Federal Register, Volume 64 Issue 243 (Monday, December 20, 1999)

[Federal Register Volume 64, Number 243 (Monday, December 20, 1999)]
[Proposed Rules]
[Pages 71062-71082]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-32428]

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Proposed Rules
Federal Register
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This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.

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Federal Register / Vol. 64, No. 243 / Monday, December 20, 1999 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 330

[Docket No. 96N-0277]
RIN 0910-AA01

Additional Criteria and Procedures for Classifying Over-the-
Counter Drugs as Generally Recognized as Safe and Effective and Not
Misbranded

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing
additional criteria and procedures by which over-the-counter (OTC)
conditions may become eligible for consideration in the OTC drug
monograph system. The proposed criteria and procedures address how OTC
drugs initially marketed in the United States after the OTC drug review
began in 1972 and OTC drugs without any U.S. marketing experience could
meet the statutory definition of marketing ``to a material extent'' and
``for a material time'' and become eligible. If found eligible, the
condition would be evaluated for general recognition of safety and
effectiveness in accordance with FDA's OTC drug monograph regulations.
FDA is also proposing changes to the current OTC drug monograph
procedures to streamline the process and provide additional information
in the review.

DATES: Submit written comments by March 22, 2000. See section V of this
document for the effective date of any final rule that may issue based
on this proposal.

ADDRESSES: Submit written comments on the proposed rule to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Submit written comments on the
information collection requirements to the Office of Information and
Regulatory Affairs, Office of Management and Budget (OMB), New
Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC
20503, ATTN: Wendy Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Donald Dobbs, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

The OTC drug monograph system was established to evaluate the
safety and effectiveness of all OTC drug products marketed in the
United States before May 11, 1972, that were not covered by new drug
applications (NDA's) and all OTC drug products covered by ``safety''
NDA's that were marketed in the United States before enactment of the
1962 drug amendments to the Federal Food, Drug, and Cosmetic Act (the
act). In 1972, FDA began its OTC drug review to evaluate OTC drugs by
categories or classes (e.g., antacids, skin protectants), rather than
on a product-by-product basis, and to develop ``conditions'' under
which classes of OTC drugs are generally recognized as safe and
effective (GRAS/E) and not misbranded.
FDA publishes these conditions in the Federal Register in the form
of OTC drug monographs, which consist primarily of active ingredients,
labeling, and other general requirements. Final monographs for OTC
drugs that are GRAS/E and not misbranded are codified in part 330 (21
CFR part 330). Manufacturers desiring to market an OTC drug covered by
an OTC drug monograph need not seek FDA clearance before marketing.
In the Federal Register of October 3, 1996 (61 FR 51625), FDA
published an advance notice of proposed rulemaking (ANPRM) stating that
it was considering proposing to amend its regulations to include
criteria under which certain additional OTC drug conditions may become
eligible for inclusion in the OTC drug monograph system. Interested
persons were invited to submit written comments by January 2, 1997. The
agency received 16 comments, which it discusses in section III. of this
document.
Under this proposal, eligibility for consideration in the OTC drug
monograph system would be determined by showing a condition's use ``to
a material extent'' and ``for a material time'' in compliance with the
existing statutory requirements of the act. A number of ingredients
have been marketed in OTC drug products under NDA's approved after May
11, 1972. The agency is providing criteria and procedures in this
proposal for manufacturers who wish to have ingredients such as these
considered for OTC drug monograph status.
For OTC drug products without any U.S. marketing experience, this
proposal represents a change in the agency's previous interpretation of
``use'' requirements in section 201(p) of the act (21 U.S.C. 321(p)).
Previously, the agency interpreted the use provision to mean use in the
United States only. The agency is proposing this change in policy to
expand use to include foreign marketing experience because it believes
that under certain circumstances use outside the United States may
appropriately be considered to satisfy the use requirements in section
201(p) of the act.
In the ANPRM, the agency used the term ``condition'' to refer to
OTC drug active ingredients, indications, dosage forms, dosage
strengths, routes of administration, and active ingredient
combinations. In this proposal, the agency is clarifying that the term
``condition'' refers to an active ingredient or botanical drug
substance (or a combination of active ingredients or botanical drug
substances), dosage form, dosage strength, or route of administration,
marketed for a specific OTC use. The agency is adding the reference to
botanical drug substance to clarify that the agency recognizes that the
information needed for consideration of a botanical substance for
inclusion in the OTC drug monograph system may differ from the
information needed to evaluate other types of active ingredients for
this purpose.

II. Description of the Proposed Rule

Currently, the OTC drug regulations in part 330 do not define
eligibility requirements for consideration in the OTC drug monograph
system or what constitutes marketing to a material extent or for a
material time. This proposed rule sets forth criteria for defining
material extent and material

[[Page 71063]]

time and procedures for considering additional ``conditions'' (as
clarified in section I. of this document) in the OTC drug monograph
system. The definition of ``conditions'' is included in proposed
Sec. 330.14(a).
Proposed Sec. 330.14(b) describes the criteria for consideration
for inclusion in the OTC drug monograph system. Proposed
Sec. 330.14(b)(1) would require that the condition be marketed for OTC
purchase by consumers. If the condition is marketed in another country
in a class of OTC drug products that may be sold only in a pharmacy,
with or without the personal involvement of a pharmacist, it must be
established that this marketing restriction does not indicate safety
concerns about the condition's toxicity or other potentiality for
harmful effect, the method of its use, or the collateral measures
necessary to its use (section 503(b)(1)(A) of the act (21 U.S.C.
353(b)(1)(A))). If the restriction is related to such concerns, FDA
would not consider this type of marketing to be similar to the broad
OTC drug marketing in the United States, where products are marketed in
a variety of outlets (e.g., grocery stores, convenience stores,
drugstores), with no opportunity or requirement for professional
consultation.
Proposed Sec. 330.14(b)(2) would require that if the condition
under consideration is marketed OTC in a foreign country, and its
marketing in the United States is limited to prescription drug use, it
would not be eligible for inclusion in an OTC drug monograph. FDA has
determined that such a condition requires a prescription and cannot be
considered GRAS/E for OTC use. Therefore, any request for OTC marketing
status should be made under the NDA.
Proposed Sec. 330.14(b)(3) would require OTC marketing for a
minimum of 5 continuous years in the same country or countries and in
sufficient quantity, as described in Sec. 330.14(c)(2)(ii),
(c)(2)(iii), and (c)(2)(iv). FDA is proposing these requirements to
ensure that marketing is of sufficient duration to detect infrequent
but serious adverse drug experiences (ADE's) that are occurring.
At this time, OTC drug monographs do not include timed-release
formulations. These products are regulated as new drugs under
Sec. 310.502(a)(14) (21 CFR 310.502(a)(14)), and this document does not
propose to change that status.
The agency is proposing a specific format for the submission of
eligibility information to the agency. This format is intended for
sponsors to provide specific information in a uniform manner to enable
the agency to streamline the review process. Proposed Sec. 330.14(c)
describes the new time and extent application (TEA) sponsors would be
required to submit when requesting consideration of a condition subject
to this section. All of the information in proposed Sec. 330.14(c)(1)
through (c)(5) needs to be included in accordance with the procedures
in proposed Sec. 330.14(d). The information requested in
Sec. 330.14(c)(2), (c)(2)(i) through (c)(2)(iv), and (c)(3) is to be
provided in a table format. If the condition is found eligible, then
safety and effectiveness data would subsequently be submitted under the
procedures proposed in Sec. 330.14(f) and reviewed under the procedures
in proposed Sec. 330.14(g). If the agency initially determines that the
condition can be considered safe and effective, then it will propose
monograph status under the procedures in proposed Sec. 330.14(g)(3).
Under proposed Sec. 330.14(c)(1), sponsors must submit basic
information about the condition that includes a detailed description of
the active ingredient(s) or botanical drug substance(s), which are more
fully described in Sec. 330.14(c)(1)(i) and (c)(1)(ii), pharmacologic
class(es), intended OTC use(s), OTC strength(s) and dosage form(s),
route(s) of administration, directions for use, and the applicable
existing OTC drug monograph(s) under which the condition would be
marketed or the request and rationale for creation of a new OTC drug
monograph(s). Proposed Sec. 330.14(c)(1)(iii) allows reference to the
current edition of the U.S. Pharmacopeia (USP)-National Formulary (NF)
to help satisfy the requirements of the description of the active
ingredient(s) or botanical drug substance(s).
Under proposed Sec. 330.14(c)(2), sponsors must submit a list of
all countries in which the condition has been marketed. This
information is important to determine if the marketing experience is
broad enough to ensure that an adequate safety profile exists.
Proposed Sec. 330.14(c)(2)(i) would require sponsors to describe
how the condition has been marketed in each country (e.g., OTC general
sales direct-to-consumer; sold only in a pharmacy, with or without the
personal involvement of a pharmacist; dietary supplement; or cosmetic).
If marketed as an OTC pharmacy-only product, the sponsor must establish
that this marketing restriction does not indicate safety concerns about
the condition's toxicity or other potentiality for harmful effect, the
method of its use, or the collateral measures necessary to its use
(section 503(b)(1)(A) of the act). This information is important
because diversity in the way products are marketed in other countries
may indicate safety concerns that would be important to consider in
determining suitability for OTC drug sale in the United States.
Proposed Sec. 330.14(c)(2)(ii) would require sponsors to submit
data on the number of dosage units sold in each country. Information
presented should include: (1) The total number of dosage units sold,
(2) the number of units sold by package sizes (e.g., 24 tablets, 120
milliliters (mL)), and (3) the number of doses per package based on the
labeled directions for use. This information is important to FDA's
assessment of the extent of marketing. This information is to be
presented in two formats: (1) On a year-by-year basis, and (2)
cumulative totals. The agency will maintain the year-to-year sales data
as confidential, unless the sponsor waives this confidentiality. The
agency will make the cumulative totals public should the condition be
found eligible for consideration in the OTC drug monograph system.
Proposed Sec. 330.14(c)(2)(iii) would require sponsors to
adequately describe each country's marketing exposure (e.g., race,
gender, ethnicity, and other pertinent factors) to ensure that
marketing experience can be reasonably extrapolated to the U.S.
population. Sponsors would have to explain any cultural or geographical
differences in the way the condition is used in the foreign country and
in the United States. The agency considers it important that OTC
marketing experience be relevant to populations who would use such an
OTC drug in the United States. The information in this paragraph need
not be provided for OTC drugs that have been marketed for more than 5
years in the United States under an NDA.
Under proposed Sec. 330.14(c)(2)(iv), sponsors must submit data on
the condition's use pattern in each country, that is, how often it is
to be used (according to the label) and for how long. If the use
pattern varies in different countries based on the product's packaging
and labeling, or if changes in use pattern have occurred over time, the
sponsor must describe the use pattern for each country and explain why
there are differences or changes. This information is important for
evaluating whether the extent of use is adequate to detect infrequent
but serious ADE's.
Proposed Sec. 330.14(c)(2)(v) would require sponsors to describe
each country's (where the condition is

[[Page 71064]]

