Nonprescription Drug Product With an Additional Condition for Nonprescription Use, 105288-105331 [2024-30261]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 89, Number 247 (Thursday, December 26, 2024)]
[Rules and Regulations]
[Pages 105288-105331]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-30261]



[[Page 105287]]

Vol. 89

Thursday,

No. 247

December 26, 2024

Part III





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Parts 201 and 314





Nonprescription Drug Product With an Additional Condition for 
Nonprescription Use; Final Rule

Federal Register / Vol. 89 , No. 247 / Thursday, December 26, 2024 / 
Rules and Regulations

[[Page 105288]]


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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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule to establish requirements for a nonprescription 
drug product with an additional condition for nonprescription use 
(ACNU). A nonprescription drug product with an ACNU 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 practitioner licensed by law to administer such drug. 
The final rule is intended to increase options for applicants to 
develop and market safe and effective nonprescription drug products and 
increase consumer access to appropriate, safe, and effective drug 
products, which could improve public health.

DATES: This rule is effective January 27, 2025.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 
240-402-7500.

FOR FURTHER INFORMATION CONTACT: 
    With regard to the final rule: Myla Dellupac, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Silver Spring, MD 20993-0002, 301-837-7461.
    With regard to the information collection: Amber Sanford, Office of 
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-8867, 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Benefits, Costs, and Transfers
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Need for the Regulation
    B. FDA's Regulatory Framework
    C. History of the Rulemaking
    D. Summary of Comments to the Proposed Rule
    E. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of General Comments and FDA Responses
    C. Comments on Applicability and FDA Responses
    D. Comments on Definition and FDA Responses
    E. Comments on Separate Application Required for a 
Nonprescription Drug Product With an ACNU and FDA Responses
    F. Comments on Specific Requirements for an Application for a 
Nonprescription Drug Product With an ACNU and FDA Responses
    G. Comments on Nonprescription and Prescription Approval and 
Simultaneous Marketing and FDA Responses
    H. Comments on Refusal To Approve an Application With an ACNU 
and FDA Response
    I. Comments on Other Postmarketing Reports and FDA Responses
    J. Comments on General Labeling Requirements and FDA Responses
    K. Comments on Format Requirements for Required ACNU Statement 
and FDA Responses
    L. Comments on Exemption From Adequate Directions for Use and 
FDA Responses
    M. Comment on Misbranding and FDA Response
    N. Miscellaneous Comments and FDA Responses
VI. Effective Date
VII. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Benefits, Costs, and Transfers
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 Final Rule

    FDA is finalizing this rule to establish requirements for a 
nonprescription drug product with an ACNU. A nonprescription drug 
product with an ACNU is a drug product that could be legally 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 practitioner 
licensed by law to administer such drug. Without this rule, 
nonprescription drug products are limited to drug products that can be 
labeled with sufficient information for consumers to appropriately 
self-select and use the drug product without the supervision of a 
practitioner licensed by law to administer such drug. For certain drug 
products, labeling alone cannot adequately communicate the information 
needed for consumers to appropriately self-select or use the drug 
product without the supervision of a practitioner licensed by law to 
administer such drug. The final rule is intended to increase options 
for applicants \1\ to develop and market safe and effective 
nonprescription drug products and increase consumer access to 
appropriate, safe, and effective drug products, which could improve 
public health.
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    \1\ While we recognize that in certain circumstances ``sponsor'' 
is the correct term for the person who would be developing a 
nonprescription drug product with an ACNU, we used the term 
``applicant'' throughout the final rule for consistency (see the 
definition for applicant in 21 CFR 314.3(b) and for sponsor in 21 
CFR 312.3(b)).
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B. Summary of the Major Provisions of the Final Rule

    This final rule establishes requirements for a nonprescription drug 
product with an ACNU, including application, labeling, and 
postmarketing reporting requirements. In addition to applicable 
existing application requirements, the final rule establishes the 
specific requirements for a new drug application (NDA) or abbreviated 
new drug application (ANDA) for a nonprescription drug product with an 
ACNU. In circumstances where a prescription drug product is already 
approved, the rule requires an applicant to submit a separate 
application for the approval of a nonprescription drug product with an 
ACNU, rather than a supplement to the existing application for the 
approved prescription drug product. The final rule establishes specific 
labeling requirements, including the content and format of specific 
labeling statements. Additionally, the rule requires that an applicant 
submit a postmarketing report of an ACNU failure.
    The final rule clarifies that an ACNU constitutes a meaningful 
difference \2\

[[Page 105289]]

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 practitioner licensed by law to administer 
such drug; therefore, a prescription drug product and a nonprescription 
drug product with an ACNU with the same active ingredient may be 
simultaneously marketed even if they do not have meaningful differences 
other than the ACNU, such as different indications or strengths.
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    \2\ FDA has used the terms ``meaningful difference'' and 
``clinically meaningful difference'' interchangeably. Both refer to 
the same scientific determination. See, e.g., 83 FR 13994 (April 2, 
2018) and 87 FR 68702 (November 16, 2022).
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    The final rule specifies that FDA will refuse to approve an 
application for a nonprescription drug product with an ACNU if the 
application fails to meet applicable requirements.
    The final rule exempts a nonprescription drug product with an ACNU 
from the requirement to be labeled with adequate directions for use, 
provided that certain labeling conditions are met and the ACNU is 
implemented by the applicant as approved by FDA.
    Finally, the final rule explains certain circumstances in which a 
nonprescription drug product with an ACNU would be misbranded.
    FDA received many comments supporting the proposed rule's intent to 
increase options for applicants to develop and market safe and 
effective nonprescription drug products and increase consumer access to 
appropriate, safe, and effective drug products. Additionally, we 
received comments expressing concerns about certain proposed 
requirements and the burden of those requirements for applicants. In 
response to several comments expressing concerns about the proposed 
postmarketing reporting requirements for nonprescription drug products 
with an ACNU, we are revising the proposed requirements to provide 
greater clarity for when a postmarketing report of ACNU failure must be 
submitted to FDA and to reduce the burden on applicants by decreasing 
any potential unnecessary reporting and ensuring consistency with 
existing postmarketing reporting requirements. In response to several 
comments about the proposed labeling statements on the principal 
display panel (PDP) and Drug Facts labeling (DFL), we are revising the 
proposed labeling requirements to allow FDA to approve an applicant's 
proposed labeling statements that vary somewhat from the labeling 
statements in the codified text, under certain circumstances. 
Additionally, we are revising the proposed labeling requirements to 
allow flexibility for the placement of the labeling statement on the 
DFL depending on the purpose of the ACNU.

C. Legal Authority

    This final rule, which establishes requirements for a 
nonprescription drug product with an ACNU, is authorized by sections 
201(n), 502, 503(b), 505, and 701(a) of the Federal Food, Drug, and 
Cosmetic Act (FD&C Act) (21 U.S.C. 321(n), 352, 353(b), 355, and 
371(a)).

D. Benefits, Costs, and Transfers

    The final rule establishes requirements for a nonprescription drug 
product with an ACNU. Compared to traditional nonprescription drug 
products, which consumers must be able to self-select and use based on 
their labeling, this approved ACNU, in addition to the labeling, will 
ensure the appropriate self-selection, the appropriate use, or both of 
a nonprescription drug product without the supervision of a 
practitioner licensed by law to administer such drug. We expect this 
rule will expand consumer access to certain drug products in a 
nonprescription setting and increase options for applicants to develop 
and market safe and effective nonprescription drug products.
    We estimate a reduction in access costs to consumers who could 
transfer from a prescription to a nonprescription drug product with an 
ACNU. In our analysis, access costs include the time to see a doctor to 
obtain a prescription, including waiting time and other transportation 
costs. We also include co-pay and out-of-pocket costs in our estimate 
of access costs. We compare the baseline access costs to the access 
costs under potential scenarios with the final rule to estimate the 
potential benefits for each consumer purchase. In this analysis, we use 
the costs to obtain candidate prescription-only products as our 
baseline access cost. Our primary estimate of reduction in access costs 
is $33.62 per consumer per purchase with a range of $0 to $67.23. We 
also quantify the value of the potential reduction in the number of 
meetings with applicants that will occur during the approval process. 
This estimate includes benefits to FDA and industry. Our primary 
estimate is $68,773.11 per applicant with a range of $56,332.65 to 
$81,763.56. 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, and purchases that might occur; and 
consumer preferences to switch drug products. However, we present 
estimates in the uncertainty section of this analysis.
    Although an applicant will incur the costs to develop and submit an 
application for a nonprescription drug product with an ACNU, for this 
analysis, we assume that applicants submit applications only when they 
believe that the profits from the approval will exceed the costs of the 
application. We lack information to monetize these potential profits 
and costs over a 10-year horizon.
    Monetized costs include a one-time cost of reading and 
understanding the rule per interested party in pursuing this path for 
their drug products. We do not monetize these estimates for more than 
one interested party because of the high uncertainty about the number 
of interested parties over this time horizon. The primary estimate 
equals $1,156.74 with a range of $533.88 to $1,779.60.
    Government-sponsored and commercial insurance payers may experience 
cost savings because the availability of nonprescription drug products 
with an ACNU may decrease insurance claims and, potentially, future 
medical costs. For example, access to drug products under this new 
paradigm will allow consumers to treat some medical conditions using 
nonprescription drug products with an ACNU without the supervision of a 
practitioner licensed by law to administer such drug. We do not 
estimate such cost savings due to lack of data.

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

------------------------------------------------------------------------
          Abbreviation/acronym                    What it means
------------------------------------------------------------------------
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
FTC....................................  Federal Trade Commission
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
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[[Page 105290]]

III. Background

A. Need for the Regulation

    Nonprescription drug products are important for the treatment of 
many conditions and diseases. Unlike prescription drug products, 
nonprescription drug products may be accessed and used safely and 
effectively by consumers without the supervision of a practitioner 
licensed by law to administer such drugs for their intended use. At 
present, the majority of nonprescription drug products are intended to 
provide temporary relief of minor symptoms or to treat self-limited 
conditions and diseases. 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 certain chronic diseases or conditions. This rule will 
increase options for applicants to develop and market safe and 
effective nonprescription drug products and increase consumer access to 
appropriate, safe, and effective drug products. The availability of 
nonprescription drug products with an ACNU may provide public health 
benefits by facilitating consumers' ability to care for themselves and 
access to appropriate medical treatment. For more information on the 
need for regulation, see 87 FR 38313 (June 28, 2022; 2022 proposed 
rule).

B. FDA's 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 (21 U.S.C. 355). 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 in the FD&C Act and implementing 
regulations.
    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 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. For more on FDA's regulatory framework for 
nonprescription drug products, see the 2022 proposed rule entitled 
``Nonprescription Drug Product With an Additional Condition for 
Nonprescription Use'' (87 FR 38313).

C. History of the Rulemaking

    In the 2022 proposed rule, FDA proposed requirements for a 
nonprescription drug product with an ACNU, 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. The proposed rule proposed additional 
application requirements, labeling requirements, and postmarketing 
reporting requirements for a nonprescription drug product with an ACNU. 
For more information on the history of rulemaking for the proposed 
rule, see 87 FR 38313.

D. Summary of Comments to the Proposed Rule

    We received approximately 200 comments. Comments were submitted by 
different entities and individuals including private citizens, consumer 
groups, trade organizations, pharmaceutical industry, and public 
advocacy groups. We received comments on different topics including:
     General support for or opposition to the proposed rule;
     The applicability of the proposed rule and whether certain 
drug products are appropriate for development as a nonprescription drug 
product with an ACNU;
     The proposed definition of ACNU;
     The proposed requirements for an application for a 
nonprescription drug product with an ACNU, including specific 
application requirements such as the submission of a separate 
application, labeling, and postmarketing reports;
     The simultaneous marketing of prescription drug products 
and nonprescription drug products with an ACNU; and
     The role of the pharmacist with a nonprescription drug 
product with an ACNU.

E. General Overview of the Final Rule

    FDA considered all comments received on the proposed rule, and in 
response, we have made changes for clarity and to reduce the burden on 
applicants in meeting certain requirements. The following is a summary 
of certain changes from the proposed rule:
     Revising the postmarketing reporting requirement to 
further clarify that a report must be submitted when there is an ACNU 
failure, and further explain the meaning of ACNU failure, to enhance 
consistency with current processes for the submission of other required 
postmarketing reports;
     Revising the requirements for required labeling statements 
on the PDP and DFL to permit applicants to propose revisions to the 
content of the required statements under certain circumstances;
     Revising the placement for the required labeling statement 
on the DFL depending on the purpose of the ACNU; and
     Clarifying certain circumstances when a nonprescription 
drug product with an ACNU would be misbranded by providing more detail 
about what it means when an ACNU is not implemented by the applicant as 
approved by FDA in the application.

IV. Legal Authority

    We are issuing this final rule under sections 201(n), 502, 503(b), 
505, and 701(a) of the FD&C Act. 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 issuing 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.
    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

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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 drug. 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 NDA 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 
requiring that a drug product be dispensed by prescription when it is 
not safe for use except under the supervision of a practitioner 
licensed by law to administer such drug product because of toxicity or 
other potentiality for harmful effect, or the method of the drug 
product's use, or the collateral measures necessary to the drug 
product's use (see section 503(b)(1) of the FD&C Act). If a drug 
product does not require a prescription under these provisions, it can 
be marketed as nonprescription. Section 503(b) gives authority for the 
Secretary, which is delegated to FDA, to make certain decisions 
regarding a drug's applicable category (see, e.g., section 503(b)(1) 
and (b)(3); see also the FDA Staff Manual Guide 1410.10 (Delegations of 
Authority to the Commissioner of Food and Dugs), available at https://www.fda.gov/about-fda/reports-manuals-forms/staff-manual-guides.).
    Finally, section 701(a) of the FD&C Act authorizes FDA to issue 
regulations for the efficient enforcement of the FD&C Act.

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received approximately 200 comment letters on the proposed rule 
by the close of the comment period, each containing one or more 
comments on one or more issues. We received comments from entities and 
individuals including private citizens, consumer groups, trade 
organizations, pharmaceutical industry, and public advocacy groups. The 
120-day comment period was extended by an additional 30 days based on 
requests from members of the public.
    We describe and respond to the comments in sections V.B through V.N 
of this document. We have numbered each comment to help distinguish 
between different comments. We have grouped similar comments together 
under the same number, and in some cases, we have separated different 
issues discussed in the same comment and designated them as distinct 
comments for purposes of our responses. The number assigned to each 
comment or comment topic is purely for organizational purposes and does 
not signify the comment's value or importance or the order in which 
comments were received.

