[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR330.10]

[Page 204-210]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 330_OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY RECOGNIZED AS 
 
                   Subpart B_Administrative Procedures
 
Sec.  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-the-counter (OTC) drugs as drugs 
generally recognized among qualified experts as safe and effective for 
use and as not misbranded drugs, the following regulations shall apply:
    (a) 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 effective 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unpublished data and information pertinent to a designated category of 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 or

[[Page 205]]

until the Commissioner places the panel's recommendations on public 
display at the office of the Division of Dockets Management. Thirty days 
thereafter such data and information shall be made publicly available 
and may be viewed at the office of the Division of Dockets Management 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 8\1/2\x11 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. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of each individual active component.
    5. Pertinent medical and scientific literature.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of combinations of the individual active 
components.
    5. Pertinent medical and scientific literature.
    C. Finished drug product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of the finished drug product.
    5. Pertinent medical and scientific literature.
    V. Efficacy data.
    A. Individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of each individual active component.
    5. Pertinent medical and scientific literature.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of combinations of the individual active 
components.
    5. Pertinent medical and scientific literature.
    C. Finished drug product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of the finished drug product.
    5. Pertinent medical and scientific literature.
    VI. A summary of the data and views setting forth the medical 
rationale and purpose (or lack thereof) for the drug and its ingredients 
and the scientific basis (or lack thereof) for the conclusion that the 
drug and its ingredients have been proven safe and effective for the 
intended use. If there is an absence of controlled studies in the 
material submitted, an explanation as to why such studies are not 
considered necessary must be included.
    VII. An official United States Pharmacopeia (USP)-National Formulary 
(NF) drug monograph for the active ingredient(s) or botanical drug 
substance(s), or a proposed

[[Page 206]]

standard for inclusion in an article to be recognized in an official 
USP-NF drug monograph for the active ingredient(s) or botanical drug 
substance(s). Include information showing that the official or proposed 
compendial monograph for the active ingredient or botanical drug 
substance is consistent with the active ingredient or botanical drug 
substance used in the studies establishing safety and effectiveness and 
with the active ingredient or botanical drug substance marketed in the 
OTC product(s) to a material extent and for a material time. If 
differences exist, explain why.

    (3) 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:
    (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 Sec.  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.

[[Page 207]]

    (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 may 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 active ingredients, labeling claims or other 
statements, or other conditions reviewed and excluded from the monograph 
on the basis of the panel's determination that they would result in the 
drug's not being generally recognized as safe and effective or would 
result in misbranding (Category II).
    (iii) A statement of active ingredients, labeling claims or other 
statements, or other conditions reviewed and excluded from the monograph 
on the basis of the panel's determination that the available data are 
insufficient to classify such condition under either paragraph (a)(5) 
(i) or (ii) of this section and for which further testing is therefore 
required (Category III). The report may recommend the type of further 
testing required and the time period within which it might reasonably be 
concluded.
    (6) 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 or a specific or specific OTC drugs are generally 
recognized as safe and effective and not misbranded (Category I).
    (ii) A statement of the conditions excluded from the monograph on 
the basis of the Commissioner's determination that they would result in 
the drug's not being generally recognized as safe and effective or would 
result in misbranding (Category II).
    (iii) A statement of the conditions excluded from the monograph on 
the basis of the Commissioner's determination that the available data 
are insufficient to classify such conditions under either paragraph 
(a)(6)(i) or (ii) of this section (Category III).
    (iv) The full report(s) of the panel to the Commissioner. The 
proposed order shall specify a reasonable period of time within which 
conditions falling within paragraph (a)(6)(iii) of this section may be 
continued in marketed products while the data necessary to support them 
are being obtained for evaluation by the Food and Drug Administration. 
The summary minutes of the panel meetings shall be made available to 
interested persons upon request. Any interested person may, within 90 
days after publication of the proposed order in the Federal Register, 
file with the Division of Dockets Management of the Food and Drug 
Administration written comments in triplicate. Comments may be 
accompanied by a memorandum or brief in support thereof. All comments 
may be reviewed at the office of the Division of Dockets Management 
between the hours of 9