marketed) system for identifying ADE's, especially those found in OTC
marketing experience, including method of collection if applicable. The
agency considers this information important to assess the ability of
the system to detect ADE's that are occurring.
Under proposed Sec. 330.14(c)(3), sponsors must submit a statement
of how long the condition has been marketed in each country,
accompanied by all labeling used during the marketing period,
specifying the time period that each labeling was used. All labeling
that is not in English must be translated to English, in accord with
Sec. 10.20(c)(2) (21 CFR 10.20(c)(2)). This information is important to
determine whether the condition has been marketed for a material time
and whether changes occurred in its labeling (e.g., formulation,
warnings, and directions). The agency proposes that this information
need not be provided for conditions that have been marketed OTC for
more than 5 years in the United States under an NDA.
Under proposed Sec. 330.14(c)(4), sponsors must submit a list of
all countries where the condition is marketed only as a prescription
drug and the reason(s) why its marketing is restricted to prescription
in these countries. This information is useful because the same drug
marketed OTC in one country may be limited to prescription in another
country, and the agency is interested in knowing the reason(s) why its
marketing is restricted to prescription in other countries.
Under proposed Sec. 330.14(c)(5), sponsors must submit a list of
all countries in which the condition has been withdrawn from marketing
or in which an application for OTC marketing approval has been denied,
and include the reasons for such withdrawal or application denial. This
information is important to determine why other countries did not grant
or withdrew OTC marketing status.
Under proposed Sec. 330.14(c)(6), sponsors must provide the
information in Sec. 330.14(c)(2), (c)(2)(i) through (c)(2)(iv), and
(c)(3) in a table format. This format is requested to provide for easy
comparison of information from one country to another.
Proposed Sec. 330.14(d) would require sponsors to submit three
copies of the TEA, which would be handled as confidential until the
agency makes a decision on the eligibility of the condition for
consideration in the OTC drug monograph system. The TEA would be placed
on public display in the Dockets Management Branch only if the
condition is found eligible for consideration in the OTC monograph
system. This procedure is necessary to allow sponsors to provide all
pertinent eligibility information, some of which may be considered
confidential under 18 U.S.C. 1905, 5 U.S.C. 552(b), or section 301(j)
of the act (21 U.S.C. 331(j)). Certain manufacturing information might
be considered confidential. Year-to-year sales data would be considered
confidential, but cumulative sales data over a period of years would
not be considered confidential. Any proposed compendial standards would
not be considered confidential. If the condition is not found eligible,
the TEA will not be placed on public display, but a letter from the
agency to the sponsor stating why the condition was not found
acceptable will be placed on public display in the Dockets Management
Branch.
Under proposed Sec. 330.14(e), if a condition is found eligible,
the agency would publish a notice of eligibility in the Federal
Register and provide the sponsor and other interested parties an
opportunity to submit data to demonstrate safety and effectiveness. The
agency is proposing this two-step approach to: (1) Prevent sponsors
from incurring unnecessary costs for developing safety and
effectiveness data for a condition that may not meet basic eligibility
requirements, (2) avoid expending agency resources evaluating safety
and effectiveness data for a condition that does not meet the basic
eligibility requirements, and (3) provide all other interested parties
an opportunity to submit data and information on eligible conditions.
Under proposed Sec. 330.14(f), the notice of eligibility will
include a request for safety and effectiveness data to be submitted.
Under proposed Sec. 330.14(f)(1), sponsors must submit all data and
information listed in Sec. 330.10(a)(2) under the outline ``OTC Drug
Review Information,'' items III through VII.
Under proposed Sec. 330.14(f)(2), sponsors would be required to
include all serious ADE's, as defined in Secs. 310.305 and 314.80 (21
CFR 310.305 and 314.80), from each country where the condition has been
or is currently marketed as a prescription drug or as an OTC drug or
product. Sponsors would be required to provide individual ADE reports
(Form FDA 3500A or a format that provides equivalent information) along
with a detailed summary of: (1) All serious ADE's, and (2) expected or
frequently reported side effects for the condition. Individual reports
should be translated if not provided in English. Information derived
from individual ADE reports is important in assessing safety, and
expected or frequently reported side effects help identify information
that should appear in product labeling.
Proposed Sec. 330.14(g) describes the administrative procedures for
FDA to use to evaluate the safety and effectiveness data. The agency
could: (1) Use an advisory review panel to evaluate the safety and
effectiveness data and make recommendations following the provisions of
Sec. 330.10(a)(3), (2) evaluate the data in conjunction with the
advisory review panel, or (3) evaluate the data on its own without
using an advisory review panel. These mechanisms provide the agency
with flexibility in determining the most efficient method to evaluate
data submissions consistent with the safety, effectiveness, and
labeling standards in Sec. 330.10(a)(4)(i) through (a)(4)(vi).
Under proposed Sec. 330.14(g)(1), an advisory review panel may
submit a report following the provisions of Sec. 330.10(a)(5), or the
panel may provide recommendations in its official minutes of
meeting(s). This latter approach provides the agency with a mechanism
to receive an advisory review panel's recommendations more quickly, and
it eliminates unnecessary administrative burdens.
Under proposed Sec. 330.14(g)(2), the agency may act on an advisory
review panel's recommendations following the proposed revised
procedures in Sec. 330.10(a)(2) and (a)(6) through (a)(10). This
approach provides the agency with a mechanism to be able to act on an
advisory review panel's recommendations in a more expeditious manner.
The agency is proposing to revise Sec. 330.10(a)(6), (a)(7), and
(a)(10) to incorporate these new procedures of placing an advisory
review panels's recommendations on public display in the Dockets
Management Branch and then acting on those recommendations.
Proposed Sec. 330.14(g)(3) states that if the condition is
initially determined to be safe and effective for OTC use in the United
States, it will be proposed for inclusion in an appropriate OTC drug
monograph(s), either by amending an existing monograph(s) or
establishing a new monograph(s), if necessary.
Proposed Sec. 330.14(g)(4) states how the agency will treat a
condition that is initially determined not to be GRAS/E for OTC use in
the United States.
Proposed Sec. 330.14(g)(5) provides an opportunity for public
comment on a proposal to include or exclude a condition and for
publication of a final rule.
Proposed Sec. 330.14(h) would permit marketing only under a final
OTC drug

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monograph(s) after the agency determines that the condition is GRAS/E
and includes it in the appropriate OTC drug final monograph(s), and the
condition complies with Sec. 330.14(i). The agency is proposing this
approach for several reasons: (1) It allows for thorough public
consideration of any safety and effectiveness issues that might arise
before marketing begins; (2) it allows for completion of compendial
monograph standards for identity, strength, quality, and purity for all
manufacturers to use; and (3) it allows manufacturers to avoid
expensive relabeling when changes occur between the proposal and the
final rule.
Under proposed Sec. 330.14(i), any active ingredient or botanical
drug substance included in a final OTC drug monograph must be
recognized in an official USP-NF drug monograph, setting forth its
standards of identity, strength, quality, and purity, prior to any
marketing. The official USP-NF monograph should be consistent with the
active ingredient(s) or botanical drug substance(s) used to establish
general recognition of safety and effectiveness. The agency is
proposing this compendial monograph requirement because the public
availability of chemical standards would ensure that all OTC drug
products contain ingredients that are equivalent to the active
ingredients or botanical drug substances included in an OTC drug
monograph. Inclusion in an official compendium of an ingredient's
standards of identity, strength, quality, and purity would help ensure
that OTC drugs are safe and effective for their intended uses. This
USP-NF monograph requirement has been agency policy since 1989 (54 FR
13480 at 13486, April 3, 1989, and 54 FR 40808 at 40810, October 3,
1989).
After further considering how to best evaluate additional
conditions that might be included in an OTC drug monograph, the
agency's proposal in this document differs in a number of ways from the
advance notice of proposed rulemaking. The agency is proposing certain
new procedures for consideration of additional conditions in the OTC
drug monograph system and amending existing OTC drug review procedures
in Sec. 330.10 to provide consistency with the use of these new
procedures. The agency is proposing that a TEA containing certain
information be submitted when a sponsor requests that an OTC drug
initially marketed in the United States after the OTC drug review began
in 1972 or an OTC drug without any U.S. marketing experience be
considered for inclusion in an OTC drug monograph. Sponsors of
additional conditions under these categories will be required to use
these new procedures.
The agency will continue to use the existing OTC drug review
procedures for conditions subject to the original OTC drug review. This
includes: (1) Rulemakings that have not been completed to date (e.g.,
external analgesic drug products), (2) drug categories that were in the
calls-for-data for OTC miscellaneous internal drug products (38 FR
31696, November 16, 1973, and 40 FR 38179, August 27, 1975) and for OTC
miscellaneous external drug products (38 FR 31697, November 16, 1973,
and 40 FR 38179, August 27, 1975) which the agency has not reviewed to
date (e.g., urinary antiseptic drug products), and (3) drug categories
that were not included in any of the calls-for-data but in which it can
be unequivocally established that eligible products were marketed OTC
before the OTC drug review began in 1972.
The new procedures will apply to all conditions marketed initially
in the United States after the OTC drug review began in 1972 and all
conditions for which the original OTC drug review has been completed
but where sponsors want further consideration (e.g., a condition
determined as nonmonograph in the original OTC drug review but for
which additional data and information are now being presented).
Sponsors of conditions in this last category will be required to follow
the new procedures so that the agency can obtain the most recent
marketing, safety, effectiveness, and compendial standard data and
information available for the condition. In addition, because such
conditions have been previously determined to be nonmonograph, no
interim marketing would be allowed under existing procedures until the
condition is included in a final monograph, which is consistent with
newly proposed Sec. 330.14(h).
The TEA will be handled as confidential, like the original
submissions to an advisory review panel, until the agency makes a
decision on the eligibility of the condition for consideration in the
OTC monograph system. If the condition is not found eligible, the
agency will notify the sponsor by letter, a copy of which will be
placed in the Dockets Management Branch, and the TEA will not be placed
on public display. If the condition is found eligible, the TEA will be
placed on public display in the Dockets Management Branch, after
deletion of information deemed confidential under 18 U.S.C. 1905, 5
U.S.C. 552(b), or section 301(j) of the act. Sponsors should identify
such information and request that it be considered confidential under
these provisions. The agency will publish a notice of eligibility in
the Federal Register and provide the sponsor of the TEA and other
interested parties an opportunity to submit data to demonstrate safety
and effectiveness according to proposed Sec. 330.14(f).
The agency will then evaluate the safety and effectiveness data,
using the existing OTC drug review standards in Sec. 330.10(a)(4)(i)
through (a)(4)(vi). The agency may either convene an advisory review
panel to assist in this evaluation or may elect to complete the
evaluation alone. If a panel is used, a notice of meeting(s) will be
published in the Federal Register, and the meeting(s) will be public.
If the agency uses an advisory review panel, the panel may submit its
recommendations to the agency in its official minutes of meeting(s) or
in a separate report. These recommendations will be publicly available
(in the docket). The agency will agree or disagree with the panel's
recommendations, and proceed directly to a tentative order (notice of
proposed rulemaking).
If the agency initially determines that a condition can be GRAS/E
for OTC use in the United States, it will propose to include it in an
appropriate OTC drug monograph(s). This will be done either by amending
an existing monograph(s) or establishing a new monograph(s), if
necessary.
If the agency initially determines that a condition cannot be GRAS/
E for OTC use in the United States, it will notify the sponsor and
other interested parties who submitted data by letter and place a copy
of this letter in the Dockets Management Branch. The agency has used
this ``feedback'' letter approach for many years during the ongoing OTC
drug review, and it has resulted in the resolution of the monograph/
nonmonograph status of many conditions prior to publication of a final
determination in the Federal Register. The agency is proposing the
letter approach as a way to provide early notification about the
agency's scientific assessment of the data presented. The agency will
publish a notice of proposed rulemaking to include the condition in
Sec. 310.502, which lists certain drugs determined by rulemaking
procedures to be new drugs within the meaning of section 201(p) of the
act (21 U.S.C. 321(p)). Interested parties will have an opportunity to
submit comments and new data. The agency will subsequently publish a
final rule (or reproposal if necessary) in the Federal Register.

[[Page 71066]]

While the agency generally intends to use a two-step publication
process for expediency, the agency may, in rare instances, elect to
publish an advance notice of proposed rulemaking (three step process)
when it needs to obtain additional public comment before determining
whether to propose a regulation (see Sec. 10.40(f)(3) (21 CFR
10.40(f)(3))).
The procedures for additional conditions in this proposal require
that a compendial monograph exist for any ingredient included in an OTC
drug monograph (a policy that has been in effect since 1989). Sponsors
are encouraged to begin development of this compendial monograph at an
early stage in the process. Therefore, the agency is proposing that
sponsors include an official (if one exists) or proposed compendial
monograph as an element of their safety and effectiveness data
submission.
Once the agency publishes a proposal to amend or establish an OTC
drug monograph to include a condition, it will then review the comments
and publish a final rule (or reproposal if necessary) in the Federal
Register. OTC marketing of the condition may begin when a final
monograph is published.
The new procedures are outlined in the flow chart in Table 1 below.
[GRAPHIC] [TIFF OMITTED] TP20DE99.000

[[Page 71067]]

These proposed new procedures are intended to streamline the
process for additional conditions that will be evaluated. However,
there are still some OTC drug rulemakings that need to be completed
under the existing procedures.
Current Sec. 330.10 sets forth the existing procedures for
classifying OTC drugs as GRAS/E and not misbranded and for establishing
monographs. FDA is proposing to amend Sec. 330.10 to update some
aspects of these procedures so that the existing procedures for the
ongoing OTC drug review are consistent with the new proposed
procedures.
The ``OTC Drug Review Information'' format and content requirements
in Sec. 330.10(a)(2) would be amended by revising items IV.A.3, IV.B.3,
IV.C.3, V.A.3, V.B.3, and V.C.3 to add the words ``Identify expected or
frequently reported side effects.'' after ``document case reports,''
and by adding new item VII to read:
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 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 FDA is proposing these requirements
for all conditions because this type of information will assist the
agency in determining: (1) Appropriate warning statements, and (2)
general recognition of safety and effectiveness by providing
assurance that a proposed OTC active ingredient or botanical drug
substance is consistent with the active ingredient or botanical drug
substance formulation in the marketed OTC product(s) and the active
ingredient or botanical drug substance used in establishing safety
and effectiveness.
Current Sec. 330.10(a)(5) describes the contents of the advisory
review panel report on conditions considered for inclusion in an OTC
drug monograph. The report includes 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 GRAS/E or
would result in misbranding. FDA is proposing to amend
Sec. 330.10(a)(5)(ii) and (a)(5)(iii) by deleting the requirement that
a statement of ``all'' active ingredients, labeling claims or other
statements, or other conditions be included. FDA is proposing this
revision because the statement ``all'' refers to an initial panel's
review of an entire class of OTC drugs for inclusion in the OTC drug
monograph system. Under the new procedures proposed in Sec. 330.14, the
agency may at times only consider one or more conditions for inclusion
into an appropriate OTC drug monograph(s).
Current Sec. 330.10(a)(6)(i) on proposed monographs, (a)(7)(i) on
tentative final monographs, and (a)(9) on final monographs describe
requirements affecting a category of OTC drugs. FDA is proposing to
revise these paragraphs to add a provision for a specific OTC
ingredient or ingredients as well as categories of drugs. These
paragraphs would be revised by deleting the word ``is'' and adding the
phrase ``or a specific or specific OTC drugs are.'' FDA is proposing
these revisions because the agency may at times only consider adding
one or more conditions to a designated category of OTC drugs.
Current Sec. 330.10(a)(6)(iv) and (a)(12)(i) state that four copies
of public comments must be submitted on a proposed monograph published
in the Federal Register. FDA is proposing to reduce the number of
copies to three because the fourth copy has proven to be unnecessary.
FDA is also proposing to delete the phrase ``during regular business
hours'' in Sec. 330.10(a)(6)(iv) and replace it with ``between the
hours of 9 a.m. and 4 p.m.''
FDA is proposing to revise Sec. 330.10(a)(6)(iv) to permit the
agency to place the advisory review panel's recommendations and the
data it considered on public display in the Dockets Management Branch
and publish a notice of their availability in the Federal Register,
rather than publishing the panel's proposed monograph in the Federal
Register as an ANPRM. FDA is proposing this revision to make
recommendations available earlier. FDA may include this notice of
availability as part of the tentative order under Sec. 330.10(a)(7).
Current Sec. 330.10(a)(7)(i) states that after reviewing all
comments, reply comments, and any new data and information, the
Commissioner of Food and Drugs (the Commissioner) shall publish in the
Federal Register a tentative order containing a monograph establishing
conditions under which a category of OTC drugs is GRAS/E and not
misbranded. FDA is proposing to add the phrase, ``or alternatively,
after reviewing a panel's recommendations'' to allow the agency to
publish a tentative order at an earlier date. FDA is also proposing to
change the 60-day comment period in Sec. 330.10(a)(7)(i), (a)(7)(ii),
and (a)(12)(i) to 90 days because the agency currently routinely
provides 90 days for comment at these stages of an OTC drug monograph
rulemaking.
Current Sec. 330.10(a)(7)(ii) describes procedures for issuing a
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 GRAS/E or would result in misbranding. Currently, the
Commissioner may issue such an order if no substantive comments in
opposition to the panel report or new data or information were received
by the agency. FDA is proposing to also allow publication of a
tentative order when the Commissioner has evaluated and concurs with a
panel's recommendation that a condition be excluded from the monograph.
FDA is proposing this change to add another procedural option that the
agency may use to speed up completion of a rulemaking.
Current Sec. 330.10(a)(10)(i) and (a)(10)(iii) establish procedures
for responding to requests for data and information to create an
administrative record for use in proceedings under this section. FDA is
proposing to add a new procedure for the submission of data by
inserting in Sec. 330.10(a)(10)(i) ``in response to any other notice
published in the Federal Register.'' FDA is proposing this change to
allow the agency to request data and information by publishing a notice
in the Federal Register in addition to the other procedures because the
agency may at times only consider one or more conditions to add to a
designated class of OTC drug products and may not have the data
reviewed and evaluated by an advisory review panel. FDA is proposing to
insert the same language in Sec. 330.10(a)(10)(iii) to correspond with
the change in Sec. 330.10(a)(10)(i).
Current Sec. 330.13 describes conditions for marketing ingredients
recommended for OTC use under the OTC drug review. The agency is adding
new paragraph (e) to Sec. 330.13 to state that it applies only to
conditions under consideration as part of the OTC drug review initiated
on May 11, 1972, and evaluated under the procedures set forth in
Sec. 330.10. Section 330.14(h) will apply to the marketing of all
conditions under consideration using the additional criteria and
procedures set forth in Sec. 330.14.

III. Comments on the ANPRM

Sixteen comments were submitted in response to the ANPRM. Those
comments and the agency's responses are summarized below.

[[Page 71068]]

A. Comments Related to Eligibility Criteria

1. Several comments agreed that the countries listed under section
802(b)(1) of the act (21 U.S.C. 382(b)(1)) are appropriate for
obtaining relevant OTC marketing experience because their regulatory
systems are at a level of sophistication similar to the system in the
United States. Other comments opposed limiting marketing experience
solely to these countries. One comment considered limiting marketing
experience from select countries listed in the act for other purposes
to be arbitrary. Another comment contended that it is the quality of
the information, not the source, that should be controlling. Several
comments contended that the proposed eligibility criteria should not
limit marketing experience to that derived from Western European
cultures. The comments stated that if valid data are available from a
foreign source to make a determination of safe and effective use, those
data should be accepted for consideration into the OTC drug monograph
system, regardless of the particular country or countries involved. One
comment added that while marketing in the section 802(b)(1) of the act
countries is usually well defined, marketing in Latin America and much
of Asia is increasingly as sophisticated.
One comment suggested that any country adopting and using the
International Conference on Harmonization (ICH) format, criteria, and
guidelines for ADE reporting and premarketing approval (NDA) safety
documentation be considered for inclusion into section 802(b)(1) of the
act. Another comment suggested that if any new countries are added to
section 802(b)(1) of the act, marketing from these countries should
automatically become acceptable for obtaining relevant OTC marketing
experience.
The agency believes that conditions with relevant OTC marketing
experience in section 802(b)(1) of the act countries would be more
likely to succeed in meeting the criteria for consideration in the OTC
drug monograph system because the marketing experience would be more
like that in the United States and because the regulatory systems in
those countries are similar to those in the United States. Similar
marketing experience and regulatory controls should provide the agency
more comparable information on which to base decisions.
Nonetheless, at this time, the agency sees no reason to limit
marketing experience solely to section 802(b)(1) of the act countries.
If manufacturers can provide the type of data described in
Sec. 330.14(c) from any foreign country, the agency will consider these
data in making an eligibility determination.
2. Several comments stated that foreign marketing experience from
the class of nonprescription drugs sold only in a pharmacy, with or
without the personal involvement of a pharmacist, should qualify as OTC
marketing. The comments contended that such experience is analogous to
OTC drug marketing in the United States and that ingredients such as
aspirin, acetaminophen, benzoyl peroxide, doxylamine, ibuprofen, and
loperamide, for example, are all restricted to pharmacy-only sales in
Europe. Several comments noted that a number of countries restrict some
or all nonprescription drug products to pharmacy-only sales. Some
comments suggested that the agency is misguided in its understanding of
how drugs are distributed abroad. One of the comments pointed out that
the determination of channels of distribution for OTC drugs largely
differs in various countries because of different medical and
pharmaceutical traditions. Another comment noted that the class of
nonprescription drugs distributed for pharmacy-only sale, with or
without the personal involvement of a pharmacist, is used for economic
and cultural reasons and has become a method of protecting pharmacy
competition, not a method of enhancing the public health. Some comments
noted that in countries where OTC drug products are restricted to sale
in pharmacies, sale of a drug product rarely involves actual advice and
counsel by a pharmacist. One comment contended that the words
``prescription,'' ``OTC,'' and ``third class of drugs'' may describe
different concepts from country to country. The comment concluded that
the agency should not exclude data on foreign marketing experience on
the basis of such artificial categories.
The agency recognizes that a number of countries have a class of
nonprescription drugs required to be sold only in pharmacies with or
without the personal involvement of a pharmacist, and that the reasons
for this class of drugs may vary from country to country. The agency is
concerned when this restriction is deemed necessary because a
particular country considers intervention by a health professional
necessary. While the agency has determined that it will consider
marketing experience from this class of pharmacy-only sales, the
sponsor needs to establish that this marketing restriction in a
particular country does not indicate safety concerns about the
condition's toxicity or other potentiality for harmful effect, the
method of its use, or the collateral measures necessary to its use.
3. A number of comments stated that foreign cosmetic marketing
experience should be accepted to support eligibility of marketing to a
material extent and for a material time if the products are marketed in
the United States as OTC drugs. Several comments noted that many
topical product categories, for example, sunscreen, antiperspirant,
dental, antidandruff, hair growth stimulants, and skin protectants, are
regulated as cosmetics in Europe but classified as drugs in the United
States. Two comments added that direct-to-consumer marketing of
cosmetic products in foreign countries is substantially
indistinguishable from OTC drug marketing in the United States and
should be acceptable to satisfy the material extent/time requirements.
One comment stated that the agency should consider dietary supplement
marketing histories during the safety and effectiveness determination
process. One comment argued that the statutory language and legislative
history of section 201(p)(2) of the act do not limit ``use to a
material extent and for a material time'' to use solely from products
regulated as OTC drugs. The comment concluded that such a regulatory
limitation would be in excess of the agency's grant of authority under
the act and, therefore, in violation of the Administrative Procedure
Act (APA).
The agency is aware that certain conditions regulated as OTC drugs
in the United States may be regulated differently (e.g., as cosmetics
or dietary supplements) in foreign countries. The agency does not wish
to exclude these OTC conditions from consideration for inclusion in the
OTC drug monograph system simply because they are regulated differently
in various countries. When making an eligibility determination, the
agency will consider any OTC condition that would be regulated as an
OTC drug in the United States.
4. Three comments maintained that the agency should recognize the
low level of risk associated with topically applied foreign OTC
products and have more moderate regulatory requirements for these
products in order to accelerate their availability in accordance with
public health care needs. One comment argued that 5 years of marketing
to demonstrate material time for topically applied foreign OTC products
should automatically qualify them to be

[[Page 71069]]

marketed to a material extent. Another comment requested priority for
products regulated as cosmetics in Europe if a final rule is not
forthcoming in the immediate future.
The agency disagrees with the comments' suggestions. The agency
does not find that there is automatically a low level of risk
associated with products just because they are applied topically. The
agency has identified concerns with a number of topically applied OTC
active ingredients (e.g., benzoyl peroxide, coal tar, diphenhydramine,
hydroquinone). While these concerns have not prevented OTC marketing,
they do not allow for more moderate regulatory requirements or
accelerated consideration of these conditions. Similarly, marketing of
a topically applied foreign OTC product for 5 years or more does not
assure that it has been marketed to a material extent nor that problems
may not arise or exist. Some of the problems encountered with benzoyl
peroxide, diphenhydramine, and hydroquinone became apparent only after
years of OTC marketing in the United States. Therefore, the agency sees
no reason to give priority specifically to topical products.
5. One comment requested clarification regarding the nature of
marketing experience, including: (1) Whether a condition marketed OTC
in one or more foreign countries would be deemed ineligible because of
prescription marketing in other foreign countries, and (2) the agency's
statement that it is ``essential that any prescription drug have some
U.S. marketing experience before its OTC marketing is permitted in this
country'' under an OTC drug monograph. The comment was concerned that
the agency intends to disqualify foreign prescription drugs from OTC
marketing in the United States under an NDA.
The fact that a condition is prescription in some foreign countries
and OTC in others does not preclude its consideration for OTC status in
the United States. In order to be considered in the OTC drug monograph
system under this proposal, a condition would have to be marketed for
OTC purchase in at least one country for a material extent and to a
material time. However, broad OTC marketing experience in many
different ethnic, cultural, and racial populations would help ensure
that an adequate safety profile exists. The agency is proposing to
require that sponsors provide a list of all countries where the
condition is marketed as a prescription drug and a description of the
reasons why the condition is not marketed OTC in these countries. This
information would enable the agency to notify sponsors beforehand if
specific safety data may be required in order to demonstrate that a
condition is appropriate for marketing in the United States under an
OTC drug monograph.
Concerning the comment that the agency intends to exclude foreign
prescription drugs from switching to OTC in the United States under an
NDA, this rulemaking does not prohibit or otherwise affect submission
of an NDA for OTC marketing of a foreign prescription drug.
6. A number of comments agreed with the proposed 5-year minimum
requirement to satisfy marketing for a material time. Two comments
urged that the 5-year minimum marketing period be used as a guideline
and not as a rigid requirement. The comments believed that 5 years of
marketing would often be unnecessarily long for a condition whose
extent of distribution is substantial. One comment stated that it was
Congress' intent that a combination of total exposure from breadth and
length of marketing provide assurance that the product is suitable for
old drug status. The comment concluded that a mandatory minimum
marketing period could be overly restrictive, particularly for OTC
products that are used for limited treatment periods. One comment
believed that a condition should be evaluated on the basis of the
quality of data rather than on an arbitrary minimum 5-year marketing
standard.
The agency has determined that the condition must be marketed both
for a sufficient time and to a sufficient extent to detect infrequent
but serious ADE's. Based on its experience with post marketing
surveillance spontaneous reporting systems, the agency proposes that a
minimum of 5 years of OTC marketing experience should be required to
provide an appropriate margin of safety to ensure that marketing is of
sufficient duration to detect infrequent but serious ADE's that are
occurring. Additional parameters will be used to assess whether a
condition has been marketed to a material extent (see proposed
Sec. 330.14(c)(3)(ii), (c)(2)(iii), and (c)(2)(iv)).
7. A number of comments agreed with the six proposed factors for
determining marketing to a material extent. These proposed factors were
as follows: (1) Number of dosage units sold; (2) number and types of
ADE reports, and the requirements of the reporting system; (3) risks
and consequences associated with the therapeutic category and
indication; (4) use pattern (frequency: Occasional, acute, chronic);
(5) potential toxicity (including dosage form and route of
administration); and (6) history of use (i.e., use indications and
exposures, including their toxicities). One comment stated that the
third and fourth factors should only be applicable if an ingredient has
been used for an indication that is not currently covered by the OTC
drug monograph system. The comment claimed that the agency has made
these assessments for indications already included in OTC drug
monographs. The comment also stated that the fifth and sixth factors
should be combined into a single factor. The comment contended that the
agency has no need to review potential toxicity issues because it will
be able to review actual toxicity based on widespread historical use.
The comment recommended the creation of an additional factor, ``other
general safety information.'' The comment stated that this factor could
include safety information other than ADE reports, such as prescription
ADE reports and consumer complaints regarding safety issues.
The agency has determined that certain of these factors pertain
more directly to an evaluation of safety than to the determination of
material extent and has decided to remove them from the list of factors
used to determine material extent. The number and types of ADE reports,
the risks and consequences associated with the condition, and toxicity
information will now be addressed as part of the safety evaluation
under proposed Sec. 330.14(f). The agency is including the number of
dosage units sold, the description of the ADE reporting system, the use
pattern, and the history of use as part of the material extent
determination. The number of dosage units sold is necessary to
demonstrate if the condition's extent of use is sufficient to detect
infrequent but serious ADE's that are occurring. The description of the
ADE system is necessary to assess the ability of the system to detect
ADE reports. Use pattern is necessary to determine if a product's use
is different in other countries than it would be in the United States.
Use indications and exposures are important to determine the scope of
the condition's use.
8. Several comments stated that section 201(p)(2) of the act
provides that an ingredient be used to a material extent or for a
material time. The comments contended that the agency misinterprets the
statutory language by requiring that a condition be marketed for both a
material extent and a material time. These comments suggested that
sponsors be granted the alternative of either complying with the
material

[[Page 71070]]

extent or the material time criterion. Another comment disagreed with
the approach of material extent and material time being two distinct
entities. The comment recommended that a formula be developed that
considers marketing to a material extent over marketing for a material
time in order not to exclude an important health care solution based on
marketing time alone. Two comments suggested that if a condition could
only meet either the material extent or the material time criterion, a
more stringent requirement to establish either material extent or
material time be employed to compensate for the condition not meeting
both criteria (e.g., require 10 years to demonstrate marketing for a
material time instead of 5 years).
Section 201(p) of the act defines ``new drug'' as:
(1) Any drug * * * the composition of which is such that such
drug is not generally recognized, among [qualified] experts * * * as
safe and effective for use under the conditions prescribed,
recommended, or suggested in the labeling * * *; or
(2) Any drug * * * the composition of which is such that such
drug * * * has become so recognized, but which has not * * * been
used to a material extent or for a material time under such
conditions.
Section 201(p) of the act establishes two general parts to the
``new drug'' definition, joined by the conjunction ``or,'' both of
which must be satisfied to escape ``new drug'' status. Similarly,
within section 201(p)(2) of the act there are two criteria joined by
``or,'' both of which must also be satisfied to escape ``new drug''
status. As one appellate court has explained: ``Stated another way, a
drug is not a ``new drug,'' and is therefore exempt from regulation
under section [505(a)], only if such drug both (1) is generally
recognized, among [qualified] experts * * *, as safe and effective for
its labeled purposes; and (2) has been used to a material extent and
for a material time'' (United States v. Atropine Sulfate, 843 F.2d 860,
861-62 (5th Cir. 1988)). See USV Pharmaceutical Corp. v. Weinberger,
412 U.S. 655, 660 (1973) (definition of ``new drug'' includes ``one
that has not been used to a material extent and for a material time'').
This interpretation of section 201(p) of the act is also consistent
with the Supreme Court's directive that the ``new drug'' definition
must be liberally construed in order to effectuate the policy of the
act to protect the public health and safety (United States v. Article
of Drug * * * Bacto-Unidisk, 394 U.S. 784, 798 (1969)). Conversely, the
situations in which a drug product is not a ``new drug'' are to be
narrowly defined (Premo Pharmaceutical Laboratories, Inc. v. United
States, 629 F.2d 795, 802 (2d Cir. 1980)).
Permitting a drug to drop out of regulation as a ``new drug''
without satisfying both the material time and the material extent
prongs of section 201(p)(2) of the act would not satisfy the statute's
underlying public health protection goal. For example, marketing a few
units of a drug each year for many years would not provide enough
information to ensure that infrequent but serious ADE's had been
identified. Marketing many units of a drug for a very short period of
time would be similarly inadequate to detect safety problems.
Accordingly, the agency disagrees with the comments. A condition
that is considered ``not a new drug'' must satisfy both the material
extent and the material time criteria in section 201(p)(2) of the act.
9. A number of comments suggested that the eligibility criteria
should be flexible without rigid standards in specific areas. One
comment contended that very specific criteria would reduce the
eligibility of foreign marketing experience to an administrative
effort, which would eliminate good judgment from the process. One
comment contended that there should be no limitation on the type of
marketing experiences that can be submitted. The comment added that
sponsors should be permitted to provide evidence why the agency should
consider certain marketing experience to be relevant. One comment
stated that the agency should recognize that foreign marketing
experiences may have many facets that are not necessarily less valid
than those found in the United States. The comment contended that the
eligibility criteria should be designed to equally and strictly apply
to conditions that have been tested in a wide variety of foreign
marketing experiences. The comment concluded that a rating system
should be used, i.e., a low rating on one criterion could be
compensated by a high rating on another criterion. Two comments
suggested that the eligibility criteria be a guideline and not a rigid
regulatory requirement. One comment requested the agency to provide
specific eligibility criteria applicable to individual monographs
rather than establish arbitrary criteria that may be irrelevant to
particular categories of products.
The agency intends the proposed criteria and procedures to be a
regulatory framework within which additional conditions will be
evaluated for consideration in the OTC drug monograph system. The
criteria are intended to be general in nature and to provide the agency
flexibility and allow the use of judgment in evaluating eligibility
requests. While any marketing experience can be submitted, sponsors
will have to convince the agency that some experiences are relevant and
appropriate, even though different from U.S. marketing experience.
However, the agency intends to apply the criteria and use its judgment
in specific situations. The agency may well use its judgment to balance
a lower rating on some criteria with a higher rating on other criteria.
The agency sees no need to provide specific eligibility criteria for
each monograph. The agency considers the general criteria adequate and
appropriate for all of the OTC drug monographs. In conclusion, the
criteria and procedures provide a regulatory framework within which to
apply judgment and be flexible as appropriate and necessary in
considering additional conditions for inclusion in the OTC drug
monograph system.

B. Comments Related to Safety and Effectiveness Evaluation

10. A number of comments recognized the usefulness of assessing
ADE's that have occurred during marketing as an important element in
assessing the safety of a condition. Some comments added that the
existence of an ADE reporting system in a foreign country is a factor
in evaluating the relevance of the marketing experience, while several
comments suggested that the absence of a mandatory ADE reporting system
should not preclude a condition from being eligible in the OTC drug
monograph system. Several comments argued that the absence of a
mandatory ADE reporting system should not be determinative of safety,
but should be only one factor when determining eligibility. Two
comments stated that it is the reliability and scope of the ADE data
collection system that is important, not the form of availability.
Several comments noted that there is no mandatory ADE reporting system
currently in place for OTC drug products in the United States and the
OTC drug monograph system currently includes hundreds of ingredients
that have never been subject to mandatory ADE reporting. One comment
added that over a period exceeding 5 years, even in the absence of a
mandatory reporting system, serious safety problems would be identified
in European and other countries with adequate regulatory oversight and
sophisticated health care systems. The comment stated that literature
reports of experience in hospitals, poison control centers, clinical
studies, etc., and data from voluntary reporting channels

[[Page 71071]]

provide a mechanism for gathering sufficient information to determine
whether a serious safety problem exists. Several comments suggested
that mandatory ADE requirements for foreign marketed conditions would
establish a dual standard, with a more rigorous standard for evidence
of safety being placed on foreign marketed conditions than exists for
U.S. OTC drug products.
One comment mentioned that many U.S. OTC drug products are
regulated as cosmetics or dietary supplements in other countries and
would not be subject to ADE reporting requirements. Another comment
suggested that the agency should assess foreign ADE reporting systems
only after it has defined the parameters for a suitable OTC ADE
reporting system in the United States. Another comment suggested
listing elements of ADE reporting systems in order to generate an
overall rating of each country's monitoring system. Two comments stated
that it is unrealistic and unnecessary for the agency to require ADE
reports from every country where an ingredient is marketed. One comment
requested clarification of the term ``important'' ADE. One comment
claimed that due to sporadic or sparse marketing, not every country
will provide useful data. The other comment noted that some companies
market products in more than 100 countries and should only concentrate
on sophisticated countries with OTC sales. The comment supported a
requirement that sponsors provide all relevant and significant ADE's of
which they are aware. The comment noted, however, that in most
countries, a company is not authorized to obtain ADE reports for a
competitor's product.
One comment stated that the agency should only request ADE reports
associated with nonprescription drug marketing. Another comment
maintained that when the dosages are similar between prescription and
OTC drug uses, priority should be given to the collection of OTC ADE
reports. One comment stated that a contradiction exists between the
agency's acceptance of foreign prescription drugs' ADE reports and the
agency's belief that foreign marketing as a prescription drug should
not be part of the criteria for determining material extent and
material time.
The agency considers ADE information to be crucial in assessing the
safety of a condition for inclusion in an OTC drug monograph. The
agency acknowledges that a mandatory ADE reporting system for
monographed OTC drug products is currently not in place in the United
States, but the agency plans to propose the creation of such a system
in the near future. The agency is also aware that such a system does
not exist in many industrialized countries. Nonetheless, many countries
have a drug marketing approval process and a postmarketing surveillance
system that can identify ADE's. The system that exists needs to detect
ADE's that are occurring, i.e., both: (1) Serious ADE's and (2)
expected or frequently reported side effects for the condition. This
information enables the agency to assess the risks of using the
condition OTC and to label the product informatively for consumers.
As one comment mentioned, literature reports on experiences in
hospitals, poison control centers, clinical studies, and other similar
settings, plus data from voluntary reporting channels, provide
information for assessing a condition's safety. It will be the
sponsor's burden to provide this information to the agency to support
OTC safety. The agency points out that this type of information is
similar to the information manufacturers have routinely been requested
to submit for drugs evaluated under the OTC drug review. Safety
information under the OTC drug review procedures (Sec. 330.10(a)(2))
includes controlled studies, documented case reports, pertinent
marketing experiences that may influence a determination as to the
safety of each individual active ingredient, and pertinent medical and
scientific literature. Thus, this type of information is routinely
considered as part of the condition's safety evaluation.
The agency also considers it very important to have this ADE
information provided from every country where the condition is
marketed. This information will be helpful to address some of the
ethnic, cultural, and racial variances that may exist among users as
well as to provide a broad marketing background more relevant to the
U.S. population. The agency considers this information useful even from
countries with sporadic or sparse marketing, or where the condition has
been withdrawn. Therefore, the agency is requiring that sponsors
include all of this marketing experience as relevant information of
which they are aware. This requirement applies equally to conditions
regulated as cosmetics or dietary supplements in foreign countries, but
which would be regulated as OTC drug products in the United States. If
there is no mandatory ADE reporting system for such products in the
foreign country, the sponsor can still provide information from the
scientific literature and information obtained from voluntary reporting
channels. This would also include such information for a competitor's
product if available in the scientific literature or other public
sources (e.g., news articles, press releases).
The agency believes that prescription as well as OTC ADE reports
for the condition should be evaluated. Prescription ADE reports may
provide useful information to evaluate safety for U.S. marketing under
an OTC drug monograph. In addition, ADE reports associated with the
other doses (higher or lower) or different indications associated with
the product marketed as a prescription drug would be useful for
assessing the safety margin for OTC use. The agency finds no
contradiction in requesting prescription ADE reports for this purpose.
The agency sees no benefit in trying to rate each country's
monitoring system. As one comment noted, the reliability and scope of
the data are the important factor. Nor does the agency see a need to
wait until its OTC ADE reporting system for monographed OTC drugs is
fully defined. The type of ADE information the agency is requiring is
similar to the information manufacturers have routinely been requested
to submit for drugs evaluated under the OTC drug review.
The agency concludes that ADE information is a critical factor in
assessing the safety of a condition for inclusion in an OTC drug
monograph. However, the agency believes that ADE reports are more
appropriate as part of the assessment of safety, rather than as part of
establishing eligibility. The agency is proposing new Sec. 330.14(f)(2)
to require the submission of the following: (1) All serious ADE's, as
defined in Secs. 310.305 and 314.80, as elements of required ADE
reporting to support a foreign condition's safety, and (2) expected or
frequently reported side effects that may be important for consumer
product labeling.
11. Several comments objected to the agency's position that foreign
marketing exposure would have to be described sufficiently to ensure
that the condition can be reasonably extrapolated to the U.S.
population. Some comments contended that, because the United States has
a wide range of ethnic, cultural, racial, and foreign populations
comparable to many countries, it is improper and unjustified to
emphasize the comparability of foreign and U.S. populations as a
determinate factor. One comment noted that it is usually assumed
(absent unusual circumstances) that any drug, whether marketed in the
United States under an NDA or OTC drug monograph, is suitable for use
by the entire population.

[[Page 71072]]

Several comments added that the agency has never solicited race,
gender, or ethnicity marketing information for a condition in the OTC
drug review, nor is there a requirement under an NDA for testing a
condition in any particular demographic group. One comment suggested
that for the agency to determine that foreign products in general and
European products in particular present some significant cultural risk
would be an unlawful nontariff trade barrier in violation of the
General Agreement on Tariffs and Trade (GATT) and the North American
Free Trade Agreement (NAFTA). Another comment mentioned that marketing
in Latin America and much of Asia is also very relevant. Two comments
stated that they would support less rigid requirements. One of these
comments supported a requirement that companies disclose any concerns
they are aware of regarding medical, cultural, or genetic issues.
The agency recognizes that the United States has a wide range of
ethnic, cultural, racial, and foreign populations. The agency believes
that when a condition is included in an OTC drug monograph, there
should have been broad OTC marketing experience in many different
ethnic, cultural, and racial populations to assure that a sufficient
profile of the condition exists. For example, a sunscreen drug product
with a marketing history only in a Latin American country may not have
a sufficient marketing history to allow extrapolation to the full range
of skin types of the U.S. population. Likewise, an antacid, cholesterol
lowering drug, or vaginal contraceptive with marketing experience only
in an Asian country may not have a sufficient profile for extrapolation
to the entire U.S. population because of dietary and cultural
differences between the countries' populations.
While the agency may not routinely solicit race, gender, or
ethnicity ``marketing'' information for a drug in the OTC drug review,
the agency considers this one of the parameters that appropriately can
be assessed to evaluate material extent. The agency has considered this
parameter in developing certain OTC drug monographs. For example,
issues related to unique racial characteristics have arisen in
considering OTC skin bleaching drug products. In evaluating a protocol
for a plaster dosage form containing counterirritant ingredients, which
had a marketing history primarily in an Asian population, the agency
informed the manufacturer that skin from subjects with different ethnic
backgrounds should be studied. The agency stated that as much data as
possible was needed to provide support for the product, and the
protocol should include a diverse population regarding age, sex, and
race (Ref. 1).
In conclusion, the agency considers it important that OTC foreign
marketing experience be relevant to populations targeted for marketing
in the United States. Therefore, the agency is requiring that, as part
of the TEA, sponsors sufficiently describe the condition's foreign
marketing experience to fully support extrapolation to U.S.-targeted
populations. Sponsors may use the categories and definitions in The
Office of Management and Budget's Federal Register notice, titled
``Revisions to the Standards for the Classification of Federal Data on
Race and Ethnicity.'' The notice identifies six combined racial and
ethnic categories (1. American Indian or Alaska Native, 2. Asian, 3.
Black or African American, 4. Hispanic or Latino, 5. Native Hawaiian or
Other Pacific Islander, and 6. White (62 FR 58781, October 30, 1997)).

C. Comments on Administrative Procedures

12. Several comments supported the agency's proposed two-step
application process. One comment requested clarification on several
aspects of the process: (1) Who within the agency would be responsible
for reviewing the eligibility submission, (2) the content and format
for eligibility and data submissions, and (3) the agency's regulatory
timeline for reviewing submissions. Several comments requested the
agency to establish regulatory timelines for each step of the review
process. Three comments recommended that the agency establish a 90-day
time period for the review of eligibility data. Two comments requested
that this time period be 120 days. Three comments recommended that the
agency establish a 1-year timeline for reviewing safety and efficacy
data. Two comments requested that, within the review periods, the
agency give regulatory priority to conditions that uniquely meet
Americans' health needs.
The agency's Division of OTC Drug Products will be responsible for
evaluating all TEA's. The agency does not anticipate establishing
specific timelines for the review of the TEA or data submissions for
safety and effectiveness due to differences that may exist in the
quantity and quality of submissions. The agency is concerned that, in
the initial period of time following the publication of a final rule,
there may be substantial numbers of submissions that will require
handling and evaluation by the agency. The agency considers it
desirable to implement procedures that will streamline this process to
ensure that agency resources are used appropriately and result in
timely action on submissions.
In reviewing data submissions on safety and effectiveness, the
agency intends to use both internal and external resources, as
appropriate. The agency may request submission of data and information
for conditions in specific pharmacological classes (e.g., drug
categories listed in Sec. 330.5) and/or certain indications during
specified time periods so that an entire class of conditions (e.g.,
foreign sunscreen ingredients) can be reviewed at one time. The agency
believes that there may be other options for streamlining this review
process and invites specific comments on these matters.
13. One comment urged the agency to combine its two-step
application process into one unified process. The comment contended
that each of the two steps involves consideration of the same
information and, therefore, should be combined. The comment concluded
that a two-step application process would take twice as long as a
single simplified process. One comment objected that the agency had not
sufficiently distinguished between the eligibility of drug conditions
for inclusion in the OTC drug monograph system and the evaluation of
whether such conditions are GRAS/E. The comment argued that the initial
eligibility determination should not intrude on the separate safety and
effectiveness evaluation.
Another comment contended that FDA's proposed eligibility process
is inconsistent with the statutory language of section 201(p) of the
act. The comment argued that section 201(p)(1) and (p)(2) of the act
provides two independent criteria for finding that a product is not a
new drug, but that the agency's proposal makes the material extent and
material time criteria of section 201(p)(2) of the act part of the
safety and effectiveness requirement of section 201(p)(1) of the act.
The comment added that FDA's proposal prevents separate and independent
consideration by interpreting the material extent and material time
requirements to be evaluated by data that relate properly to the safety
of the product. The comment contended that FDA's proposed procedure
uses the material extent and material time requirement as an initial
screen to exclude drugs from the OTC drug monograph system. The comment

[[Page 71073]]

contended that this interpretation of the act is unsupported by the
plain language, judicial interpretations, or legislative history of the
act, and the agency's past and current OTC drug review practices. The
comment concluded that the agency's approach results in arbitrary and
capricious action under the APA (5 U.S.C. 706(2)(A)).
The agency believes that a two-step application process is the most
efficient and appropriate method for it to determine whether a
condition is acceptable for inclusion in the OTC drug monograph system.
The agency is proposing this two-step approach to: (1) Prevent sponsors
from incurring unnecessary costs for developing safety and
effectiveness data for a condition that may not meet basic eligibility
requirements, (2) avoid expending agency resources evaluating safety
and effectiveness data for a condition that does not meet the basic
eligibility criteria, and (3) provide all interested parties an
opportunity to submit safety and effectiveness data and information.
Based on the comments and a consideration of the options raised in
the ANPRM, the agency has decided that a number of the criteria
initially proposed as part of an eligibility determination should now
be part of the safety determination (see section III.A, comment 8 of
this document). The agency believes that this approach would provide
for a separate and expedited consideration of both elements and would
not result in a protracted process.
14. One comment requested that the agency make all positive
eligibility determinations publicly available so that all interested
parties would have a chance to submit safety and effectiveness data and
information.
The agency agrees with this comment. If the condition is found
eligible, the agency will publish a notice of eligibility in the
Federal Register and provide the sponsor and other interested parties
an opportunity to submit data to demonstrate safety and effectiveness.
15. Two comments stated that once the agency determines that a
condition is GRAS/E, it should be incorporated into a new or existing
monograph by the proposed rule/final rule publication procedure in the
Federal Register. One comment contended that the original three-step
publication procedure (i.e., advance notice of proposed rulemaking,
tentative final monograph, final monograph) used in the OTC drug review
is no longer justified due to the absence of advisory review panels.
The comment concluded that in this case where FDA would be making a
safety and effectiveness determination, a two-step procedure would be
sufficient and appropriate.
The agency generally agrees with the comments that the original
three-step publication process is no longer needed to make a
determination that an additional condition being added to the OTC drug
monograph system is GRAS/E. However, the agency may use outside experts
as part of the review process. These experts could review the safety
and effectiveness data and provide recommendations to the agency. The
agency will make those independent recommendations public by placing
them in the docket, evaluate the data and recommendations, and then
publish a notice in the Federal Register. The agency may elect to
expedite the review process by evaluating the data in conjunction with
the advisory review panel or outside experts. If the agency concurs
with the experts' recommendations to include a condition in a
monograph, the agency will publish a notice of proposed rulemaking to
amend an existing monograph(s) or create a new monograph(s).
If the agency agrees with the experts' recommendation not to
include a condition in a monograph, it will inform interested parties
by letter and place a copy in the Dockets Management Branch.
Subsequently, the agency will publish a notice of proposed rulemaking
in the Federal Register providing a summary of the experts'
recommendations and proposing to include the condition in Sec. 310.502.
The agency will provide interested parties an opportunity to submit
comments and new data, and will subsequently publish a final rule in
the Federal Register.
In conclusion, the agency generally intends to use a two-step
publication process for conditions that are evaluated under this
notice. However, the agency may elect to publish an ANPRM to obtain
public comment before publishing an actual notice of proposed
rulemaking (see Sec. 10.40(f)(3)).

D. Comments on Marketing Policy

16. Several comments objected to the agency's proposed marketing
policy. The comments stated that interim marketing should be authorized
after the agency determines a condition is eligible for consideration
in the OTC drug monograph system. One comment contended that similar
standards in the ``rush to market rule,'' codified in Sec. 330.13,
should apply for foreign OTC drugs and products. The comment noted that
this rule allowed OTC drug ingredients that were lawfully marketed
before May 11, 1972, in the United States to be marketed prior to a
final evaluation by the agency. Two comments contended that the
agency's proposed marketing policy was inconsistent with its current
policy permitting the marketing of Category III (more safety and/or
effectiveness data needed) conditions that have insufficient evidence
of safety or effectiveness. Two comments stated that the agency's
proposed marketing policy was inconsistent with its initiatives to
harmonize drug regulations by creating an unfavorable bias towards
foreign products. Two comments argued that by accepting 5 years of
marketing experience from countries listed in the Export Reform Act of
1996 (Public Law 104-134), the agency should trust that the exposure to
unnecessary risk would be minimal, thereby alleviating the need for a
different interim marketing policy for foreign products. One comment
disagreed with the agency statement that allowing any condition to be
marketed before it was evaluated for safety and effectiveness would
subject the public to ``unnecessary risk.'' The comment contended that
the minimum level of risk for many products, in particular topical and
sunscreen drug products, does not support a blanket prohibition of
interim marketing based on risk. The comment argued that there is no
scientific or legal justification for such an approach. The comment
noted that skin cancer is a serious and growing health problem, and
risks of keeping new sunscreen products from the American public
outweigh the risk of making them available. The comment recommended
that the agency adopt a more flexible interim marketing policy that
recognizes the low-level risks of certain therapeutic categories/
conditions.
The agency's proposed marketing policy in Sec. 330.14(h) would
allow marketing only after a condition is included in an applicable
final OTC drug monograph(s). Many of the conditions that may be
submitted will not have been marketed previously to the U.S.
population. Therefore, the agency considers it important that there be
thorough public consideration of any safety and effectiveness issues
that might arise before marketing begins. Interested parties and
persons with specific knowledge about the condition may offer useful
comments and suggestions regarding the OTC marketing of the condition.
If there are controversial issues regarding OTC status, the agency does
not want interim marketing to occur while these issues are being
resolved. If there are no controversial issues, then the period of time
between the proposal and the final

[[Page 71074]]

rule to add a condition to a monograph will generally be short.
For reasons stated above, the agency is not using the marketing
policy in Secs. 330.13 and 330.10(a)(6)(iv) (Category III conditions)
for additional conditions to be considered for inclusion in the OTC
drug monograph system. These sections were intended to apply to active
ingredients marketed in the United States prior to the beginning of the
OTC drug review. The current proposal applies to OTC drugs initially
marketed in the United States after the OTC drug review began in 1972
and OTC drugs without any U.S. marketing experience.
The agency acknowledges that some ingredients may have what some
people consider a minimal level of risk. As discussed earlier, many
topical conditions raise concerns that require agency evaluation before
marketing may begin. In some cases, special conditions (e.g., label
warnings) may be necessary for marketing. In the case of sunscreens,
the agency has evaluated substantial safety data (e.g., primary
irritation potential, phototoxicity, photosensitization) before
proposing several sunscreen ingredients for inclusion in the sunscreen
monograph. Thus, the agency has determined that topical and sunscreen
drug products should not qualify for a different status based on the
nature of the products.

E. Comments on Compendial Monograph Requirements

17. Several comments stated that the agency should recognize all
national and international compendia. One comment interpreted
``official compendia'' to mean not only the USP, but also the European
Pharmacopeia and pharmacopeias from the export countries identified in
section 802(b)(1) of the act. Another comment expressed concern that
the USP may be delayed in establishing herbal monographs due to the
chemical complexity of plant ingredients. The comment suggested that
the agency accept a compendial monograph from the European Pharmacopeia
or pharmacopeias from the export countries as long as the development
of a USP monograph is being pursued. One comment stated that requiring
only single ingredients to be recognized in an official compendium
would be too narrow an approach.
The proposed rule would require an official USP-NF drug monograph
for the active ingredient(s) or botanical drug substance(s). These
compendia recognize monographs for both single ingredient and botanical
products where appropriate. Although the USP-NF does not presently
recognize foreign compendial monographs, it does review foreign
compendial monographs on a case-by-case basis to determine if they can
be used in developing a USP-NF monograph. However, the agency would not
recognize a foreign compendial monograph until USP-NF determined it was
acceptable and incorporated it into an official drug monograph.
The USP-NF is currently taking steps to facilitate international
commerce and product registrations. USP-NF recently proposed a new
general chapter 13, ``Concordance of Foreign Pharmacopeial Tests and
Assays'' (Ref. 2). This chapter would allow alternative tests and
assays established by the European Pharmacopeia and the Pharmacopeia of
Japan to demonstrate that an article meets USP standards. As
international harmonization progresses, USP states that it will also
consider the applicability of other pharmacopeias. The agency notes
that while the USP proposal rests on a presumption that articles of
acceptable quality can emerge where they are produced in accordance
with recognized principles of good manufacturing practice and foreign
official methods of analysis, USP requires that its General Committee
of Revision examine each test or assay with a view to acceptable
concordance with the USP test or assay. USP also cautions that these
individual determinations of concordance are made solely and
independently by USP; no corresponding provision or lack thereof by
another pharmacopeia is to be presumed (Ref. 2).
18. Two comments objected to the agency's requirement that a USP
monograph be in place before FDA allows any interim marketing. The
comments stated that a USP monograph should be in place at the time an
OTC drug final monograph is completed.
As discussed in section III.D, comment 16 of this document, the
agency is not proposing to allow any interim marketing. The agency
agrees that a compendial monograph should be in place when an
ingredient is included in a final monograph. It has been agency policy
since April 3, 1989 (54 FR 13480 at 13486) that before any ingredient
is included in a final OTC drug monograph, it must have a compendial
monograph. That monograph sets forth the identity, strength, quality,
and purity of the drug substance and drug products made from the drug
substance and would include, for example, specifications relating to
stability, sterility, particle size, crystalline form, and analytical
methods. If necessary, the agency will require additional compendial
standard criteria in the OTC drug final monograph based on the data
that support generally recognized safe and effective status. A
compendial monograph helps ensure that OTC drug products contain
ingredients that are equivalent to active ingredients or botanical drug
substance(s) included in OTC drug monographs. This requirement will
also encourage interested sponsors to work with USP to develop a
compendial monograph as expeditiously as possible.

F. General Comments

19. One comment urged the agency to issue a final rule, rather than
a proposed rule, as the next step in this rulemaking. The comment
stated that there had been a considerable delay since it submitted its
petition, and contended there is no legal requirement or administrative
need for FDA to first issue a proposed rule. The comment concluded that
if FDA issues a proposed rule, it should provide a 60-day comment
period and issue a final rule within 120 days. Another comment urged
the agency to move forward promptly on this rulemaking and to begin
accepting petitions for additional conditions in the OTC drug monograph
system upon publication of the proposed rule.
The agency disagrees with the comments' suggestions. In order to
solicit a broad range of comments on the approach FDA was considering
on eligibility for consideration under the OTC drug monograph system,
the agency published an ANPRM. Under the agency's procedural
regulations in Sec. 10.40(f)(3), FDA may publish an ANPRM to request
information and views on a matter from the public before it decides to
publish a proposed rule. Having considered the comments submitted in
response to this ANPRM, the agency believes it is now appropriate to
propose specific revisions to the codified text of its current OTC drug
monograph system regulations and to solicit comments on these specific
revisions. The agency is providing a 90-day comment period, rather than
the 60 days as suggested by the comment, because it anticipates that
most interested parties will want a longer period of time to respond to
the criteria and procedures proposed in this document, and the agency
wishes to avoid requests for an extension of the comment period.
The agency also disagrees that it would be efficient to begin
accepting petitions for additional conditions upon publication of the
proposed rule. FDA's consideration of the comments in response to this
proposed rule may result in changes to the proposed requirements.
Encouraging submissions following the proposal before the final

[[Page 71075]]

rule issues may result in considerable wasted and inefficient efforts
by sponsors and by agency employees. The agency intends to move
expeditiously to consider the comments and develop a final rule after
the close of the comment period.
20. One comment requested clarification whether the final
regulation would apply to the review of any condition proposed for
inclusion in a final, pending, or newly proposed OTC drug monograph.
The comment stated that this approach would ensure that a condition
currently being considered for inclusion in an OTC drug monograph will
be reviewed by the same standards as a condition reviewed after
finalization of the proposed rulemaking. Another comment asked the
agency to confirm that it will consider ingredients marketed in foreign
countries for OTC indications that are not currently covered by
existing OTC drug monographs.
This rulemaking addresses how OTC marketing experience in the
United States or other countries could be used to qualify additional
conditions for consideration under the OTC drug monograph system. Once
found eligible, whether for a final, pending, or newly proposed OTC
drug monograph, the condition will be reviewed using the same OTC drug
standards in Sec. 330.10(a)(4) that have been used throughout the OTC
drug review process. The agency has included such a provision in
proposed Sec. 330.14(g). Conditions not covered by existing OTC drug
monographs will be considered under this proposal.
21. One comment noted that the agency did not differentiate between
the various dosage forms under its definition of ``conditions.'' The
comment stated that it interpreted ``dosage form'' to mean that
immediate-release, solid oral dosage forms (e.g., tablets) and liquid
oral dosage forms (e.g., drops or syrups) were grouped together, with
no further differentiation being made. Another comment contended that
if an ingredient intended for oral ingestion is approved for marketing,
manufacturers should be able to include the ingredient in a variety of
oral, immediate-release dosage forms, such as, tablets, capsules, or
liquids. The comment added that the same principle should apply to
topical ingredients. The comment mentioned that when the agency
evaluates ingredient eligibility, it should not require 5 years of
marketing for each dosage form.
Most OTC drug monographs do not limit the dosage forms for listed
ingredients. One exception is timed-release formulations. These
products are regulated as new drugs under Sec. 310.502(a)(14). In some
cases, there are other reasons to limit allowable dosage forms or
dosage forms that have specific requirements. For example, the agency
discussed dosage forms (vehicles) for topical drug products when it
amended the external analgesic tentative final monograph to include 1
percent hydrocortisone (55 FR 6932 at 6947 and 6948, February 27,
1990). The agency expressed concerns about 1 percent hydrocortisone
being incorporated into a dosage form that would increase absorption
through the skin, thus creating the possibility of an increased safety
risk.
While most OTC drug monographs will not limit dosage forms, there
may be specific situations where it is necessary to require 5 years of
marketing experience for a novel or special dosage form.

IV. Legal Authority

FDA's proposal to amend its regulations to include criteria for
additional conditions and procedures for classifying OTC drugs as GRAS/
E and not misbranded is authorized by the act. Since the passage of the
act in 1938, submission of an NDA has been required before marketing a
new drug (section 505 of the act (21 U.S.C. 355)). Section 201(p) of
the act defines a new drug as:
(1) Any drug * * * the composition of which is such that such
drug is not generally recognized, among experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, as safe and effective for use under the
conditions prescribed, recommended, or suggested in the labeling
thereof, * * *; or
(2) Any drug * * * the composition of which is such that such
drug, as a result of investigations to determine its safety and
effectiveness for use under such conditions, has become so
recognized, but which has not, otherwise than in such
investigations, been used to a material extent or for a material
time under such conditions.
To market a new drug, an NDA must be submitted to, and approved by, FDA
before marketing. Only drugs that are not new drugs may be covered by
an OTC drug monograph. Section 701(a) of the act (21 U.S.C. 371(a))
authorizes FDA to issue regulations for the efficient enforcement of
the act. Under part 330, FDA's regulations outline the requirements for
OTC human drugs that are GRAS/E and not misbranded. Proposed
Sec. 330.14 adds additional requirements.

V. Proposed Implementation Plan

FDA proposes that any final rule that may issue based on this
proposal become effective 30 days after its date of publication in the
Federal Register. After that date, the agency will begin accepting
TEA's.

VI. Requests for Comments

Interested persons may, on or before March 22, 2000, submit to the
Dockets Management Branch (address above) written comments regarding
this proposal. Written comments on the information collection
requirements may, on or before January 19, 2000, be submitted by
interested persons to the Office of Information and Regulatory Affairs,
OMB (address above). Three copies of all comments are to be submitted,
except that individuals may submit one copy. Comments are to be
identified with the docket number found in brackets in the heading of
this document and may be accompanied by a supporting memorandum or
brief. Written comments received regarding this proposal may be seen by
interested persons in the Dockets Management Branch between 9 a.m. and
4 p.m., Monday through Friday.

VII. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (2 U.S.C. 1501 et seq.).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; and distributive impacts and equity). Unless an agency
certifies that a rule will not have a significant economic impact on a
substantial number of small entities, the Regulatory Flexibility Act
requires an analysis of regulatory options that would minimize any
significant economic impact of a rule on small entities. The Unfunded
Mandates Reform Act requires that agencies prepare an assessment of
anticipated costs and benefits before proposing any rule that may
result in an expenditure in any one year by State, local, and tribal
governments, in the aggregate, or by the private sector, of $100
million (adjusted annually for inflation).
The agency believes that this rule is consistent with the
pronciples set out in the Executive Order and in these two statutes.
OMB has determined that the proposed rule is a significant regulatory
action as defined by the Executive Order and so is subject to review.
Because this rule does not impose any mandates on

[[Page 71076]]

State, local, or tribal governments, it is not a significant regulatory
action under the Unfunded Mandates Reform Act. Although the agency does
not believe that this rule will have a significant economic impact on a
substantial number of small entities, there is some uncertainty with
respect to the estimated future impact. Thus, a regulatory flexibility
analysis is presented below.

A. Regulatory Benefits

The purpose of the proposed rule is to establish criteria and
procedures for classifying OTC drugs as GRAS/E and not misbranded.
Currently, a sponsor wishing to introduce into the United States an OTC
drug condition marketed solely in a foreign country must prepare and
submit an NDA. Likewise, companies with OTC drugs initially marketed in
the United States after the 1972 initiation of the OTC drug review must
have an NDA. This proposed rule provides procedures for these NDA drugs
to become eligible for inclusion in the OTC drug monograph system by
first submitting a TEA to show marketing ``to a material extent'' and
``for a material time.'' Once determined eligible, safety and effective
data would be submitted and evaluated. The agency is proposing the two-
step process to allow sponsors to demonstrate that eligibility criteria
are met prior to requiring the expenditure of resources to prepare
safety and effectiveness data.
The flexibility to obtain U.S. marketing approval through FDA's OTC
drug monograph system will provide an overall net benefit to the
companies seeking these approvals, as well as to the American public.
One important benefit to sponsoring companies would be the saving of
NDA user fees. The Prescription Drug User Fee Act (section 736 of the
act (21 U.S.C. 379h)) requires a one-time application fee for each NDA
submitted, and yearly product and establishment fees, as applicable,
for each NDA approved. In 1998, these fees were $256,846 (applications
with clinical data), $18,591, and $141,966 respectively. Therefore,
one-time user fees of $256,846, and ongoing fees of up to $160,557
($18,591 + $141,966) would be avoided if the company can establish that
the condition should be included in an OTC drug monograph.
Also, most manufacturers would experience a paperwork savings when
applying for OTC drug monograph status instead of an NDA. For example,
in most instances, the manufacturing controls information needed for
submitting an NDA will not be required for a monograph submission.
Ongoing recordkeeping and reporting requirements associated with
periodic and annual reports would also be avoided. Based on previous
estimates of the paperwork hours needed to comply with these
requirements and assuming a 33 percent reduction in paperwork
activities, FDA estimates that eliminating manufacturing controls
information from an application would bring a one-time savings of
approximately 530 hours and an annual savings of 40 hours per
submission. Applying the 1995 labor rate of $29.50 per hour for an
industrial engineer (Ref. 3) (with a 40 percent adjustment for
benefits), these one-time savings are approximately $15,635 (530 x
$29.50/hour) per submission. Likewise, using the 1995 professional and
managerial labor rate of $24.60 per hour (Ref. 3) (including a 40
percent benefit rate), the ongoing savings from the elimination of
periodic and annual reports would equal approximately $984 (40 x
$24.60/hour) per product.
Moreover, once a condition has been included in an OTC drug
monograph, other companies could achieve similar benefits, as they
would be permitted to enter the marketplace without submitting an NDA
or an abbreviated NDA (ANDA), hereafter referred to as an application.
These companies would even avoid the costs associated with achieving
the inclusion of a condition in a monograph. In addition, these
companies, as well as the sponsoring companies, would be permitted to
market variations of a product, such as different product
concentrations or dosage forms, if allowed by the monograph, saving the
cost of an application or supplement when required.
Consumers would also benefit from this rule. As conditions not
previously marketed in the United States obtain OTC drug monograph
status, a greater selection of OTC drug products would become
available. In addition, competition from these additional products may
restrain prices for the entire product class.

B. Regulatory Costs

FDA estimates that the information needed for a TEA to meet the
eligibility criteria for ``material time'' and ``material extent''
would take firms approximately 480 hours to prepare. Using the 1995
professional and managerial labor rate of $24.60 per hour (Ref. 3)
(including a 40 percent benefit rate), this cost amounts to
approximately $12,000 (480 hours x $24.60/hour) per submission. The
costs associated with requiring publication in an official compendium,
where applicable, would be minimal as similar information is often
prepared for publication in a foreign pharmacopeia and most companies
already have such standards as part of their manufacturing quality
control procedures.
Considering the potential one-time cost savings described above of
$272,481 ($256,846 + $15,635) associated with prescription drug user
fees and reduced recordkeeping requirements, FDA calculates a one-time
net cost savings to industry of up to $260,481 ($272,481 - $12,000) per
submission. Future yearly cost savings could total $19,575 ($18,591 +
$984) per product and $141,966 per establishment if this were the
establishment's only product. Accordingly, if FDA receives 25 to 50 TEA
submissions a year, the industry would save between $8.2 million and
$16.4 million in one-time costs alone. The agency notes, however, that
companies would submit conditions for OTC drug monograph status only
where it would be profitable for them to do so.
There are several situations, however, where the rule may result in
lost sales for some future applicants. Since 1991, FDA has approved a
total of six requests for the inclusion of post-1972 U.S. OTC drug
conditions in a monograph. The sponsors requested permission to market
these conditions before the issuance of a final monograph, and FDA
granted these requests. Several other requests are currently under
agency review. This proposed rule, however, would not permit interim
marketing for post-1972 conditions without an application or without
inclusion of the condition in a final monograph. Therefore, this rule
could result in lost sales dollars for those few manufacturers who, in
the absence of this rule, might have successfully petitioned FDA to
market a variation of their product prior to publication in a final
monograph. Likewise, other manufacturers might experience some future
lost sales dollars because they also would be restricted from marketing
the product or a product variation. Although the agency cannot estimate
the value of these lost sales, the limited number of requests approved
to date implies that very few manufacturers would be adversely affected
by this interim marketing change. Moreover, because FDA expects a short
period of time between a proposal to add a condition to a monograph and
the final rule, any lost sales would occur over a limited timespan.
Four of the six requests approved since 1991 involved a previously
unapproved concentration, dosage form, dual claim, and product
combination without OTC marketing experience.

[[Page 71077]]

Similar conditions would not be allowed under the proposed rule
without a minimum of 5 continuous years of adequate OTC marketing
experience. Therefore, these manufacturers would need to either market
their product under an application for 5 years in the United States or
have 5 years of sufficient marketing experience abroad to qualify for
inclusion in a monograph. Other manufacturers would have to wait until
the condition is included in a final monograph publication before they
could market the product or a product variation without an application.
Due to the limited number of requests approved to date, it is likely
that few manufacturers would be significantly affected by these
requirements.

C. Small Business Analysis

Although the agency believes that this rule is unlikely to have a
significant economic impact on a substantial number of small entities,
FDA is uncertain about the extent of the future impact. Therefore, the
following regulatory flexibility analysis has been prepared:
1. Description and Objective of the Proposed Rule
As stated elsewhere in this preamble, the proposed rule would make
it easier to market certain OTC drug products in the United States by
amending current FDA regulations to include additional criteria and
procedures by which OTC conditions may become eligible for
consideration in the OTC drug monograph system. The additional criteria
and procedures would specify how OTC drugs initially marketed in the
United States after the OTC drug review began in 1972 and OTC drugs
without any U.S. marketing experience could meet the monograph
eligibility requirements. Once eligibility has been determined for a
particular condition, safety and effectiveness data would be evaluated.
2. Description and Estimate of the Number of Small Entities
Census data provide aggregate industry statistics on the number of
manufacturers of pharmaceutical preparations, but do not distinguish
between manufacturers of prescription and OTC products. According to
the Small Business Administration (SBA), manufacturers of
pharmaceutical preparations with 750 or fewer employees are considered
small entities. The U.S. Census does not disclose data on the number of
drug manufacturing firms by employment size, but between 92 and 96
percent of drug manufacturing establishments, or approximately 650
establishments, are small under this definition (Ref. 4). Although the
number of firms that are small would be less than the number of
establishments, FDA still concludes that the majority of pharmaceutical
preparation manufacturing firms are small entities.
The agency finds that at least 400 firms manufacture U.S.-marketed
OTC drug products. Using the SBA size designation, 31 percent of these
firms are large, 46 percent are small, and size data are not available
for the remaining 23 percent. Therefore, approximately 184 to 276 of
the affected manufacturing firms may be considered small. The agency
cannot project how many of these OTC drug manufacturers would submit a
TEA for consideration of an additional condition in the OTC drug
monograph system.
3. Description of Reporting, Recordkeeping, and Other Compliance
Requirements
To demonstrate eligibility for consideration in the OTC drug
monograph system, sponsors must submit data in a TEA showing that the
condition has been marketed ``for a material time'' and ``to a material
extent.'' Specific requirements of the TEA are discussed in section II.
of this document. All companies who choose to be considered in the OTC
drug monograph system must submit these data. FDA expects that all
sponsoring companies employ or have ready access to individuals who
possess the skills necessary for this data preparation.
4. Identification of Federal Rules That Duplicate, Overlap, or Conflict
With the Proposed Rule
The agency is not aware of any relevant Federal rules which may
duplicate, overlap, or conflict with the proposed rule. The agency
requests any information that may show otherwise.
5. Impact on Small Entities
As described above, this rule could result in some future lost
sales dollars for a few manufacturers of post-1972 OTC drug products
who would not be permitted to market a product or a product variation
without an application or without the inclusion of the condition in a
final OTC monograph. The agency anticipates, however, that the time
between a proposal to add a condition to a monograph and the final rule
will generally be short, thus limiting the impact of the change in
procedures concerning interim marketing. In addition, some
manufacturers could be adversely affected by the 5-year material extent
and material time requirements, similarly causing a loss in future
sales dollars. The agency cannot quantify these impacts. However, based
on the limited number of post-1972 conditions approved to date, FDA
believes that few manufacturers would be significantly affected. The
agency requests comment on this issue.
6. Description of Alternatives
In developing the requirements of this proposed rule, the agency
considered two alternatives. Initially, FDA thought of proposing a one-
step evaluation process, where sponsors would submit safety and
effectiveness data concurrently with their TEA. However, the agency
decided that this process would be less efficient because it would
require sponsoring companies to expend resources to prepare safety and
effectiveness data before the agency determines whether eligibility
criteria have been met. Likewise, the agency determined that it would
be an inefficient use of its resources to review safety and
effectiveness data prior to making a decision on eligibility.
The agency also considered allowing manufacturers of post-1972 U.S.
OTC drugs to market prior to inclusion in a final OTC drug monograph,
as long as the agency had tentatively determined that the condition is
GRAS/E. This approach would be consistent with the current process for
pre-1972 U.S. OTC drug conditions and with the six requests for interim
marketing that the agency has granted for post-1972 OTC drug
conditions. However, in order to protect the American public from
unnecessary risk, the agency decided that interim marketing should not
be allowed under the OTC drug monograph system either for post-1972
U.S. conditions or for conditions with no previous U.S. marketing
experience. This policy is believed necessary to allow for thorough
public consideration of any safety and effectiveness issues that might
arise before broad marketing of the condition begins under the OTC drug
monograph system. Further, post-1972 U.S. OTC conditions marketed under
NDA's will continue marketing in that manner until the condition is
included in the OTC drug monograph system. Finally, the policy allows
for the completion of compendial monograph standards for all
manufacturers to use. Because FDA expects a relatively short period of
time to elapse between a proposal to add a condition to a monograph and
the final rule, the agency believes the public health benefits of this
rule would outweigh any sales lost over this limited timespan.

VIII. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or

[[Page 71078]]

cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.

IX. Paperwork Reduction Act of 1995

This proposed rule contains collections of information which are
subject to review by OMB under the Paperwork Reduction Act of 1995 (44
U.S.C. 3501-3520). ``Collection of information'' includes any request
or requirement that persons obtain, maintain, retain, or report
information to the agency, or disclose information to a third party or
to the public (44 U.S.C. 3502(3) and 5 CFR 1320.3(c)). The title,
description, and respondent description of the information collection
are shown below with an estimate of the annual reporting burden.
Included in the estimate is the time for reviewing instructions,
gathering and maintaining the data needed, and completing and reviewing
the collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Additional Criteria and Procedures for Classifying Over-the-
Counter Drugs as Generally Recognized as Safe and Effective and Not
Misbranded.
Description: FDA is proposing additional criteria and procedures by
which OTC conditions may become eligible for consideration in the OTC
drug monograph system. The proposed criteria and procedures address how
OTC drugs initially marketed in the United States after the OTC drug
review began in 1972 and OTC drugs without any U.S. marketing
experience could meet the statutory definition of marketing ``to a
material extent'' and ``for a material time'' and become eligible. If
found eligible, the condition would be evaluated for general
recognition of safety and effectiveness in accord with FDA's OTC drug
monograph regulations.
Current Sec. 330.10(a)(2) sets forth the requirements for the
submission of data and information that is reviewed by FDA to evaluate
a drug for general recognition of safety and effectiveness. FDA
receives approximately three safety and effectiveness submissions from
three sponsors each year, and FDA estimates that it takes approximately
798 hours to prepare each submission.
FDA anticipates that the number of safety and effectiveness
submissions would increase to 93 annually as a result of this
rulemaking. (Although FDA estimates that the number of TEA's submitted
annually would be 50, the agency anticipates that 30 TEA's would be
approved, and that this would result in approximately 3 safety and
effectiveness submissions for each approved TEA). The time required to
prepare each safety and effectiveness submission would also increase as
a result of two amendments to current Sec. 330.10(a)(2) under this
proposed rule.
One proposed amendment would require the revision of the ``OTC Drug
Review Information'' format and content requirements in
Sec. 330.10(a)(2) by revising items IV.A.3, IV.B.3, IV.C.3, V.A.3,
V.B.3, and V.C.3 to add the words ``Identify common or frequently
reported side effects'' after ``documented case reports.'' This is a
clarification of current requirements for submitting documented case
reports and would only require sponsors to ensure that side-effects
information is identified in each submission. FDA estimates that it
would take sponsors approximately 1 hour to comply with this
requirement.
A second proposed amendment to current Sec. 330.10(a)(2) would
require sponsors to submit an official USP-NF drug monograph for the
active ingredient(s) or botanical drug substance(s), or a proposed
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). (This proposed requirement is also stated in proposed
Sec. 330.14(f)(1).) FDA believes that the burden associated with this
requirement would also be minimal because similar information may
already have been prepared for previous publication in a foreign
pharmacopeia, or companies would already have these standards as part
of their quality control procedures for manufacturing the product. FDA
estimates that the time required for photocopying this material would
be approximately 1 hour.
Thus, the time required for preparing each safety and effectiveness
submission would increase by a total of 2 hours as a result of the
proposed amendments to current Sec. 330.10(a)(2), increasing the
approximate hours per each submission from 798 to 800 hours.
Under proposed Sec. 330.14(c), sponsors must submit a TEA when
requesting that a condition subject to the proposed regulation be
considered for inclusion in the OTC drug monograph system. Based on the
data provided and explained in the ``Analysis of Impacts'' section VII
above, FDA estimates that approximately 50 TEA's would be submitted to
FDA annually by approximately 25 sponsors, and the time required for
preparing and submitting each TEA would be approximately 480 hours.
Under proposed Sec. 330.14(f)(2), sponsors would be required to
include in each safety and effectiveness submission all serious ADE's
from each country where the condition has been or is currently marketed
as a prescription or OTC drug product. Sponsors would be required to
provide individual ADE reports along with a detailed summary of all
serious ADE's and expected or frequently reported side effects for the
condition. FDA believes that the burden associated with this
requirement would be minimal because individual ADE reports are already
required as part of the ``documented case reports'' in the ``OTC Drug
Review Information'' under current Sec. 330.10(a)(2). FDA estimates
that the time required for preparing and submitting a detailed summary
of all serious ADE's and expected or frequently reported side effects
would be approximately 2 hours.
Due to the anticipated number of foreign conditions seeking
immediate consideration in the OTC drug monograph system, the annual
reporting burden estimated in the chart below is the annual reporting
for the first 3 years following publication of the final rule. FDA
anticipates a reduced burden after this time period.
Description of Respondents: Persons and businesses, including small
businesses and manufacturers.

[[Page 71079]]

Table 2.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR Section No. of Responses per Total Annual Hours per Total Hours
Respondents Respondent Responses Response
----------------------------------------------------------------------------------------------------------------
330.10(a)(2)
Safety and Effectiveness 93 1 93 800 74,400
Submission
330.14(c)
Time and Extent Application 25 2 50 480 24,000
330.14(f)(2)
Adverse Drug Experience 90 1 90 2 180
Reports
Total 98,580
----------------------------------------------------------------------------------------------------------------

In compliance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3507(d)), the agency has submitted the information
collection provisions of this proposed rule to OMB for review.
Interested persons are requested to send comments regarding the
information collection by January 19, 2000, to the Office of
Information and Regulatory Affairs, OMB (address above).

X. References

The following references are on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
(1) Memorandum of meeting between Hisamitsu Pharmaceutical Co.,
Inc., and FDA, October 4, 1994, Comment No. MM9, Docket No. 78N-
0301, Dockets Management Branch.
(2) United States Pharmacopeial Convention, ``Concordance of
Foreign Pharmacopeial Tests and Assays,'' Pharmacopeial Forum,
23(3):4009-4013, 1997.
(3) U.S. Department of Labor, Bureau of Labor Statistics,
``Employment and Earnings,'' January 1996, p. 205.
(4) U.S. Department of Commerce, Economics and Statistics
Administration, Bureau of the Census, ``Industry Series Drugs,''
1992 Census of Manufactures, Table 4, p. 28C-12.

List of Subjects in 21 CFR Part 330

Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 330 be amended as follows:

PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED

1. The authority citation for 21 CFR part 330 continues to read as
follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
2. Section 330.10 is amended as follows:
a. In paragraph (a)(2) by adding the words ``or until the
Commissioner places the panel's recommendations on public display at
the office of the Dockets Management Branch'' at the end of the second
sentence;
b. In paragraph (a)(2) by adding the words ``Identify expected or
frequently reported side effects.'' after the words ``Documented case
reports.'' in items IV.A.3, IV.B.3, IV.C.3, V.A.3, V.B.3, and V.C.3 in
the outline of ``OTC Drug Review Information''; and
c. In paragraph (a)(2) by adding item VII at the end of the outline
of ``OTC Drug Review Information'';
d. In paragraph (a)(5) introductory text by removing the word
``shall'' and adding in its place the word ``may'';
e. In paragraphs (a)(5)(ii) and (a)(5)(iii) by removing the word
``all'' from the first sentence;
f. In paragraphs (a)(6)(i) and (a)(9) by removing the word ``is''
and adding in its place the words ``or a specific or specific OTC drugs
are'';
g. In paragraph (a)(6)(iv) by removing the word ``quintuplicate''
and by adding in its place ``triplicate'' in the fourth sentence, by
removing the words ``during regular working hours'' and by adding in
their place ``between the hours of 9 a.m. and 4 p.m.'' in the sixth
sentence, and by adding two sentences at the end;
h. In paragraphs (a)(7)(i) and (a)(7)(ii) by revising the first and
second sentences;
i. In paragraphs (a)(10)(i) and (a)(10)(iii) by adding in the first
sentence the phrase ``in response to any other notice published in the
Federal Register,'' after the phrase ``paragraph (a)(2) of this
section''; and
j. In paragraph (a)(12)(i) in the fourth sentence by removing the
number ``60'' and by adding in its place the number ``90'' and by
removing the word ``quadruplicate'' and by adding in its place the word
``triplicate'' to read as follows:

Sec. 330.10 Procedures for classifying OTC drugs as generally
recognized as safe and effective and not misbranded, and for
establishing monographs.

(a) * * *
(2) * * *

OTC DRUG REVIEW INFORMATION

* * * * *
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 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.
* * * * *
(6) * * *
(iv) * * * Alternatively, the Commissioner may satisfy this
requirement by placing the panel's recommendations and the data it
considered on public display at the office of the Dockets Management
Branch and by publishing a notice of their availability in the Federal
Register. This notice of availability may be included as part of the
tentative order in accord with paragraph (a)(7) of this section.
(7) * * *
(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 a specific or specific OTC drugs are
generally recognized as safe and effective and not misbranded. Within
90 days, any interested person may file with the Dockets Management
Branch, Food and Drug Administration, written comments or written
objections

[[Page 71080]]

specifying with particularity the omissions or additions requested. * *
*
(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 Dockets Management Branch, Food and Drug Administration,
written objections specifying with particularity the provision of the
tentative order to which objection is made. * * *
* * * * *
3. Section 330.13 is amended by adding paragraph (e) to read as
follows:

Sec. 330.13 Conditions for marketing ingredients recommended for
over-the-counter (OTC) use under the OTC drug review.

* * * * *
(e) This section applies only to conditions under consideration as
part of the OTC drug review initiated on May 11, 1972, and evaluated
under the procedures set forth in Sec. 330.10. Section 330.14(h)
applies to the marketing of all conditions under consideration and
evaluated using the criteria and procedures set forth in Sec. 330.14.
4. Section 330.14 is added to subpart B to read as follows:

Sec. 330.14 Additional criteria and procedures for classifying OTC
drugs as generally recognized as safe and effective and not misbranded.

(a) Introduction. This section sets forth additional criteria and
procedures by which OTC drugs initially marketed in the United States
after the OTC drug review began in 1972 and OTC drugs without any U.S.
marketing experience can be considered in the OTC drug monograph
system. This section also addresses conditions regulated as a cosmetic
or dietary supplement in a foreign country, that would be regulated as
OTC drugs in the United States. For purposes of this section,
``condition'' means an active ingredient or botanical drug substance
(or a combination of active ingredients or botanical drug substances),
dosage form, dosage strength, or route of administration, marketed for
a specific OTC use, except as excluded in paragraphs (b)(2) and (b)(3)
of this section. For purposes of this part, ``botanical drug
substance'' means a drug substance derived from one or more plants,
algae, or macroscopic fungi, but does not include a highly purified or
chemically modified substance derived from such a source.
(b) Criteria. To be considered for inclusion in the OTC drug
monograph system, the condition must meet the following criteria:
(1) The condition must be marketed for OTC purchase by consumers.
If the condition is marketed in another country in a class of OTC drug
products that may be sold only in a pharmacy, with or without the
personal involvement of a pharmacist, it must be established that this
marketing restriction does not indicate safety concerns about the
condition's toxicity or other potentiality for harmful effect, the
method of its use, or the collateral measures necessary to its use.
(2) A condition is not eligible for OTC drug monograph status if
marketing in the United States is limited to prescription drug use.
(3) The condition must have been marketed OTC for a minimum of 5
continuous years in the same country or countries and in sufficient
quantity, as determined in paragraphs (c)(2)(ii), (c)(2)(iii), and
(c)(2)(iv) of this section.
(c) Time and extent application. Certain information must be
provided when requesting that a condition subject to this section be
considered for inclusion in the OTC drug monograph system. The
following information must be provided in the format of a time and
extent application (TEA):
(1) Basic information about the condition that includes a
description of the active ingredient(s) or botanical drug substance(s),
pharmacologic class(es), intended OTC use(s), OTC strength(s) and
dosage form(s), route(s) of administration, directions for use, and the
applicable existing OTC drug monograph(s) under which the condition
would be marketed or the request and rationale for creation of a new
OTC drug monograph(s).
(i) A detailed chemical description of the active ingredient(s)
that includes a full description of the drug substance, including its
physical and chemical characteristics, the method of synthesis (or
isolation) and purification of the drug substance, and any
specifications and analytical methods necessary to ensure the identity,
strength, quality, and purity of the drug substance.
(ii) For a botanical drug substance(s), a detailed description of
the botanical ingredient (including proper identification of the plant,
plant part(s), alga, or macroscopic fungus used; a certificate of
authenticity; and information on the grower/supplier, growing
conditions, harvest location and harvest time); a qualitative
description (including the name, appearance, physical/chemical
properties, chemical constituents, active constituent(s) (if known),
and biological activity (if known)); a quantitative description of the
chemical constituents, including the active constituent(s) or other
chemical marker(s) (if known and measurable); the type of manufacturing
process (e.g., aqueous extraction, pulverization); and information on
any further processing of the botanical substance (e.g., addition of
excipients or blending).
(iii) Reference to the current edition of the U.S. Pharmacopeia
(USP)-National Formulary (NF) may help satisfy the requirements in this
section.
(2) A list of all countries in which the condition has been
marketed, including the following information for each country:
(i) How the condition has been marketed (e.g., OTC general sales
direct-to-consumer; sold only in a pharmacy, with or without the
personal involvement of a pharmacist; dietary supplement; or cosmetic).
If the condition has been marketed as a nonprescription pharmacy-only
product, establish that this marketing restriction does not indicate
safety concerns about its toxicity or other potentiality for harmful
effect, the method of its use, or the collateral measures necessary to
its use.
(ii) The number of dosage units sold. This should include: The
total number of dosage units sold, the number of units sold by package
sizes (e.g., 24 tablets, 120 milliliters (mL)), and the number of doses
per package based on the labeled directions for use. This information
shall be presented in two formats: On a year-by-year basis, and
cumulative totals. The agency will maintain the year-to-year data as
confidential, unless the sponsor waives this confidentiality. The
agency will make the cumulative totals public if the condition is found
eligible for consideration in the OTC drug monograph system.
(iii) A description of the marketing exposure (e.g., race, gender,
ethnicity, and other pertinent factors) to ensure that the condition's
use(s) can be reasonably extrapolated to the U.S.

[[Page 71081]]

population. If desired, sponsors may use the categories and definitions
in The Office of Management and Budget's Federal Register notice,
titled ``Revisions to the Standards for the Classification of Federal
Data on Race and Ethnicity,'' which identifies the following racial/
ethnic groups: American Indian or Alaska Native, Asian, Black or
African American, Hispanic or Latino, Native Hawaiian or Other Pacific
Islander, and White (62 FR 58781, October 30, 1997). Explain any
cultural or geographical differences in the way the condition is used
in the foreign country and would be used in the United States. The
information in this paragraph need not be provided for OTC drugs that
have been marketed for more than 5 years in the United States under a
new drug application.
(iv) The use pattern of the condition (i.e., how often it is to be
used (according to the label) and for how long). If the use pattern
varies in different countries based on the condition's packaging and
labeling, or changes in use pattern have occurred over time, describe
the use pattern for each country and explain why there are differences
or changes.
(v) A description of the country's system for identifying adverse
drug experiences, especially those found in OTC marketing experience,
including method of collection if applicable.
(3) A statement of how long the condition has been marketed in each
country, accompanied by all labeling used during the marketing period,
specifying the time period that each labeling was used. All labeling
that is not in English must be translated to English in accord with
Sec. 10.20(c)(2) of this chapter. The information in this paragraph
need not be provided for OTC drugs that have been marketed for more
than 5 years in the United States under a new drug application.
(4) A list of all countries where the condition is marketed only as
a prescription drug and the reasons why its marketing is restricted to
prescription in these countries.
(5) A list of all countries in which the condition has been
withdrawn from marketing or in which an application for OTC marketing
approval has been denied. Include the reasons for such withdrawal or
application denial.
(6) The information requested in paragraphs (c)(2), (c)(2)(i)
through (c)(2)(iv), and (c)(3) of this section must be provided in a
table format. The labeling required by paragraph (c)(3) of this section
must be attached to the table with identification of each time period
that it was used.
(d) Submission of information; confidentiality. The sponsor must
submit three copies of the TEA to the Central Document Room, 12229
Wilkins Ave., Rockville, MD 20852. The Food and Drug Administration
will handle the TEA as confidential until such time as a decision is
made on the eligibility of the condition for consideration in the OTC
drug monograph system. If the condition is found eligible, the TEA will
be placed on public display in the Dockets Management Branch after
deletion of information deemed confidential under 18 U.S.C. 1905, 5
U.S.C. 552(b), or 21 U.S.C. 331(j). Sponsors must identify information
that is considered confidential under these provisions. If the
condition is not found eligible, the TEA will not be placed on public
display, but a letter from the agency to the sponsor stating why the
condition was not found acceptable will be placed on public display in
the Dockets Management Branch.
(e) Notice of eligibility. If the condition is found eligible, the
agency will publish a notice of eligibility in the Federal Register and
provide the sponsor and other interested parties an opportunity to
submit data to demonstrate safety and effectiveness. When the notice of
eligibility is published, the agency will place the TEA on public
display in the Dockets Management Branch.
(f) Request for data and views. The notice of eligibility shall
request interested persons to submit published and unpublished data to
demonstrate the safety and effectiveness of the condition for its
intended OTC use(s). These data shall be submitted to a docket
established in the Dockets Management Branch and shall be publicly
available for viewing at that office, except data deemed confidential
under 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j). Data
considered confidential under these provisions must be clearly
identified. Any proposed compendial standards for the condition shall
not be considered confidential. The safety and effectiveness
submissions shall include the following:
(1) All data and information listed in Sec. 330.10(a)(2) under the
outline ``OTC Drug Review Information'' items III through VII.
(2) All serious adverse drug experiences as defined in
Secs. 310.305 and 314.80 of this chapter, from each country where the
condition has been or is currently marketed as a prescription drug or
as an OTC drug or product. Provide individual adverse drug experience
reports (FDA form 3500A or equivalent) along with a summary of all
serious adverse drug experiences, and expected or frequently reported
side effects for the condition. Individual reports that are not in
English must be translated to English in accord with Sec. 10.20(c)(2)
of this chapter.
(g) Administrative procedures. The agency may use an advisory
review panel to evaluate the safety and effectiveness data in accord
with the provisions of Sec. 330.10(a)(3). Alternatively, the agency may
evaluate the data in conjunction with the advisory review panel or on
its own without using an advisory review panel. The agency will use the
safety, effectiveness, and labeling standards in Sec. 330.10(a)(4)(i)
through (a)(4)(vi) in evaluating the data.
(1) If the agency uses an advisory review panel to evaluate the
data, the panel may submit its recommendations in its official minutes
of meeting(s) or by a report under the provisions of Sec. 330.10(a)(5).
(2) The agency may act on an advisory review panel's
recommendations using the procedures in Sec. 330.10(a)(2) and (a)(6)
through (a)(10).
(3) If the condition is initially determined to be generally
recognized as safe and effective for OTC use in the United States, the
agency will propose to include it in an appropriate OTC drug
monograph(s), either by amending an existing monograph(s) or
establishing a new monograph(s), if necessary.
(4) If the condition is initially determined not to be generally
recognized as safe and effective for OTC use in the United States, the
agency will inform the sponsor and other interested parties who have
submitted data of its determination by letter, a copy of which will be
placed on public display in the docket established in the Dockets
Management Branch. The agency will publish a notice of proposed
rulemaking to include the condition in Sec. 310.502 of this chapter.
(5) Interested parties will have an opportunity to submit comments
and new data. The agency will subsequently publish a final rule (or
reproposal if necessary) in the Federal Register.
(h) Marketing. A condition submitted under this section for
consideration in the OTC drug monograph system may be marketed in
accordance with an applicable final OTC drug monograph(s) only after
the agency determines that the condition is generally recognized as
safe and effective and includes it in the appropriate OTC drug final
monograph(s) and the condition complies with paragraph (i) of this
section.
(i) Compendial monograph. Any active ingredient or botanical drug

[[Page 71082]]

substance included in a final OTC drug monograph must be recognized in
an official USP-NF drug monograph that sets forth its standards of
identity, strength, quality, and purity. Sponsors must include an
official or proposed compendial monograph as part of the safety and
effectiveness data submission under item VII of the OTC Drug Review
Information in Sec. 330.10(a)(2).

Dated: September 10, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-32428 Filed 12-17-99; 8:45 am]
BILLING CODE 4160-01-F