B. Description of General Comments and FDA Responses

    We received many general comments supporting and opposing the 
purpose, necessity, and appropriateness of the proposed rule. In the 
following paragraphs, we discuss and respond to these general comments. 
We did not make any changes to the final rule based on consideration of 
these general comments.
    (Comment 1) Many comments generally support the proposed rule 
because it could broaden the types of nonprescription drug products 
available to consumers. For example, these commenters believe the 
proposed rule has the potential to improve consumer access, improve 
consumer autonomy, expand the market for companies, address 
undertreatment of many common and chronic conditions in the United 
States, and reduce the number of routine visits to a healthcare 
practitioner.
    (Response 1) We appreciate the general support. The rule is 
intended to increase options for applicants to develop and market safe 
and effective nonprescription drug products and increase consumer 
access to appropriate, safe, and effective drug products, which could 
improve public health.
    (Comment 2) We received a comment recommending that Congress, in 
conjunction with State boards of pharmacy, State health departments, 
and State/national pharmacist associations, is better positioned to 
increase options for the development and marketing of safe and 
effective nonprescription drug products through legislative changes, as 
compared to FDA acting through regulatory changes. The same comment 
sought clarity on whether FDA has the legal authority to approve 
nonprescription drug products with ACNUs that restrict distribution and 
sales of the drug product.
    (Response 2) As part of the statutory framework for regulation of 
drug products, Congress recognized the need for specific considerations 
and requirements for prescription drugs. As explained further in the 
response to comment 41, Congress amended section 503(b) of the FD&C Act 
in 1951 to reduce confusion and uncertainty in the market as to when a 
drug is safe for use without the supervision of a practitioner licensed 
by law to administer such drug, as well as to remove unnecessary 
restrictions on dispensing, and to protect public health from abuses in 
the sale of potent prescription drugs. Several provisions of the FD&C 
Act, including section 503(b), demonstrate that Congress envisioned 
that FDA would determine which drugs must be dispensed only upon a 
prescription and which drugs would not require a prescription. For 
example, section 503(b)(1) of the FD&C Act states, in relevant part, 
that a drug intended for human use that, ``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 administer 
such drug,'' must be limited to prescription use. That section 
authorizes FDA, in approving an application under section 505 of the 
FD&C Act, to require the supervision of a practitioner licensed by law 
to administer such a drug. Conversely, FDA may approve drugs that do 
not fall within section 503(b)(1) of the FD&C Act for nonprescription 
use. In addition, section 503(b)(3) of the FD&C Act authorizes FDA to 
issue regulations to remove the prescription-only dispensing 
requirements from drugs when such requirements are not necessary for 
the protection of the public health. Congress explicitly delegated FDA 
authority to use its scientific judgement to determine which drugs 
should be prescription or nonprescription, within the statutory 
criteria.
    Further, section 503(b)(1)(A) of the FD&C Act specifies certain 
identified features of a drug, such as its ``toxicity or other 
potentiality for harmful effect, or the method of its use, or the 
collateral measures necessary for its use,'' that are relevant to the 
determination of prescription or nonprescription status. The statute 
only states these factors in describing the prescription drug category, 
while leaving the nonprescription drug category described in opposition 
to the prescription

[[Page 105292]]

category. See section 503(b)(4)(A) and (B) (separately prescribing 
labeling requirements for ``[a] drug that is subject to [section 
503(b)(1)]'' and, by contrast, ``[a] drug to which [section 503(b)(1)] 
does not apply''). However, these factors are not unique to 
prescription drugs; all drugs have a ``method of . . . use,'' all or 
nearly all drugs have some level of ``toxicity or other potentiality 
for harmful effect,'' and many drugs require at least some ``collateral 
measures'' for safe use. Merriam-Webster defines the adjective 
``collateral'' to mean, among other things, ``accompanying as secondary 
or subordinate. . .[and/or] serving to support or reinforce.'' \3\ Thus 
the key distinction in the statute between prescription and 
nonprescription drugs is not that certain drugs have these factors 
while others do not; rather prescription drugs are those that, when 
considering these factors, are not safe for use except under the 
supervision of a practitioner licensed by law to administer such a 
drug.
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    \3\ https://www.merriam-webster.com/dictionary/collateral.
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    Features of a drug that qualify as ``collateral measures'' vary 
from drug to drug, and can include, for example, things which a 
layperson, because of their lack of education, training, and 
experience, cannot do to safely manage the disease. These include, but 
are not limited to, taking a proper history, doing a physical exam, 
ordering appropriate laboratory tests, having a knowledge of the 
relevant diseases, integrating the results of the history, exam, and 
tests with this knowledge, making a diagnosis, designing a treatment 
plan, and carrying the plan through with proper continuing evaluation. 
If the collateral measures necessary for safe use of the drug require 
the supervision of a practitioner licensed by law to administer such 
drug, section 503(b)(1)(A) requires that it can only be dispensed 
pursuant to a prescription.
    This rule recognizes that drugs approved with certain types of 
collateral measures do not require supervision of a practitioner 
licensed by law to administer such drug. Some such measures may be 
things that used to require a practitioner's direct involvement, but 
that no longer require such supervision because of the availability of 
technological advancements. For example, with Drug X (see more 
information about Drug X, a fictitious nonprescription drug product 
with an ACNU, in the proposed rule (87 FR 38313 at 38319)), 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. Using a consumer's answers to the 
questions, the underlying program or other operating information used 
by the secure website, not the consumer, calculates the risk score for 
a serious side effect and determines if the consumer has an acceptable 
disease-specific risk score to use Drug X and therefore purchase Drug 
X.
    This type of collateral measure could also be accomplished through 
the direct involvement of a practitioner licensed by law to administer 
such drug, as the practitioner integrates their knowledge of the 
patient with their knowledge of the disease and the drug--but now, in 
certain cases, this has the potential to be done without a 
practitioner's direct involvement because of the availability of 
technology that can conduct the necessary evaluation. By carefully 
evaluating whether such advancements in collateral measures mean that 
the drug ``is not safe for use except under the supervision of a 
practitioner licensed by law to administer such drug . . .'', section 
503(b)(1)(A) for the FD&C Act (emphasis added), FDA is implementing the 
statute's direction to limit the burdens of dispensing drugs by 
prescription to only those drugs for which they are truly necessary.
    More generally, as part of its broad authority to approve and 
regulate drug products, including to establish specific regulations for 
drug products, FDA is authorized to determine the conditions under 
which a drug is safe and effective for use without a prescription, 
including a determination that an ACNU is needed where labeling alone 
will not suffice (see, e.g., sections 505, 505G, and 701 of the FD&C 
Act). Until now, FDA's approval of nonprescription drug products has 
been limited to those that can be labeled with sufficient information 
for consumers to appropriately self-select and use the drug product. 
These nonprescription drug products are generally available ``over-the-
counter'' (e.g., on a retail shelf). However, nothing in the FD&C Act 
compels nonprescription drug products to be limited in this way, nor 
does the FD&C Act dictate a particular manner in which a 
nonprescription drug must be made available to consumers.
    For certain drug products, labeling alone may not adequately 
communicate the information needed for consumers to appropriately self-
select or use the drug product, but consumers may still be able to use 
the product safely and effectively without the supervision of a 
practitioner licensed by law to administer such drug under certain 
conditions. Nonprescription drug products approved with ACNUs have an 
additional condition of use, beyond labeling, that allows consumers to 
appropriately self-select or use the drug product without the 
supervision of a practitioner licensed by law to administer such drug. 
Thus, a nonprescription drug product with an ACNU, although not an 
``over-the-counter'' drug product, is a nonprescription drug product 
under section 503(b) of the FD&C Act, because, when approved with an 
ACNU, it is safe and effective for consumers to use without the 
supervision of a practitioner licensed by law to administer such drug.
    Additionally, FDA disagrees with this comment's suggestion that 
legislative change is needed to authorize this rule. As explained 
above, FDA has adequate statutory authority to issue this rule. See 
also the responses to comments 39 through 43 below. FDA has long 
determined which drug products are ones that consumers can 
appropriately self-select or use without the supervision of a 
practitioner licensed by law to administer such drug, and under what 
conditions, and these determinations are squarely within FDA's 
scientific expertise and authority under the FD&C Act. Additionally, 
FDA has engaged the public in various ways throughout the development 
of this rule. For example, 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 2022 proposed rule (see 87 FR 38313). FDA also 
carefully considered public comments in developing the final rule.
    (Comment 3) We received many comments on the role of a pharmacist 
in relation to nonprescription drug products with ACNUs. One comment 
suggests that nonprescription drug products with ACNUs be available 
only from State-licensed pharmacies, where there is a licensed 
pharmacist available to assist consumers. Many of these comments 
suggest that FDA require nonprescription drug products with ACNUs to be 
sold only after consultation with a pharmacist. The comments assert 
that pharmacists should: (1) assist with determining whether a 
nonprescription drug product with an ACNU is appropriate for the 
consumer; (2) ensure consumer fulfillment of the ACNU; and (3) provide 
a stopgap for consumer

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questions or concerns regarding the benefits and risks of the 
nonprescription drug product with an ACNU.
    Additionally, we received many comments about the practice of 
pharmacy or medicine that are outside the scope for this rulemaking, 
including comments about reimbursement for pharmacist professional 
services, increased prescribing authority for pharmacists, pharmacy 
recordkeeping, documentation of nonprescription drug products in 
profiles for the consumer or drug history data repositories, State laws 
about sales of nonprescription drug products, and legal liability for 
pharmacists.
    (Response 3) FDA disagrees that a nonprescription drug product with 
an ACNU should be available only from State-licensed pharmacies, where 
there is a licensed pharmacist available to assist consumers, or sold 
only after consultation with a pharmacist. The purpose of this rule is 
to increase options for applicants to develop and market safe and 
effective nonprescription drug products, which in turn may increase 
consumer access to appropriate, safe, and effective drug products. 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. Nonprescription drug products are 
generally available for consumers to purchase at such as pharmacies, 
supermarkets, or other retail locations, and from online retailers. FDA 
anticipates that nonprescription drug products with an ACNU would be 
sold similarly. FDA recognizes the potential benefit of providing 
consumers with appropriate access to nonprescription drug products. As 
long as consumers can fulfill the ACNU, limiting the locations in which 
nonprescription drug products with an ACNU can be sold, or requiring 
consultation with a healthcare professional (i.e., a pharmacist), when 
not necessary for safe and effective use of the drug product, would 
limit consumer access to appropriate, safe, and effective drug 
products, which would unnecessarily undermine these public health 
benefits of this rule.
    Such a system also would be inconsistent with this final rule, 
which pertains to nonprescription drug products. Section 503(b) of the 
FD&C Act requires that a drug product be dispensed by prescription when 
it is not safe for use except under the supervision of a practitioner 
licensed by law to administer such drug because of toxicity or other 
potentiality for harmful effect, or the method of the drug product's 
use, or the collateral measures necessary to the drug product's use 
(see section 503(b)(1) of the FD&C Act). If an approved drug product 
does not meet the criteria for prescription-only dispensing, it may be 
marketed as nonprescription (see 87 FR 38313 at 38316).

C. Comments on Applicability and FDA Responses

    We proposed requirements for NDAs and ANDAs for nonprescription 
drug products with ACNUs (see proposed 21 CFR 201.67, 201.130, 314.56, 
314.81, 314.125, and 314.127). In the following paragraphs, we discuss 
comments on the applicability of the rule. After consideration of 
public comments received, we are finalizing our proposals without 
change.
    (Comment 4) We received several comments on how the rule will be 
applied to already marketed drug products. We received a comment 
asserting that an ACNU cannot be retroactively required for a 
nonprescription drug product that FDA has already approved without an 
ACNU. However, the comment requests FDA make clear in the final rule 
that FDA has the authority to revisit the approval of a nonprescription 
drug product when information emerges in the postmarketing setting 
regarding the safety and efficacy of the nonprescription drug product. 
Further, we received a comment that FDA approval of a nonprescription 
drug product with an ACNU should not become the ``temporary stopping 
ground'' for every drug moving from prescription to nonprescription 
status.
    (Response 4) We do not intend, as a result of this rule, to revisit 
nonprescription drug products marketed under approved applications. The 
approval of an application for a nonprescription drug product prior to 
the finalization of this rule was based on FDA's finding, in part, that 
labeling alone is sufficient for the drug product to be used safely and 
effectively by consumers. Under this rule, such a finding by FDA would 
obviate the need for the approved nonprescription drug product to have 
an ACNU in order for the drug product to be used safely and 
effectively. In addition, we do not think that FDA approval of a 
nonprescription drug product with an ACNU will generally become a 
``temporary stopping ground'' as a step toward nonprescription approval 
without an ACNU (i.e., the applicant would regularly propose to remove 
the ACNU after approval) because the applicant would have demonstrated 
and FDA would have determined that labeling, alone, was insufficient to 
ensure appropriate self-selection or appropriate actual use, or both.
    We agree that FDA has authority to address safety and efficacy 
concerns observed for an approved drug product in the postmarketing 
setting, including existing authority under the FD&C Act and current 
regulations to withdraw approval of an application in certain 
circumstances (see section 505(e) of the FD&C Act and 21 CFR 314.150). 
This includes withdrawal of an approval of an application for a 
nonprescription drug product with or without an ACNU for safety or 
efficacy concerns. In certain situations, if FDA withdraws approval of 
an application for a nonprescription drug product due to the emergence 
of a safety issue with regard to appropriate self-selection or actual 
use of the drug product, the applicant could submit a new application 
for the product as a nonprescription drug product with an ACNU to 
ensure appropriate self-selection or actual use, as appropriate.
    (Comment 5) We received over 100 comments recommending that 
specific drug products be available as nonprescription (e.g., 
antibiotics) or that specific drug products not be made available as 
nonprescription (e.g., albuterol inhaler). The majority of these 
comments recommend that oral contraceptives should be available as 
nonprescription. We also received one comment advocating FDA use the 
rule to increase access to naloxone. These comments did not discuss 
whether ACNUs would be appropriate for these drug products if available 
as nonprescription.
    Additionally, we received a few comments discussing the 
appropriateness of approving nonprescription drug products with ACNUs 
for certain general types of drug products. We received one comment 
recommending FDA only approve a nonprescription drug product with an 
ACNU if it has a low risk for misuse. We received a few comments 
expressing concerns about the appropriateness of nonprescription drug 
products with ACNUs for the treatment of chronic conditions and 
asserting that consumers may not be able to appropriately manage 
chronic health conditions without the communication and supervision by 
a healthcare practitioner. We also received a comment discussing that 
FDA may have unintentionally implied that a drug product to treat 
chronic conditions or intended for long-term use must have an ACNU to 
be available as nonprescription. We received several comments 
expressing concern about the approval of a nonprescription drug

