product provided each labeling complies with all applicable statutory and regulatory labeling requirements in all respects. (v) The term "prominent and conspicuous location" as used in paragraphs (c)(2) (i) and (ii) of this section means that the labeling within the boxed or nonboxed area shall be presented and displayed in such a manner as to render it likely to be read as understood by the ordinary individual under customary conditions at both time of purchase and use. (vi) Regardless of the alternative selected by the manufacturer to describe indications, paragraphs (c)(2)(i), (ii), and (iii) of this section require other labeling established under this subchapter and subchapter C of this chapter to be stated in the exact language where exact language has been established and identified by quotation marks in an applicable monograph or by regulation (e.g., §201.63 of this chapter). (d) The advertising for the product prescribes, recommends, or suggests its use only under the conditions stated in the labeling. (e) The product contains only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity. Color additives may be used only in accordance with section 721 of the act and subchapter A of this chapter. (f) The product container and container components meet the requirements of § 211.94 of this chapter. (g) The labeling for all drugs contains the general warning: "Keep this and all drugs out of the reach of children." The labeling of drugs used for oral administation shall also state: "In case of accidental overdose, seek professional assistance or contact a poison control center immediately." The labeling for drugs administered rectally or used topically shall state: "In case of accidental ingestion, seek professional assistance or contact a Poison Control Center immediately.” The Food and Drug Administration will grant an exemption from these general warnings where appropriate upon petition, which shall be maintained in a permanent file for public review by the Dockets Management Branch, Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857. (h) Where no maximum daily dosage limit for an active ingredient is established in this part, it is used in a product at a level that does not exceed the amount reasonably required to achieve its intended effect. (i) The following terms may be used interchangeably in any of the labeling established in parts 331 through 358 of this chapter: (1) "Ask" or "consult". (j) It is recommended that the labeling of the product contain the quantitative amount of each active ingredient, expressed in terms of the dosage unit stated in the directions for use (e.g., tablet, teaspoonful). [39 FR 11741, Mar. 29, 1974, as amended at 40 FR 11718, Mar. 13, 1975; 40 FR 13496, Mar. 27, 1975; 42 FR 15674, Mar. 22, 1977; 46 FR 8459, Jan. 27, 1981; 50 FR 8996, Mar. 6, 1985; 51 FR 16266, May 1, 1986; 55 FR 11581, Mar. 29, 1990; 59 FR 4000, Jan. 28, 1994; 59 FR 14365, Mar. 28, 1994] § 330.2 Pregnancy-nursing warning. A pregnancy-nursing warning for OTC drugs is set forth under §201.63 of this chapter. [47 FR 54758, Dec. 3, 1982] § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form drug products is set forth under part 206 of this chapter. [58 FR 47959, Sept. 13, 1993] § 330.5 Drug categories. Monographs promulgated pursuant to the provisions of this part shall be established in this part 330 and following § 330.10 Procedures for classifying OTC drugs as generally recognized as safe and effective and not misbranded, and for establishing monographs. For purposes of classifying over-thecounter (OTC) drugs as drugs generally recognized among qualified experts as safe and effective for use and as not misbranded drugs, the following regulations shall apply: (a) Procedure for establishing OTC drug monographs—(1) Advisory review panels. The Commissioner shall appoint advisory review panels of qualified experts to evaluate the safety and effectiveness of OTC drugs, to review OTC drug labeling, and to advise him on the promulgation of monographs establishing conditions under which OTC drugs are generally recognized as safe and effec tive and not misbranded. A single advisory review panel shall be established for each designated category of OTC drugs and every OTC drug category will be considered by a panel. The members of a panel shall be qualified experts (appointed by the Commissioner) and may include persons from lists submitted by organizations representing professional, consumer, and industry interests. The Commissioner shall designate the chairman of each panel. Summary minutes of all meetings shall be made. (2) Request for data and views. The Commissioner will publish a notice in the FEDERAL REGISTER requesting interested persons to submit, for review and evaluation by an advisory review panel, published and unpublished data and information pertinent to a designated category of OTC drugs. Data and information submitted pursuant to a published notice, and falling within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the advisory review panel and the Food and Drug Administration as confidential until publication of a proposed monograph and the full report(s) of the panel. Thirty days thereafter such data and information shall be made publicly available and may be viewed at the office of the Dockets Management Branch of the Food and Drug Administration, except to the extent that the person submitting it demonstrates that it still falls within the confidentiality provisions of one or more of those statutes. To be considered, eight copies of the data and/or views on any marketed drug within the class must be submitted, preferably bound, indexed, and on standard sized paper (approximately 81⁄2 x 11 inches). When requested, abbreviated submissions should be sent. All submissions must be in the following format: OTC DRUG REVIEW INFORMATION I. Label(s) and all labeling (preferably mounted and filed with the other data-facsimile labeling is acceptable in lieu of actual container labeling). II. A statement setting forth the quantities of active ingredients of the drug. III. Animal safety data. A. Individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. B. Combinations of the individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. C. Finished drug product. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. IV. Human safety data. A. Individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the safety of each individual active component. 5. Pertinent medical and scientific literature. B. Combinations of the individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the safety of combinations of the individual active components. 5. Pertinent medical and scientific literature. C. Finished drug product. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination as to the safety of the finished drug product. 5. Pertinent medical and scientific literature. V. Efficacy data. A. Individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination on the efficacy of each individual active component. 5. Pertinent medical and scientific literature. B. Combinations of the individual active components. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination on the efficacy of combinations of the individual active components. 5. Pertinent medical and scientific literature. C. Finished drug product. 1. Controlled studies. 2. Partially controlled or uncontrolled studies. 3. Documented case reports. 4. Pertinent marketing experiences that may influence a determination on the efflcacy of the finished drug product. 5. Pertinent medical and scientific literature. VI. A summary of the data and views setting forth the medical rationale and purpose (or lack thereof) for the drug and its ingredients and the scientific basis (or lack thereof) for the conclusion that the drug and its ingredients have been proven safe and effective for the intended use. If there is an absence of controlled studies in the material submitted, an explanation as to why such studies are not considered necessary must be included. (3) Deliberations of an advisory review panel. An advisory review panel will meet as often and for as long as is appropriate to review the data submitted to it and to prepare a report containing its conclusions and recommendations to the Commissioner with respect to the safety and effectiveness of the drugs in a designated category of OTC drugs. A panel may consult any individual or group. Any interested person may request an opportunity to present oral views to the panel; such request may be granted or denied by the panel. Such requests for oral presentations should be in written form including a summarization of the data to be presented to the panel. Any interested person may present written data and views which shall be considered by the panel. This information shall be presented to the panel in the format set forth in paragraph (a)(2) of this section and within the time period established for the drug category in the notice for review by a panel. (4) Standards for safety, effectiveness, and labeling. The advisory review panel, in reviewing the data submitted to it and preparing its conclusions and recommendations, and the Commissioner, in reviewing the conclusions and recommendations of the panel and the published proposed, tentative, and the final monographs, shall apply the following standards to determine general recognition that a category of OTC drugs is safe and effective and not misbranded: 179-070 0—98———8 (i) Safety means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for harm which may result from abuse under conditions of widespread availability. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the drug is safe under the prescribed, recommended, or suggested conditions of use. This proof shall include results of significant human experience during marketing. General recognition of safety shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data. (ii) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed. Proof of effectiveness shall consist of controlled clinical investigations as defined in §314.126(b) of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the drug or essential to the validity of the investigation and that an alternative method of investigation is adequate to substantiate effectiveness. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered. General recognition of effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data. (iii) The benefit-to-risk ratio of a drug shall be considered in determining safety and effectiveness. (iv) An OTC drug may combine two or more safe and effective active ingredients and may be generally recognized as safe and effective when each active ingredient makes a contribution to the claimed effect(s); when combining of the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients; and when the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent therapy for a significant proportion of the target population. (v) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall state the intended uses and results of the product; adequate directions for proper use; and warnings against unsafe use, side effects, and adverse reactions in such terms as to render them likely to be read and understood by the ordinary individual, including individuals of low