330.14 (c) and (d) - Time and Extent Application/Submission of Information; Confidentiality

Guidance for Industry
Time and Extent Applications
for Nonprescription Drug
Products

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 2011

OTC

Guidance for Industry
Time and Extent Applications
for Nonprescription Drug
Products
Additional copies are available from:

Office of Communications, Division of Drug Information

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Bldg. 51, rm. 2201

Silver Spring, MD 20993-0002

Tel: 301-796-3400; Fax: 301-847-8714; E-mail: [email protected]

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 2011

OTC

TABLE OF CONTENTS

I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

A. Where can I find the regulations concerning OTC drug monographs and TEAs? ................. 2

B. What is an OTC condition? .......................................................................................................... 2

C. What OTC conditions are covered by this guidance? ................................................................ 2

D. How were conditions added to an OTC drug monograph before 21 CFR 330.14 was

established?..................................................................................................................................... 2

E. Who can submit a TEA? ............................................................................................................... 3

F.

Is a TEA the only information I should submit to have my condition included in a

monograph?.................................................................................................................................... 3

G. Why can’t I submit safety and effectiveness data with my TEA? ............................................. 3

III.

SHOULD I SUBMIT AN APPLICATION UNDER SECTION 505 OF THE FD&C

ACT, CITIZEN PETITION, OR TEA? ......................................................................... 4

A. Application under section 505 of the FD&C Act ........................................................................ 4

B. Citizen petition ............................................................................................................................... 5

C. TEA ................................................................................................................................................. 5

IV.

WHAT DO I NEED TO KNOW ABOUT THE CONTENT OF THE TEA?............. 6

A. What information must be included about the condition?......................................................... 6

B. Do I need to list every country in which the condition is marketed? ........................................ 7

C. What information is not required if the TEA is for an OTC drug product that has been

marketed under an FDA-approved application for more than 5 years in the United States? 7

D. Do I need to include the marketing information listed in 21 CFR 330.14(c)(2) for each

country in which the condition is marketed? .............................................................................. 7

E. Is a condition that is marketed in a country as a nonprescription pharmacy-only drug

product eligible to be considered for inclusion in the OTC monograph system? .................... 9

F.

Do I need to submit information about the number of dosage units sold and copies of retail

labeling even if I am not the manufacturer or supplier of a finished dosage form? ................ 9

G. What is use pattern information and when should I include it in the TEA?............................ 9

H. Should I submit reports from countries regarding adverse drug experiences?....................... 9

I.

What product labeling information should I include in the TEA? ......................................... 10

J.

Am I required to include in the TEA any non-OTC marketing information for currently

marketed drug products?............................................................................................................ 10

i

K. How can I obtain the appropriate information on population demographics for each

country? ........................................................................................................................................ 10

V.

WHAT FORMAT SHOULD I USE IN THE TEA?.................................................... 11

A. Information describing the condition......................................................................................... 11

B. Information listed by country (including the United States) ................................................... 12

VI.

WHAT ELSE DO I NEED TO KNOW ABOUT A TEA?.......................................... 12

A. Where can I submit the TEA and how many copies?............................................................... 12

B. Is confidentiality protected?........................................................................................................ 13

VII.

WHAT HAPPENS AFTER I SUBMIT A TEA? ......................................................... 13

A. How long does an eligibility determination take, and what happens when eligibility is

determined? .................................................................................................................................. 13

B. If a condition is found eligible, what information should I provide in response to the notice

of eligibility to support my claim that the condition is safe and effective? ............................. 14

C. What types of studies should I submit to support my claim that a condition is safe and

effective? ....................................................................................................................................... 14

D. Do I need to prepare an environmental assessment with my safety and effectiveness data? 15

E. Where do I send my safety and effectiveness data submission? .............................................. 16

F.

What happens after I submit safety and effectiveness data? ................................................... 16

G. How long does a safety and effectiveness review take? ............................................................ 16

ii

Contains Nonbinding Recommendations

Guidance for Industry1

Time and Extent Applications for

Nonprescription Drug Products

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

I.

INTRODUCTION

This guidance is intended to explain what information an applicant should submit to the Food
and Drug Administration (FDA) to request that a drug product be included in the over-thecounter (OTC) drug monograph system and to describe the process for submitting that
information. FDA regulations set forth criteria and procedures by which OTC drugs that initially
were 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 for inclusion in the OTC drug
monograph system (21 CFR 330.14). The regulations establish a two-part process. First, to
determine whether a drug product is eligible to be considered for inclusion in the OTC drug
monograph system, certain information must be submitted in a time and extent application
(TEA) to show that a drug product can meet the statutory standard of marketing to a material
extent and for a material time.2 Second, if the drug product is found eligible to be considered for
inclusion in the OTC drug monograph system, we will publish a notice of eligibility in the
Federal Register that requests that interested persons submit data to demonstrate the safety and
effectiveness of the drug product for its OTC use(s) (21 CFR 330.14(e) and (f)).
This guidance describes the format and content of a TEA that is used to determine if a drug has
been marketed OTC to a material extent and for a material time, and what happens after a TEA
1

This guidance has been prepared by the Division of Nonprescription Regulation Development in the Center for
Drug Evaluation and Research (CDER) at the Food and Drug Administration.

2

For a drug to not be a “new drug” under section 201(p)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C
Act), the drug must have been marketed “to a material extent” and “for a material time” under its conditions for use.
FDA regulations at 21 CFR 330.14 explain what applicants must submit to establish that an OTC drug has been
marketed to a material extent and for a material time, thereby qualifying it to be eligible to be considered for
inclusion in the OTC drug monograph system. See 21 CFR 330.14(b) and (c) and the final rule “Additional Criteria
and Procedures for Classifying Over-the-Counter Drugs as Generally Recognized as Safe and Effective and Not
Misbranded” (67 FR 3060, January 23, 2002).

1

Contains Nonbinding Recommendations
is submitted. Drug products covered by this guidance are those OTC drug products that: (1)
were initially marketed in the United States after the OTC drug review began on May 11, 1972;
or (2) are without any U.S. marketing experience.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.

II.

B
ACKGROUND
A.

Where can I find the regulations concerning OTC drug monographs and
TEAs?

Part 330 (21 CFR part 330) describes the monograph criteria and procedures for classifying OTC
drug products as generally recognized as safe and effective (GRASE) and not misbranded. The
additional criteria and procedures, for OTC drug products initially marketed in the United States
after the OTC drug review began in 1972 or without any U.S. marketing experience, which are
described in this guidance, can be found at 21 CFR 330.14. These regulations were established
in an amendment to part 330 in the Federal Register in 2002 (67 FR 3060). You can find a copy
of the final rule on the Internet at http://www.fda.gov/OHRMS/DOCKETS/98fr/012302a.pdf.
B.

What is an OTC condition?

The TEA regulations state that, for the purposes of 21 CFR 330.14, a condition means an active
ingredient or botanical drug substance (or combination of both), dosage form, dosage strength, or
route of administration marketed for a particular OTC use. Under this definition, conditions
include products regulated as cosmetic products or dietary supplements in a foreign country that
would be regulated as OTC drug products in the United States.
C.

What OTC conditions are covered by this guidance?

Conditions subject to this guidance are those conditions marketed in the United States after the
beginning of the OTC drug review in 1972 or those without any U.S. marketing experience
(21 CFR 330.14(a)). These conditions have not been previously evaluated for eligibility for
inclusion in the OTC drug monograph system or general recognition of safety and effectiveness,
and are not addressed in 21 CFR 310.545, current tentative final monographs, or current final
monographs (21 CFR parts 331-358).
D.

How were conditions added to an OTC drug monograph before
21 CFR 330.14 was established?

Before 21 CFR 330.14 was published in 2002, many conditions covered by this guidance could
not be added to an OTC drug monograph and instead could be marketed only under an approved

2

Contains Nonbinding Recommendations
application pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
If an OTC drug condition had been marketed solely in a foreign country, a company was
required to obtain premarket approval under section 505 of the FD&C Act before the condition
could be marketed in the United States. Companies also were required to obtain premarket
approval under section 505 of the FD&C Act if their OTC drug products were initially marketed
in the United States after the beginning of the OTC drug review in 1972.
E.

Who can submit a TEA?

Any interested party can submit a TEA.
F.

Is a TEA the only information I should submit to have my condition included
in a monograph?

No, submission of the TEA is the first step in a two-step process to include a new condition in a
monograph:
1. Time and Extent Application: As explained in more detail in section III.C. of this
guidance, a TEA should provide the information needed to determine if a condition is
eligible to be considered for inclusion in the OTC drug monograph system
(21 CFR 330.14(c)).
2. Safety and Effectiveness Data Submission: If we review a TEA and determine that a
condition is eligible for inclusion in the OTC drug monograph system, we will publish a
notice of eligibility that requests the submission of data to demonstrate general
recognition of the safety and effectiveness of the condition, and place the TEA on public
display (21 CFR 330.14(e) and (f)). We then evaluate the safety and effectiveness data
submitted using the standards in 21 CFR 330.10(a)(4) (21 CFR 330.14(g)).
G.

Why can’t I submit safety and effectiveness data with my TEA?

We believe that a two-step process, as described in section II.F., is the most efficient and
appropriate method for us to determine whether a condition is acceptable for inclusion in the
OTC drug monograph system. This two-step process has the following advantages:
• It prevents applicants from incurring unnecessary costs for developing safety and

effectiveness data for a condition that may not meet basic eligibility requirements

• It avoids expending FDA resources evaluating safety and effectiveness data for a

condition that does not meet the basic eligibility criteria

• It provides all interested parties (not just the applicant) an opportunity to submit safety
and effectiveness data and information

3

Contains Nonbinding Recommendations
III.

SHOULD I SUBMIT AN APPLICATION UNDER SECTION 505 OF THE FD&C
ACT, CITIZEN PETITION, OR TEA?
A.

Application under section 505 of the FD&C Act

An applicant can submit an application under section 505 of the FD&C Act for a new OTC drug
condition.3 An applicant can also submit an application under section 505 to request approval of
an OTC drug product that deviates in any respect from a monograph that has become final (21
CFR 330.11). An application under section 505 of the FD&C Act seeks approval of a specific
product that is formulated and labeled as it is to be marketed (21 CFR 314.50). Benefits of this
approach may include the following:
• Confidentiality during the approval process (21 CFR 314.430)
• A period of marketing exclusivity, for certain applications, upon approval if certain
conditions are met (21 CFR 314.108)
• Historically, less time for review of the application from submission to a final decision,
compared to other routes to market drugs (i.e., citizen petitions and TEAs)4
However, an application under section 505 of the FD&C Act generally includes the following:
•

Approval only for a specific drug product (including formulation and labeling) (21 CFR
314.50 and 314.94)

• Reporting requirements subsequent to approval, in addition to adverse event reporting (21
CFR 314.80, 314.81, and 314.98)5
• Prior approval requirements for certain subsequent labeling and formulation changes to
the drug product (21 CFR 314.70 and 314.97)
Certain applications are also subject to required fees (sections 735 and 736 of the FD&C Act).

3

See section 505 of the FD&C Act and 21 CFR part 314.

4

See 21 CFR 314.100 for a description of the time frames for review of applications.

5

We note that there are some reporting requirements for OTC drugs marketed under a monograph. Under section
760 of the FD&C Act, manufacturers, packers, and distributers of OTC drugs marketed under a monograph are
required to report certain kinds of information about serious adverse events associated with their drugs. See the
guidance for industry Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed
Without an Approved Application. We update guidances periodically. To make sure you have the most recent
version of a guidance, check the FDA Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

4

Contains Nonbinding Recommendations
B.

Citizen petition

A citizen petition may be used to request the amendment or repeal of conditions covered by
proposed or final OTC drug monographs (21 CFR 10.30 and 21 CFR 330.10(a)(12)). The citizen
petition process should not be used to make an initial request to include in the OTC drug
monograph system conditions marketed in the United States after the beginning of the OTC drug
review in 1972 or those without any U.S. marketing experience; these must first be determined to
be eligible for potential inclusion through submission of a TEA in accordance with 21 CFR
330.14.6
FDA regulations (21 CFR 330.10(a)(12)) explain the process by which we may amend or repeal
an existing monograph in response to a citizen petition. We may grant a petitioner’s request to
amend or repeal a condition covered by an existing monograph if the petitioner’s request is
supported by adequate accompanying data (21 CFR 330.10(a)(12)). For example, if a petitioner
requests that a condition be amended, we may grant the request if the petition is accompanied by
data that demonstrate general recognition of safety and effectiveness of the amended condition in
accordance with 21 CFR 330.10. If we believe a request should be granted, we will issue a
notice of proposed rulemaking (proposed rule) that states the proposed action and explains the
reason for the action. Any interested person would then have the opportunity to comment on the
proposed rule, we would review these comments, and then publish a final rule that amends the
monograph or withdraws the proposed rule (21 CFR 330.10(a)(12)(i)).
This citizen petition process is open to the public and does not require payment of a fee to the
FDA. However, the process of filing a citizen petition that leads to a public rulemaking process
to amend the monograph for an OTC drug product historically has taken more time than a final
decision on a new drug application (NDA).
C.

TEA

The purpose of a TEA is to request that we determine whether a condition is eligible for
inclusion in the OTC drug monograph system. A TEA should be submitted only for conditions
that the applicant believes have been marketed OTC to a material extent and for a material time
(67 FR 3060). Under 21 CFR 330.14, a TEA may be submitted for:
• Conditions initially marketed (under an approved application under section 505 of the
FD&C Act) in the United States after the OTC drug review began in 19727
• Conditions marketed only outside the United States (and that would be regulated as OTC
drugs in the United States)
6

If a condition is found eligible for potential inclusion in a monograph based on the submission of a TEA, it is not
necessary to submit a citizen petition to request that the condition be considered for inclusion in a monograph (see
section VII). However, after the safety and effectiveness data for such a condition has been submitted and the FDA
has made a determination regarding the condition’s safety and effectiveness and either included it in a monograph or
in 21 CFR 310.502, a citizen petition may then be used to request additional changes to the monograph.

7

See also 67 FR 3060.

5

Contains Nonbinding Recommendations
To be eligible for inclusion in the OTC drug monograph system, a condition must be marketed
for OTC purchase by consumers (21 CFR 330.14(b)). In addition, the condition must have been
marketed OTC for at least 5 continuous years in the same country in sufficient quantity (although
marketing in more than one country may be necessary depending on the extent of marketing)
(21 CFR 330.14(b)).
As explained in section II.F., the TEA is only the first step in a two-step process. If a condition
is determined to be eligible for inclusion in the monograph system, the TEA will be placed on
public display and a notice of eligibility will be published in the Federal Register
(21 CFR 330.14(e)). This notice will request data that demonstrate general recognition of safety
and effectiveness for the condition (21 CFR 330.14(f)). The safety and effectiveness data
submission and evaluation is the second step in the process (21 CFR 330.14(f)). After reviewing
the safety and effectiveness data, if we initially determine that the condition is GRASE for OTC
use in the United States, we will publish a proposed rule to incorporate the new condition into an
existing monograph, or create a new monograph if necessary (21 CFR 330.14(g)(3)). After
considering comments and other information submitted regarding the proposed rule, we will
publish a final rule, or reproposal if necessary, in the Federal Register (21 CFR 330.14(g)(5)).
We typically make an eligibility determination within 1 year of receiving a TEA, and a fee is not
required. After a condition has been incorporated into a final monograph (or, if a finalization of
the monograph is not imminent, has been subject to a notice of enforcement policy in accordance
with 21 CFR 330.14(h)), the condition may be marketed in accordance with the applicable
monographs by any interested party without prior approval by us (21 CFR 330.14(h)). For
inclusion in a final monograph or in a notice of enforcement policy, 21 CFR 330.14(i) requires
that the active ingredient or botanical drug substance be recognized in an official U.S.
Pharmacopeia-National Formulary (USP-NF) drug monograph that sets forth its standards for
identity, strength, quality, and purity.

IV.

WHAT DO I NEED TO KNOW ABOUT THE CONTENT OF THE TEA?
A.

What information must be included about the condition?

All TEAs must include the basic information required under 21 CFR 330.14(c)(1), including:
•

A description of the active ingredients or botanical drug substances

•

Pharmacologic classes

•

Intended OTC uses

•

OTC strengths

•

OTC dosage forms

•

Routes of administration

6

Contains Nonbinding Recommendations

• Directions for use
• Applicable OTC drug monograph or request and rationale for creation of a new

monograph

Reference to the USP-NF or a foreign compendium may satisfy, or help to satisfy, the
requirements in 21 CFR 330.14(c)(1)(i) and (ii) for a detailed description of an active ingredient
or botanical substance (21 CFR 330.14(c)(1)(iii)). If reference to the USP-NF or a foreign
compendium is sufficient to satisfy these requirements, we expect that the method of synthesis
and other confidential information would not ordinarily need to be included in the TEA.
B.

Do I need to list every country in which the condition is marketed?

Under 21 CFR 330.14(c)(2), the applicant is required to provide a list of all countries in which
the condition has been marketed.
C.

What information is not required if the TEA is for an OTC drug product
that has been marketed under an FDA-approved application for more than 5
years in the United States?

Under 21 CFR 330.14(c)(8), if the TEA is for an OTC drug product that has been marketed
under an FDA-approved application in the United States for more than 5 years, it is not required
to include the following information for any country:
• Information on how the condition has been marketed required under

21 CFR 330.14(c)(2)(i)

• A description of the population demographics required under 21 CFR 330.14(c)(2)(iii)
• A description of the reporting system for adverse drug experiences required under

21 CFR 330.14(c)(2)(v)

• Product labeling information required under 21 CFR 330.14(c)(3)
• 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, as required under
21 CFR 330.14(c)(5)
All other information required under 21 CFR 330.14(c) must be included in the TEA.
D.

Do I need to include the marketing information listed in 21 CFR 330.14(c)(2)
for each country in which the condition is marketed?

The number of countries in which the condition is marketed, and whether the drug product has
been marketed OTC under an FDA-approved application for more than 5 years in the United

7

Contains Nonbinding Recommendations
States (see section IV.C.), determines whether marketing information listed in 21 CFR
330.14(c)(2) must be submitted for each country. If the condition is marketed OTC in four or
fewer countries (and has not been marketed OTC under an FDA-approved application for more
than 5 years in the United States), the applicant must include the following general types of
information required under 21 CFR 330.14(c)(2) for each country:
• How the condition has been marketed
• The cumulative total number of dosage units sold for each dosage form of the condition
• A description of the population demographics and the source or sources from which this
information has been compiled
• Any use pattern differences between countries, and, if there are use pattern differences,
an explanation of why those differences exist
• A description of each country’s system for identifying adverse drug experiences
Under 21 CFR 330.14(c)(2), there is more detail about what specific information should be
provided in each of the above listed areas.
Under 21 CFR 330.14(c)(4), if the condition is marketed in five or more countries (with a
minimum of 5 continuous years of marketing in at least one country), then the applicant may
select five (or more) countries from which to submit the information required under
21 CFR 330.14(c)(2). Under 21 CFR 330.14(c)(4), the selected countries must include a country
with a minimum of 5 continuous years of OTC marketing, countries that have the longest
duration of marketing, and countries having the most support for extent of marketing. In
addition, if the condition meets these criteria in any countries listed in section 802(b)(1)(A) of
the FD&C Act, some of those countries should be included among the five selected
(21 CFR 330.14(c)(4)). We recommend that the countries for which all 21 CFR 330.14(c)(2)
information is submitted include those countries that have the most marketing experience
because they are most likely to support eligibility. Additionally, under 21 CFR 330.14(c)(4),
applicants should explain in the TEA the basis for the countries selected.
Under 21 CFR 330.14(c)(3) and (c)(5), information in certain categories (e.g., copies of labeling,
and prescription-only sales) must be reported for all countries in which the condition has been
marketed, even if the information required under 21 CFR 330.14(c)(2) is only given for five
countries, unless the condition has been marketed OTC under an FDA-approved application for
more than 5 years in the United States. The information required under 21 CFR 330.14(c)(6)
must be for all countries in which the condition has been marketed, even if the information
required under 21 CFR 330.14(c)(2) is only given for five countries or the condition has been
marketed OTC under an FDA-approved application for more than 5 years in the United States.

8

Contains Nonbinding Recommendations
E.

Is a condition that is marketed in a country as a nonprescription pharmacyonly drug product eligible to be considered for inclusion in the OTC
monograph system?

Such a condition may be eligible to be considered for inclusion in the OTC drug monograph
system. Under 21 CFR 330.14(b)(1), if the drug product is sold only in a pharmacy, with or
without involvement of a pharmacist, in addition to demonstrating that the drug product meets
the other applicable criteria, the applicant must establish that this marketing restriction does not
indicate safety concerns about: (1) its toxicity or other potentially harmful effects; (2) the
method of its use; or (3) the collateral measures necessary to its use.
F.

Do I need to submit information about the number of dosage units sold and
copies of retail labeling even if I am not the manufacturer or supplier of a
finished dosage form?

Under 21 CFR 330.14(c)(2)(ii) and (c)(3), respectively, TEA applicants must submit information
about the number of dosage units and copies of retail labeling, even if they are not the
manufacturer or supplier of a finished dosage form. However, the manufacturers and suppliers
of OTC active ingredients may submit information on dosage units as the total weight of active
ingredient sold and submit information on potential consumer exposure in accordance with the
calculations provided in 21 CFR 330.14(c)(2)(ii). Like any applicant submitting a TEA (for a
condition not marketed in the United States for more than 5 years), manufacturers or suppliers of
OTC active ingredients must also submit a copy of current finished product labeling and provide
the information about labeling as listed in 21 CFR 330.14(c)(3) for each country where the
condition is marketed.8 Section IV.I. describes in more detail what product labeling information
should be included in the TEA.
G.

What is use pattern information and when should I include it in the TEA?

Under 21 CFR 330.14(c)(2)(iv), use pattern is defined as how often a drug product is to be used
(according to the label) and for how long. Under 21 CFR 330.14(c)(2)(iv), if the use pattern
varies between countries or changes have occurred over time in one or more countries, then the
applicant must describe the use pattern for each country and provide information on why there
are differences or changes.
H.

Should I submit reports from countries regarding adverse drug experiences?

Reports on adverse drug experiences do not need to be submitted with the TEA. However, under
21 CFR 330.14(c)(2)(v), we require the applicant to describe the countries’ systems for
identifying adverse drug experiences, especially those found in OTC marketing experience.
Additionally, the applicant must include in this description how the information is collected, if
applicable (21 CFR 330.14(c)(2)(v)). If the condition is subsequently determined to be eligible
for inclusion in the OTC drug monograph system, submissions in response to the notice of
eligibility must include all serious adverse drug experiences (as defined in 21 CFR 310.305 and
314.80) (21 CFR 330.14(f)(2)).
8

See 67 FR 3060 at 3064-65.

9

Contains Nonbinding Recommendations

I.

What product labeling information should I include in the TEA?

According to 21 CFR 330.14(c)(3), the applicant must include an English version of the current
product labeling from each country in which the condition is marketed. For each example of
product labeling, the regulation requires that the applicant include a statement of: (1) how long
the condition has been marketed; (2) how long the current labeling has been in use; and (3)
whether the current labeling has or has not been authorized, accepted, or approved by a
regulatory body in each country where marketed. We do not expect applicants to submit a copy
of every piece of labeling used in a country and related to the condition if the labeling
information for that country (i.e., active ingredients and corresponding dosage strengths,
indications, warnings, and directions for use) is substantially the same on every piece of labeling
used in that country. If an applicant does not submit copies of all labeling for a particular
country, the TEA should inform the FDA that the labeling that was not submitted for that
country is substantially the same as the labeling that was submitted.
J.

Am I required to include in the TEA any non-OTC marketing information
for currently marketed drug products?

The applicant must include non-OTC marketing information in certain circumstances. TEA
regulations (21 CFR 330.14(c)(5) and (c)(6)) require the listing of specific information: (1)
when the condition is marketed only as a prescription drug in a country; and (2) when the
condition has been withdrawn from marketing or an application for OTC marketing has been
denied.
K.

How can I obtain the appropriate information on population demographics
for each country?

There are various sources that may provide information on population demographics that must
be included in a TEA under 21 CFR 330.14(c)(2)(iii). The following Web sites are two
examples of sources that provide population demographics information:
• The U.S. Central Intelligence Agency World Factbook:

https://www.cia.gov/library/publications/the-world-factbook/index.html

• The U.S. Department of State Background Notes: http://www.state.gov/r/pa/ei/bgn/
The national statistical office for a particular country may also provide relevant information.

The U.S. Census Bureau International Statistical Agencies Web page lists countries and links to

the countries’ national statistical offices: http://www.census.gov/aboutus/stat_int.html.

In addition to providing population demographics, under 21 CFR 330.14(c)(2)(iii), the TEA must

describe the source(s) from which the population demographic information was compiled.

10

Contains Nonbinding Recommendations
V.

WHAT FORMAT SHOULD I USE IN THE TEA?
A.

Information describing the condition

The basic information and detailed description of the ingredient or ingredients required by
21 CFR 330.14(c)(1) can be presented in any format. Although not required, we recommend that
applicants include this information at the beginning of the TEA to identify the purpose of the
application before providing particular marketing information. We also recommend that the
applicant present this information in a table format with any attachments following the table.
Table 1 shows an example of how the information can be presented.
Table 1. Basic Information Describing New Condition
Active ingredient or botanical drug substance
Pharmacologic class
Intended OTC use
Strength
Dosage form
Route of administration
Directions for use
Current OTC drug monograph under which the condition would be marketed or request and
rationale for creation of a new OTC drug monograph
Active Ingredient Description
Chemical and physical characteristic
Method of synthesis or isolation
Method of purification
Additional specifications or analytical methods
References to USP-NF or foreign compendia
Botanical Drug Substance Description
Identification of plant, plant part, alga, or fungus
Grower and/or supplier identification
Growth conditions
Harvest location and harvest time
Drug substance name
Drug substance appearance
Chemical and physical properties
Chemical constituents
Biological activity
Active constituents (or chemical markers) — qualitative and quantitative descriptions
Type of manufacturing process
Any further processing information
References to USP-NF or foreign compendia
If applicants use such a table format, they should separately provide a certificate of authenticity
for botanical drug substances, as required under 21 CFR 330.14(c)(1)(ii).

11

Contains Nonbinding Recommendations

B.

Information listed by country (including the United States)

Certain information requested for each country must be submitted in a table format
(21 CFR 330.14(c)(7)). In addition, we recommend that the applicant include as much of the
TEA information as possible in a table with other information as attachments (e.g., labeling).
Table 2 is an example of a table that can be included for each country.
Table 2. Information Describing Marketing Experience by Country
Country
Marketing status (If limited to pharmacy sale, list reason why and collateral measures.)1,2
Length of current marketing status1,2
Population demographics1,2
Cumulative total number of dosage units sold for each dosage form2
Labeled use pattern, as applicable2
Label approval1,2
System for identifying adverse drug experiences1
1

Not necessary for conditions that have been marketed OTC in the United States for more than 5 years. See 21 CFR

330.14(c)(8).

2
Section 330.14(c)(7) states that this information must be included in a table.

Applicants may also summarize some of the marketing experience information in a format that
allows easy comparisons among countries. For example, information in Table 2 could be
presented in one table providing this information for all of the selected countries (by creating a
column for each country).

VI.

WHAT ELSE DO I NEED TO KNOW ABOUT A TEA?
A.

Where can I submit the TEA and how many copies?

You must submit three copies of the TEA to the address provided in 21 CFR 330.14(d). You can
also find the address on the Dockets Management Web site at
http://www.fda.gov/RegulatoryInformation/Dockets/default.htm.
You may also mail a copy of the TEA directly to the Division of Nonprescription Regulation
Development. See the Regulation of Nonprescription Products Web site for mailing addresses:
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm093452.htm.
You can mail your TEA copies through the Post Office or by courier (e.g., FedEx or UPS).
Identify the submission as a “Confidential Time and Extent Application (TEA).”
Two weeks after submitting your TEA, we recommend that you telephone the Division of
Nonprescription Regulation Development to ensure that we have received the TEA. The phone
number for the Division of Nonprescription Regulation Development can be found at:
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm093452.htm.

12

Contains Nonbinding Recommendations

B.

Is confidentiality protected?

Certain information is considered confidential and is protected to the extent allowed under
applicable laws and regulations. Under 21 CFR 330.14(d), all TEAs are handled as confidential
upon receipt until such time as a decision is made on the eligibility of the condition. If the
condition were found to be eligible for inclusion in the OTC drug monograph system, any
information that we deem confidential under 18 U.S.C. 1905, 5 U.S.C. 552(b), or section 301(j)
of the FD&C Act will be removed from the TEA, and the remainder of the application will be
placed on public display in the Division of Dockets Management when the notice of eligibility is
published (21 CFR 330.14(d)). If the condition is not found to be eligible, the TEA will not be
placed on public display, but a letter from the FDA to the applicant stating why the condition
was not found to be eligible will be placed on public display in the Division of Dockets
Management (21 CFR 330.14(d)).
TEA applicants must identify the information, if any, that is considered confidential under 18
U.S.C. 1905, 5 U.S.C. 552(b), or section 301(j) of the FD&C Act (21 U.S.C. 331(j))
(21 CFR 330.14(d)). Applicants should identify the confidential information in their applications
and mark as confidential in the TEA only the pages that they consider to be confidential. The
“confidential” stamp mark should be placed at the top or bottom of a page and not stamped
directly over submission text. Applicants should mark “confidential” on a page only if there is
specific confidential information on that page. Alternatively, applicants can submit two versions
of the TEA: (1) a redacted version for public display; and (2) an unredacted version containing
all information, including confidential information. The redacted version can summarize
marketing information according to continent or region. The unredacted version should contain
marketing information for each country.

VII. WHAT HAPPENS AFTER I SUBMIT A TEA?
A.

How long does an eligibility determination take, and what happens when
eligibility is determined?

After you submit a TEA, we review the TEA to determine whether your condition is eligible to
be considered for inclusion in the OTC drug monograph system. We typically make an
eligibility determination within 1 year of receiving the TEA.
If we determine that the condition is not eligible for inclusion in the OTC drug monograph
system, the TEA will not be placed on public display, but a letter from the FDA to the applicant
stating why the condition was not found to be eligible will be placed on public display in the
Division of Dockets Management (21 CFR 330.14(d)).
If we determine that the condition is eligible for inclusion in the OTC drug monograph system,
the TEA will be placed on public display and a notice of eligibility will be published in the
Federal Register (21 CFR 330.14(e)). This notice will request that interested persons submit

13

Contains Nonbinding Recommendations
data that demonstrate general recognition of safety and effectiveness for the condition (21 CFR
330.14(f)).
B.

If a condition is found eligible, what information should I provide in response
to the notice of eligibility to support my claim that the condition is safe and
effective?

Under 21 CFR 330.14(f), submissions in response to a notice of eligibility must include: (1) all
data and information listed in 21 CFR 330.10(a)(2) under the outline “OTC Drug Review
Information,” items III through VII; and (2) all serious adverse drug experiences as defined in
21 CFR 310.305 and 314.80.
Data and information should be presented in a clear and complete manner to facilitate our
review. Submitted study reports should include complete descriptions of study methodology.
They should not only contain summaries of results but should also include raw data. Inclusion of
all cited references (rather than simply including a bibliography) is helpful because we may have
difficulty obtaining some references.
C.

What types of studies should I submit to support my claim that a condition is
safe and effective?

We use the safety, effectiveness, and labeling standards in 21 CFR 330.10(a)(4)(i) through (vi) to
evaluate the data submitted to support the safety and effectiveness of a condition
(21 CFR 330.14(g)). Accordingly, submitted studies should support safety and effectiveness
under those standards.
Data and information that support a finding that a condition is generally recognized as safe
“consist of adequate tests by methods reasonably applicable to show the drug is safe under the
prescribed, recommended, or suggested conditions of use. This proof shall include results of
significant human experience during marketing. General recognition of safety shall ordinarily be
based upon published studies which may be corroborated by unpublished studies and other data”
(21 CFR 330.10(a)(4)(i)).
Under 21 CFR 330.10(a)(4)(ii), proof of effectiveness ordinarily shall consist of adequate and
well-controlled studies as defined in 21 CFR 314.126(b). Five typical features of studies
considered to be adequate and well-controlled are that the studies are randomized, are blinded,
have sufficient number of subjects, include an appropriate target population, and contain a
control arm.9 The control arm of an adequate and well-controlled trial may use various types of
controls, including a placebo, a comparator product, or historical control (21 CFR
314.126(b)(2)).
In addition, only relevant studies should be submitted. An example of a study that we ordinarily
would consider irrelevant would be an in vitro effectiveness study when we would require
clinical effectiveness studies to approve an NDA for the condition.
9

See 21 CFR 314.126(b) and the guidance for industry Providing Clinical Evidence of Effectiveness for Human
Drug and Biological Products.

14

Contains Nonbinding Recommendations

Other recommended characteristics are formulations similar to U.S. formulations, ideally with
multiple formulations studied, appropriate arms to assess each active ingredient independently in
combination products, and a use pattern similar to the intended U.S. OTC use pattern. Studies
should be conducted according to applicable good laboratory or good clinical practices, as
described in 21 CFR parts 58 and 312. In addition, it is useful to provide safety and
effectiveness data from other countries as well as any safety and/or effectiveness evaluations
from any other regulatory body.
D.

Do I need to prepare an environmental assessment with my safety and
effectiveness data?

As stated in 21 CFR 25.1, our regulations must be administered in accordance with the policies
set forth in the National Environmental Policy Act of 1969 (NEPA). To comply with NEPA, an
environmental assessment (EA) of our actions is required unless we determine that a categorical
exclusion is warranted (21 CFR 25.20(f) and 25.21).
Most actions on OTC drug monographs have been categorically excluded from the EA
requirement under 21 CFR 25.31(a), because the actions generally have not increased the use of
active ingredients previously marketed in the United States. However, if we determine that an
active ingredient not previously marketed in the United States is GRASE and include it in a
monograph, this exclusion from the EA requirement would not apply because our action would
increase the use of the active ingredient. Thus, the exclusion under 21 CFR 25.31(a) may not
apply to many active ingredients found eligible for inclusion in an OTC drug monograph under
the TEA process.
Even when 21 CFR 25.31(a) does not apply, active ingredients found eligible for inclusion in an
OTC drug monograph under the TEA process may qualify for the categorical exclusions
provided under 21 CFR 25.31(b) or (c). Under 21 CFR 25.31(b), an action on an OTC
monograph is excluded from the EA requirement if the action increases the use of an active
ingredient, but the estimated concentration of the active ingredient will not exceed 1 part per
billion10 in the aquatic environment. If the action is for an active ingredient that naturally occurs
in the environment, 21 CFR 25.31(c) excludes the action from the EA requirement if it does not
significantly alter the concentration or distribution of the ingredient, its metabolites, or
degradation products in the environment.
To determine whether an action on an OTC monograph meets the requirements for exclusion
from the EA requirement under 21 CFR 25.31(b) or (c), we need additional data and information.
Therefore, when submitting safety and efficacy data, you should also submit information that
will help us make this determination.
To help us determine whether the action meets the requirements for exclusion under
21 CFR 25.31(b), you should submit an estimate of the expected introductory concentration of
the eligible active ingredient in the aquatic environment (as described in section III of the
guidance for industry Environmental Assessment of Human Drug and Biologics Applications
10

1 microgram per liter

15

Contains Nonbinding Recommendations
(EA guidance)). If the eligible active ingredient naturally occurs in the environment, we will
determine on a case-by-case basis the appropriateness of applying the categorical exclusion
under 21 CFR 25.31(c), as described in section III of the EA guidance.
If no categorical exclusion applies to a particular FDA action on a monograph, the preparation of
an EA is ordinarily required (21 CFR 25.20). Section IV of the EA guidance explains how to
prepare an EA for submission to the FDA.
E.

Where do I send my safety and effectiveness data submission?

You can submit your safety and effectiveness data, identified by the docket number, through the
following Web site: http://www.regulations.gov. Alternatively, data can be submitted by fax,
mail, hand delivery, or courier to the Division of Dockets Management. For contact information
for the Division of Dockets Management, see
http://www.fda.gov/RegulatoryInformation/Dockets/default.htm.
F.

What happens after I submit safety and effectiveness data?

After interested persons have submitted safety and effectiveness data in response to the notice of
eligibility, we review the data. We may use an advisory review panel in accord with the
provisions in 21 CFR 330.10(a)(3) to evaluate the data, evaluate the data in conjunction with the
advisory review panel, or evaluate the data on our own (21 CFR 330.14(g)).
If we make an initial determination that the condition is GRASE based on our review of the data,
we will propose to include the condition in a monograph, by amending an existing monograph or
creating a new monograph if needed (21 CFR 330.14(g)(3)).
If we make an initial determination that the condition is not GRASE, we will notify the TEA
applicant and other interested persons who submitted data, and publish a notice of proposed
rulemaking to include the condition in 21 CFR 310.502 (21 CFR 330.14(g)(4)).
In both cases, TEA applicants and interested persons will have an opportunity to comment on the
FDA’s initial determination and proposed rule, and to submit additional data
(21 CFR 330.14(g)(5)). We will subsequently publish a final rule (or a reproposal if necessary)
in the Federal Register (21 CFR 330.14(g)(5)).
G.

How long does a safety and effectiveness review take?

The TEA route is not an expedited process for revising OTC drug monographs or for getting a
particular OTC drug to market. As explained above, after a condition is found eligible for
inclusion in the OTC drug monograph system, we evaluate the safety and effectiveness of the
condition using the same standards and processes that we use to evaluate any condition under the
OTC drug monograph system (21 CFR 330.14(g)). We cannot specify a typical time frame for
completion of our evaluation because it is dependent on FDA resources and priorities. In
addition, the quality of data submitted to the FDA can affect how long the evaluation takes (see
section VII.B.).

16