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product with an ACNU that has potentially harmful interactions and 
recommending that the ACNU needs to include information on possible 
interactions (e.g., drug-drug interactions, questions about diet, 
vitamins, complementary and alternative medicine, and other 
nonprescription drug products) to avoid potential life-threatening 
adverse drug experiences.
    (Response 5) We disagree that we need to clarify the rule to 
address comments regarding approval of specific drug products or 
categories of drug products or restrict the types of drug products that 
FDA may consider for approval as a nonprescription drug product with an 
ACNU. FDA considers the specifics of each application during its 
review, including the potential risk for misuse of the drug product. As 
long as the application meets the existing evidentiary standards under 
the FD&C Act and current FDA regulations to demonstrate the safety and 
effectiveness of the drug product, and the drug product does not meet 
the criteria for prescription-only dispensing (see section 503(b)(1) of 
the FD&C Act), FDA may approve the application as nonprescription. FDA 
has the authority to approve a nonprescription drug product intended 
for a chronic disease or condition, or for long-term use, that meets 
the existing evidentiary standards and FDA regulations. In fact, FDA 
has approved nonprescription drug products for chronic diseases or 
conditions, or for long-term use, based on FDA's finding, in part, that 
labeling alone is sufficient for the drug product to be used safely and 
effectively by consumers. For example, on January 25, 2013, FDA 
approved NDA 202211 Oxytrol for Women (oxybutynin) extended-release 
film, 3.9 milligrams (mg), for the treatment of overactive bladder in 
women. When relevant, the applicant must ensure consumers understand 
information on potential interactions to safely and effectively use a 
nonprescription drug product with an ACNU. Further, consistent with the 
existing requirements for all nonprescription drug products, an 
applicant of a nonprescription drug product with an ACNU must include 
specific warnings, including all major drug-drug and drug-food 
interaction warnings in the DFL (see Sec.  201.66(c)(5)(v) (21 CFR 
201.66(c)(5)(v))).
    We appreciate the public's interest in advocating for specific drug 
products or types of drug products to be approved or not be approved 
for nonprescription use, such as oral contraceptives and naloxone. Of 
note, on July 13, 2023, FDA approved supplemental NDA 017031 for Opill 
(norgestrel) tablet, 0.075 mg, as a nonprescription daily oral 
contraceptive to prevent pregnancy. On March 29, 2023, FDA approved 
supplemental NDA 208411 for Narcan (naloxone hydrochloride) nasal 
spray, 4 mg, for nonprescription use to reverse the effects of a life-
threatening opioid emergency. Additionally, on July 28, 2023, FDA 
approved NDA 217722 for RiVive (naloxone hydrochloride) nasal spray, 3 
mg, for nonprescription use for emergency treatment of opioid overdose 
in adults and children. Based on FDA's review under relevant statutory 
and regulatory standards for approval, FDA determined the labeling for 
these drug products was sufficient to ensure consumers' appropriate 
self-selection and use of the products without the supervision of a 
practitioner licensed by law to administer such drug.
    (Comment 6) We received several comments asking FDA to clarify when 
an applicant should propose an ACNU for a nonprescription drug product. 
We received a comment that asserts that the definition of an ACNU 
should be limited to those conditions that are most feasible to 
implement at the pharmacy-patient level and suggests that FDA provide a 
finite list of additional conditions that would be applied to real-
world situations. We received several comments asking FDA to provide 
examples when labeling is inherently insufficient for appropriate self-
selection or actual use, if these examples exist, or examples of 
specific drug products that FDA considers as possible candidates for 
approval.
    (Response 6) We decline to establish such inflexible limits on when 
an ACNU should be proposed. The rule is intended to increase options 
for an applicant to develop and market safe and effective 
nonprescription drug products and increase consumer access to 
appropriate, safe, and effective drug products. The rule is 
intentionally flexible, mindful that technologies evolve and ACNUs may 
be developed for many different nonprescription drug products. FDA 
placing limits on the types of conditions that can be proposed or the 
creation of a finite list of additional conditions is not warranted and 
may unnecessarily restrict the type and number of drug products that 
could be marketed nonprescription, contrary to the intent of this rule.
    We expect applicants may submit applications for nonprescription 
drug products with ACNUs for a wide range of indications, including for 
drug products intended to treat both acute and chronic diseases. 
However, FDA cannot predetermine the full range of indications for 
which nonprescription drug products with ACNUs could be approved, nor 
can the Agency predetermine that all proposed nonprescription drug 
products with ACNUs for a given indication would be safe and effective, 
because FDA considers the specifics of each application during its 
review. Further, we cannot provide a general list or guideline of when 
labeling alone is insufficient to ensure appropriate self-selection or 
appropriate actual use, or both, because the determination of when 
labeling is insufficient is made for a specific nonprescription drug 
product based upon the data or other information that the applicant 
submits to FDA as part of an application.

D. Comments on Definition and FDA Responses

    We proposed to establish a definition for additional condition for 
nonprescription use (ACNU) (see proposed 21 CFR 201.67(b)(1) and 
314.56(a)(1)). As proposed, an 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. 
As an example, an ACNU for appropriate self-selection could be a 
questionnaire that consumers are required to complete on a secure 
website or mobile application created by the applicant to determine 
whether the drug product is appropriate for the consumer. The 
questionnaire would contain a series of questions that the consumer 
answers. The underlying program or other operating information used by 
the secure website or mobile application would determine if the drug is 
appropriate for the consumer based on these responses. If the drug is 
indeed appropriate for the consumer, the consumer could then access and 
purchase the drug product. For a more specific example, see the 
proposed rule (87 FR 38313 at 38319), in which we discuss Drug X, a 
fictitious nonprescription drug product with an ACNU.
    In the following paragraphs, we discuss comments on the proposed 
definition. After consideration of public comments received, we are 
finalizing our proposal with revisions for consistency with the wording 
in section 503(b) of the FD&C Act. Therefore, we

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are revising the phrase ``of a healthcare practitioner'' to ``of a 
practitioner licensed by law to administer such drug.''
    (Comment 7) We received one comment supporting FDA's proposed 
definition of an ACNU because it provides sufficient flexibility for 
the applicant to develop and tailor the ACNU to a specific drug 
product.
    (Response 7) We agree that the proposed definition of ACNU is 
sufficiently broad, as was intended, to give applicants flexibility 
regarding the types of additional conditions that may be proposed and 
how those conditions can be implemented (87 FR 38313 at 38318). This 
flexibility will allow applicants to consider the unique benefit and 
risk considerations for a particular drug product while developing an 
ACNU to ensure consumers' appropriate self-selection or appropriate 
actual use, or both, of the drug product.
    (Comment 8) We also received several comments disagreeing with 
FDA's proposed definition of ACNU. Some comments disagree with the use 
of the term ``ensure'' in the definition and recommend FDA revise the 
definition to replace the term ``ensure'' with ``enable.'' The comments 
assert that the term ``ensure'' implies that any risk to consumers from 
the nonprescription drug product with an ACNU has been eliminated even 
though all drug products have residual risk regardless of any 
mitigation steps taken. We received one comment asserting that the 
proposed definition is vague and suggesting that FDA provide a 
definition of ``appropriate actual use'' and ``appropriate self-
selection.''
    (Response 8) We disagree with replacing the term ``ensure'' with 
``enable'' in the definition. The Merriam-Webster dictionary defines 
``ensure'' as ``to make sure, certain, or safe.'' The Merriam-Webster 
dictionary defines ``enable'' as ``to make possible, practical, or easy 
or to provide with the means or opportunity.'' The term ``ensure'' 
reflects a greater level of certainty that is consistent with FDA's 
approval standards. All drug products, including nonprescription drug 
products, have risks. As part of our regulatory decision-making 
process, we conduct a structured benefit-risk assessment to facilitate 
the balanced consideration of benefits and risks (see, e.g., section 
505(d) of the FD&C Act and Sec.  314.50 (21 CFR 314.50)). Nothing in 
the rule affects this benefit-risk assessment for an application for a 
nonprescription drug product with an ACNU.
    FDA disagrees that specifically defining ``appropriate actual use'' 
and ``appropriate self-selection'' is necessary for nonprescription 
drug products with an ACNU. The terms ``actual use'' and ``self-
selection'' are used in the context of all nonprescription drug 
products. In general, applicants of nonprescription drug products 
conduct consumer studies such as label comprehension studies, self-
selection studies, actual use studies, and human factors studies to 
help demonstrate that consumers can correctly self-select and correctly 
use the drug products (see also 87 FR 38313 at 38316). FDA has defined 
``self-selection'' in FDA guidance for industry (Ref. 1 and 87 FR 38313 
at 38315).
    (Comment 9) Several comments recommend FDA revise the proposed 
definition to make clear that applicants, not FDA, should determine 
when an ACNU is necessary. The comments assert that the applicant 
should have the ability to evaluate the need for an ACNU and propose 
the use of an ACNU without seeking prior agreement from FDA.
    (Response 9) We disagree with revising the definition to permit the 
applicant, not FDA, to make the final determination on the necessity of 
the ACNU. To approve a drug product, FDA must determine whether the 
specific application meets the applicable statutory and regulatory 
requirements. FDA will not require a nonprescription drug product to 
have an ACNU if the drug product can be used safely and effectively by 
consumers, without the supervision of a practitioner licensed by law to 
administer such drug, based on labeling alone. Requiring unnecessary 
ACNUs would be inconsistent with the goal of this rulemaking, which is 
to increase consumer access to safe and effective nonprescription drug 
products.
    While applicants are not required to meet with FDA prior to the 
submission of an application for a nonprescription drug product with an 
ACNU, we encourage applicants to meet with FDA to discuss their drug 
development plans and seek feedback, including whether an ACNU may be 
necessary. However, it is during FDA's review of an application that 
FDA must determine whether the application meets the applicable 
statutory and regulatory requirements, including whether the applicant 
demonstrates the necessity of the ACNU to ensure appropriate self-
selection or appropriate actual use, or both (see, e.g., Sec.  
314.56(c)(1)(v)) in order to approve the nonprescription drug product 
with an ACNU.

E. Comments on Separate Application Required for a Nonprescription Drug 
Product With an ACNU and FDA Responses

    We proposed that an applicant must submit a separate application 
for a nonprescription drug product with an ACNU (proposed 21 CFR 
314.56(b)). For cases where there is an approved prescription drug 
product, we proposed that initial approval for a nonprescription drug 
product with an ACNU cannot be obtained through a supplement to the 
approved application for prescription use of the drug product.
    In the following paragraphs, we discuss comments on this proposed 
requirement. After consideration of public comments received, we are 
finalizing our proposal with a clarifying revision to explain that this 
provision supersedes Sec.  310.200(b) (21 CFR 310.200(b)) with regard 
to nonprescription drug products with an ACNU. To clarify and avoid 
ambiguity, we are adding the clause ``Notwithstanding Sec.  
310.200(b)'' to the beginning of the first sentence in 21 CFR 
314.56(b).
    (Comment 10) We received a few comments supporting the proposed 
requirement for the submission of a separate application for a 
nonprescription drug product with an ACNU because it would improve 
consumer options. Additionally, a commenter asserted that the proposed 
requirement increases equity and access to drug products. We also 
received several comments opposing this proposed requirement and 
asserting that an applicant should be allowed to submit a supplement to 
an approved prescription application rather than a separate 
application. One comment asserts that an applicant should not be 
required to submit a separate application simply because the ACNU is 
part of a development program, especially where the formulation is 
similar to the approved prescription application. We received a comment 
requesting FDA remove the proposed requirement and, instead, address 
the issue on a case-by-case basis to determine the circumstances when 
it would be appropriate for an applicant to seek approval of a 
nonprescription drug product with an ACNU by submitting a supplement. 
The comment argues that the proposed requirement for a separate 
application is inconsistent with the FDA guidance for industry from 
December 2004 ``Submitting Separate Marketing Applications and Clinical 
Data for Purposes of Assessing User Fees'' (available at https://www.fda.gov/media/72397/download) and FDA

[[Page 105296]]

practices, which, according to the comment, contemplate that labeling 
changes may be the subject of a supplement. In addition, some comments 
assert that requiring a separate application would disincentivize 
innovation and limit utilization of the ACNU pathway because the 
separate application would allow for the potential continued marketing 
of generic prescription drugs that would compete with the 
nonprescription drug with an ACNU. The commenters assert that 
incorporating an ACNU into a development program for a nonprescription 
drug product is expected to increase the overall costs and time in 
developing the nonprescription drug product. The commenters explain 
that there is typically a limited period of marketing exclusivity when 
a new nonprescription drug product is approved, a ``long-accepted means 
of incentivizing'' applicants to undertake such investment. Therefore, 
the commenters argue that potential continued simultaneous marketing of 
a generic prescription drug product that could compete with the 
nonprescription drug product with an ACNU would render any marketing 
exclusivity moot.
    (Response 10) We disagree with removing the requirement for the 
submission of a separate application. This requirement is essential to 
achieving the key policy goal of increasing consumer access to 
appropriate drug products. In cases where there is an approved 
prescription drug product, this requirement creates a pathway for the 
simultaneous marketing of the prescription drug product, along with the 
nonprescription drug product with an ACNU. While many consumers will 
benefit from the availability of nonprescription drug products with 
ACNUs, FDA also recognizes that some may not be able to access the 
nonprescription drug product with an ACNU. For example, a consumer may 
not be able to access the technology that operationalizes the ACNU. 
Therefore, continued availability of the prescription drug product 
along with the nonprescription drug product with an ACNU promotes the 
greatest access to needed drug products.
    We are also clarifying that a separate application must be 
submitted for a nonprescription drug product with an ACNU 
notwithstanding Sec.  310.200, which states that an interested person 
may submit a supplement to an approved new drug application to propose 
to exempt a drug from the prescription-dispensing requirements of 
section 503(b)(1)(B) of the FD&C Act. Under Sec.  310.200(b), 
applicants may continue to submit a supplement to switch a drug from 
prescription to nonprescription status if the nonprescription drug 
product would not have an ACNU and the resulting approved application 
would only address the nonprescription drug product. Nonprescription 
drug products without ACNUs do not implicate the same issues regarding 
continued consumer access to appropriate drug products, because they 
are generally available to consumers and do not have additional 
conditions of approval that restrict consumer access.
    Additionally, we do not agree that the proposed separate 
application requirement is inconsistent with existing FDA guidance. The 
guidance entitled ``Submitting Separate Marketing Applications and 
Clinical Data for Purposes of Assessing User Fees'' did not contemplate 
and, therefore, did not address the submission of an application for a 
nonprescription drug product with an ACNU. Therefore, the guidance is 
not relevant to the question of whether a separate application or a 
supplement is appropriate for such a product. Furthermore, the guidance 
document merely provides FDA's recommendations on submission of certain 
applications to FDA. The guidance document does not set forth any 
requirements, and the recommendations therein are not binding on FDA or 
applicants.
    We also do not agree that requiring a separate application would 
necessarily disincentivize innovation and limit utilization of the ACNU 
pathway. This assertion is speculative and does not outweigh the 
potential benefits from requiring a separate application, which would 
increase consumer access to appropriate drug products. We acknowledge 
that the cost to develop a nonprescription drug product with an ACNU is 
higher than a nonprescription drug product without an ACNU. The 
Appendix of the Regulatory Impact Analysis estimates that the core 
development cost of a nonprescription drug product is $31.1 million 
while the estimated cost to develop cost of a nonprescription drug 
product with an ACNU is $47.3 million, an estimated markup of $16.2 
million for ACNU-related development. However, as noted in section I.C. 
of the Regulatory Impact Analysis, evidence shows that roughly 60 
percent of purchases for a nonprescription drug product are from new-
to-therapy consumers who had not previously taken the drug before it 
switched from prescription status, suggesting that the potential to 
attract new-to-therapy consumers for nonprescription drug products is 
substantial (Ref. 13). Further, section V.B. of the Regulatory Impact 
Analysis estimates that every year nonprescription drug manufacturers 
get $112.02 million of additional revenue from switching a drug to 
nonprescription status (Ref. 13), which also indicates there will be 
incentives for drug manufacturers to innovate and use the ACNU pathway. 
We disagree that simultaneous marketing would reduce or render moot the 
benefit of any statutory exclusivity that may be associated with a 
nonprescription drug product. For example, three-year new clinical 
investigation exclusivity (e.g., section 505(c)(3)(E)(iii) and 
(j)(5)(F)(iii) of the FD&C Act) rewards an applicant for sponsoring or 
conducting additional studies on previously approved drug products 
containing an active moiety that has been previously approved, and an 
NDA applicant for a nonprescription drug product with an ACNU could be 
eligible for such exclusivity, provided the relevant statutory 
requirements are met. We discuss the issue of ``market exclusivity'' or 
``statutory exclusivity'' for nonprescription drug products with an 
ACNU further in our responses to Comments 36 and 72.
    (Comment 11) Several comments express concerns that submitting an 
application is more burdensome than submitting a supplement. Although 
another comment acknowledges FDA's explanation that applicants can 
cross-reference information in an approved application, the comment 
asserts that the applicant would be required to pay a new application 
user fee, even though the commenter believes that FDA's review would be 
less resource-intensive compared to other NDAs.
    (Response 11) We acknowledge that submitting a separate application 
may be more burdensome than submitting a supplement to the approved 
prescription drug application; however, an applicant may cross-
reference information from its approved NDA for the prescription drug 
product and would not need to duplicate studies already conducted for 
and submitted in its NDA for the prescription drug product (87 FR 38313 
at 38318). While we acknowledge that a new application user fee will be 
required, we disagree that FDA's review of an application for a 
nonprescription drug product with an ACNU is less resource intensive 
for the Agency compared to other NDAs. As required for other NDAs, the 
application must include data and information from studies to support 
the safety and efficacy of the drug product as nonprescription as well 
as meet the additional specific requirements for a