comprehension, under customary conditions of purchase and use. (vi) A drug shall be permitted for OTC sale and use by the laity unless, because of its toxicity or other potential for harmful effect or because of the method or collateral measures necessary to its use, it may safely be sold and used only under the supervision of a practitioner licensed by law to administer such drugs. (5) Advisory review panel report to the Commissioner. An advisory review panel shall submit to the Commissioner a report containing its conclusions and recommendations with respect to the conditions under which OTC drugs falling within the category covered by the panel are generally recognized as safe and effective and not misbranded. Included within this report shall be: (i) A recommended monograph or monographs covering the category of OTC drugs and establishing conditions under which the drugs involved are generally recognized as safe and effective and not misbranded (Category I). This monograph may include any conditions relating to active ingredients, labeling indications, warnings and adequate directions for use, prescription or OTC status, and any other conditions necessary and appropriate for the safety and effectiveness of drugs covered by the monograph. (ii) A statement of all active ingredients, labeling claims or other statements, or other conditions reviewed and excluded from the monograph on the basis of the panel's determination that they would result in the drug's not being generally recognized as safe and effective or would result in misbranding (Category II). (iii) A statement of all active ingredients, labeling claims or other statements, or other conditions reviewed and excluded from the monograph on the basis of the panel's determination that the available data are insufficient to classify such condition under either paragraph (a)(5) (i) or (ii) of this section and for which further testing is therefore required (Category III). The report may recommend the type of further testing required and the time period within which it might reasonably be concluded. (6) Proposed monograph. After reviewing the conclusions and recommendations of the advisory review panel, the Commissioner shall publish in the FEDERAL REGISTER a proposed order containing: (i) A monograph or monographs establishing conditions under which a category of OTC drugs is generally recognized as safe and effective and not misbranded (Category I). (ii) A statement of the conditions excluded from the monograph on the basis of the Commissioner's determination that they would result in the drug's not being generally recognized as safe and effective or would result in misbranding (Category II). (iii) A statement of the conditions excluded from the monograph on the basis of the Commissioner's determination that the available data are insufficient to classify such conditions under either paragraph (a)(6)(i) or (ii) of this section (Category III). (iv) The full report(s) of the panel to the Commissioner. The proposed order shall specify a reasonable period of time within which conditions falling within paragraph (a)(6)(iii) of this section may be continued in marketed products while the data necessary to support them are being obtained for evaluation by the Food and Drug Administration. The summary minutes of the panel meetings shall be made available to interested persons upon request. Any interested person may, within 90 days after publication of the proposed order in the FEDERAL REGISTER, file with the Dockets Management Branch of the Food and Drug Ad ministration written comments in quintuplicate. Comments may be accompanied by a memorandum or brief in support thereof. All comments may be reviewed at the office of the Dockets Management Branch during regular working hours, Monday through Friday. Within 30 days after the final day for submission of comments, reply comments may be filed with the Dockets Management Branch; these comments shall be utilized to reply to comments made by other interested persons and not to reiterate a position. The Commissioner may satisfy this requirement by publishing in the FEDERAL REGISTER a proposed order summarizing the full report of the advisory review panel, containing its conclusions and recommendations, to obtain full public comment before undertaking his own evaluation and decision on the matters involved. (7) Tentative final monograph. (i) After reviewing all comments, reply comments, and any new data and information, the Commissioner shall publish in the FEDERAL REGISTER a tentative order containing a monograph establishing conditions under which a category of OTC drugs is generally recognized as safe and effective and not misbranded. Within 60 days, any interested person may file with the Dockets Management Branch, Food and Drug Administration, written comments or written objections specifying with particularity the omissions or additions requested. These objections are to be supported by a brief statement of the grounds therefor. A request for an oral hearing may accompany such objections. the (ii) The Commissioner may publish in the FEDERAL REGISTER a separate tentative order containing a statement of those active ingredients reviewed and proposed to be excluded from monograph on the basis of the Commissioner's determination that they would result in a drug product not being generally recognized as safe and effective or would result in misbranding, and for which no substantive comments in opposition to the panel report or new data and information were received by the Food and Drug Administration pursuant to paragraph (a)(6)(iv) of this section. Within 60 days, any interested |