[[Page 208]]

a.m. and 4 p.m., Monday through Friday. Within 30 days after the final 
day for submission of comments, reply comments may be filed with the 
Division of Dockets Management; 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 or, alternatively, 
after reviewing a panel's recommendations, the Commissioner shall 
publish in the Federal Register a tentative order containing a monograph 
establishing conditions under which a category of OTC drugs or specific 
OTC drugs are generally recognized as safe and effective and not 
misbranded. Within 90 days, any interested person may file with the 
Division of Dockets Management, 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.
    (ii) The Commissioner may also publish in the Federal Register a 
separate tentative order containing a statement of those active 
ingredients reviewed and proposed to be excluded from the 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. This order may be published when no 
substantive comments in opposition to the panel report or new data and 
information were received by the Food and Drug Administration under 
paragraph (a)(6)(iv) of this section or when the Commissioner has 
evaluated and concurs with a panel's recommendation that a condition be 
excluded from the monograph. Within 90 days, any interested person may 
file with the Division of Dockets Management, Food and Drug 
Administration, written objections specifying with particularity the 
provision of the tentative order to which objection is made. These 
objections are to be supported by a brief statement of the grounds 
therefor. A request for an oral hearing may accompany such objections.
    (iii) Within 12 months after publishing a tentative order pursuant 
to paragraph (a)(7)(i) of this section, any interested person may file 
with the Division of Dockets Management, Food and Drug Administration, 
new data and information to support a condition excluded from the 
monograph in the tentative order.
    (iv) Within 60 days after the final day for submission of new data 
and information, comments on the new data and information may be filed 
with the Division of Dockets Management, Food and Drug Administration.
    (v) New data and information submitted after the time specified in 
this paragraph but prior to the establishment of a final monograph will 
be considered as a petition to amend the monograph and will be 
considered by the Commissioner only after a final monograph has been 
published in the Federal Register unless the Commisisoner finds that 
good cause has been shown that warrants earlier consideration.
    (8) Oral hearing before the Commissioner. After reviewing objections 
filed in response to the tentative final monograph, the Commissioner, if 
he finds reasonable grounds in support thereof, shall by notice in the 
Federal Register schedule an oral hearing. The notice scheduling an oral 
hearing shall specify the length of the hearing and how the time shall 
be divided among the parties requesting the hearing. The hearing shall 
be conducted by the Commissioner and may not be delegated.
    (9) Final monograph. After reviewing the objections, the entire 
administrative record including all new data and information and 
comments, and considering the arguments made at any oral hearing, the 
Commissioner shall publish in the Federal Register a final

[[Page 209]]