[[Page 105297]]

nonprescription drug product with an ACNU (see 21 CFR 314.56(c) in this 
final rule). Generally, these requirements would include the submission 
of newly generated data and information that FDA would not have 
previously reviewed, including but not limited to, label comprehension 
studies, self-selection studies, actual use studies, and human factors 
studies to demonstrate both the necessity and the effect of the ACNU. 
In some cases, device information may also be submitted. Additionally, 
FDA's review of an application for a nonprescription drug product with 
an ACNU will typically involve many offices in the Center for Drug 
Evaluation and Research, and in some instances, consults to other 
Centers within FDA.
    (Comment 12) We also received one comment requesting that FDA 
establish a process for the applicant to revise or remove an approved 
ACNU for a nonprescription drug product with an ACNU. The comment notes 
that an ACNU should not be expected to remain unchanged or permanent.
    (Response 12) We disagree that we need to establish a new, separate 
process specific for making post approval changes to an application for 
a nonprescription drug product with an ACNU. An applicant may propose 
revisions to an approved application for a nonprescription drug product 
with an ACNU by submitting a supplement and may describe certain 
changes in the annual report, consistent with our current regulations 
for making changes to an FDA-approved application (see Sec. Sec.  
314.70, 314.81, 314.97, and 314.98 (21 CFR 314.70, 314.81, 314.97, and 
314.98)). 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 (see Sec. Sec.  314.60 and 314.96 (21 CFR 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 (see Sec. Sec.  314.70 and 314.97) (87 FR 
38313 at 38319).

F. Comments on Specific Requirements for an Application for a 
Nonprescription Drug Product With an ACNU and FDA Responses

    We proposed to establish specific NDA and ANDA requirements for a 
nonprescription drug product with an ACNU (proposed 21 CFR 314.56(c)). 
After consideration of public comments received, we are finalizing 
these proposals with a few editorial modifications to provide clarity. 
The changes are described below in sections V.F.1. and V.F.2.
1. NDA
    In addition to existing content and format requirements for an NDA 
(Sec.  314.50), FDA proposed specific requirements for an NDA for a 
nonprescription drug product with an ACNU. We discuss the specific 
requirements in the following paragraphs.
    a. Statement regarding the purpose of the ACNU. We proposed to 
require the applicant to provide 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 practitioner licensed by law to administer 
such drug (proposed Sec.  314.56(c)(1)(i)). We received no comment 
specifically regarding this proposed requirement. We are finalizing our 
proposal with a few editorial modifications to provide greater clarity. 
We are revising the sentence to add the word ``whether'' after the 
phrase ``A statement regarding. . . .'' We are also removing the colon 
after ``ACNU'' and replacing it with the phrase ``is to.''.
    b. Statement of necessity of the ACNU. We proposed to require the 
applicant explain why the ACNU is necessary to ensure appropriate self-
selection or appropriate actual use, or both, by consumers of the 
nonprescription drug product (proposed Sec.  314.56(c)(1)(ii)). We 
received no comment regarding this proposed requirement, and we are 
finalizing it without change.
    c. Description of how the ACNU ensures appropriate self-selection 
or appropriate actual use, or both. We proposed to require the 
applicant describe how the ACNU will ensure appropriate self-selection 
or appropriate actual use, or both, by consumers (proposed 21 CFR 
314.56(c)(1)(iii)). After consideration of public comments received, we 
are finalizing our proposal without change.
    (Comment 13) We received a few comments asserting that the proposed 
rule lacks clarity on how often an ACNU must be fulfilled by consumers. 
A few commenters question if the consumer would be required to fulfill 
an ACNU each time the consumer repurchases the drug product, which 
would be burdensome, particularly if the drug product is indicated for 
a chronic condition. One comment recommends that FDA require the 
application to include information on how the consumer would repurchase 
a nonprescription drug product with an ACNU.
    (Response 13) There is not one standard for the frequency in which 
an ACNU must be fulfilled by the consumer; this will be determined on a 
case-by-case basis as we consider the specifics of each application for 
a nonprescription drug product with an ACNU during our review. As 
finalized in this final rule, we require that the application include a 
description of how the ACNU ensures appropriate self-selection or 
appropriate actual use, or both (21 CFR 314.56(c)(1)(iii) in this final 
rule), and describe the additional condition(s) implemented and the 
criteria by which the consumer would successfully fulfill the ACNU, 
including a description of the specific actions to be taken by a 
consumer as part of the description of key elements of the ACNU (21 CFR 
314.56(c)(1)(iv) in this final rule). Therefore, the application may 
include information describing how a consumer would make subsequent 
purchases of the nonprescription drug product with an ACNU, if 
appropriate. For example, an applicant may explain that a consumer 
would fulfill an ACNU (e.g., complete a self-selection questionnaire) 
upon the first time purchasing the nonprescription drug product with an 
ACNU and at a specific time interval (e.g., every 3 months) in order to 
repurchase the drug product.
    d. Description of the key elements of the ACNU. We proposed to 
require the applicant to include a description of the key elements of 
the ACNU, including: the additional condition implemented by the 
applicant to be fulfilled by the consumer to obtain the nonprescription 
drug product with an ACNU; the labeling specifically associated with 
the ACNU; and 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 
(see proposed 21 CFR 314.56(c)(1)(iv)). We received no comment 
regarding this proposed requirement. We are making an editorial 
modification for clarity. We are adding the introductory clause: ``Key 
elements of the ACNU'' to better explain the required information and 
to allow for ease of reference to discuss the requirement.
    e. Adequate data or other information that demonstrate the 
necessity of the ACNU to ensure appropriate self-selection or 
appropriate actual use, or both. We proposed to require an applicant to 
include adequate data or other information that demonstrate the 
necessity of the ACNU to ensure

[[Page 105298]]

appropriate self-selection or appropriate actual use, or both (proposed 
21 CFR 314.56(c)(1)(v)). After consideration of public comments 
received, we are finalizing our proposal without change.
    FDA believes that the requirement for demonstrating that the ACNU 
is necessary, as reflected in the ACNU definition and in 21 CFR 
314.56(c)(1)(v), and as determined by FDA, is necessary to fulfill the 
key goals of this rulemaking. The key goals are to: (1) increase 
options for applicants to develop and market safe and effective 
nonprescription drug products, which would broaden the types of 
nonprescription drug products available to consumers and (2) increase 
consumer access to appropriate, safe, and effective drug products, by 
providing for the availability of prescription versions of 
nonprescription drug products approved with ACNUs, both of which in 
turn could improve public health (see the discussion in this section 
F.1.e.). Allowing a product to be approved as a nonprescription drug 
product with an ACNU, when the ACNU is not necessary, would not 
increase options for applicants to develop and market safe and 
effective nonprescription drug products because they could already be 
marketed as a nonprescription drug product without an ACNU. Approving a 
nonprescription drug product with an ACNU that is not necessary also 
would not necessarily increase consumer access because, although this 
rule has the potential to provide consumers with access to additional 
types of nonprescription drug products, FDA recognizes that ACNUs 
necessarily restrict consumer access, which is appropriate when they 
are needed to ensure appropriate self-selection or appropriate actual 
use, or both. However, nonprescription drug products without ACNUs do 
not necessarily implicate the same issues regarding continued consumer 
access to drug products because they are generally available to 
consumers and do not have additional conditions of approval that 
restrict consumer access. Therefore, if the definition in 21 CFR 
201.67(b)(1) and 314.56(a)(1), or the provision at 21 CFR 
314.56(c)(1)(v), is stayed or determined to be invalid or 
unenforceable, the entire rule should be invalidated.
    (Comment 14) We received several comments requesting that FDA 
provide further guidance on the meaning of ``adequate data'' as it 
pertains to demonstrating the necessity of the ACNU and the effect of 
the ACNU. FDA received one comment stating the proposed rule does not 
address the types of consumer studies that would be needed to provide 
adequate data. A few comments assert that FDA should not limit adequate 
data to prospective consumer behavior studies if other sources 
referenced by the applicant are reliable and fit for purpose.
    (Response 14) Consistent with our proposal, 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 (87 FR 38313 at 38320 and 21 CFR 314.56(c)(1)(vi) in this final 
rule). Further, the applicant must submit data that show that consumers 
appropriately self-select or actually use the drug product, or both, 
safely and effectively using the ACNU. To clarify, adequate data need 
to be relevant to the specific application and need to be interpretable 
for FDA to evaluate the scientific finding. The types of data that can 
be submitted are not limited. Applicants can submit data from consumer 
studies such as label comprehension studies, self-selection studies, 
actual use studies, and human factors studies (87 FR 38313 at 38315) to 
demonstrate the necessity of the ACNU and the effect of the ACNU. The 
specific types of consumer studies an applicant would conduct depends 
on the development program for the particular nonprescription drug 
product with an ACNU.
    FDA has issued guidances on some types of consumer studies (Refs. 
1, 2, and 3). We may provide advice (e.g., specific verbal or written 
feedback) to applicants on adequate data or other information that 
demonstrate the necessity and effect of the ACNU in the context of a 
pending or proposed application, as appropriate. Additionally, 
applicants can request to meet with FDA staff to discuss questions that 
arise during the development of a nonprescription drug product with an 
ACNU. FDA may consider issuing guidance in the future to address 
general considerations that may arise and are applicable to all 
applicants developing nonprescription drug products with an ACNU.
    (Comment 15) We received many comments asserting that FDA should 
remove the proposed requirement that the applicant must develop or 
reference adequate data to demonstrate that labeling is insufficient 
for safe and effective use of a nonprescription drug product. We 
received many comments expressing concerns that, before developing an 
ACNU, an applicant must first generate data from a failed labeling 
study (i.e., fail first) and FDA must then agree with the applicant's 
assessment that labeling alone is insufficient. Several comments state 
that the fail-first concept would put the onus on the applicant to 
prove a negative, rather than developing the key self-selection or use 
question(s) that trigger the need for an ACNU. One comment asserts that 
the rigidity of trying to prove a negative is inconsistent with 
scientific methods in developing a label. A few comments assert that it 
can become apparent for a variety of reasons that labeling is not 
adequate throughout the development program. Although the comments note 
that applicants can utilize meetings with FDA during the development 
program to obtain alignment, many commenters believe that applicants 
should have the ability to evaluate the necessity of an ACNU without 
seeking prior agreement with FDA.
    (Response 15) We disagree with removing the requirement that the 
applicant must provide adequate data or other information to show that 
labeling alone would not support the safe and effective use of the 
nonprescription drug product and disagree that the requirement is 
inconsistent with the methods of developing labeling for 
nonprescription drug products. An ACNU cannot be proposed merely to 
provide consumers with additional information when the labeling could 
be sufficient to ensure appropriate self-selection or actual use or 
both. In such case, the use of an ACNU can present potential barriers 
for another applicant developing a nonprescription drug product. We 
cannot make a determination about whether labeling alone is 
insufficient without adequate data or other information. While the data 
or other information will typically come from consumer testing or by 
reference, it does not necessarily need to come from a failed labeling 
study. Further, the necessity for adequate data or other information, 
which typically comes from consumer testing or by reference is 
consistent with FDA's approval requirements for all nonprescription 
drug products. For a nonprescription drug product, the applicant 
develops and optimizes the labeling using an iterative process and 
conducts consumer studies (e.g., label comprehension studies, self-
selection studies, actual use studies, and human factors studies) to 
demonstrate whether consumers appropriately self-select and use the 
drug product using labeling alone. In certain circumstances, an ACNU 
may only be required for appropriate self-selection or appropriate 
actual use, but not both, of the nonprescription drug product. For 
example, if the applicant demonstrates that labeling alone is 
insufficient to ensure appropriate self-selection (but

