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

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

[[Page 71065]]

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