order containing a monograph establishing conditions under which a 
category of OTC drugs or a specific or specific OTC drugs are generally 
recognized as safe and effective and not misbranded. The monograph shall 
become effective as specified in the order.
    (10) Administrative record. (i) All data and information to be 
considered in any proceeding pursuant to this section shall be submitted 
in response to the request for data and views pursuant to paragraph 
(a)(2) of this section, in response to any other notice published in the 
Federal Register, or accepted by the panel during its deliberations 
pursuant to paragraph (a)(3) of this section or submitted to the 
Division of Dockets Management as part of the comments during the 90-day 
period and 30-day rebuttal comment period permitted pursuant to 
paragraph (a)(6) of this section or submitted to the Division of Dockets 
Management during the 12-month period or as part of the comments during 
the 60-day period permitted pursuant to paragraph (a)(7) of this 
section.
    (ii) The Commissioner shall make all decisions and issue all orders 
pursuant to this section solely on the basis of the administrative 
record, and shall not consider data or information not included as part 
of the administrative record.
    (iii) The administrative record shall consist solely of the 
following material: All notices and orders published in the Federal 
Register, all data and views submitted in response to the request 
published pursuant to paragraph (a)(2) of this section, in response to 
any other notice published in the Federal Register, or accepted by the 
panel during its deliberations pursuant to paragraph (a)(3) of this 
section, all minutes of panel meetings, the panel report(s), all 
comments and rebuttal comments submitted on the proposed monograph and 
all new data and information submitted pursuant to paragraph (a)(6) of 
this section, all objections submitted on the tentative final monograph 
and all new data and information and comments submitted pursuant to 
paragraph (a)(7) of this section, the complete record of any oral public 
hearing conducted pursuant to paragraph (a)(8) of this section, all 
other comments requested at any time by the Commissioner, all data and 
information for which the Commissioner has reopened the administrative 
record, and all other material that the Commissioner includes in the 
administrative record as part of the basis for the Commissioner's 
decision.
    (11) Court appeal. The monograph contained in the final order 
constitutes final agency action from which appeal lies to the courts. 
The Food and Drug Administration will request consolidation of all 
appeals in a single court. Upon court appeal, the Commissioner may, at 
his discretion, stay the effective date for part or all of the monograph 
pending appeal and final court adjudication.
    (12) Amendment of monographs. (i) The Commissioner may propose on 
the Commissioner's own initiative to amend or repeal any monograph 
established pursuant to this section. Any interested person may petition 
the Commissioner for such proposal pursuant to Sec.  10.30 of this 
chapter. The Commissioner may deny the petition if the Commissioner 
finds a lack of safety or effectiveness employing the standards in 
paragraph (a)(4) of this section (in which case the appeal provisions of 
paragraph (a)(11) of this section shall apply), or the Commissioner may 
publish a proposed amendment or repeal in the Federal Register if the 
Commissioner finds general recognition of safety and effectiveness 
employing the standards in paragraph (a)(4) of this section. Any 
interested person may, within 90 days after publication of the proposed 
order in the Federal Register, file with the Division of Dockets 
Management, Food and Drug Administration, written comments in 
triplicate. Comments may be accompanied by a memorandum or brief in 
support thereof. All comments may be reviewed in the Division of Dockets 
Management between the hours of 9 a.m. and 4 p.m., Monday through 
Friday. After reviewing the comments, the Commissioner shall publish a 
final order amending the monograph established under the provisions of 
paragraph (a)(9) of this section or withdraw the proposal if comments 
opposing the amendment are persuasive. A new drug application

[[Page 210]]

may be submitted in lieu of, or in addition to, a petition under this 
paragraph.
    (ii) A new drug application may be submitted in lieu of a petition 
to amend the OTC drug monograh only if the drug product with the 
condition that is the subject of the new drug application has not been 
marketed on an interim basis (such as under the provisions of paragraph 
(a)(6)(iii) of this section), all clinical testing has been conducted 
pursuant to a new drug application plan, and no marketing of the product 
with the condition for which approval is sought is undertaken prior to 
approval of the new drug application. The Food and Drug Administration 
shall handle a new drug application as a petition for amendment of a 
monograph, and shall review it on that basis, if the provisions of this 
paragraph preclude approval of a new drug application but permit the 
granting of such a petition.
    (b) Regulatory action. Any product which fails to conform to an 
applicable monograph after its effective date is liable to regulatory 
action.
    (c) Information and data submitted under this section shall include, 
with respect to each nonclinical laboratory study contained in the 
application, either a statement that the study was conducted in 
compliance with the good laboratory practice regulations set forth in 
part 58 of this chapter, or, if the study was not conducted in 
compliance with such regulations, a brief statement of the reason for 
the noncompliance.
    (d) [Reserved]
    (e) Institutional review and informed consent. Information and data 
submitted under this section after July 27, 1981, shall include 
statements regarding each clinical investigation involving human 
subjects, from which the information and data are derived, that it 
either was conducted in compliance with the requirements for 
institutional review set forth in part 56 of this chapter, or was not 
subject to such requirements in accordance with Sec. Sec.  56.104 or 
56.105, and that it was conducted in compliance with the requirements 
for informed consent set forth in part 50 of this chapter.
    (f) Financial certification or disclosure statement. Any clinical 
data submitted under this section must be accompanied by financial 
certifications or disclosure statements or both as required by part 54 
of this chapter.

[39 FR 11741, Mar. 29, 1974, as amended at 39 FR 39556, Nov. 8, 1974; 42 
FR 19141, Apr. 12, 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460, 8955, 
Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; 46 FR 21360, Apr. 10, 1981; 
46 FR 47738, Sept. 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR 11581, 
Mar. 29, 1990; 63 FR 5253, Feb. 2, 1998; 67 FR 3073, Jan. 23, 2002]