[[Page 105299]]

not appropriate actual use) of the nonprescription drug product and 
proposes an ACNU for self-selection, the applicant must still conduct 
consumer studies to demonstrate that consumers will appropriately use 
the drug product based on labeling, alone. In addition to reflecting 
the reality of developing a nonprescription drug product, this policy 
is also intended to help ensure consumers can access nonprescription 
drug products without barriers or hurdles to access that are 
unnecessary when that drug product could be approved as nonprescription 
without an ACNU.
    We encourage applicants to meet with FDA to discuss their drug 
development plans and seek advice. However, these meetings are not 
required; applicants that view these meetings as unnecessary are not 
required to have them.
    (Comment 16) We received a few comments recommending that FDA 
clarify when an applicant can submit ``other information'' explaining 
the necessity of the ACNU. One comment recommends FDA define the 
criteria for when an applicant can submit ``other information''; for 
example, situations that require additional tests, lab values, or other 
ancillary values or measurements as part of self-selection or actual 
use; literature; and medical practice guidelines. One comment 
recommends that FDA clarify how FDA will signal to an applicant when 
labeling alone is insufficient because clear communication with FDA 
will allow the applicant to proceed in its development program.
    (Response 16) FDA disagrees with providing criteria in the rule for 
when an applicant can submit ``other information'' to demonstrate the 
necessity of the ACNU. Because this determination is specific to the 
circumstances surrounding each individual drug development program, FDA 
does not think specifying such criteria in the rule would be feasible 
and may instead unnecessarily limit the options available to applicants 
for development program designs.
    An applicant may be able to 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. FDA is available to meet with 
applicants to discuss drug development plans, which can include 
discussing questions about when ``other information'' can demonstrate 
the necessity of the ACNU. FDA encourages applicants to discuss their 
drug development plans with FDA and seek advice.
    (Comment 17) We received a few comments suggesting that FDA revise 
the rule to permit the submission of adequate data or other information 
that demonstrate ``the rationale for use of an ACNU,'' rather than 
adequate data or other information that demonstrate ``the necessity of 
the ACNU.'' Another comment also asserts that the results of the self-
selection and label comprehension studies or other adequate data or 
information should justify, rather than demonstrate, that consumers 
cannot appropriately self-select the drug product with labeling alone.
    (Response 17) While this rule has the potential to provide 
consumers with access to additional types of nonprescription drug 
products, FDA recognizes that nonprescription drug products without 
ACNUs do not necessarily implicate the same issues regarding continued 
consumer access to appropriate drug products, because they are 
generally available to consumers and do not have additional conditions 
of approval that restrict consumer access. Therefore, we disagree with 
the commenters' assertions because providing adequate data or other 
information that simply provides a rationale or justification for the 
use of an ACNU is a lower threshold. A lower threshold may result in an 
applicant submitting an application for a nonprescription drug product 
with an ACNU even when an ACNU is not necessary to ensure consumers' 
appropriate self-selection or appropriate actual use or both (i.e., 
labeling was sufficient to ensure appropriate self-selection or actual 
use or both). Consistent with the rigorous scientific data necessary 
for an application to meet the evidentiary standards under the FD&C Act 
and current FDA regulations for demonstrating safety and effectiveness, 
we expect the applicant to provide adequate data or other information 
that demonstrates the necessity of the ACNU.
    (Comment 18) We received a few comments recommending that FDA 
provide a streamlined process for demonstrating the necessity of an 
ACNU because, in certain instances, the need for an ACNU may be obvious 
and requiring data may delay drug product development. One comment 
requests that FDA clarify--in situations where the need for an ACNU is 
uncertain--that applicants may streamline the drug development process 
by running simultaneous trials that test the effectiveness of labeling 
both with and without an ACNU.
    (Response 18) FDA disagrees with providing a streamlined process 
applicable to all applications. Because each development program is 
unique, establishing a ``streamlined'' process and standards that 
applicants must follow as part of the development program may be overly 
restrictive. FDA acknowledges that applicants may choose to conduct 
simultaneous trials to demonstrate the necessity of the ACNU and the 
effect of the ACNU. However, because the results of the studies needed 
to demonstrate the necessity of the ACNU could affect the studies 
needed to demonstrate the effect of the ACNU, conducting simultaneous 
studies may result in the need to conduct additional trials. In 
general, FDA recommends the development program for a nonprescription 
drug product with an ACNU proceed in a stepwise approach. The 
development of labeling for all nonprescription drug products, 
including a nonprescription drug product with an ACNU, is an iterative 
process that may depend upon testing and retesting as the label evolves 
(Ref. 1). The applicant should begin by creating the complete labeling 
for the drug product that includes consumer-friendly language for all 
directions, warnings, and precautions, that is consistent with the 
available prescription labeling, in cases where there is an approved 
prescription drug product. FDA expects that the applicant will then 
optimize the labeling using an iterative process and conduct or 
reference adequate testing (e.g., label comprehension studies, self-
selection studies, actual use studies, and human factors studies) to 
determine if consumer comprehension can be improved to the point where 
labeling is sufficient for appropriate self-selection or appropriate 
actual use, or both, without an ACNU. If the conducted or referenced 
consumer studies demonstrate the necessity for an ACNU, information 
that is part of the ACNU may need to be aligned with the optimized 
label. In addition, when it is necessary to conduct pivotal actual use 
trials, an optimized label is needed before proceeding because 
consumers will need to refer to the label for use instructions after 
the point of purchase (e.g., throughout the trial), and the study may 
be invalid if there are subsequent substantive changes to the labeling. 
Because each development program is different, we encourage the 
applicant to discuss its drug development plans with FDA.

[[Page 105300]]

    (Comment 19) We received one comment questioning whether applicants 
should assume that the statutory standard for approving an NDA applies 
to NDAs for nonprescription drug products with ACNUs (e.g., two phase 3 
clinical trials to demonstrate safety and effectiveness).
    (Response 19) Yes, the statutory standard that an application 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 with an ACNU just 
as they apply to any other NDAs and ANDAs (see section 505(b)(1) or (2) 
and (j) of the FD&C Act). For example, an NDA for a nonprescription 
drug product with an ACNU must demonstrate the proposed drug product's 
safety and effectiveness. Therefore, the NDA must include 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 (e.g., phase 3 clinical trials or 
cross reference information in its approved NDA for the prescription 
product, where applicable (see section 505(d) and (b) of the FD&C Act).
    f. Adequate data or other information that demonstrate the effect 
of the ACNU to ensure appropriate self-selection or appropriate actual 
use, or both. We proposed to require the applicant to 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 (proposed 21 CFR 
314.56(c)(1)(vi)). After consideration of public comments received, we 
are finalizing our proposal without change.
    (Comment 20) A comment recommends that health literacy be a 
significant factor in determining adequate data or other information 
that demonstrates the effect of the ACNU.
    (Response 20) FDA understands this comment to be suggesting that 
health literacy be considered when enrolling study participants. An 
application for a nonprescription drug product with an ACNU must 
include 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 (21 CFR 
314.56(c)(1)(vi)). The data must show that consumers appropriately 
self-select or use the drug product safely and effectively, or both, 
with the ACNU. Because a nonprescription drug product with an ACNU, 
like other nonprescription drug products, would be used by consumers 
from the general population without the supervision of a practitioner 
licensed by law to administer such drug, an applicant is expected to 
include a wide range of subjects in consumer studies. Specifically, in 
self-selection studies, exclusion criteria should be minimal (e.g., 
excluding only those who cannot read and understand English) (Ref. 2). 
While FDA does not have specific recommendations on enrolling subjects 
with varying levels of health literacy, applicants should include an 
adequate number of subjects who have limited literacy skills in their 
consumer studies. The proportion of low-literacy subjects in the study 
sample should be representative of the proportion of adults in the 
United States with low-literacy skills based on available national data 
(Ref. 1) to help ensure that the study population is representative of 
the population that may use the nonprescription drug product.
    g. Description of the specific way the ACNU is operationalized. We 
proposed to require that the applicant describe the specific way the 
ACNU is operationalized (proposed 21 CFR 314.56(c)(1)(vii)). We stated 
that 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 (87 FR 38313 at 38320) (see 21 CFR 
314.56(c)(1)(iv) of this final rule regarding key elements of the 
ACNU). The purpose of the ACNU is to 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 practitioner 
licensed by law to administer such drug (21 CFR 314.56(c)(1)(i) of this 
final rule). The ACNU can be operationalized in different ways provided 
it reliably meets the objective. In the following paragraphs, we 
discuss and respond to comments on this requirement. After 
consideration of public comments received, we are finalizing the 
proposal with editorial modifications for clarity. We are adding the 
introductory clause: ``Operationalization of the ACNU'' for clarity and 
to allow for ease of reference to discuss the requirement. We are 
revising the word ``way'' to ``way(s)'' to add clarity because an 
application may include more than one way to operationalize the ACNU.
    (Comment 21) We received a few comments that support FDA's position 
that an ACNU can be operationalized in different ways as long as it 
reliably meets its objective. Specifically, one comment supports the 
flexibility in how an ACNU may be operationalized given that the 
technologies used may change over time. One comment requests that FDA 
clarify its expectation for the description of how the applicant will 
operationalize the ACNU.
    (Response 21) We appreciate commenters' support and firmly believe 
that the ACNU can be operationalized in different ways provided it 
reliably meets the objective. The applicant should describe the 
specific way the ACNU is operationalized so that we can understand how 
the ACNU is ensuring appropriate self-selection or appropriate actual 
use, or both. Because each development program is different, we 
encourage the applicant to discuss its drug development plans with FDA. 
Additionally, FDA may consider issuing guidance in the future to 
address general considerations that may arise and are applicable to all 
applicants developing nonprescription drug products with an ACNU, or to 
address new technology, if appropriate.
    (Comment 22) We received a few comments that request that FDA add 
language to the rule clarifying that ACNUs must be operationalized in 
ways that do not restrict the sale of a nonprescription drug product 
with an ACNU so that the ACNU does not become a barrier to long-term 
use of a drug product.
    (Response 22) We do not think that additional language needs to be 
added to the rule to address this comment. Because the ACNU is 
necessary to ensure appropriate self-selection or appropriate actual 
use, or both, by consumers of the drug product, the nonprescription 
drug product with an ACNU must only be made available to the consumer 
after the ACNU has been fulfilled by the consumer. However, in the case 
of long-term use of a nonprescription drug product with an ACNU where 
there is the need to repurchase the drug product, there is not one 
standard for the frequency in which an ACNU must be fulfilled by the 
consumer; this will be determined on a case-by-case basis as we 
consider the specifics of each application for a nonprescription drug 
product with an ACNU during our review. Therefore, the application may 
include information describing how a consumer would make subsequent 
purchases of the nonprescription drug product, if appropriate. For 
example, an applicant may explain that a consumer would fulfill an ACNU 
(e.g., complete a self-selection questionnaire) upon the first time 
purchasing the nonprescription drug product with an ACNU and at a

[[Page 105301]]

specific time interval (e.g., every 3 months) when repurchasing the 
drug product.
    (Comment 23) Several comments suggest that the operationalization 
of an ACNU may have potential implications on access, health equity, 
privacy, and ultimately health outcomes. A few comments state that 
applicants should consider how to prevent or mitigate potential access 
issues for older adults, people with disabilities, people in long-term 
care facilities, incarcerated persons, and for people with limited 
English proficiency, health literacy, or digital literacy. One comment 
recommends that FDA require the applicant to describe considerations of 
ease of use, health equity, access, and privacy in deciding how to 
operationalize the ACNU. Some comments suggest that applicants should 
implement more than one way of operationalizing an ACNU to accommodate 
various health and digital literacy or comfort levels to ensure 
equitable access. One comment recommends that FDA clarify that 
applicants and FDA will abide by existing and future Federal, State, 
and local protections against discrimination in designing, approving, 
and implementing ACNUs such as the Federal Americans with Disabilities 
Act and section 1557 of the Affordable Care Act, which prohibits 
discrimination based on race, color, national origin, sex, age, or 
disability in any health program administered by the Department of 
Health and Human Services.
    (Response 23) We acknowledge and understand the concerns and 
emphasize the importance of access to appropriate drug products. FDA 
recognizes the potential benefit of providing consumers with access to 
additional types of nonprescription drug products and the rule has the 
potential to broaden the types of drug products that FDA could approve 
as nonprescription (87 FR 38313 at 38316). As discussed in Response 20, 
because a nonprescription drug product with an ACNU, like other 
nonprescription drug products, would be used by consumers from the 
general population without the supervision of a practitioner licensed 
by law to administer such drug, an applicant is expected to include a 
wide range of subjects in consumer studies. While FDA does not have 
specific recommendations for enrolling subjects with varying levels of 
health literacy, applicants should include an adequate number of 
subjects who have limited literacy skills in their consumer studies 
(including human factors validation studies of the user interface) to 
help ensure that the study population is representative of the 
population that may use ACNU for the nonprescription drug product. As 
discussed further in our response to Comment 59, FDA acknowledges the 
benefits of having translated drug information for individuals with 
limited English proficiency. FDA strongly encourages applicants to work 
with retailers and other organizations to ensure that a nonprescription 
drug product with an ACNU is accessible to individuals with limited 
English proficiency. Additionally, FDA recognizes that in certain 
situations, an individual may need assistance in fulfilling an ACNU. 
Therefore, FDA acknowledges the possibility an individual other than 
the intended user might be the person who fulfills the ACNU and obtains 
the drug product. For example, a caregiver may fulfill the ACNU on 
behalf of a child or an older adult.
    We disagree with revising the requirement regarding the specific 
way the ACNU is operationalized because the requirement is 
intentionally broad to allow applicants significant flexibility 
regarding how the ACNU can be operationalized, mindful that 
technologies evolve and ACNUs may be developed for many different 
nonprescription drug products. The flexibility in this requirement will 
allow applicants to develop an ACNU appropriate for the specific drug 
product while taking into consideration a diverse group of consumers 
who may use the drug product if approved. While FDA will not require an 
applicant to operationalize an ACNU in more than one way, an applicant 
may submit and FDA may approve an application that includes more than 
one way to operationalize an ACNU for a particular nonprescription drug 
product with an ACNU provided that the ways the ACNU is operationalized 
reliably meets the objective (e.g., appropriate self-selection). For 
example, an ACNU that includes the administration of a questionnaire as 
a key element might operationalize the ACNU by administering the 
questionnaire using a website and might alternatively operationalize 
the ACNU by administering the questionnaire using a mobile application 
or an automated telephone response system (see also 87 FR 38313 at 
38320).
    Additionally, continued availability of the prescription drug 
product, if one is approved, along with the availability of the 
nonprescription drug product with an ACNU, will promote greater access 
to needed drugs by providing flexibility in how people can obtain them. 
Patients can continue interacting with their healthcare practitioner 
and obtain the drug by prescription, or choose to purchase a 
nonprescription drug product with an ACNU after fulfilling the ACNU, if 
appropriate (21 CFR 314.56(b) and see also 87 FR 38313 at 38319).
    We agree that FDA and applicants must comply with all applicable 
statutory and regulatory requirements, including Federal, State, and 
local protections against discrimination. However, FDA does not provide 
guidance on how to comply with any legal obligations stemming from a 
source outside of the statutes and regulations that FDA administers. To 
the extent the comments summarized here also pertain to privacy 
considerations, those portions of the comments are addressed in our 
response to Comment 70.
    (Comment 24) We received a comment expressing concern that remote, 
technological access to fulfill an ACNU for a nonprescription drug 
product may not ensure that the individual fulfilling the ACNU is in 
fact the consumer.
    (Response 24) FDA acknowledges the possibility that an individual 
other than the intended user might be the person who fulfills the ACNU 
and obtains the drug product. In some cases, this might be acceptable. 
For example, a caregiver may fulfill the ACNU on behalf of a child or 
an older adult. However, in other cases, an individual might attempt to 
misrepresent themself as the intended user to inappropriately access 
the nonprescription drug product with an ACNU. FDA expects applicants 
to mitigate this by incorporating safeguards against such attempts. For 
example, an applicant may consider bot detection, unique user 
identification, requirements for affirmation of truthfulness, or other 
methods.
    (Comment 25) We received a few comments requesting guidance on the 
use of technology. We received a comment recommending that when 
operationalization of an ACNU is based on software (e.g., via a kiosk 
or web-based application), the software should be considered a key 
element of the ACNU. Further, the comment suggests that because the 
software is being used to direct access, the software should be 
regulated as a device and the quality assurance system should meet part 
4 (21 CFR part 4) for combination products.
    (Response 25) We disagree that software should be considered a key 
element of the ACNU. The applicant must describe the specific way the 
ACNU is operationalized (see 21 CFR 314.56(c)(1)(vii)). While it is 
important for FDA to understand how the ACNU

