provisions of section 505(b) of the act shall be submitted in triplicate. If any part of the application is in a foreign language, an accurate and complete English translation shall be appended to such part; translations of literature printed in a foreign language shall be accompanied by copies of the original publication. If the applicant does not reside or maintain a place of business within the United States or any territory or possession of the United States, the application shall be countersigned by a duly authorized attorney, agent, or other representative of the applicant who resides in the United States.

(b) Pertinent information may be incorporated in, and will be considered as part of, an application on the basis of specific reference to such information, including information submitted under the provisions of § 130.3, in the files of the Food and Drug Administration. However, any reference to information furnished by a person other than the applicant will not be considered unless use of such information is authorized in a written statement signed by the person who submitted it.

(c) Applications shall be submitted in the following form: