[Federal Register Volume 87, Number 123 (Tuesday, June 28, 2022)]
[Proposed Rules]
[Pages 38313-38331]
[FR Doc No: 2022-13309]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 314

[Docket No. FDA-2021-N-0862]
RIN 0910-AH62

Nonprescription Drug Product With an Additional Condition for
Nonprescription Use

AGENCY: Food and Drug Administration, Department of Health and Human
Services (HHS).

ACTION: Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA, the Agency, or we) is
proposing to establish requirements for a nonprescription drug product
with an additional condition for nonprescription use (ACNU). The
proposed rule, if finalized, would establish requirements for a
nonprescription drug product that has an ACNU that an applicant must
implement to ensure appropriate self-selection or appropriate actual
use, or both, by consumers without the supervision of a healthcare
practitioner. The proposed rule is intended to increase options for
applicants to develop and market safe and effective nonprescription
drug products, which could improve public health by broadening the
types of nonprescription drug products available to consumers.

DATES: Either electronic or written comments on the proposed rule must
be submitted by October 26, 2022. Submit comments (including
recommendations) on information collection issues under the Paperwork
Reduction Act of 1995 by July 28, 2022.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of October 26, 2022. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2021-N-0862 for ``Nonprescription Drug Product with an Additional
Condition for Nonprescription Use.'' Received comments, those filed in
a timely manner (see ADDRESSES), will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at https://www.regulations.gov or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.
    Submit comments on information collection issues under the
Paperwork Reduction Act of 1995 to the Office of Management and Budget
(OMB) at https://www.reginfo.gov/public/do/PRAMain. Find this
particular information collection by selecting ``Currently Under
Review--Open for Public Comments'' or by using the search function. The
title of this proposed collection is ``Premarket applications,
postmarketing reports and recordkeeping, and labeling for
Nonprescription Drug Products With an Additional Condition for
Nonprescription Use.''

FOR FURTHER INFORMATION CONTACT:
    With regard to the proposed rule: Chris Wheeler, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 3330, Silver Spring, MD 20993-0002, 301-
796-0151, [email protected].
    With regard to the information collection: Domini Bean, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852,<PHONE_NUMBER>,
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Need for the Regulation
    B. FDA's Current Regulatory Framework
    C. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
    A. Applicability
    B. Definitions (Proposed Sec. Sec.  314.56(a) and 201.67(b))
    C. Separate Application Required for a Nonprescription Drug
Product With an ACNU (Proposed Sec.  314.56(b))
    D. Specific Requirements for an Application for a
Nonprescription Drug Product With an ACNU (Proposed Sec.  314.56(c))
    E. Nonprescription and Prescription Approval and Simultaneous
Marketing (Proposed Sec.  314.56(d))
    F. Refusal To Approve an Application With an ACNU (Proposed
Sec. Sec.  314.125(b)(20) and 314.127(a)(15))
    G. Other Postmarketing Reports (Proposed Sec.  314.81(b)(3)(v))
    H. General Labeling Requirements (Proposed Sec.  201.67(c))
    I. Format Requirements for Required ACNU Statement (Proposed
Sec.  201.67(d))
    J. Exemption From Adequate Directions for Use (Proposed Sec.
201.130)
    K. Misbranding (Proposed Sec.  201.67(e))
VI. Proposed Effective Date
VII. Preliminary Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to establish requirements for a nonprescription
drug product with an additional condition for nonprescription use
(ACNU), which is a drug product that could be marketed without a
prescription if an applicant implements an additional condition to
ensure appropriate self-selection or appropriate actual use, or both,
by consumers without the supervision of a healthcare practitioner.
Currently, nonprescription drug products are limited to drugs that can
be labeled with sufficient information for consumers to appropriately
self-select and use the drug product. For certain drug products,
limitations of labeling present challenges for adequate communication
of information needed for consumers to appropriately self-select or use
the drug product without the supervision of a healthcare practitioner.
The proposed rule is intended to increase options for applicants to
develop and market safe and effective nonprescription drug products,
which could improve public health by broadening the types of
nonprescription drug products available to consumers.

B. Summary of the Major Provisions of the Proposed Rule

    The proposed rule, if finalized, would establish requirements for a
nonprescription drug product with an ACNU. The evidentiary standards
that an application must meet under the Federal Food, Drug, and
Cosmetic Act (FD&C Act) and current FDA regulations for demonstrating
safety and effectiveness would continue to apply to nonprescription
drug products approved with an ACNU. This proposed rule would establish
additional application requirements, labeling requirements, and
postmarketing reporting requirements for a nonprescription drug product
with an ACNU.
    The proposed rule would establish the requirements for a new drug
application (NDA) or abbreviated new drug application (ANDA) for a
nonprescription drug product with an ACNU. An applicant would be
required

to submit a separate application for the approval of a nonprescription
drug product with an ACNU, rather than a supplement to an application
approved as a prescription drug product. In addition to applicable
existing application requirements, NDA applicants would also be
required to describe the ACNU and submit information to support the
ACNU.
    The proposed rule would clarify that an ACNU would constitute a
meaningful difference between a prescription drug product and a
nonprescription drug product that makes the nonprescription drug
product safe and effective for use without the supervision of a
healthcare practitioner licensed by law to administer the drug. For
instance, two drug products could have the same active ingredient,
dosage form, strength, route of administration, and indication, with
one made available as a nonprescription drug product with an ACNU and
the other product made available only by prescription.
    The proposed rule would specify that FDA would refuse to approve an
NDA or ANDA for a nonprescription drug product with an ACNU if the
application fails to meet the applicable requirements of proposed Sec.
314.56 (21 CFR 314.56).
    The proposed rule would establish postmarketing reporting
requirements for a nonprescription drug product with an ACNU. NDA and
ANDA applicants would be required to submit a report with information
concerning any incident of failure in the implementation of an ACNU,
such as a consumer gaining access to the drug product without
fulfilling the ACNU.

C. Legal Authority

    FDA's proposal to establish requirements for a nonprescription drug
product with an ACNU is authorized by sections 201(n), 502, 503(b),
505, and 701(a) of the FD&C Act (21 U.S.C. 321(n), 352, 353(b), 355,
and 371(a)).

D. Costs and Benefits

    The proposed rule, if finalized, would establish, for any
applicant, the requirements for a nonprescription drug product with an
ACNU. Compared to the traditional labeling paradigm of nonprescription
drug products, this approved ACNU in addition to the labeling would
ensure the appropriate self-selection, appropriate use, or both, of a
drug product. We expect that this proposed rule, if finalized, would
expand consumer access to certain drug products in a nonprescription
setting.
    Greater access to drug products would allow consumers to treat
certain medical conditions using nonprescription drug products with an
ACNU without the supervision of a healthcare practitioner. We estimate
a reduction in access costs to consumers who could transfer from a
prescription to a nonprescription drug product with an ACNU. Our
primary estimate for this item is $26.70 with a range of $0 to $53.40
per consumer per purchase. There may also be cost savings associated
with a potential reduction in the number of repetitive meetings between
FDA and industry. Our primary estimate is $55,469 per applicant with a
range of $45,260 to $66,174. Government and private insurance payers
may also experience cost savings because the availability of
nonprescription drug products with an ACNU may decrease future medical
costs and the number of submitted insurance claims. In addition, we
assume that applicants would submit applications when they believe that
the profits from a potential approval would exceed the costs of the
application. We lack information to monetize these potential profits
and costs. We do not monetize our estimates of benefits over a 10-year
horizon because of the high uncertainty about the number of applicants,
applications, potential approvals, the number of purchases that might
occur, and consumer preferences to switch products. For details, see
the Preliminary Regulatory Impact Analysis (PRIA), the Uncertainty and
Sensitivity section, as well as the Appendix of the same document.
    Monetized costs include a one-time cost of reading and
understanding the rule for those applicants potentially interested in
submitting applications for their nonprescription drug products with an
ACNU. Our primary estimate of these costs equals $821 with a range of
$379 and $1,264 using a 7-percent discount rate annualized over a ten-
year horizon.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

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             Abbreviation/acronym                    What it means
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ACNU.........................................  Additional Condition for
                                                Nonprescription Use.
ANDA.........................................  Abbreviated New Drug
                                                Application.
DFL..........................................  Drug Facts Labeling.
FAERS........................................  FDA Adverse Event
                                                Reporting System.
FD&C Act.....................................  Federal Food, Drug, and
                                                Cosmetic Act.
FDA..........................................  Food and Drug
                                                Administration.
ICSR.........................................  Individual Case Safety
                                                Report.
NDA..........................................  New Drug Application.
NDC..........................................  National Drug Code.
OMB..........................................  Office of Management and
                                                Budget.
OTC..........................................  Over-the-Counter.
PDP..........................................  Principal Display Panel.
RLD..........................................  Reference Listed Drug.
------------------------------------------------------------------------

III. Background

A. Need for the Regulation

    Nonprescription drug products are important for the treatment of
many conditions and diseases, although at present most nonprescription
drug products are intended to provide temporary relief of minor
symptoms or self-diagnosable, self-limited conditions and diseases,
rather than chronic diseases. Unlike prescription drug products,
nonprescription drug products may be accessed and used safely and
effectively by consumers without the supervision of a healthcare
practitioner when certain conditions are met. Currently,
nonprescription drug products are limited to drugs that can be labeled
with sufficient information to enable consumers to appropriately self-
select and use the drug product without the supervision of a healthcare
practitioner. Self-selection is the decision consumers make to use or
not to use a drug product based on reading the information on the drug
product labeling and applying knowledge of their personal medical
history (Ref. 1). Nonprescription drug products are usually available
for consumers to purchase at pharmacies, supermarkets,

or other retail locations, and from online retailers.
    FDA recognizes the potential benefit of providing consumers with
access to additional types of nonprescription drug products, such as
some drug products that are currently available only by prescription
and that treat chronic diseases or conditions. However, there are
certain drug products that an applicant may seek to market on a
nonprescription basis where labeling alone cannot adequately
communicate the information needed for consumers to appropriately self-
select, use, or both self-select and use the drug product safely and
effectively without the supervision of a healthcare practitioner.
    The proposed rule has the potential to broaden the types of drug
products that FDA could approve as nonprescription. Under the proposed
rule, when labeling alone is not sufficient to ensure that the consumer
can appropriately self-select or appropriately actually use, or both, a
drug product correctly in a nonprescription setting, an applicant may
submit an application proposing an ACNU that a consumer must
successfully fulfill to obtain the nonprescription drug product with an
ACNU. For example, an applicant may submit an application for a
nonprescription drug product with an ACNU that enables a consumer to
treat a chronic condition that currently does not have a
nonprescription treatment. The availability of nonprescription drug
products with an ACNU may provide public health benefits by
facilitating consumers' self-care and autonomy over their medical
treatment (Ref. 2).

B. FDA's Current Regulatory Framework

    There are two regulatory pathways to bring a nonprescription drug
product to market in the United States: (1) the over-the-counter (OTC)
drug review process under section 505G of the FD&C Act (21 U.S.C.
355h); and (2) the new drug application process under section 505 of
the FD&C Act. Under the OTC drug review process, a nonprescription drug
product may be marketed without an approved NDA or ANDA under section
505 of the FD&C Act if the nonprescription drug product meets the
requirements of section 505G of the FD&C Act, and other applicable
requirements.
    FDA approves drugs as either prescription or nonprescription drug
products under section 505 of the FD&C Act. A drug must be dispensed by
prescription when it is not safe for use except under the supervision
of a healthcare practitioner licensed by law to administer such drug
product because of its toxicity or other potentiality for harmful
effect, or the method of its use, or the collateral measures necessary
to its use (see section 503(b)(1) of the FD&C Act). If the approved
drug does not meet the criteria for prescription-only dispensing, it
may be marketed as nonprescription.
    Section 503(b)(4)(B) of the FD&C Act provides that a drug product
to which the prescription provisions of the FD&C Act do not apply
(i.e., a nonprescription drug product) will be deemed to be misbranded
if at any time before dispensing, the label of the drug bears the ``Rx
only'' symbol. Read together with section 503(b)(4)(A) of the FD&C Act,
which requires prescription drug products to bear the ``Rx only''
symbol, this effectively means that absent a meaningful difference
between the products, simultaneous marketing of two drug products with
the same active ingredient as both a prescription and a nonprescription
drug would result in one of the two products being misbranded. Examples
of meaningful differences that can make a prescription drug product
safe and effective only under the supervision of a healthcare
practitioner licensed by law to administer such drug include the
indication, strength, route of administration, dosage form, or patient
population (see 83 FR 13994 at 13995, April 2, 2018; see also 70 FR
52050, September 1, 2005).
    An applicant may submit an NDA for a nonprescription drug product
using the pathways described in section 505(b)(1) or (2) of the FD&C
Act to market a new drug product. A 505(b)(1) NDA includes full reports
of investigations to demonstrate that the proposed drug product is safe
and effective under the conditions prescribed, recommended, or
suggested in its proposed labeling (see sections 505(d) and (b)(1) of
the FD&C Act). Thus, an NDA for a nonprescription drug product must
include, among other things, information to demonstrate that consumers
can appropriately self-select and use the proposed drug product safely
and effectively without the supervision of a healthcare practitioner.
An NDA submitted under section 505(b)(2) of the FD&C Act also includes
information to demonstrate that the proposed drug product is safe and
effective under the conditions prescribed, recommended, or suggested in
its proposed labeling, but at least some of the information required
for approval comes from studies not conducted by or for the applicant
and for which the applicant has not obtained a right of reference or
use (21 U.S.C. 355(b)(2)).
    Applicants may submit an ANDA using the pathway described in
section 505(j) of the FD&C Act for a drug product that is a generic
version of a previously approved drug product. An ANDA for a
nonprescription drug product generally references a nonprescription
drug product previously approved under section 505(c) of the FD&C Act
(known as the RLD) and relies on the Agency's finding that the RLD is
safe and effective. An ANDA generally must contain information to show
that the proposed generic product (1) is the same as the RLD with
respect to the active ingredient(s), conditions of use, route of
administration, dosage form, strength, labeling (with certain
permissible differences) and (2) is bioequivalent to the RLD. The
procedures and requirements for the submission and approval of NDAs,
ANDAs, and supplements to those applications are provided in part 314
(21 CFR part 314).
    Generally, nonprescription drug products must be labeled with
adequate directions for use so the consumer: (1) can use the drug
product safely and for the purposes for which it is intended and (2)
make an appropriate self-selection decision and appropriately use the
nonprescription drug product (see section 502(f)(1) of the FD&C Act and
Sec.  201.5 (21 CFR 201.5)). Consumer studies can help demonstrate that
the requirement for adequate directions for use is met. These studies
may include label comprehension studies (Ref. 3), self-selection
studies (Ref. 1), actual-use studies, and other human factors studies.
    Nonprescription drug products must also comply with applicable
labeling requirements under part 201 (21 CFR part 201), including the
format and content requirements for OTC drug product labeling under
Sec.  201.66. Labeling created to satisfy the requirements in Sec.
201.66 is commonly referred to as the Drug Facts labeling (DFL). The
DFL is intended to enable consumers to appropriately self-select and
use the nonprescription drug product safely and effectively. In
addition to the DFL, FDA may approve additional labeling for
nonprescription drug products.

C. History of the Rulemaking

    FDA has received a number of inquiries from stakeholders about
whether applications may be submitted for nonprescription drug products
with one or more additional conditions that consumers must fulfill to
ensure that the drug product is safe and effective for nonprescription
use. As explained in detail below, FDA held a public hearing

and participated in a series of workshops convened by the Engelberg
Center for Health Care Reform at the Brookings Institution (Brookings
Institution) to solicit public input on expanding the approval of
nonprescription drug products. FDA used stakeholder input from the
public hearing and the workshops to develop the proposed rule.
1. FDA 2012 Public Hearing
    In the Federal Register of February 28, 2012 (77 FR 12059), FDA
announced a public hearing under part 15 (21 CFR part 15) entitled
``Using Innovative Technologies and Other Conditions of Safe Use to
Expand Which Drug Products Can Be Considered Nonprescription'' (2012
public hearing). FDA held this public hearing on March 22 and 23, 2012,
to: (1) seek input from interested stakeholders on a potential new
paradigm where FDA would approve certain drug products for
nonprescription use with certain conditions specific to a drug product
that would otherwise require a prescription and (2) obtain information
and comments on the feasibility of this paradigm and its potential
benefits and costs. As part of the public hearing, FDA requested
information and public comment on the types of technology that could be
used; the types of conditions of safe use; and the potential impacts on
pharmacies, consumers, and healthcare practitioners, as well as other
issues that might arise under the paradigm. FDA received comments from
various stakeholders, including consumers, private industry, healthcare
professional associations, academic institutions, and patient advocacy
organizations, on a broad range of topics such as: (1) access to care,
(2) medication nonadherence, (3) practitioner oversight, (4) potential
effect on healthcare and healthcare costs, (5) potential impact on
medical conditions or diseases, (6) use of diagnostic aids and
technologies as possible conditions of safe use, and (7) potential
barriers to successful implementation and adoption (see Docket No. FDA-
2012-N-0171).
2. Brookings Institution Workshops
    The Brookings Institution convened a series of three expert
workshops, based on a cooperative agreement with FDA, to seek
stakeholder feedback on practical considerations for the development of
a new paradigm focused on developing innovative approaches for
consumers to self-select nonprescription drug products appropriately
and maintain their safe and effective use and to explore potential
practical strategies. Participants included a diverse set of
stakeholders from both public and private sectors, including FDA and
other Government agencies, healthcare professional associations, trade
associations, technology developers, pharmaceutical manufacturers,
healthcare professionals, academic institutions, retail pharmacy
representatives, and patient advocacy organizations.
    On November 8, 2012, the Brookings Institution convened the first
expert workshop, ``Nonprescription Medications With Conditions of Safe
Use as a Novel Solution for Undertreated Diseases or Conditions.'' This
workshop explored issues and practical considerations for the
development of this new paradigm (Ref. 4).
    On May 9, 2013, the Brookings Institution held the second expert
workshop, ``Innovative Technologies and Nonprescription Medications:
Addressing Undertreated Diseases and Conditions Through Technology
Enabled Self-Care.'' This workshop explored the potential for
innovative technologies to facilitate safe and effective use of
nonprescription drug products (Ref. 5).
    On November 4, 2013, the Brookings Institution held the final
expert workshop, ``Exploring Implications of the Nonprescription Drug
Safe Use Regulatory Expansion Initiative on Reimbursement and Access.''
This workshop focused on assessing this paradigm's potential impact on
consumer access and reimbursement (Ref. 6).
3. Innovative Approaches for Nonprescription Drug Products; Draft
Guidance for Industry
    In the Federal Register of July 18, 2018 (83 FR 33938), FDA
published a notice of availability of a draft guidance entitled
``Innovative Approaches for Nonprescription Drug Products'' and
established Docket No. FDA-2018-D-2281. This draft guidance describes
two innovative approaches that may be useful for applicants to consider
in cases where the DFL alone is not sufficient to ensure that a drug
product can be used safely and effectively in a nonprescription
setting. These approaches include the development of labeling in
addition to the DFL and the implementation of additional conditions so
that consumers can appropriately self-select and use the product.

IV. Legal Authority

    FDA's proposal to establish requirements for a nonprescription drug
product with an ACNU is authorized by sections 201(n), 502, 503(b),
505, and 701(a) of the FD&C Act (21 U.S.C. 321(n), 352, 353(b), 355,
and 371(a)). Section 502(f) of the FD&C Act deems a drug to be
misbranded unless its labeling bears adequate directions for use and
adequate warnings against use in those conditions where its use may be
dangerous to health, as well as adequate warnings against unsafe dosage
or methods or duration of administration or application, in such manner
and form, as are necessary for the protection of users. Section 502(f)
also authorizes the promulgation of regulations exempting a drug or
device from the requirement to bear adequate directions for use upon a
determination that such directions are not necessary for the protection
of public health.
    We are proposing to add an exemption for human nonprescription drug
products approved with an ACNU from the requirement in section
502(f)(1) of the FD&C Act for drug products to have labeling that
provides adequate directions for use (see proposed Sec.  201.130). When
labeling alone cannot provide adequate directions for use for a human
nonprescription drug product, FDA may approve the nonprescription drug
product with an ACNU under proposed Sec.  314.56.
    In addition, section 502(a) of the FD&C Act deems a drug to be
misbranded if its labeling is false or misleading in any particular.
Under section 201(n) of the FD&C Act, in determining whether labeling
is misleading, there shall be taken into account (among other things),
not only representations made or suggested but also the extent to which
the labeling fails to reveal facts material in the light of such
representations or material with respect to consequences that may
result from the use of the drug under the conditions of use prescribed
in the labeling or under usual or customary conditions of use.
    In addition, under section 505 of the FD&C Act, FDA will approve an
NDA only if the drug is shown to be both safe and effective for use
under the conditions prescribed, recommended, or suggested in the
proposed labeling for the product. See section 505(c)(1) and (d) of the
FD&C Act. If, for example, on the basis of information submitted as
part of the application or on the basis of any other information before
the Agency with respect to such drug, there is insufficient information
to determine whether such drug is safe for use under such conditions,
the Agency will not approve the drug. Section 505(j) of the FD&C Act
describes the requirements

for ANDAs. In particular, section 505(j)(2)(A) specifies the
information that must be included in an ANDA, and section 505(j)(4)
describes the approval standard for an ANDA.
    In addition, section 503(b) of the FD&C Act contains provisions
regarding the marketing of a drug as either a prescription drug product
or a nonprescription drug product.
    Finally, section 701(a) of the FD&C Act authorizes FDA to issue
regulations for the efficient enforcement of the FD&C Act.

V. Description of the Proposed Rule

    We are proposing to add Sec.  314.56 to part 314, subpart B, to
establish additional application requirements for a nonprescription
drug product with an ACNU under an NDA or an ANDA. The evidentiary
standards that an NDA for a nonprescription drug product must meet
under the FD&C Act and current FDA regulations to demonstrate the
safety and effectiveness of the drug product would apply to a
nonprescription drug product approved with an ACNU. An ANDA referencing
a nonprescription drug product with an ACNU previously approved under
an NDA may rely on FDA's finding that the listed drug product is safe
and effective for use under the conditions described in the labeling.
We are proposing to add Sec.  314.125(b)(20) to part 314, subpart D, to
specify that FDA would refuse to approve an NDA for a nonprescription
drug product with an ACNU that does not meet the applicable
requirements established in Sec.  314.56. We are also proposing to add
Sec.  314.127(a)(15) to part 314, subpart D, to specify that FDA would
refuse to approve an ANDA for a nonprescription drug product with an
ACNU that does not meet the applicable requirements established in
Sec.  314.56. We are proposing to add Sec.  314.81(b)(3)(v) to part
314, subpart B, to establish postmarketing reporting requirements for a
nonprescription drug product with an ACNU. We are also proposing to add
Sec.  201.67 to part 201, subpart C, to establish labeling requirements
for a nonprescription drug product with an ACNU. We are proposing to
add Sec.  201.130 to part 201, subpart D, to establish an exemption
from the statutory requirement for adequate directions for use for a
nonprescription drug product with an ACNU. The proposed rule is
intended to increase options for applicants to develop and market safe
and effective nonprescription drug products, which could improve public
health by broadening the types of nonprescription drug products
available to consumers. For example, FDA may approve a nonprescription
drug product with an ACNU to treat a chronic condition that currently
does not have nonprescription treatments.
    A detailed description of each proposed section is provided in
sections V.A through V.K of this document.

A. Applicability

    The proposed rule would apply to NDAs and ANDAs for nonprescription
drug products with an ACNU (see proposed Sec. Sec.  314.56, 314.81,
314.125, 314.127, 201.67, and 201.130). Nonprescription drug products
currently marketed under an approved application do not need an ACNU to
ensure appropriate self-selection and appropriate actual use because
FDA previously determined that labeling alone is sufficient for these
drugs to be used safely and effectively without a prescription. The
proposed rule would not apply to nonprescription drugs marketed under
section 505G of the FD&C Act. Therefore, a requestor (as defined in
section 505G(q)(3) of the FD&C Act) cannot submit a request under
section 505G(b) of the FD&C Act for a nonprescription drug product with
an ACNU.

B. Definitions (Proposed Sec. Sec.  314.56(a) and 201.67(b))

    We are proposing to define the term ``additional condition for
nonprescription use'' (ACNU) as one or more FDA-approved conditions
that an applicant of a nonprescription drug product must implement to
ensure consumers' appropriate self-selection or appropriate actual use,
or both, of the nonprescription drug product without the supervision of
a healthcare practitioner if the applicant demonstrates and FDA
determines that labeling alone is insufficient to ensure appropriate
self-selection or appropriate actual use, or both (see proposed
Sec. Sec.  314.56(a) and 201.67(b)). If the ACNU is intended to address
appropriate self-selection only, the labeling must enable appropriate
actual use of the nonprescription drug product by consumers.
Alternatively, if the ACNU is intended to address appropriate actual
use only, the labeling must enable consumers to appropriately self-
select the nonprescription drug product.
    The proposed definition for an ACNU is intentionally broad to give
applicants flexibility regarding the types of additional conditions
applicants may propose and how those additional conditions can be
implemented. For example, an applicant could propose an ACNU that
requires a consumer, in order to purchase the nonprescription drug
product, to respond with specific answers to a set of questions on a
self-selection test available by either a mobile application or an
automated telephone response system. An applicant may also propose that
before purchasing the nonprescription drug product with an ACNU, a
consumer be required to view labeling (for example, text or images in a
video), that describes how to appropriately use the nonprescription
drug product and to respond to questions to confirm understanding.

C. Separate Application Required for a Nonprescription Drug Product
With an ACNU (Proposed Sec.  314.56(b))

    The proposed rule would not require a nonprescription drug product
with an ACNU to be first marketed as a prescription drug product.
However, in cases where there is an approved prescription drug product,
the proposed rule would establish the requirement that a
nonprescription drug product with an ACNU cannot be approved through a
supplement to the approved prescription application. Rather, an
applicant must submit a separate application for a nonprescription drug
product with an ACNU. Although a separate application would be
required, an applicant may cross reference information in its approved
NDA for the prescription product and would not need to duplicate
studies already conducted for and submitted in its NDA for the
prescription product. As explained in Section III.B., a different
applicant may submit an NDA under section 505(b)(2) of the FD&C Act,
where at least some of the information required for approval comes from
studies not conducted by or for the applicant and for which the
applicant has not obtained a right of reference or use. This is
provided the 505(b)(2) applicant establishes that the relied upon NDA
or literature is relevant to its nonprescription drug product with an
ACNU and its application includes support for any differences between
the applicant's proposed drug product and the listed drug on which the
applicant is relying to demonstrate the safety and effectiveness of the
proposed nonprescription drug product with an ACNU.
    As explained in section V.E of this document, the approved
prescription drug product and the approved nonprescription drug product
with an ACNU are two different products and could be simultaneously
marketed.
    Requiring a separate application for the nonprescription drug
product with an ACNU would enable continued marketing of the
prescription product under the original NDA and would

allow it to serve as an RLD for ANDAs for the prescription product.
Continued access to the prescription drug product, along with
availability of the nonprescription drug product approved with an ACNU,
would ensure greater access to needed drugs by providing flexibility in
how to obtain them. For example, if a nonprescription drug product
approved with an ACNU is available through a kiosk in a pharmacy,
patients who do not live near a pharmacy with such a kiosk may find it
easier to obtain the drug through a prescription.
    Additionally, patients who prefer to continue interacting with
their healthcare providers and obtain the drug by prescription would
have that option. Patients who had not previously used the drug may
also feel more comfortable initiating treatment and obtaining the drug
with the involvement of their healthcare providers. While FDA would
generally expect any technology that is used to operationalize an ACNU
to be easily usable to the majority of consumers, there may be some
consumers who may not be comfortable using such technology. Continued
availability of the prescription drug product would provide greater
flexibility in obtaining the drug and enable these patients to continue
their care without potential interruption.
    An applicant seeking an initial approval of an ANDA to market a
nonprescription drug product with an ACNU may submit an ANDA
referencing a nonprescription drug product with an ACNU previously
approved under an NDA and may rely on FDA's finding that the RLD is
safe and effective. This ANDA would also be required to have a separate
application from an existing ANDA approved as a prescription drug
product. Because the RLD nonprescription drug product with an ACNU
would have a separate NDA from the NDA approved as a prescription drug
product, the ANDA would be using a different NDA as its RLD from the
RLD for the ANDA for the prescription product. Section 505(j)(2)(D) of
the FD&C Act prohibits an applicant from amending or supplementing its
ANDA to rely on a different listed drug from the listed drug identified
in the ANDA submitted to FDA.
    An applicant may submit an amendment, supplement, or annual report
to an application for a nonprescription drug product with an ACNU,
consistent with FDA regulations (Sec. Sec.  314.60, 314.96, 314.70, and
314.97). An applicant seeking to make changes to an NDA or ANDA
submitted for a nonprescription drug product with an ACNU that is under
review by FDA would submit an amendment to the application to request a
change (Sec. Sec.  314.60 and 314.96). An applicant seeking to make
changes to an FDA-approved NDA or ANDA for a nonprescription drug
product with an ACNU would submit a supplement to the approved NDA or
ANDA (Sec. Sec.  314.70 and 314.97).

D. Specific Requirements for an Application for a Nonprescription Drug
Product With an ACNU (Proposed Sec.  314.56(c))

    The proposed rule would establish the specific NDA and ANDA
requirements for a nonprescription drug product with an ACNU (see
proposed Sec.  314.56(c)).
1. New Drug Application
    In addition to applicable existing application requirements, NDA
applicants would also be required to describe the ACNU and submit
information to support the ACNU. Specifically, the proposed rule would
require that an NDA for a nonprescription drug product with an ACNU
must, when fulfilling the content and format requirements under Sec.
314.50, include the following information about the ACNU in the
application: (1) a statement regarding the purpose of the ACNU (i.e.,
appropriate self-selection or appropriate actual use, or both, by
consumers of the nonprescription drug product without the supervision
of a healthcare practitioner) (see proposed Sec.  314.56(c)(1)(i)); (2)
a statement of the necessity of the ACNU (see proposed Sec.
314.56(c)(1)(ii)); (3) a description of how the ACNU ensures
appropriate self-selection or appropriate actual use, or both (see
proposed Sec.  314.56(c)(1)(iii)); (4) a description of the key
elements of the ACNU (see proposed Sec.  314.56(c)(1)(iv)); (5)
adequate data or other information that demonstrate the necessity of
the ACNU to ensure appropriate self-selection or appropriate actual
use, or both (see proposed Sec.  314.56(c)(1)(v)); (6) adequate data or
other information that demonstrate the effect of the ACNU on the
appropriate self-selection or appropriate actual use, or both (see
proposed Sec.  314.56(c)(1)(vi)); and (7) a description of the specific
way the ACNU is operationalized (see proposed Sec.  314.56(c)(1)(vii)).
The first four requirements for the ACNU in the application (see
proposed Sec.  314.56(c)(1)(i) through (iv)) and the last requirement
for the ACNU in the application (see proposed Sec.  314.56(c)(1)(vii)
provide statements, including explanations, descriptions, and
justifications, about the ACNU; the remaining requirements for the ACNU
in the application (see proposed Sec.  314.56(c)(1)(v) through (vi))
provide data or other information to support these statements. Each of
these seven requirements for the ACNU to be included in the application
are further described in this section.
    We are providing an example of one fictitious nonprescription drug
product with an ACNU, Drug X, to provide a simplified illustration of a
product that may potentially be considered under this proposed
regulatory framework. We will use Drug X to explain examples of
information that the applicant would submit in the NDA for a
nonprescription drug product with an ACNU. This is only one type of
example; many other types of ACNUs for nonprescription drug products
could be possible.
    Drug X is proposed as a nonprescription drug product indicated for
the treatment of symptom Y in adults who have a disease-specific risk
score below the threshold for developing serious side effect E when
taking Drug X. As part of the nonprescription development program, the
applicant conducted robust self-selection and label comprehension
studies. The results of the self-selection and label comprehension
studies demonstrated that consumers cannot appropriately self-select
Drug X with labeling alone. FDA acknowledges these self-selection and
label comprehension studies were well designed and conducted and
concurs that consumers cannot self-select Drug X with labeling alone.
Results of the self-selection and label comprehension studies show
that, although consumers recognize that they have symptom Y, they
cannot appropriately calculate their disease-specific risk score for
side effect E. Therefore, the applicant proposes an ACNU for Drug X to
ensure consumers' appropriate self-selection and now seeks approval of
Drug X as a nonprescription drug product with an ACNU. The ACNU
requires all consumers to complete a questionnaire located on a secure
website created by the applicant to determine whether Drug X is
appropriate for the consumer. The questionnaire has a series of
questions that the consumer answers. The underlying program or other
operating information used by the secure website calculates the risk
score for serious side effect E using the consumer's answers and
determines if the consumer has an acceptable disease-specific risk
score to use Drug X. A consumer with an acceptable risk score can then
either: (1) purchase Drug X on the applicant's secure website or (2)
purchase Drug X