[[Page 105302]]

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 ensure 
appropriate self-selection, appropriate actual use, or both, of the 
drug product without the oversight of a healthcare practitioner. The 
ACNU can be operationalized in different ways provided it reliably 
meets the objective (87 FR 38313 at 38320). However, any technology, 
including software, used to operationalize the ACNU must comply with 
relevant requirements. FDA considers a software function that meets the 
definition of a device in section 201(h) of the FD&C Act and does not 
meet the criteria under section 520(o) of the FD&C Act to be a device 
software function. Software used to operationalize an ACNU that meets 
the definition of a device and is not otherwise excluded from that 
definition will generally be regulated as such. Consistent with FDA's 
approach to other device software functions, we recommend that 
applicants of such software consult the policies and recommendations 
set forth in FDA's guidance documents, such as FDA's ``Policy for 
Device Software Functions and Mobile Medical Applications'' (Ref. 4). 
FDA acknowledges that certain nonprescription drug products with ACNUs 
may be considered drug-device combination products as defined in Sec.  
3.2(e) (21 CFR 3.2(e)).
    (Comment 26) We received one comment asserting that an applicant 
must ensure that safeguards are in place to deny access to the 
nonprescription drug product with an ACNU if a technology failure in 
the operationalization of the ACNU occurs and the ACNU cannot be 
completed. The comment also suggests that FDA could allow a 
manufacturer's representative, a pharmacist, or a pharmacy technician 
to be able to administer a questionnaire to consumers in the event that 
the technology fails (e.g., kiosks or online portals are not working).
    (Response 26) We agree that the applicant must ensure that 
consumers cannot access the nonprescription drug product with an ACNU 
without fulfilling the ACNU. ``Additional condition for nonprescription 
use'' (ACNU) is defined 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 
practitioner licensed by law to administer such drug if the applicant 
demonstrates and FDA determines that labeling alone is insufficient to 
ensure appropriate self-selection or appropriate actual use, or both 
(21 CFR 314.56(a) and 201.67(b) of this final rule). The requirement 
that the applicant describe the specific way the ACNU is 
operationalized is intentionally broad to allow significant flexibility 
regarding how the ACNU can be operationalized (21 CFR 314.56(c)(1)(vii) 
of this final rule). An applicant may submit, and FDA may approve, more 
than one way to operationalize an ACNU, which could also increase 
consumers' ability to access the drug product with an ACNU if one way 
the ACNU is operationalized fails. There is no requirement that an ACNU 
be operationalized using particular technology.
    (Comment 27) We received a few comments recommending that FDA 
provide clarity about the process and information needed for an 
applicant to update how an approved ACNU is operationalized. One 
comment seeks clarity on the process an applicant would use to notify 
FDA when software upgrades and technology updates are needed for the 
ACNU. The comment suggests most technical changes and software upgrades 
should be submitted in the applicant's annual report. However, the 
comment suggests if the change is expected to result in a substantive 
change in how a consumer interacts with the ACNU, impacts the drug 
product's intended use, significantly improves safety and effectiveness 
of the ACNU, impacts risk controls, or increases risk to consumers, 
then the applicant would be expected to seek prior approval from FDA 
before proceeding with the change. The comment further states that the 
principles outlined in the existing Center for Devices and Radiological 
Health (CDRH) guidances, including the guidance for industry and FDA 
staff from October 2017, entitled ``Deciding When to Submit a 510(k) 
for a Software Change to an Existing Device'' (available at https://www.fda.gov/media/99785/download), should apply to applicants that may 
need to make technical or software changes. The comment requests FDA 
issue new guidance advising applicants how to inform FDA of the changes 
needed when the ACNU does not involve software.
    (Response 27) An applicant of an approved NDA or ANDA for a 
nonprescription drug product with an ACNU must follow the same 
requirements as holders of other approved NDAs and ANDAs to make 
changes to a drug product. This means that an applicant must propose 
revisions to an approved application for a nonprescription drug product 
with an ACNU by submitting a supplement, or, if applicable, by 
describing changes in an annual report, consistent with our current 
regulations for making changes to an FDA-approved application (see 
Sec. Sec.  314.70, 314.81, 314.97, and 314.98). FDA may consider 
issuing guidance in the future to address general considerations that 
may arise applicable to all applicants on changes to the 
operationalization of, or software or technology associated with, an 
ACNU, if appropriate.
    (Comment 28) FDA sought comment on any unique retail issues that 
might arise for retailers or consumers based on the way the applicant 
operationalizes the ACNU. We received two comments asking FDA to 
clarify whether consumers who satisfy the ACNU for the reference listed 
drug (RLD) (i.e., branded drug product) could purchase the generic 
product. These two comments noted that this question may arise, for 
example, if a retailer does not currently have in stock the specific 
nonprescription drug product with an ACNU for which the ACNU was 
fulfilled, or a consumer fulfills the ACNU for the RLD but prefers to 
purchase the generic version. We received a comment that states FDA 
should only approve technology-neutral ACNUs and limit the 
proliferation of excessive proprietary platforms. We received a few 
comments asserting that if each applicant uses its own mechanism to 
provide a nonprescription drug product with an ACNU, pharmacies and 
other retailers may be unable to accommodate the many different 
mechanisms.
    (Response 28) We acknowledge and appreciate the retail concerns 
expressed in the comments. During the development program of a 
nonprescription drug product with an ACNU, we encourage applicants to 
consider the feasibility of the specific way the ACNU is 
operationalized and the potential impact on retailers so as not to 
impede consumer access.
    As our review is inherently application-specific, we expect a 
consumer seeking a particular nonprescription drug product with an ACNU 
will fulfill the ACNU as operationalized for that specific product. 
Accordingly, in general, consumers could not purchase the generic drug 
product without fulfilling the ACNU as operationalized for the generic 
drug product. FDA will review and approve NDAs and ANDAs for 
nonprescription drug products with an ACNU consistent with applicable 
requirements, which includes

[[Page 105303]]

consideration and review of, the statement of purpose of the ACNU, key 
elements of the ACNU, and the way(s) the ACNU is operationalized, as 
finalized in this rule at 21 CFR 314.56(c)(2). FDA must review and 
understand how the ACNU is operationalized to ensure that the ACNU 
achieves appropriate self-selection or use. As noted above, 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 ensure appropriate self-selection, 
appropriate actual use, or both, of the drug product without the 
supervision of a practitioner licensed by law to administer such drug, 
and the ACNU can be operationalized in different ways provided it 
reliably meets the objective (see also 87 FR 38313 at 38320). (See our 
response to Comment 25 and section V.F.g. of this document.) The 
regulations are intentionally broad and provide applicants significant 
flexibility in determining the specific way the ACNU may be 
operationalized, and FDA will not require an ACNU to use any specific 
technology or be ``technology-neutral.'' Thus, as stated above, since 
our review is inherently application-specific, and because we are 
specifically reviewing and approving how the ACNU is operationalized to 
ensure that the ACNU achieves appropriate self-selection, appropriate 
actual use, or both, we expect a consumer seeking a particular 
nonprescription drug product with an ACNU will fulfill the ACNU as 
operationalized for that specific product. Also, even if a generic 
applicant operationalizes the ACNU in a different way (e.g., uses a 
different technology) than its RLD, the purpose and key elements of the 
ACNU must be the same between RLD and generic drug. As a result, we 
expect that a consumer who can fulfill the brand drug's ACNU would also 
be able to fulfill the generic drug's ACNU.
    In addition to the content and format requirements under Sec.  
314.94, FDA proposed specific requirements for an ANDA for a 
nonprescription drug product with an ACNU (proposed 21 CFR 
314.56(c)(2)). We are making a few editorial modifications to the 
proposed requirement. The first editorial modification is adding the 
word ``include'' at the end of the introductory statement for ease of 
reading, and other changes are described below in section V.F.2. In the 
following paragraphs, we discuss a general comment on the topic of 
ANDAs as a whole prior to discussing each of the specific requirements.
    h. General comment on ANDAs.
    (Comment 29) We received one comment that asserts that when there 
are significant differences in efficacy or side effect profiles between 
the RLD nonprescription drug product with an ACNU and an ANDA 
nonprescription drug product with an ACNU, such discrepancies should be 
addressed in the ANDA. The comment further asserts that different 
formulations should require a separate process which might not require 
a de novo application but would be more rigorous than an ANDA, which 
could include additional pharmacokinetic data and evidence 
demonstrating that consumers can safely use the drug product.
    (Response 29) We disagree with the comment. To be approved, an ANDA 
for a nonprescription drug product with an ACNU must meet the standards 
specified in section 505(j) of the FD&C Act and relevant FDA 
regulations (see part 314, subpart C (21 CFR part 314, subpart C)) (see 
also 87 FR 38313 at 38318), as is true for any other ANDA. These 
standards do not change as a result of this final rule. For example, 
consistent with all ANDAs (other than ANDAs with differences approved 
under a petition filed under Sec.  314.93), an ANDA for a 
nonprescription drug product with an ACNU must contain information to 
show that the drug product is pharmaceutically equivalent and 
bioequivalent to its RLD, and thus is expected to have the same 
clinical effect and safety profile as its RLD when used under the 
conditions specified in the labeling (see 87 FR 38313 at 38321).
    i. Statement regarding the purpose of the ACNU. We proposed to 
require an ANDA applicant state the purpose of the ACNU (proposed 21 
CFR 314.56(c)(2)(i)). We explained that as part of the submission, an 
ANDA applicant would state the purpose of the ACNU (the same purpose as 
the ACNU for the RLD) (87 FR 38313 at 38321). The heading in the 
preamble of the proposed rule was entitled, ``Statement regarding the 
purpose of the ACNU'' while both the preamble discussion and proposed 
codified text used the slightly different wording, ``state the purpose 
of the ACNU'' (see 87 FR 38313 at 38321 and 38330, respectively).
    We received no comment regarding this proposed requirement, and we 
are finalizing it with editorial modifications for clarity and 
consistency. We are making a modification by revising the wording from 
``State the purpose of the ACNU'' to ``A statement regarding whether 
the purpose of the ACNU is to 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 practitioner 
licensed by law to administer such drug, which must be the same as the 
purpose of the ACNU for its reference listed drug (RLD)'' for 
consistency and to capture the requirement more clearly. This 
modification clarifies that the ACNU for the ANDA must have the same 
purpose as the ACNU for the RLD, consistent with the discussion in the 
proposed rule (87 FR 38313 at 38321). This modification also makes the 
language consistent with the requirement for NDAs for a nonprescription 
drug product with an ACNU (see 87 FR 38313 at 38320 and 21 CFR 
314.56(c)(1)(i) in this final rule).
    j. Information demonstrating that the key elements of the ACNU are 
the same as the key elements of the ACNU for its RLD.\4\ We proposed to 
require an ANDA applicant 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) (proposed 21 CFR 
314.56(c)(2)(ii)). After consideration of public comment received, we 
are finalizing the proposal with only minor editorial modifications to 
provide greater clarity. We are revising the heading at 21 CFR 
314.56(c)(2)(ii) to remove the word ``include'' since we moved 
``include'' to be the last word of the introductory sentence under the 
broader heading at 21 CFR 314.56(c)(2) for ease of reading as discussed 
previously. We also shortened ``reference listed drug'' to ``RLD.''
---------------------------------------------------------------------------

    \4\ We note that the heading for this section was ``Description 
of key elements of the ACNU'' in the proposed rule (87 FR 38313 at 
38321). Nonsubstantive edits made here in this final rule for 
increased clarity.
---------------------------------------------------------------------------

    (Comment 30) We received a few comments that specifically support 
the requirement that an ANDA demonstrate that the key elements of the 
ACNU are the same as the key elements of the ACNU for its RLD. We also 
received a comment that suggests FDA reconsider what it defines as the 
key elements of the ACNU and provide more flexibility than the rule 
already provides for differences in how an ACNU is implemented by the 
RLD and ANDA applicants. The commenter further states that it does not 
believe that if the purpose of the ACNU is to ensure adequate self-
selection by screening out consumers with certain conditions, that 
purpose can only be achieved through a single set of questions and 
responses that might be proprietary to the RLD.

[[Page 105304]]

    (Response 30) We appreciate the comments supporting the requirement 
that an ANDA demonstrate that the key elements of the proposed ACNU are 
the same as the key elements of the ACNU for its RLD. We disagree that 
FDA should reconsider what it defines as the key elements of the ACNU 
and provide more flexibility for differences in how an ACNU is 
implemented by the RLD and ANDA applicants.
    Based on existing statutory and regulatory requirements for ANDAs, 
applicants may submit an ANDA referencing a listed drug (including 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 (see 87 FR 38313 at 38321). Because FDA is approving the 
description of the key elements of the ACNU for the NDA (see 21 CFR 
314.56(c)(1)(iv)), which includes 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), which are necessary for the safe and effective 
use of the nonprescription drug product with the ACNU, and because the 
ANDA is relying upon FDA's previous finding that the RLD is safe and 
effective, the ANDA must demonstrate that the key elements of the 
proposed ACNU are the same as the key elements of the ACNU approved for 
its RLD. 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)(iv) and 314.127(a)(7)). Generally, we 
anticipate that the ANDA applicant would use the same questions and 
responses as the RLD in its labeling.
    Lastly, consistent with 505(j) of the FD&C Act and our general 
approach to ANDAs, we are providing flexibility in how an ANDA 
applicant can operationalize its ACNU in a different way from its RLD 
(87 FR 38313 at 38321). The ANDA would contain information to support 
that the way in which the ACNU is operationalized achieves the same 
purpose as the ACNU for its RLD, and the differences from the RLD are 
otherwise acceptable in an ANDA (87 FR 38313 at 38321).
    (Comment 31) We received a few comments that express concern about 
the complexities of consumer selection of ANDAs. A comment expresses 
concerns that allowable differences between the RLD and ANDA(s) for a 
nonprescription drug product with an ACNU could lead to increased 
consumer confusion and limit the ability of consumers to transition to 
a generic drug product, which could undermine the cost-saving potential 
that accompanies generic drug products. Another comment states that 
generic drug product applicants may conceivably be able to devise a 
completely novel ACNU that achieves substantially the same result as 
the ACNU for the RLD, which could cause consumer confusion. A few 
comments assert that consumers who have become accustomed to fulfilling 
an ACNU for a nonprescription drug product may be hesitant to change to 
a generic drug product if the ACNU varies too drastically from the RLD. 
One comment requests FDA clarify that all similar drug products that 
require an ACNU for nonprescription use will be subject to the same 
ACNU to limit consumer confusion and asserts that such a clarification 
could aid in retailers' ability to stock multiple nonprescription drug 
products with an ACNU.
    (Response 31) While we agree that the rule permits an ANDA 
applicant to operationalize its ACNU in a different way from its RLD, 
we disagree that this rule permits the ANDA applicant to devise a 
completely novel ACNU. An ANDA for a nonprescription drug product with 
an ACNU must meet the evidentiary standards under the FD&C Act and FDA 
regulations for approval of an ANDA (see 87 FR 38313 at 38318). This 
final rule does not affect the applicability of these standards. As 
with all ANDAs (other than ANDAs with differences approved under a 
petition filed under Sec.  314.93), an ANDA for a nonprescription drug 
product with an ACNU must contain information to show that the drug is 
pharmaceutically equivalent and bioequivalent to its RLD, and thus is 
expected to have the same clinical effect and safety profile as its RLD 
when used under the conditions specified in the labeling. Applicants 
submitting an ANDA referencing a listed drug that has been approved 
with an ACNU under section 505(c) of the FD&C Act are relying on FDA's 
previous finding that the RLD is safe and effective. Therefore, because 
FDA would have previously approved the description of the key elements 
of the ACNU for the NDA, which are necessary for the safe and effective 
use of the nonprescription drug product with the ACNU, and the ANDA is 
relying upon FDA's previous finding that the RLD is safe and effective, 
the ANDA must demonstrate that the purpose and key elements of the 
proposed ACNU are the same as the purpose and key elements of the ACNU 
approved for its RLD (see 21 CFR 314.56(c)(2)(i) and (ii) of this final 
rule). As noted, the requirement provides flexibility for ANDAs in how 
the applicant operationalizes the ACNU. The rule requires that the ANDA 
contain information to support that the way in which the ACNU is 
operationalized achieves the same purpose as the ACNU for its RLD, and 
to show that differences from the RLD are otherwise acceptable in an 
ANDA. Moreover, 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 section 505(j)(2)(A) and (j)(4) of the FD&C Act and 
Sec. Sec.  314.94(a)(8)(iv) and 314.127(a)(7)).
    Therefore, while we appreciate concerns that consumers may be 
hesitant to use a generic drug product with an ACNU that is 
operationalized differently from the RLD, we disagree that the 
differences between the RLD and the ANDA would be so great as to impede 
consumers' consideration of using a generic nonprescription drug 
product with an ACNU.
    (Comment 32) We received a comment that recommends FDA require an 
ANDA include information demonstrating that the key elements of the 
ACNU are ``equivalent to'' the key elements of the ACNU for its RLD, 
rather than ``the same as'' the key elements of the ACNU for its RLD.
    (Response 32) We disagree. The use of the term ``same as'' is 
consistent with current regulations applicable to ANDAs. For example, 
when determining the appropriateness of an ANDA, the term ``same as'' 
generally means identical in active ingredient(s), dosage form, 
strength, route of administration, and conditions of use (see Sec.  
314.92(a)(1) (21 CFR 314.92(a)(1))).
    k. Information on the way the ACNU would be operationalized.\5\ We 
proposed to require that an ANDA applicant include information on the 
way the ACNU would be operationalized, as follows. If an

[[Page 105305]]

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 (proposed 21 CFR 314.56(c)(2)(iii)). 
After consideration of public comments received, we are finalizing the 
proposal with editorial modifications for clarity. We revised the 
heading at 21 CFR 314.56(c)(2)(iii) to remove the word ``include.'' As 
previously discussed in section V.F.2., we moved ``include'' to be the 
last word of the introductory sentence under the broader section, 21 
CFR 314.56(c)(2), for ease of reading. We are adding the introductory 
clause: ``Operationalization of the ACNU:'' to the first sentence of 
the requirement for clarity and to allow for ease of reference to 
discuss the requirement. We are revising ``include information on the 
way the ACNU would be operationalized'' of the first sentence to ``a 
description of the specific way(s) the ACNU is operationalized'' for 
consistency with the NDA requirement in 21 CFR 314.56(b)(1)(vii) of 
this final rule. We are revising the word ``way'' to ``way(s)'' to add 
clarity because an application may include more than one way to 
operationalize the ACNU.
---------------------------------------------------------------------------

    \5\ We note that the heading for this section was ``Description 
of how the applicant will operationalize the ACNU'' in the proposed 
rule (87 FR 38313 at 38321). Nonsubstantive edits made here in this 
final rule for increased clarity.
---------------------------------------------------------------------------

    (Comment 33) We received a comment asserting that FDA's proposed 
rule incorrectly suggested that ACNUs are not ``conditions of use'' 
under section 505(j) of the FD&C Act. The comment states that although 
the proposed rule contends that ``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,'' the proposed 
rule does not provide a basis for distinguishing an ACNU from other 
labeling elements that qualify as ``conditions of use.''
    (Response 33) We agree with the comment that an ACNU is a 
``condition of use'' under section 505(j) of the FD&C Act, and we 
appreciate the opportunity to clarify, as relevant to section 505(j), 
the differences between the ACNU and the way(s) the ACNU is 
operationalized.
    An ANDA for a nonprescription drug product with an ACNU must meet 
the standards specified under section 505(j) of the FD&C Act and 
applicable FDA regulations for approval of an ANDA. This final rule 
does not affect the applicability of these standards, as noted in our 
responses to Comments 29 and 31. Under section 505(j), an ANDA 
applicant can rely on FDA's previous finding that the RLD is safe and 
effective so long as the ANDA applicant demonstrates that the proposed 
drug product and the RLD are the same with respect to active 
ingredient(s), conditions of use, dosage form, route of administration, 
strength, and, with certain exceptions, labeling. (An ANDA must also 
include sufficient information to demonstrate that the proposed product 
is bioequivalent to the RLD and that the ANDA meets the approval 
requirements relating to chemistry, manufacturing, and controls. See 
sections 505(j)(2)(A) and (4) of the FD&C Act.) This means that for an 
RLD with an ACNU, FDA would have previously approved the NDA with the 
description of the key elements of the ACNU (including the additional 
condition implemented by the applicant to be fulfilled by the consumer, 
the labeling specifically associated with the ACNU, and the criteria by 
which the consumer would successfully fulfill the ACNU) as necessary 
for the safe and effective use of the nonprescription drug product with 
the ACNU (see 21 CFR 314.56(c)(1)(i) through (vii)). This also means 
that for an ANDA--which relies upon FDA's previous finding that the RLD 
is safe and effective--the ANDA must demonstrate that the purpose and 
key elements of the proposed ACNU are the same as the purpose and key 
elements of the ACNU approved for its RLD (see 21 CFR 314.56(c)(2)(i) 
and (ii) of this final rule) as part of meeting section 505(j)'s 
requirements for sameness (see section 505(j)(2)(A)(ii) of the FD&C 
Act).
    However, an ANDA generally is not required to be the same as the 
listed drug it references in all respects (see section 505(j)(2)(A)). 
For example, a generic drug generally can differ from its RLD in 
certain respects, such as with regard to device configuration or with 
respect to inactive ingredients. As explained in response to Comment 
31, this rule intentionally provides the ANDA applicant flexibility to 
operationalize its ACNU in a different way from its RLD, as long as the 
ANDA applicant is able to show that it achieves the same purpose as the 
ACNU for its RLD and that any differences from the RLD are otherwise 
acceptable in an ANDA. Moreover, 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 section 505(j)(2)(A) and (j)(4) of the 
FD&C Act and Sec. Sec.  314.94(a)(8)(iv) and 314.127(a)(7)). 
Differences in operationalization between an ANDA and its RLD, and 
differences in labeling that stem from those differences in operational 
design, may be permissible; the extent to which such differences affect 
the approvability of a proposed ANDA will be evaluated on a case-by-
case basis. See section 505(j)(2)(A)(v) and (j)(4)(B) of the FD&C Act. 
We would expect an ANDA that meets the statutory and regulatory 
sameness requirements for an ANDA, and that operationalizes the ACNU in 
a different way than the RLD yet achieves the same purpose as the ACNU 
for its RLD, to be as safe and effective as its RLD.
    (Comment 34) We received a comment that recommends that when an 
ANDA applicant proposes a different way to operationalize the ACNU, the 
applicant is required to include information to show that this 
different way to operationalize the proposed ACNU achieves ``an 
equivalent'' purpose as the ACNU for its RLD, rather than ``the same'' 
purpose as the ACNU for its RLD.
    (Response 34) We disagree. The use of the term ``same as'' is 
consistent with section 505(j) of the FD&C Act and current regulations 
applicable to ANDAs. For example, when determining the appropriateness 
of an ANDA, the term ``same as'' generally means identical in active 
ingredient(s), dosage form, strength, route of administration, and 
conditions of use (see Sec.  314.92(a)(1)).
    (Comment 35) We received a few comments that encourage FDA to 
consider the use of shared system ACNUs between the RLD and ANDA 
applicants. One comment encourages FDA to establish processes to have 
ANDA applicants use the same ACNU as the RLD to maintain consistency, 
similar to the use of shared risk evaluation and mitigation strategy 
(REMS) programs by generic and brand manufacturers. Another comment 
states that use of shared system ACNUs could facilitate implementation 
of the systems in pharmacies and other points of sale and provide a 
simpler ACNU experience for consumers; however, the comment further 
states that FDA should not require the use of shared system ACNUs 
because they could be used to block generic competition.
    (Response 35) FDA disagrees with the comment that FDA should 
encourage ANDA applicants to use a shared system to operationalize the 
ACNU. While ANDA applicants are required to

[[Page 105306]]

demonstrate that the purpose and key elements of the ACNU are the same 
as that of the ACNU for the RLD, we intentionally proposed a broad 
requirement to allow significant flexibility regarding how the ACNU can 
be operationalized. An ANDA applicant may operationalize its ACNU in a 
different way from its RLD so long as it achieves the same purpose as 
the ACNU for its RLD and that the differences from the RLD are 
otherwise acceptable in an ANDA (Sec.  314.56(c)(2)(iii) of this final 
rule). Requiring a shared system to operationalize the ACNU would limit 
the ability of the ANDA applicant to operationalize the ACNU in a 
different manner than the RLD.
    (Comment 36) We received a few comments that state that patents 
claiming aspects of an ACNU for a nonprescription drug product should 
be eligible for patent listing in FDA's publication ``Approved Drug 
Products With Therapeutic Equivalence Evaluations'' (commonly known as 
the Orange Book) if they meet the criteria outlined in the FD&C Act and 
FDA's patent listing regulations. One comment states that the statute, 
which was amended by the Orange Book Transparency Act (Pub. L. 116-290, 
134 Stat. 4889 (2021)), and existing regulations already identify the 
factors that govern whether an ACNU-related patent must be listed. 
Another comment asserts that the ACNU itself should be given the same 
full purview of patent protection afforded in the ANDA drug review 
process and require the follow-on applicant to consider and certify as 
to the NDA holder's patents. The comment further states that this would 
serve to put the original ACNU applicant on notice and allow them to 
take any necessary action regarding potential patent infringement 
before the follow-on nonprescription drug product with an ACNU comes to 
market. A separate comment discusses patentability of the ACNU and 
recommends that an ACNU be afforded similar intellectual patent 
protection as the drug formulation but only as it relates to drug 
products indicated to treat a specific condition or symptom. The 
comment further states that such protection is not advisable for the 
operationalization of the ACNU because it is unlikely that a 
sufficiently broad array of possibilities exists to operationalize 
ACNUs to justify any periods of market exclusivity.
    FDA also received a comment recommending that patents claiming 
aspects of an ACNU for the nonprescription drug product should not be 
submitted for listing because allowing patents claiming aspects of the 
ACNU to be listed in the Orange Book would allow a patent holder to try 
to delay FDA approval of an ANDA for a nonprescription drug product 
with an ACNU.
    (Response 36) We appreciate the comments received in response to 
our request for comments on whether patents claiming aspects of the 
ACNU for the nonprescription drug product may be submitted consistent 
with applicable laws and regulations. To the extent the comments opined 
on whether an ACNU should be subject to patent protection, FDA notes 
that questions of patentability are overseen by the U.S. Patent and 
Trademark Office, and not FDA.
    As a general matter, any applicant who submits an NDA must submit 
applicable patent information to FDA. Such submission of patent 
information must be consistent with section 505(b)(1)(A)(viii) and 
(c)(2) of the FD&C Act and 21 CFR 314.53, and a patent must not be 
submitted for listing unless the patent claims the drug that is the 
subject of the application and is a drug substance (active ingredient) 
patent or drug product (formulation or composition) patent, or claims a 
method of using the drug described in the drug's approved labeling. In 
turn, a 505(b)(2) or ANDA applicant must provide an appropriate patent 
certification or statement with respect to each such patent. The status 
of each patent listed for the listed drug(s) relied upon or reference 
listed drug, and the relevant patent certification or statement, must 
be considered in determining the timing of the approval of a 505(b)(2) 
or ANDA application.
    Taking into consideration patent certification and other 
requirements that might serve as potential barriers to ANDA applicants 
developing nonprescription drug products, we proposed significant 
flexibility in the rule to allow an ANDA applicant to operationalize 
its ACNU in a different way from its RLD. As described throughout this 
rule (e.g., Responses 5, 6, and 7), this rule gives applicants 
flexibility regarding the types of ACNUs that may be developed, as well 
as how those ACNUs may be operationalized. Given this flexibility, and 
without knowing what patents an RLD application holder may ultimately 
have with respect to a nonprescription drug product with an ACNU (as 
noted above, the U.S. Patent and Trademark Office oversees 
determinations of patentability), FDA is unable to predict the patent 
issues that may be relevant to nonprescription drug products with an 
ACNU. However, we reiterate that in all cases, submission of patent 
information must be consistent with section 505(b)(1)(A)(viii) and 
(c)(2) of the FD&C Act and 21 CFR 314.53, and a patent must not be 
submitted for listing unless the patent claims the drug that is the 
subject of the application and is a drug substance (active ingredient) 
patent or drug product (formulation or composition) patent, or claims a 
method of using the drug described in the drug's approved labeling.
    To the extent the comments summarized here about ``market 
exclusivity'' also pertain to statutory exclusivity, those portions of 
the comments are addressed in our response to Comment 72.