at a retail site specified by the applicant after presenting a barcoded
voucher that can be printed or downloaded onto the consumer's mobile
device from the applicant's secure website.
    a. Statement regarding the purpose of the ACNU. The proposed rule
would require the applicant to provide a statement regarding the
purpose of the ACNU (see proposed Sec.  314.56(c)(1)(i)). This
statement would indicate whether the ACNU is intended for: (1)
appropriate self-selection, (2) appropriate actual use, or (3) both.
For example, the purpose of the ACNU for Drug X is to ensure
appropriate self-selection by consumers.
    b. Statement of the necessity of the ACNU. The proposed rule would
require the applicant to explain why the ACNU is necessary to ensure
appropriate self-selection or appropriate actual use, or both, by
consumers of the nonprescription drug product (see proposed Sec.
314.56(c)(1)(ii)). The applicant must explain why labeling alone cannot
be sufficient for the purposes of meeting the approval requirements for
a nonprescription drug product. The applicant may include a summary of
the adequate data or other information that is submitted as part of an
application for a nonprescription drug product with an ACNU, pursuant
to proposed Sec.  314.56(c)(1)(v), to explain why labeling alone cannot
be sufficient.
    c. Description of how the ACNU ensures appropriate self-selection
or appropriate actual use, or both. The proposed rule would require the
applicant to describe how the ACNU will ensure appropriate self-
selection or appropriate actual use, or both, by consumers (see
proposed Sec.  314.56(c)(1)(iii)). For example, with Drug X, the
applicant would describe that the ACNU requires a consumer to complete
a questionnaire, located on a website, created by the applicant, that
would assist in calculating a consumer's risk score for developing
serious side effect E. This questionnaire would determine whether Drug
X is appropriate for the consumer. The applicant may be expected, among
other things, to justify the appropriateness of the self-selection
questions, including the criteria and/or considerations used in
calculating the risk score for a particular consumer. This may include
a description of the algorithm in the underlying program or other
operating information used by the website that calculates the risk
score for serious side effect E to determine if the consumer has an
acceptable risk score to use Drug X. The applicant would also describe
how a consumer with an acceptable risk score can then purchase Drug X.
    d. Description of key elements of the ACNU. The proposed rule would
require the applicant to describe the key elements of the ACNU (see
proposed Sec.  314.56(c)(1)(iv)). The description of the key elements
must include: (1) the additional condition(s) implemented by the
applicant to be fulfilled by the consumer to be able to obtain or use
the nonprescription drug product with an ACNU, (2) the labeling
specifically associated with the ACNU, and (3) the criteria by which
the consumer would successfully fulfill the ACNU, including a
description of the specific actions to be taken by a consumer or
required responses to be provided by a consumer. Labeling specifically
associated with the ACNU should be annotated with each specific element
of the ACNU. All labeling, including labeling specifically associated
with the ACNU, should be provided in editable documents whenever
possible. For example, labeling specifically associated with Drug X
would include the carton and container annotated with the elements
specific to the ACNU. All questions in the questionnaire would be
submitted as labeling. The applicant for Drug X would describe the
criteria by which the consumer would fulfill the ACNU including the
questions and all potential consumer responses that would determine
that Drug X was appropriate or not appropriate for the consumer.
    e. Adequate data or other information that demonstrates the
necessity of the ACNU to ensure appropriate self-selection or
appropriate actual use, or both. The proposed rule would require an
applicant to include data or other information that demonstrates the
necessity of the ACNU to ensure appropriate self-selection or
appropriate actual use, or both (see proposed Sec.  314.56(c)(1)(v)).
To do so, the applicant must conduct or reference adequate testing to
show that labeling alone would not support the safe and effective use
of the nonprescription drug product. For example, the applicant of Drug
X would submit adequate data from robust self-selection studies and
label comprehension studies that demonstrate that consumers could not
appropriately self-select Drug X with labeling alone.
    Alternatively, the applicant can submit information explaining the
necessity of the ACNU for appropriate self-selection or appropriate
actual use, or both, when FDA has previously signaled that labeling
alone is not sufficient to ensure appropriate self-selection or
appropriate actual use, or both. For example, this might apply if FDA
has previously approved multiple nonprescription drug products for the
same indication with a similar ACNU. The applicant is encouraged to
discuss its drug development plans with FDA if the applicant has
questions about whether an ACNU would be appropriate.
    f. Adequate data or other information that demonstrates the effect
of the ACNU on the appropriate self-selection or appropriate actual
use, or both. The applicant must also submit adequate data or
information that demonstrates the effect of the ACNU on the appropriate
self-selection or appropriate actual use, or both, by the consumer of
the nonprescription drug product (see proposed Sec.  314.56(c)(1)(vi)).
The data must show that consumers can appropriately self-select or use
the drug product safely and effectively, or both, with the ACNU. For
example, the applicant of Drug X would submit adequate data from robust
self-selection studies that demonstrate that consumers could
appropriately self-select Drug X with the ACNU.
    g. Description of how the applicant will operationalize the ACNU.
The proposed rule would require that the applicant describe the
specific way the ACNU is operationalized (see proposed Sec.
314.56(c)(1)(vii)). While it is important for FDA to understand how the
ACNU is operationalized because this is part of achieving appropriate
self-selection or use, the specific way an ACNU is operationalized is
not a key element of the ACNU. The purpose of the ACNU is to enable
self-selection and appropriate use without the oversight of a
healthcare practitioner. The ACNU can be operationalized in different
ways provided it reliably meets the objective. Alternatives to the way
the ACNU is operationalized in the previous example, which involves
administration of a questionnaire using a website, might include: (1)
administering the questionnaire using a display screen at a pharmacy
kiosk, (2) administering the questionnaire using a mobile application,
and (3) administering the questionnaire using an automated telephone
response system. These examples differ in the way the ACNU is
operationalized (i.e., how the questionnaire is being administered),
but the key elements (including the questions in the questionnaire and
responses that ensure appropriate self-selection) remain the same. FDA
seeks comment on any unique issues that might arise for retailers or
consumers based on the way the applicant operationalizes the ACNU in
the previous examples, e.g., in a store kiosk, online, or otherwise.
    h. Additional considerations. If an NDA applicant submits an
application

for a nonprescription drug product with an ACNU that proposes to use
certain technologies, but FDA determines that labeling alone is
sufficient to enable appropriate self-selection and appropriate actual
use, FDA would refuse to approve the application for the
nonprescription drug product with the ACNU (see proposed Sec. Sec.
314.125(b)(20) and 314.127(a)(15)). However, FDA may approve an
application for a nonprescription drug product with technologies that
do not meet the definition of an ACNU. In cases where FDA determines
that labeling alone is sufficient to enable appropriate self-selection
and appropriate actual use, the labeling statements specifically
required for a nonprescription drug product with an ACNU under this
proposed rule (see proposed Sec.  201.130) must not appear on the drug
product labeling.
2. Abbreviated New Drug Application
    Applicants may submit an ANDA referencing a listed drug that has
been approved with an ACNU under section 505(c) of the FD&C Act and
rely on FDA's previous finding that the RLD is safe and effective. The
proposed rule would require that an ANDA for a nonprescription drug
product with an ACNU must, when fulfilling the content and format
requirements under Sec.  314.94: (1) state the purpose of the ACNU (the
same purpose as the ACNU for the RLD), (2) include information
demonstrating that the key elements of the proposed ACNU are the same
as the key elements of the ACNU for its RLD, and (3) include
information on the way the ANDA applicant intends to operationalize the
proposed ACNU. If an applicant believes the ACNU is operationalized in
the same way as the RLD (e.g., both use a mobile application), the ANDA
must include information demonstrating the operationalization of the
ACNU is the same as the RLD. If the ANDA proposes a different way to
operationalize the proposed ACNU, the ANDA must include information to
show that this different operationalization of the proposed ACNU
achieves the same purpose as the ACNU for its RLD and the differences
from the RLD are otherwise acceptable in an ANDA (see proposed Sec.
314.56(c)(2)). As with all ANDAs, an ANDA for a nonprescription drug
product with an ACNU also would be expected to be pharmaceutically
equivalent and bioequivalent to its RLD and to have the same clinical
effect and safety profile as its RLD when administered to patients
under the conditions specified in the labeling. Information concerning
the purpose of the reference product's ACNU and the description of the
key elements should be available in the approval letter for the
reference product or in the publicly available approval package.
    The labeling for the ANDA drug product must be the same as the
labeling for its RLD at the time of the ANDA's approval, except for
changes required because of differences approved under a petition filed
under Sec.  314.93 or because the drug product for which an ANDA is
submitted and the RLD are produced or distributed by different
manufacturers (see sections 505(j)(2)(A) and (j)(4) of the FD&C Act)
and Sec. Sec.  314.94(a)(8) and 314.127(a)(7)).
    a. Statement regarding the purpose of the ACNU. As part of the
submission, an ANDA applicant would state the purpose of the ACNU (the
same purpose as the ACNU for the RLD) (see proposed Sec.
314.56(c)(2)(i)). Although an ANDA must state the purpose of the ACNU,
an ANDA would not be required to include the explanation of the
necessity for the ACNU or how the ACNU would ensure appropriate self-
selection, appropriate actual use, or both. As a general matter, the
ANDA would rely on FDA's findings of safety and effectiveness for an
RLD with an ACNU.
    b. Description of key elements of the ACNU. An ANDA applicant would
also provide information to show that the key elements of the proposed
ACNU are the same as the key elements of the ACNU approved for its RLD
(see proposed Sec.  314.56(c)(2)(ii)).
    c. Description of how the applicant will operationalize the ACNU.
An ANDA applicant would include information on how the ACNU would be
operationalized. The proposed rule would allow ANDA applicants to
operationalize its ACNU in a different way from its RLD. For instance,
an ANDA applicant may consider proposing to make available on the
internet a self-selection aid for its nonprescription drug product with
an ACNU, whereas the self-selection aid for its RLD is made available
at a physical retail store via an electronic display. Consistent with
section 505(j) of the FD&C Act and our general approach to ANDAs, an
ANDA would have a variety of ways to achieve the same purpose as the
ACNU for its RLD. The ANDA would contain information to support that
the way in which it is operationalized, as proposed, achieves the same
purpose as the ACNU for its RLD and the differences from the RLD are
otherwise acceptable in an ANDA (see proposed Sec.  314.56(c)(2)(iii)).
As with all ANDAs, an ANDA for a nonprescription drug product with an
ACNU also would be expected to be pharmaceutically equivalent and
bioequivalent to its RLD and have the same clinical effect and safety
profile as its RLD when administered to patients under the conditions
specified in the labeling.
    FDA requests comment on the proposal to allow potential permissible
differences between the NDA and the ANDA in the ways to operationalize
the ACNU and how an applicant would demonstrate that the ACNU for the
ANDA achieves the same purpose as the ACNU for its RLD.
    As stated earlier in this proposed rule, the specific ways to
operationalize the ACNU are not considered key elements of the ACNU and
otherwise are not considered a condition of use of the drug product.
For example, to the extent NDA applicants operationalize their ACNUs
using proprietary means, ANDA applicants can use different ways than
their RLD for operationalizing the ACNU (provided that the purpose of
the ACNU is achieved through the same key elements).
    Although FDA plays a ministerial role in listing patents in the
publication ``Approved Drug Products with Therapeutic Equivalence
Evaluations'' (commonly known as the Orange Book), FDA seeks comment on
whether patents claiming aspects of the ACNU for the nonprescription
drug product may be submitted for listing consistent with Sec.  314.53
and section 505(b)(1)(A)(viii) and (c)(2) of the FD&C Act. FDA seeks
comments on this topic and other issues FDA should consider in
implementing this proposal that will help avoid unnecessarily delaying
the entry of ANDA nonprescription drug products with an ACNU to the
drug market.

E. Nonprescription and Prescription Approval and Simultaneous Marketing
(Proposed Sec.  314.56(d))

    FDA has interpreted the language in section 503(b)(4) of the FD&C
Act to allow simultaneous marketing of drug products with the same
active ingredient as prescription and nonprescription if some
meaningful difference, such as indication, strength, route of
administration, dosage form, or patient population, exists between the
drug products that makes the prescription product safe and effective
only under the supervision of a healthcare practitioner licensed by law
to administer the drug (see 83 FR 13994, April 2, 2018; see also 70 FR
52050, September 1, 2005). Section 503(b)(1) of the FD&C Act requires a
drug which: (1) because of its toxicity or other potentiality for
harmful effect, or the method of its use, or the collateral measures
necessary to its use, is not safe for use except under the supervision
of

a practitioner licensed by law to dispense such drug or (2) is limited
by an approved application under section 505 of the FD&C Act to use
under the professional supervision of a practitioner licensed by law to
administer such drug, to be dispensed only upon prescription of a
practitioner licensed to administer such drug. Under section
503(b)(4)(B) of the FD&C Act, a drug, for which the prescription
dispensing provisions of section 503(b)(1) of the FD&C Act do not
apply, shall be deemed to be misbranded if at any time before
dispensing, the label of the drug bears the ``Rx only'' symbol.
Likewise, under section 503(b)(4)(A), drugs that are subject to the
prescription dispensing provisions of section 503(b)(1) must bear the
``Rx only'' symbol, or else they are misbranded. This effectively means
that, absent a meaningful difference between the products, simultaneous
marketing of two drug products with the same active ingredient as both
a prescription and a nonprescription drug product would result in one
of the two products being misbranded.
    Under this proposed rule, the additional condition(s) that allow a
nonprescription drug product to be safely used without the supervision
of a healthcare practitioner would be a meaningful difference between
the prescription drug product and the nonprescription drug product with
an ACNU. Therefore, under the proposed rule, a prescription drug
product and a nonprescription drug product with an ACNU that contain
the same active ingredient can be simultaneously marketed even if they
do not have other meaningful differences, such as different indications
or strengths (see proposed Sec.  314.56(d)).
    The proposed rule would require applicants seeking approval for the
first time of an NDA for a nonprescription drug product with an ACNU to
submit a separate NDA, rather than a supplement to an approved NDA (see
proposed Sec.  314.56(b)). The approval of a separate NDA would permit
simultaneous marketing and access to the drug as both a prescription
drug product and a nonprescription drug product with an ACNU.
Consistent with FDA's goal of increasing options for applicants to
develop and market safe and effective drugs for consumers, this
proposed rule would enable continued access to the drug product as a
prescription drug product, while also extending access to the drug
product in the nonprescription setting with the ACNU. Even if the
application holder of the NDA for the prescription drug product decides
to discontinue marketing of the NDA for the prescription drug product,
generic versions of the prescription drug product would be eligible for
approval relying on the discontinued NDA for the prescription product
as an RLD, so long as FDA determines that the NDA for the prescription
product was not discontinued for reasons of safety or effectiveness
(see Sec.  314.161).

F. Refusal To Approve an Application With an ACNU (Proposed Sec. Sec.
314.125(b)(20) and 314.127(a)(15))

    The proposed rule would specify that FDA would refuse to approve an
NDA for a nonprescription drug product with an ACNU if FDA has
determined the NDA failed to meet the requirements in Sec.  314.56
applicable to NDAs (see proposed Sec.  314.125(b)(20)). Similarly, the
proposed rule would specify that FDA would refuse to approve an ANDA
for a nonprescription drug product with an ACNU that fails to meet the
requirements in Sec.  314.56 applicable to ANDAs (see proposed Sec.
314.127(a)(15)). In addition to other reasons cited in Sec.  314.125 or
Sec.  314.127, FDA would refuse to approve an application for a
nonprescription drug product with an ACNU if FDA has determined that
the applicant failed to demonstrate that labeling is insufficient to
ensure consumers' appropriate self-selection or appropriate actual use,
or both, of the nonprescription drug product without the supervision of
a healthcare practitioner or if the applicant failed to demonstrate
that its proposed ACNU is adequate to ensure appropriate self-selection
or appropriate actual use, or both, by consumers without the
supervision of a healthcare practitioner. We also note that under
current Sec.  314.125(b)(8), FDA may refuse to approve an NDA if the
drug product's proposed labeling does not comply with the requirements
for labels and labeling in part 201. This authority would permit FDA to
refuse to approve an NDA with an ACNU if the labeling does not comply
with labeling requirements specific to such NDAs, such as proposed
Sec. Sec.  201.67 and 201.130. Similarly, under current Sec.
314.127(a)(7), FDA will refuse to approve an ANDA if its labeling is
not the same as the labeling of its RLD, with certain permitted
exceptions. Thus, FDA may refuse to approve an ANDA with an ACNU if its
proposed labeling does not comply with labeling requirements specific
to nonprescription products with an ACNU, such as proposed Sec. Sec.
201.67 and 201.130.

G. Other Postmarketing Reports (Proposed Sec.  314.81(b)(3)(v))

    The proposed rule would require NDA and ANDA applicants to report
to FDA information concerning any incident of failure in the
implementation of an ACNU using the FDA Adverse Event Reporting System
(FAERS) (see proposed Sec.  314.81(b)(3)(v)). A failure in
implementation of an ACNU would include any event that results from a
deviation in an applicant's implementation of the ACNU that may cause
or lead to inappropriate medication use or consumer harm, such as a
consumer gaining access to the drug product without fulfilling all
necessary conditions for the nonprescription drug product with an ACNU.
A failure in implementation of an ACNU must be reported by the
applicant whether or not the failure is associated with an adverse
event. To meet these reporting requirements, applicants will likely
need quality assurance systems in place to capture instances where
failures in implementation of an ACNU occur. A failure in
implementation of an ACNU includes the following circumstances: (1) the
consumer accessed or used the drug product without successfully
fulfilling the ACNU, (2) the consumer successfully fulfilled the ACNU
but could not access or appropriately use the drug product in the
nonprescription setting, or (3) the consumer was unable to make an
attempt to fulfill the ACNU due to systematic, technological, or
mechanical errors in the implementation of the ACNU. For example, for
the fictitious nonprescription drug product with an ACNU Drug X (as
discussed in section V.D of this document), a report would be required
to be submitted to FDA if the consumer with an acceptable risk score,
was unable to purchase Drug X on the applicant's website or receive a
voucher from the applicant's website in order to purchase Drug X at a
retail site specified by the applicant. Failure to access the drug
product could result in the consumer missing doses of the drug product.
    The applicant must submit a single report (an individual case
safety report (ICSR) of an adverse event) describing both the failure
in implementation of an ACNU and an associated adverse event when both
occur and the applicant is aware of both before submitting a report. If
the applicant determines that a failure of implementation of an ACNU
occurred that is associated with a previously submitted ICSR of an
adverse event, a followup report must be submitted to FAERS using the
same unique

identification number as the original ICSR of an adverse event and must
include the information concerning the failure in implementation of an
ACNU as required by proposed Sec.  314.81(b)(3)(v)(A). If the applicant
receives information of an adverse event associated with a previously
submitted report in FAERS of a failure in implementation of an ACNU, a
followup report must be submitted to FAERS as an ICSR of an adverse
event. Such followup report must use the same unique identification
number as the original report in FAERS of a failure in implementation
of an ACNU and must include the information concerning the adverse
event as required in Sec.  314.80(f).
    A report to FAERS for a failure in implementation of an ACNU would
be submitted when the applicant has at least the minimum dataset for a
failure in implementation, which includes the following three elements:
(1) an identifiable reporter, (2) the drug product name, and (3) a
description of the failure in implementation of the ACNU. The proposed
rule would require the report to include certain information that the
applicant is aware of about the drug product and the initial reporter,
as well as a narrative summary of the failure in implementation of an
ACNU and a description of the action initiated or completed to address
the failure in implementation of an ACNU. The applicant would be
required to submit a report for each failure in implementation of an
ACNU as soon as possible but no later than 15 calendar days from the
date when the applicant has acquired the minimum dataset for a report
of a failure in implementation of an ACNU. Additionally, if an
applicant obtains or otherwise receives any new information about
previously submitted reports about the failure in implementation of an
ACNU, the applicant would be required to investigate the new
information, assess the relationship or impact of the new information
on the initial report, and submit followup reports as soon as possible
but no later than 15 calendar days after obtaining the new information.
Proposed Sec.  314.81(b)(3)(v)(C) would require the report to be
submitted to FDA in an electronic format that FDA can process, review,
and archive unless a waiver has been requested and granted. To better
enable FDA to assess compliance with reporting requirements and to
facilitate FDA's inspection of related records, we are proposing to
require an applicant to maintain for a period of 10 years the records
of all reports of failures in implementations of an ACNU and associated
adverse events known to the applicant (proposed Sec.
314.81(b)(3)(v)(D)).
    FDA seeks specific comment on the burden and benefits of submitting
an individual report to FDA for each individual failure in
implementation of an ACNU encountered by a consumer resulting from the
same cause of failure, as opposed to a single, consolidated report for
all such failures. For example, there could be a situation where an
ACNU involves administration of a questionnaire using a pharmacy kiosk,
and the kiosk screen malfunctions, preventing multiple consumers from
fulfilling the ACNU because they cannot complete the questionnaire on
the kiosk screen. We are seeking comment on the benefits and burdens in
this type of situation of submitting individual reports for each
consumer affected by the malfunction versus one single, consolidated
report for all consumers affected.

H. General Labeling Requirements (Proposed Sec.  201.67(c))

    The proposed rule would clarify that a nonprescription drug product
with an ACNU must comply with all applicable regulatory requirements
for nonprescription drug products, including those under part 201.
Specifically, the applicant must comply with the existing content and
format requirements for nonprescription drug products in Sec.  201.66,
known as the DFL (see proposed Sec.  201.67(c)(1)). As required in
Sec.  201.66(c)(6), the labeling for all nonprescription drug products
must contain directions for use under the heading ``Directions.'' The
proposed rule would require the labeling for all nonprescription drug
products approved with an ACNU to include the following statement, as
specified in proposed Sec.  201.130(a)(1), as the first statement under
the heading ``Directions'': ``To check if this drug is safe for you, go
to [insert where or how consumers can find information about the ACNU;
for example, applicant's website, applicant's phone number, or specific
retail location] and [insert action to be taken by consumer]. Do not
take this drug without completing this step.'' This initial statement
would be followed by the other required information in Sec.
201.66(c)(6). This proposed statement would alert consumers that the
nonprescription drug product with an ACNU has a requirement that must
be fulfilled to ensure safe and effective use. The proposed statement
would further remind the original purchaser and alert persons other
than the original purchaser that the product is not suitable for all
individuals and that consumers should carefully examine any labeling
accompanying the nonprescription product with an ACNU before using the
product.
    As stated previously, FDA may currently approve labeling for
nonprescription drug products in addition to the DFL, and this would
continue if the proposed rule is finalized (see proposed Sec.
201.67(c)(2)). For example, FDA could approve information leaflets or
other documents contained inside the carton or container for a
nonprescription drug product, including for a nonprescription drug
product with an ACNU.
    A list of questions to be answered by the consumer in a self-
selection aid could be labeling necessary to effectively implement the
ACNU. All labels and other written, printed, or graphic matter that are
necessary to effectively implement the ACNU (e.g., questions associated
with a self-selection aid) would be considered to accompany the
nonprescription drug product and, therefore, would meet the definition
of labeling under the FD&C Act.
    Approved labeling for a nonprescription drug product with an ACNU
must be available to consumers at the time of purchase and use as
required in section 502(c) of the FD&C Act. In general, we believe that
the applicant should describe in their application the process for
ensuring consumers have access to the approved labeling prior to
fulfilling the ACNU.

I. Format Requirements for Required ACNU Statement (Proposed Sec.
201.67(d))

    The proposed rule would require that the statement specified in
Sec.  201.130(a)(2) meet specific format requirements (see proposed
Sec.  201.67(d)). This statement must be visible to consumers at the
time of purchase and use. Additionally, the statement would alert
persons that may have access to the drug product (e.g., family members
in the purchaser's home), including the individual who originally
purchased the product, that these nonprescription drug products are not
suitable for all individuals and should only be used after fulfilling
the ACNU. The proposed rule would require that the statement appear on
the principal display panel (see Sec.  201.60) and the immediate
container surface that the consumer is most likely to view when seeking
information about the drug product (see proposed Sec.  201.67(d)(1)).
If the immediate container is a bottle, the statement must appear on
the surface that the consumer would most likely consider to be the
front of the bottle. If

the immediate container is a blister card, the statement must appear on
the blister card surface that the consumer would most likely view when
removing the drug product from the blister card. If the blister card
contains more than one blister unit, the statement would not need to be
included on each blister unit of a blister card. However, the statement
must remain intact and be readable on the blister card when the drug
product is removed from each blister unit.
    The proposed rule would require that the statement be prominently
presented in boldface and black type in a yellow background banner (see
proposed Sec.  201.67(d)(2) and (3)). No other information or statement
may be included in the yellow background banner. The hue of the yellow
color in the background banner must be a shade that provides a high
contrast with the black type of the statement. The font size of the
statement would be at least 25 percent as large as the font size of the
largest printed words on the container surface that the consumer would
most likely view when seeking information about the drug product; in no
case could the font size be smaller than 12 point type (1 point =
0.0138 inches) (see proposed Sec.  201.67(d)(4)). For containers where
the size would render compliance with this requirement impractical, the
applicant would be able to request an exception to the minimum font
size requirement (see proposed Sec.  201.67(d)(5)). However, FDA would
not determine an exception is warranted if the statement is not
prominent in relation to other elements on the container surface
containing the statement.

J. Exemption From Adequate Directions for Use (Proposed Sec.  201.130)

    Consistent with the proposed definition of ACNU, a drug product can
only be approved with an ACNU if the applicant demonstrates and FDA
determines that labeling alone is insufficient to ensure appropriate
self-selection or appropriate actual use, or both. Therefore, it is not
possible for these products to be labeled with adequate directions for
use under section 502(f)(1) of the FD&C Act, as defined in Sec.  201.5.
The proposed rule would exempt a nonprescription drug product with an
ACNU from the statutory requirement to be labeled with adequate
directions for use, provided that certain conditions are met.
Specifically, a nonprescription drug product approved with an ACNU
under section 505(c) or (j) of the FD&C Act would be exempt from
section 502(f)(1) if the product contains the labeling required under
proposed Sec.  201.130(a) and the ACNU is implemented by the applicant
as approved by FDA in the application (see proposed Sec.  201.130). FDA
is proposing this exemption to the requirement for adequate directions
for use for a nonprescription drug product with an ACNU because we have
determined that the labeling and the ACNU are sufficient to ensure
consumers' appropriate self-selection and actual use of the
nonprescription product without the supervision of a healthcare
practitioner. Therefore, adequate directions for use, as required by
section 502(f)(1) of the FD&C Act and Sec.  201.5, would not be
necessary for the protection of the public health.
    The proposed rule would require that the following statement appear
as the first direction under the heading ``Directions'' in the
labeling, as required in Sec.  201.66(c)(6): ``To check if this drug is
safe for you, go to [insert where or how consumers can find information
about the ACNU; for example, applicant's website, phone number, or
specific retail location] and [insert action to be taken by consumer].
Do not take this drug without completing this step.'' (See proposed
Sec.  201.130(a)(1).) The applicant would include information to inform
consumers where the additional condition would be found and explain the
additional condition that the consumer must fulfill. For example, ``To
check if this drug is safe for you, go to www.XYZCompany.com and take
the self-selection questionnaire. Do not take this drug without
completing this step.'' The statement would be followed by the other
information required in Sec.  201.66(c)(6). FDA is specifically seeking
comment on the content of the statements and the ability of these
statements to sufficiently inform consumers that the product is a
nonprescription drug product with an ACNU and how consumers would
fulfill the ACNU.
    The proposed rule would also require that the following statement
appear on the immediate container label and, if one exists, the outside
container or wrapper of the retail package: ``You must complete an
extra step to see if this drug is safe for you before you use it. Do
not take this drug without completing this step. See the Drug Facts
labeling for more information.'' (See proposed Sec.  201.130(a)(2).)
This statement must meet the specific format requirements as specified
in proposed Sec.  201.67(d). The statement would remind the original
purchaser and alert persons other than the original purchaser that
these nonprescription drug products are not suitable for all
individuals and should only be used after fulfilling the ACNU. FDA is
specifically seeking comment on whether this statement would
sufficiently alert consumers that this product is a nonprescription
drug product with an ACNU.
    The proposed rule would require the ACNU to be implemented by the
applicant under the conditions set forth in the approved application
for the nonprescription drug product with an ACNU to be exempt from the
requirement to be labeled with adequate directions for use (see
proposed Sec.  201.130(b)).

K. Misbranding (Proposed Sec.  201.67(e))

    As noted immediately above, the proposed rule would exempt a
nonprescription drug product with an ACNU from the requirement to be
labeled with adequate directions for use under section 502(f)(1) of the
FD&C Act, provided that certain conditions are met (see proposed Sec.
201.130). If a nonprescription drug product with an ACNU is made
available to consumers without the labeling specified in proposed Sec.
201.130(a) or the ACNU is not implemented by the applicant as approved
by FDA in the application, the drug product would be misbranded under
section 502(f)(1) of the FD&C Act (see proposed Sec.  201.67(e)).
    As discussed in sections V.H and V.I of this document, the proposed
rule would include specific labeling requirements for a nonprescription
drug product with an ACNU. If the nonprescription drug product with an
ACNU is made available to consumers without the specific required
labeling, the product would also be misbranded under section 502(a) of
the FD&C Act, which provides that a drug's labeling must not be false
or misleading in any particular (see proposed Sec.  201.67(e)). Under
section 201(n) of the FD&C Act, in determining whether labeling is
misleading, there shall be taken into account (among other things), not
only representations made or suggested but also the extent to which the
labeling fails to reveal facts material in the light of such
representations or material with respect to consequences that may
result from the use of the drug under the conditions of use prescribed
in the labeling or under usual or customary conditions of use. The
required labeling statements described in proposed Sec.  201.130(a) are
intended to inform consumers that the product is a nonprescription drug
product with an ACNU; to instruct consumers on how to fulfill the ACNU;
and to remind the original purchaser (and alert persons other than the
original purchaser) that

the nonprescription drug product is not suitable for all individuals
and should only be used after fulfilling the ACNU. Thus, failure of a
nonprescription drug product approved with an ACNU to bear the required
labeling statements described in proposed Sec.  201.130(a) would
constitute a failure to reveal material facts about the product or with
respect to consequences that might result from its use and would
misbrand the product.
    In addition, a nonprescription drug product with an ACNU could be
misbranded under other provisions of section 502 of the FD&C Act. For
example, in certain circumstances, such a drug may be misbranded under
section 502(j) if the product does not meet the requirements of this
proposed rule.
    Under the proposed rule, a nonprescription drug product with an
ACNU must only be made available to the consumer after the ACNU has
been fulfilled by the consumer. It is a prohibited act under section
301(a) of the FD&C Act to introduce or deliver for introduction into
interstate commerce any drug that is misbranded (21 U.S.C. 331(a)). It
is also a prohibited act under section 301(k) of the FD&C Act to do any
act with respect to a drug if such act is done while such drug is held
for sale after shipment in interstate commerce and results in the drug
being misbranded.
    Additionally, a nonprescription drug product approved with an ACNU
would be an unapproved new drug if it is made available to consumers
without the ACNU. With certain limited exceptions not relevant here, it
is a violation of sections 301(d) and 505(a) of the FD&C Act to
introduce or deliver for introduction into interstate commerce an
unapproved new drug.

VI. Proposed Effective Date

    We propose that a final rule based on this proposed rule become
effective 60 days after the date the final rule publishes in the
Federal Register.

VII. Preliminary Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us 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; distributive impacts; and equity).
This proposed rule has been designated by the Office of Information and
Regulatory Affairs as a significant regulatory action as defined by
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. This rule would establish the requirements for a
nonprescription drug product with an ACNU. We cannot anticipate the
number of applicants that would submit applications or the types of
drug products that would be covered under such applications. However,
we estimate the costs for any applicant to read and understand the rule
would likely range between 0.04 percent and 0.14 percent of the gross
receipts of very small applicants. Therefore, we propose to certify
that the proposed rule, if finalized, would not have a significant
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $165 million, using the most current (2021) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.

B. Summary of Costs and Benefits

    The proposed rule, if finalized, would establish the requirements
for a nonprescription drug product with an ACNU. Compared to the
traditional labeling paradigm of nonprescription drug products, this
approved ACNU in addition to the labeling would ensure the appropriate
self-selection, appropriate use, or both, of a drug product. We expect
this rule could expand consumer access to certain drug products in a
nonprescription setting.
    Table 1 shows our quantified benefits. We estimate a reduction in
access costs to consumers who could transfer from a prescription to a
nonprescription drug product with an ACNU. Our primary estimate for
this item is $26.70 with a range of $0 to $53.40 per consumer per
purchase. We also quantify the value of the potential reduction in the
number of repetitive meetings with sponsors that the rule could
eliminate, which occur during the approval process. This estimate
includes benefits to FDA and industry. Our primary estimate is $55,469
per applicant with a range of $45,260 to $66,174. We do not monetize
our estimates of benefits over a 10-year horizon because of the high
uncertainty about number of applicants, applications, potential
approvals, the number of purchases that might occur, and consumer
preferences to switch products but present estimates in the uncertainty
section of the full preliminary analysis of economic impacts.
    Although an applicant would incur the development and
postmarketing, including reporting of failure in the implementation of
the ACNU and recordkeeping costs, we assume that applicants submit
applications when they believe that their expected profits from the
approval will exceed the costs of the application. We present a range
of these potential development and postmarketing costs in the appendix
of the complete economic analysis. However, we lack information to
monetize these costs over a 10-year horizon and request comment or data
on these potential costs.
    Monetized costs include a one-time cost of reading and
understanding the rule. Using a 7-percent discount rate, the primary
estimate, annualized over a 10-year horizon, equals $821 with a range
of $379 to $1,264. These annualized costs are the same using a 3-
percent discount rate.
    Government and private insurance payers may experience positive
transfers because consumers may decrease future medical costs and the
number of submitted insurance claims. Earlier access to drug products
would allow consumers to treat medical conditions using nonprescription
drug products with an ACNU without the supervision of a healthcare
practitioner.

                                     Table 1--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                      Primary       Low        High    --------------------------------------------
             Category                estimate    estimate    estimate      Year      Discount                                       Notes
                                                                          dollars    rate  (%)    Period  covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized $millions/
     year.
    Annualized Quantified.........  ..........  ..........  ..........        2018  ..........  ..................  Quantified reduction in access costs
                                                                                per consumer purchase range from
                                                                                $0.0 to $53.40, and a primary
                                                                                estimate of $26.70.
                                                                              2018  ..........  ..................  Quantified reduction in meetings
                                                                                between FDA and applicants range
                                                                                from $45,260 to $66,174 per
                                                                                applicant, and a primary estimate
                                                                                of $55,469.
    Qualitative.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized....................        $0.0        $0.0        $0.0        2018           7  10 years..........  Reading and understanding one-time
                                                                                costs.
    Monetized $millions/year......        $0.0        $0.0        $0.0        2018           3  10 years..........
    Annualized.
    Quantified.
    Qualitative...................  ..........  ..........  ..........  ..........  ..........  ..................  Affected firms would incur costs to
                                                                                develop and submit applications.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal.......................  ..........  ..........  ..........  ..........           7
    Annualized Monetized $millions/                                                          3
     year.
--------------------------------------------------------------------------------------------------------------------------------------------------------
    From/To.......................  From:
                                    To:                                 ..........
                                   ---------------------------------------------------------------------------------------------------------------------
    Other.........................  ..........  ..........  ..........  ..........           7
    Annualized Monetized $millions/                                                          3
     year.
                                   ---------------------------------------------------------------------------------------------------------------------
    From/To.......................  From:
                                    To:                                  Potential
                                                                          benefits
                                                                                to
                                                                        government
                                                                               and
                                                                           private
                                                                         payors if
                                                                            access
                                                                           cost of
                                                                        medication
                                                                        s decline.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government: No estimated effect..............................................................................................
    Small Business: The estimated costs to very small potential applicants in this industry would range from 0.04 percent to 0.14 percent of gross
     receipts..
    Wages: No estimated effect..........................................................................................................................
    Growth: No estimated effect.........................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 7) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.30(h) and (k) that this action
is of a type that does not individually or 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 information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3521). A description of these provisions is given in
the Description section below, with an estimate of the annual
reporting, recordkeeping, and third-party disclosure burden. Included
in the estimate is the time for reviewing instructions, searching
existing data sources, gathering and maintaining the data needed, and
completing and reviewing each collection of information.
    FDA invites comments on these topics: (1) whether the proposed
collection of information is necessary for the 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 through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Premarket applications, postmarketing reports and
recordkeeping, and labeling for Nonprescription Drug Products With an
Additional Condition for Nonprescription Use.
    Description: We are revising requirements applicable to NDA and
ANDA applicants of nonprescription drug products with an ACNU
(collectively, respondents). If finalized, the proposed rule will
modify information collections applicable to regulations in part 314
governing new and abbreviated new drug application submissions and drug
labeling provisions in part 201 pertaining to nonprescription drug
products.
    Description of Respondents: The respondents are: (1) for NDA and
ANDA

submissions, an applicant who submits an NDA (including a 505(b)(2)
application) or an ANDA under part 314 to obtain FDA approval of a
nonprescription drug with an ACNU; (2) for failure of implementation of
an ACNU reporting and recordkeeping, any person who holds an approved
NDA (including a 505(b)(2) application) or an approved ANDA that
includes an ACNU; and (3) for labeling, any person who holds an
approved NDA (including a 505(b)(2) application) or an approved ANDA
that includes an ACNU.
    We estimate the burden of the information collection as follows:

                    Table 2--Estimated Annual Reporting Burden; OMB Control No. 0910-0001\1\
----------------------------------------------------------------------------------------------------------------
Information collection activity;                                                      Average
  21 CFR part 314  (application      Number of       Number of     Total annual     burden per
for FDA approval to market a new    respondents    responses per     responses       response       Total hours
              drug)                                 respondent                        (hours)
----------------------------------------------------------------------------------------------------------------
Submission of separate                         6               1               6             320           1,920
 application for nonprescription
 drug product with an ACNU; Sec.
   314.56(b) and (c)............
Other postmarketing reports;                   6              25             150              40           6,000
 submission of each individual
 consumer affected by a failure
 in implementation of an ACNU;
 Sec.   314.81..................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............             156  ..............           7,920
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital, or operating or maintenance costs associated with the information collection.

NDA and ANDA Submissions

    Based on our experience with information collection associated with
current NDA and ANDA submissions, we estimate six applications for a
nonprescription drug product with an ACNU will be submitted annually by
six respondents. Based on Broad Agency Announcement proposals that set
forth the number of hours anticipated to produce study reports for
submission to us, we assume it will take an average of 320 hours per
application for both NDA and ANDA applicants to prepare and submit the
information required for applications for nonprescription drugs with an
ACNU (in addition to meeting the general NDA or ANDA requirements under
Sec. Sec.  314.50 and 314.94, already approved in OMB control number
0910-0001).

Reports of a Failure in Implementation of an ACNU

    We estimate six respondents will each submit 25 reports to FDA for
an individual failure in implementation of an ACNU under Sec.
314.81(b)(3)(v). We assume an average of 40 hours per response for each
applicant, for a total of 6,000 hours annually. As noted in the
preamble of the proposed rule, we are also soliciting comments on the
alternative reporting mechanism requiring the applicant to submit a
single, consolidated report for all consumers affected by the same
failure in implementation of an ACNU rather than a report for each
individual impacted by the same failure in implementation of an ACNU.
If that alternative is implemented in the final rule, we estimate that
the number of reports per respondent would be reduced from 25 annual
responses per respondent to 1 per year per respondent.

                                      Table 3--Estimated Annual Recordkeeping Burden; OMB Control No. 0910-0001 \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of                      Average  burden
   Information collection; 21 CFR part 314 (applications for FDA        Number of      responses per     Total annual    per  response     Total hours
                   approval to market a new drug)                      respondents       respondent       responses         (hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Requirements for failures in implementation of an ACNU; Sec.                      6               25              150                8            1,200
 314.81............................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital, or operating or maintenance costs associated with the information collection.

    Based on our experience with postmarket recordkeeping requirements,
we assume an average burden of 8 hours of recordkeeping for each report
and therefore have calculated 1,200 hours annually.

             Table 4--Estimated Annual Third-Party Disclosure Burden; OMB Control No. 0910-0340 \1\
----------------------------------------------------------------------------------------------------------------
Information collection activity;
   21 CFR part 201, subpart C                        Number of                        Average
(format and content requirements     Number of     responses per   Total annual     burden per      Total hours
    for over-the-counter drug       respondents     respondent       responses       response
        product labeling)
----------------------------------------------------------------------------------------------------------------
Disclosure of information on the               6               1               6              15              90
 principal display panel or
 within Drug Facts Labeling;
 Sec.   201.66 (including
 statements specified in Sec.
 201.130(a)(1)).................
Additional ACNU labeling--Sec.                 6               1               6               9              54
 201.67.........................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............              12  ..............             144
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

Labeling for Nonprescription Drugs With an ACNU

    Based on our experience with NDA and ANDA submissions, we estimate
six respondents will each submit an application for a nonprescription
drug product with an ACNU, each becoming subject to all nonprescription
labeling regulations in (21 CFR part 201, subpart C). This includes the
requirements for statements of identity and net contents (Sec. Sec.
201.61 and 201.62) which appear on the principal display panel (PDP)
(defined by Sec.  201.60); the Drug Facts labeling (DFL) requirements
of Sec.  201.66, as part of which the respondents must also include
(where applicable) labeling to satisfy sodium, calcium, magnesium, and
potassium labeling requirements (Sec. Sec.  201.64, 201.70, 201.71, and
201.72); and the statements proposed to be required by Sec.
201.130(a)(1). (The proposed requirement in Sec.  201.130(a)(2) to
place a specified ACNU statement on the product PDP is not included in
the definition of collection of information under the PRA and is
therefore not subject to review and approval by OMB. See 5 CFR
1320.3(c)(2). These products may also have additional labeling beyond
the DFL requirements (Sec.  201.67(c)(2)).
    Estimating six respondents will each have one new, approved drug
that must comply with PDP and DFL labeling requirements, including
statements specified in Sec.  201.130(a)(1), and assuming compliance
with these disclosures will require 15 hours per drug, we calculate a
total of 90 hours annually. Additionally, we estimate six respondents
will each have one new nonprescription drug product approved with an
ACNU that contains additional labeling requirements, for a total of six
annual responses. Based on our experience with nonprescription labeling
requirements, we assume an average burden per response of 9 hours, for
a total of 54 hours annually.
    To ensure that comments on this information collection are
received, OMB recommends that written comments be submitted through
reginfo.gov (see ADDRESSES). All comments should be identified with the
title of the information collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), we have submitted the information collection provisions of
this proposed rule to OMB for review. These information collection
requirements will not be effective until FDA publishes a final rule,
OMB approves the information collection requirements, and the rule goes
into effect. FDA will announce OMB approval of these requirements in
the Federal Register.

X. Federalism

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive order and,
consequently, a federalism summary impact statement is not required.

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.

XII. References

    The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they also are
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.

1. FDA, Guidance for Industry, ``Self-Selection Studies for
Nonprescription Drug Products,'' April 2013 (available at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs).
2. Chang J., A. Lizer, I. Patel, et al., ``Prescription to Over-the-
Counter Switches in the United States,'' Journal of Research in
Pharmacy Practice, vol. 5(3), pp. 149-154, doi:10.4103/2279-
042X.185706. Available at: https://www.jrpp.net/text.asp?2016/5/3/149/185706.
3. FDA, Guidance for Industry, ``Label Comprehension Studies for
Nonprescription Drug Products,'' August 2010 (available at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs).
4. Engelberg Center for Health Care Reform at the Brookings
Institution, ``Expert Workshop: Nonprescription Medications With
Conditions of Safe Use as a Novel Solution for Undertreated Diseases
or Conditions,'' November 8, 2012 (available at https://www.brookings.edu/events/nonprescription-medications-with-conditions-of-safe-use-as-a-novel-solution-for-undertreated-diseases-or-conditions), accessed July 30, 2021.
5. Engelberg Center for Health Care Reform at the Brookings
Institution, ``Expert Workshop: Innovative Technologies and
Nonprescription Medications: Addressing Undertreated Diseases and
Conditions through Technology Enabled Self-Care,'' May 9, 2013
(available at https://www.brookings.edu/events/innovative-technologies-and-nonprescription-medications-addressing-undertreated-diseases-and-conditions-through-technology-enabled-self-care), accessed July 30, 2021.
6. Engelberg Center for Health Care Reform at the Brookings
Institution, ``Expert Workshop: Exploring Implications of the
Nonprescription Drug Safe Use Regulatory Expansion (NSURE)
Initiative on Reimbursement and Access,'' November 4, 2013
(available at https://www.brookings.edu/events/exploring-implications-of-the-nonprescription-drug-safe-use-regulatory-expansion-nsure-initiative-on-reimbursement-and-access), accessed
July 30, 2021.
7. FDA, Preliminary Regulatory Impact Analysis; Initial Regulatory
Flexibility Analysis; Unfunded Mandates Reform Act Analysis,
Nonprescription Drug Product With an Additional Condition for
Nonprescription Use; Proposed Rule (available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm).

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 314

    Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, we
propose that 21 CFR parts 201 and 314 be amended as follows:

PART 201--LABELING

0
1. The authority citation for part 201 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 343, 351, 352, 353, 355, 358,
360, 360b, 360ccc, 360ccc-1, 360ee, 360gg-360ss, 371, 374, 379e; 42
U.S.C. 216, 241, 262, 264.

0
2. Add Sec.  201.67 to subpart C to read as follows:

Sec.  201.67   Labeling requirements for a nonprescription drug product
with an additional condition for nonprescription use (ACNU).

    (a) Scope. This section sets forth labeling requirements for a
nonprescription drug product with an ACNU.
    (b) Definition. The following definition applies to this section:
    (1) Additional condition for nonprescription use (ACNU) means one
or more FDA-approved conditions that an applicant of a nonprescription
drug product must implement to ensure consumers' appropriate self-
selection or appropriate actual use, or both, of the nonprescription
drug product without the supervision of a healthcare practitioner if
the applicant demonstrates and FDA determines that labeling alone is
insufficient to ensure appropriate self-selection or appropriate actual
use, or both.
    (2) [Reserved]
    (c) General labeling requirements. (1) A nonprescription drug
product with an ACNU must comply with applicable labeling requirements
for nonprescription drug products under this part, including the format
and content requirements for nonprescription drug product labeling
under Sec.  201.66 and the statements specified in Sec.  201.130(a).
    (2) A nonprescription drug product with an ACNU may also be
approved with additional labeling that supplements the format and
content requirements for nonprescription drug product labeling under
Sec.  201.66.
    (d) Format requirements for required ACNU statement. The statement
specified in Sec.  201.130(a)(2) must meet all format requirements as
follows:
    (1) The statement must appear on the principal display panel (see
Sec.  201.60) and the immediate container surface that the consumer is
most likely to view when seeking information about the drug product. If
the immediate container is a bottle, the statement must appear on the
surface that the consumer is most likely to consider the front of the
bottle. If the immediate container is a blister card (including a card
that contains more than one blister unit), the statement must appear on
the blister card surface that the consumer would most likely view when
removing the drug product from the blister card. If the blister card
contains more than one blister unit (e.g., perforated blister card
where individual blister units can be separated from one another), the
statement does not need to be included on each blister unit of a
blister card. However, the statement must remain intact and be readable
on the blister card when the drug product is removed from each blister
unit.
    (2) The statement must appear in boldface and black type.
    (3) The statement must appear in a yellow background banner. No
other information or statements may be included within the yellow
background banner.
    (4) The statement must be in one of the following font sizes,
whichever is greater:
    (i) At least 25 percent as large as the font size of the largest
printed words on the principal display panel and immediate container;
or
    (ii) At least 12 point font (1 point = 0.0138 inches).
    (5) An applicant may request an exception to the minimum font size
requirement specified in paragraph (d)(4) of this section for
containers where its size would render compliance with this requirement
impractical. FDA may allow such an exception upon request by an
applicant if FDA determines an exception is warranted.
    (e) Misbranding. A nonprescription drug product with an ACNU is
misbranded under section 502 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 352) if--
    (1) It is made available without the labeling specified in Sec.
201.130(a); or
    (2) The ACNU is not implemented by the applicant as approved by FDA
in the application.
0
3. Add Sec.  201.130 to subpart D to read as follows:

Sec.  201.130   Exemption from adequate directions for use for a
nonprescription drug product with an additional condition for
nonprescription use.

    A nonprescription drug product approved under section 505(c) or
505(j) of the Federal Food, Drug, and Cosmetic Act with an ACNU as
defined in Sec.  201.67(b) is exempt from section 502(f)(1) if all the
following conditions in paragraphs (a) and (b) of this section are met:
    (a) The label of the drug:
    (1) Bears, as the first direction under the ``Directions'' heading
required in Sec.  201.66(c)(6), the statement ``To check if this drug
is safe for you, go to [insert where or how consumers can find
information about the ACNU; for example, applicant's website,
applicant's phone number, or specific retail location] and [insert
action to be taken by consumer]. Do not take this drug without
completing this step.'' The statement must be followed by the other
information required in Sec.  201.66(c)(6).
    (2) Bears, in the form and manner required by Sec.  201.67(d), the
statement ``You must complete an extra step to see if this drug is safe
for you before you use it. Do not take this drug without completing
this step. See the Drug Facts labeling for more information.''
    (3) Complies with other applicable labeling requirements for
nonprescription drug products under this part, including the format and
content requirements for nonprescription drug product labeling under
Sec.  201.66.
    (b) The additional condition for nonprescription use is implemented
by the applicant under the conditions set forth in the approved
application.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

0
4. The authority citation for part 314 continues to read as follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 355f,
356, 356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.

0
5. Add Sec.  314.56 to subpart B to read as follows:

Sec.  314.56   Nonprescription drug product with an additional
condition for nonprescription use (ACNU).

    (a) Definition. The following definition applies to this section:
    (1) Additional condition for nonprescription use (ACNU) means one
or more FDA-approved conditions that an applicant of a nonprescription
drug product must implement to ensure consumers' appropriate self-
selection or appropriate actual use, or both, of the nonprescription
drug product without the supervision of a healthcare practitioner if an
applicant demonstrates and FDA determines that labeling alone is
insufficient to ensure appropriate self-selection or appropriate actual
use, or both.
    (2) [Reserved]
    (b) Separate application required for a nonprescription drug
product with an ACNU. An applicant must submit a separate application
for a nonprescription drug product with an ACNU. Initial approval for a
nonprescription drug product with an ACNU cannot be obtained through a
supplement to an approved application.
    (c) Specific requirements for an application for a nonprescription
drug product with an ACNU. The applicant must submit an application
that complies with the following requirements:
    (1) New drug application (NDA). When fulfilling the content and
format requirements under Sec.  314.50, an NDA for a nonprescription
drug product with an ACNU must include--

    (i) A statement regarding the purpose of the ACNU: ensure
appropriate self-selection or appropriate actual use, or both, by
consumers of the nonprescription drug product with an ACNU without the
supervision of a healthcare practitioner;
    (ii) A statement regarding the necessity of the ACNU;
    (iii) A description of how the ACNU ensures appropriate self-
selection or appropriate actual use, or both;
    (iv) A description of the key elements of the ACNU, including:
    (A) The additional condition implemented by the applicant to be
fulfilled by the consumer to obtain the nonprescription drug product
with an ACNU;
    (B) The labeling specifically associated with the ACNU; and
    (C) The criteria by which the consumer would successfully fulfill
the ACNU, including a description of the specific actions to be taken
by a consumer or required responses to be provided by a consumer;
    (v) Adequate data or other information that demonstrates the
necessity of the ACNU to ensure appropriate self-selection or
appropriate actual use, or both;
    (vi) Adequate data or other information that demonstrates the
effect of the ACNU on the appropriate self-selection or appropriate
actual use, or both; and
    (vii) A description of the specific way the ACNU is
operationalized.
    (2) Abbreviated new drug application (ANDA). When fulfilling the
content and format requirements under Sec.  314.94, an ANDA for a
nonprescription drug product with an ACNU must--
    (i) State the purpose of the ACNU;
    (ii) Include information demonstrating that the key elements of the
proposed ACNU are the same as the key elements of the ACNU for its
reference listed drug (RLD); and
    (iii) Include information on the way the ACNU would be
operationalized. If an applicant believes the ACNU is operationalized
in the same way as the RLD, include information demonstrating that the
ACNU is operationalized in the same way as the RLD. If a different way
to operationalize the proposed ACNU is used, include information to
show that this different way to operationalize the proposed ACNU
achieves the same purpose as the ACNU for its RLD and that the
differences from the RLD are otherwise acceptable in an ANDA.
    (d) Simultaneous marketing of nonprescription and prescription
products. An ACNU constitutes a meaningful difference between a
nonprescription drug product and a prescription drug product, such that
a prescription drug product and a nonprescription drug product with an
ACNU may be simultaneously marketed even if there is not another
meaningful difference between the two products that makes the
nonprescription drug product safe and effective for use without the
supervision of a healthcare practitioner licensed by law to administer
the drug (e.g., a different active ingredient, indication, strength,
route of administration, dosage form, or patient population).
0
6. Amend Sec.  314.81 by adding paragraph (b)(3)(v) to read as follows:

Sec.  314.81   Other postmarketing reports.

* * * * *
    (b) * * *
    (3) * * *
    (v) Report of failure in the implementation of an additional
condition for nonprescription use. The applicant must submit a report
when a failure in the implementation of an additional condition for
nonprescription use (ACNU) for a nonprescription drug product occurs. A
report of a failure in implementation of an ACNU includes any event
that results from a deviation in an applicant's implementation of the
ACNU that may cause or lead to inappropriate medication use or consumer
harm. All failures in implementation of an ACNU must be reported to the
FDA Adverse Event Reporting System (FAERS), whether or not the failure
in implementation of an ACNU is associated with an adverse event. If an
applicant becomes aware of both a failure in implementation of an ACNU
and an associated adverse event before the submission to FAERS, a
single individual case safety report (ICSR) that describes both the
failure in implementation of an ACNU and the associated adverse event
must be submitted and must contain the information as required in Sec.
314.80(f) and paragraph (b)(3)(v)(A) of this section. If a previously
submitted report to FAERS describes only a failure in implementation of
an ACNU or a previously submitted ICSR reports only an adverse event,
and the submitter subsequently becomes aware of an associated adverse
event or associated failure in implementation of an ACNU, the submitter
must supplement the original report to FAERS with the new information.
The supplement must include the information required in Sec.  314.80(f)
or paragraph (b)(3)(v)(A) of this section, as applicable.
    (A) Content. The report must include the following for a failure in
implementation of an ACNU:
    (1) Required information. The name, address, email, and telephone
number of the applicant; an identifiable reporter; the drug product
name; and the description of the failure in implementation of the ACNU.
    (2) Additional information, if known. In addition, the report must
include the following information, if known:
    (i) Drug product strength; National Drug Code (NDC); lot number;
and NDA or ANDA number.
    (ii) Initial reporter information including name, address, and
telephone number of the initial reporter.
    (iii) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
    (iv) Narrative summary of failure in implementation of an ACNU,
including the date of failure in implementation of an ACNU (or best
estimate); the date the failure in implementation of an ACNU was
reported to applicant; the location of failure in implementation of an