G. Comments on Nonprescription and Prescription Approval and 
Simultaneous Marketing and FDA Response

    We proposed to establish that because the ACNU allows the 
nonprescription drug product to be used safely and effectively without 
the supervision of a practitioner licensed by law to administer such 
drug, the ACNU is a meaningful difference between the prescription drug 
product and the nonprescription drug product with an ACNU. Therefore, 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 (proposed 21 CFR 314.56(d)).
    After consideration of public comments received, we are finalizing 
our proposal with an editorial correction. We are making an editorial 
correction to the proposed heading in 21 CFR 314.56(d), ``Simultaneous 
marketing of nonprescription and prescription products,'' by adding the 
word ``drug'' such that it now more accurately states, ``Simultaneous 
marketing of nonprescription and prescription drug products''.
    FDA believes that the requirement for submission of a separate 
application (21 CFR 314.56(b)) and the simultaneous marketing provision 
(21 CFR 314.56(d)) are necessary to fulfill the key goals of this 
rulemaking, which are to: (1) increase options for applicants to 
develop and market safe and effective nonprescription drug products, 
which would broaden the types of nonprescription drug products 
available to consumers and (2) increase consumer access to appropriate, 
safe, and effective drug products, by providing for the availability of 
prescription versions of nonprescription drug products approved with 
ACNUs, both of which in

[[Page 105307]]

turn could improve public health. If either of those requirements in 
the final rule is stayed or determined to be invalid or unenforceable, 
the remaining provisions of the rule should no longer continue in 
effect because the rule would not meet FDA's objectives. Without the 
requirement to submit a separate application, an applicant could submit 
a supplemental application to switch the status of an approved 
prescription drug product to a nonprescription drug product with an 
ACNU. If such a supplemental ``switch'' application were approved for 
an RLD, prescription ANDAs that reference the RLD would be required to 
submit supplemental applications to switch their drug products from 
prescription to nonprescription with an ACNU. This would potentially 
remove all the prescription drug products from the market. If a 
consumer who had been using a prescription drug product is unable to 
obtain it once it became available only as a nonprescription drug 
product with an ACNU (e.g., because the person lacks access to the 
relevant technology), the consumer would lose access to the drug. 
Similarly, consumers who prefer to interact with their healthcare 
practitioners and obtain the drug by prescription may be less likely to 
continue the treatment with a nonprescription drug product with an 
ACNU. These outcomes would be contrary to FDA's intent for the rule.
    Therefore, if 21 CFR 314.56(b) or (d) is stayed or determined to be 
invalid or unenforceable, the entire rule should be invalidated.
    (Comment 37) Many comments support the simultaneous marketing of 
the same drug as a prescription drug product and a nonprescription drug 
product with an ACNU. One comment supports simultaneous marketing to 
increase equitable access to safe and effective drug products and 
expand consumer choice. Another comment expresses support for FDA 
clarifying that an ACNU is a meaningful difference and asserts that 
there has not been clear understanding to date as to what ``meaningful 
difference'' means. We also received a comment requesting that FDA 
require the applicant to have a marketed prescription version of the 
same drug product at the same time as a marketed nonprescription drug 
product with an ACNU. However, we received a few comments that disagree 
with simultaneous marketing and assert that it does not improve or 
otherwise affect opportunities for consumer access. These commenters 
assert that simultaneous marketing would inadvertently create a less 
competitive marketplace by failing to incentivize investment in the 
process of switching prescription drug products to nonprescription 
status and, consequently, fail to realize the public health benefits 
associated with the introduction of novel nonprescription drug 
products. These commenters also assert that simultaneous marketing is 
not necessary because the applicant could choose to initiate 
discussions with FDA about possible options for product access for 
persons who cannot or choose not to fulfill the ACNU or a consumer 
would be able to speak to their healthcare practitioner about treatment 
options if they cannot fulfill the ACNU.
    (Response 37) As discussed in section V.G. of this document, we 
agree that simultaneous marketing could increase consumer access. 
Continued access to the prescription drug product, along with the 
availability of the nonprescription drug product with an ACNU, allows 
greater access to needed drugs by providing flexibility in how to 
obtain them. The consumer may obtain a nonprescription drug product 
with an ACNU however it is operationalized or continue to interact with 
their healthcare practitioner and obtain the approved prescription drug 
product, if appropriate (see also 87 FR 38313 at 38319).
    As discussed in our response to Comment 10, we disagree that 
simultaneous marketing is not necessary to promote greater access to 
drug products or that simultaneous marketing would disincentivize 
development of a nonprescription drug product with an ACNU. FDA 
recognizes that some consumers may not be able to access the 
nonprescription drug product with an ACNU. While we agree, as discussed 
in our response to comment 23, that the applicant may operationalize an 
ACNU in more than one way, there are consumers that the drug product 
would not be appropriate for in the nonprescription setting, but the 
drug product would be an appropriate use when under the supervision of 
a practitioner licensed by law to administer such drug. If there is not 
simultaneous marketing of the prescription drug product and 
nonprescription drug product with the ACNU, the prescription drug 
product would no longer be able to be marketed, which would eliminate 
the prescription drug product as a treatment option for health care 
practitioners to prescribe for patients. Therefore, continued 
availability of the prescription drug product along with the 
nonprescription drug product with an ACNU promotes the greatest access 
to needed drug products in both the prescription and nonprescription 
settings.
    We disagree with the recommendations to revise the rule to require 
that the applicant market both a prescription version of the drug 
product and a nonprescription with an ACNU version of the drug product. 
A nonprescription drug product with an ACNU is not required to first be 
marketed as a prescription drug product. If the application for a 
nonprescription drug product with an ACNU meets the evidentiary 
standards under the FD&C Act and current FDA regulations to demonstrate 
the safety and effectiveness of the drug product in the nonprescription 
setting, then FDA could approve the application even if there is not a 
marketed prescription version.
    (Comment 38) We received a comment that many stakeholders have 
misconceptions about a nonprescription drug product with an ACNU, 
including the view that nonprescription drug products with ACNUs are a 
third class of drugs or ``an expansion of dual status.'' The commenter 
states that FDA can address these misconceptions by changing the 
terminology from ``simultaneous marketing'' to ``simultaneous access.''
    (Response 38) We clarify that the rule does not establish a third 
class of drug products for purposes of section 503(b) of the FD&C Act. 
FDA approves drugs as either prescription or nonprescription drug 
products under section 505 of the FD&C Act. The rule is intended to 
increase options for applicants to develop and market safe and 
effective nonprescription drug products. Also, we interpret the comment 
about ``dual status'' to refer to simultaneous marketing of 
prescription and nonprescription drugs. While we recognize that there 
may be various misconceptions about what constitutes meaningful 
differences between prescription and nonprescription drug products, we 
disagree that changing the terminology in this rule from ``simultaneous 
marketing'' to ``simultaneous access'' will reduce any confusion that 
may exist. Based on our experience with industry, the term does not 
currently cause confusion. FDA has consistently used the term 
``simultaneous marketing'' to explain FDA's interpretation of the 
language in section 503(b) of the FD&C Act to allow the same active 
ingredient to be simultaneously marketed in both a prescription drug 
product and nonprescription drug product if a meaningful difference 
exists between the two that makes the prescription product safe only 
under the supervision

[[Page 105308]]

of a practitioner licensed by law to administer such drug (see 87 FR 
38313 at 38321, 83 FR 13994, April 2, 2018, and 70 FR 52050, September 
1, 2005). Changing this long-used term may introduce new confusion.
    (Comment 39) We received comments that agree that FDA has the legal 
authority under the FD&C Act to allow the simultaneous marketing of 
products with the same active ingredient as both a prescription drug 
product and a nonprescription drug product if there is a meaningful 
difference between the two drug products.
    (Response 39) We agree with the comments that the FD&C Act permits 
the simultaneous marketing of a prescription drug product and a 
nonprescription drug product where a meaningful difference exists 
between the two that makes the prescription product safe only under the 
supervision of a practitioner licensed by law to administer such drug.
    As noted in the proposed rule, under section 503(b) of the FD&C 
Act, the same active ingredient can be simultaneously marketed in both 
a prescription drug product and nonprescription drug product if a 
meaningful difference exists between the two that makes the 
prescription product safe only under the supervision of a practitioner 
licensed by law to administer such drug (see 87 FR 68702, 87 FR 38313 
at 38321, 83 FR 13994, and 70 FR 52050). Section 503(b)(1)(A) requires 
a drug to be limited to prescription-only status if, because of its 
toxicity or other potentiality for harmful effect, or the method of its 
use, or the collateral measures necessary to its use, it is not safe 
for use except under the supervision of a practitioner licensed by law 
to administer such drug. Conversely, a drug that can be used safely by 
consumers without the supervision of a practitioner licensed by law to 
administer such drug does not require a prescription. Under section 
503(b)(1), a drug cannot be both prescription and nonprescription at 
the same time, because it cannot be both safe and unsafe for use 
without the supervision of a practitioner licensed by law to administer 
such drug. For the same reason, two drug products with the same active 
ingredient that don't have meaningful differences also can't be 
simultaneously marketed as prescription and nonprescription. However, 
consistent with section 503(b)(1), if there is a meaningful difference 
(e.g. indication, strength, route of administration, dosage form, or 
patient population) between two drug products with the same active 
ingredient that makes one drug product safe for use only under the 
supervision of a practitioner licensed by law to administer such drug, 
while the other drug product is safe for use without such supervision, 
then the two products may be simultaneously marketed as prescription 
and nonprescription drug products, respectively. (See also the 
discussion on meaningful difference in our response to Comment 40).
    In addition, under section 503(b)(4)(B) of the FD&C Act, a drug for 
which the prescription dispensing provisions of section 503(b)(1) do 
not apply shall be deemed to be misbranded if at any time prior to 
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 them, simultaneous 
marketing of two drug products with the same active ingredient as both 
prescription and nonprescription drug products would result in one of 
the two products being misbranded. However, if there is a meaningful 
difference between two drug products with the same active ingredient 
that makes one drug product safe for use only under the supervision of 
a practitioner licensed by law to administer such drug, then 
simultaneous marketing of the two products is permitted. See also the 
responses to Comment 2 and Comments 40 through 43, below.
    (Comment 40) Some commenters contend that an ACNU is not a 
meaningful difference for purposes of simultaneous marketing of 
prescription and nonprescription drugs under section 503(b) of the FD&C 
Act (see also Comments 41-43 and FDA responses). Specifically, the 
comments argue that a meaningful difference between two drug products 
must exist in indication, strength, route of administration, dosage 
form, or patient population. The commenters assert that a switch to 
nonprescription status may be accompanied by one of these meaningful 
changes in addition to an ACNU, but the ACNU itself does not establish 
such a difference. The commenters specifically cite FDA's decision to 
withdraw ANDA drug products that referenced the prescription NDA 
020698, MiraLAX Powder (polyethylene glycol (PEG)-3350) powder for 
occasional constipation because FDA approved a full switch of NDA 02698 
from prescription to nonprescription marketing. The commenters assert 
that FDA found that while there were differences in labeling, FDA looks 
to differences in indication, strength, route of administration, dosage 
form, [and] patient population to determine whether there is a 
meaningful difference between the two products. Therefore, the 
commenters assert that the mere presence of an ACNU does not implicate 
any of these factors.
    (Response 40) FDA disagrees with these comments. FDA's considered 
judgment, based on the Agency's scientific and technical expertise, is 
that an ACNU would in fact constitute a meaningful difference between a 
prescription drug product and a nonprescription drug product with an 
ACNU, even if they do not have other meaningful differences, such as 
different indications or strengths. While we have previously provided 
some examples of what may constitute a meaningful difference, such as 
indication, strength, route of administration, dosage form, or patient 
population (see 83 FR 13994 and 70 FR 52050), we have not created a 
finite list of what may constitute a meaningful difference and will 
continue to make determinations of ``meaningful difference'' as 
appropriate.
    In circumstances where the applicant would like to market a 
previously approved prescription drug product as nonprescription, the 
applicant must demonstrate that the proposed nonprescription drug 
product does not meet the criteria in section 503(b)(1) of the FD&C 
Act. FDA evaluates the data submitted by the applicant and makes a 
scientific determination about whether consumers can use the drug 
product safely and effectively without the supervision of a 
practitioner licensed by law to administer such drug, and therefore the 
drug product can be approved as nonprescription. When FDA determines 
that, based on the data, a proposed nonprescription drug product does 
not meet the criteria in section 503(b)(1) of the FD&C Act, the Agency 
may also make a scientific determination regarding whether there is a 
meaningful difference between the nonprescription drug product and a 
prescription drug product that contains the same active ingredient. If 
there is no meaningful difference between the products, then the 
product marketed as a prescription drug product would no longer meet 
the criteria for prescription drugs in section 503(b)(1) and would need 
to switch to nonprescription status. For example, with NDA 020698, 
MiraLAX (PEG-3350) powder for occasional constipation, FDA made a 
scientific determination that there are no meaningful differences 
between the prescription and nonprescription drug

[[Page 105309]]

products. In that scenario, the following were the same for the 
prescription and the nonprescription drug product: the active 
ingredient (PEG-3350), dosage form (powder for solution), strength (17 
gram (g) dose in 4 to 8 ounces of liquid), route of administration 
(oral), indications (constipation), and patient population (17 years of 
age or older). As discussed in the response to Comment 41, in 
Breckenridge Pharm., Inc. v. FDA, 754 Fed. Appx. 1 (D.C. Cir. 2018), 
the U.S. Court of Appeals for the D.C. Circuit found no error in FDA's 
determination that differences in the duration of use between the 
prescription and nonprescription PEG-3350 products were not 
``meaningful differences'' such that the prescription and 
nonprescription products could be marketed simultaneously.
    There are also examples in which FDA has determined that, based on 
the data submitted, a drug meets the criteria in section 503(b)(1) of 
the FD&C Act for certain conditions of use; however, for other 
conditions of use, it does not meet the criteria in section 503(b)(1) 
of the FD&C Act. For example, Nasonex (mometasone furoate) nasal spray, 
50 microgram (mcg)/spray (NDA 020762) was approved with two 
indications. FDA determined that data supported that the indication 
related to treatment of allergy symptoms did not meet the criteria for 
a prescription drug in section 503(b)(1) of the FD&C Act and that 
consumers could self-select and use the drug product for that 
indication in the nonprescription setting. Therefore, on March 17, 
2022, based on data submitted by the applicant, FDA approved 
nonprescription Nasonex 24HR Allergy (mometasone furoate) nasal spray, 
50 mcg/spray (NDA 215712) for the temporary relief of allergy symptoms. 
However, Nasonex's indication of ``treatment of chronic rhinosinusitis 
with nasal polyps in adult patients 18 years of age and older'' 
continues to meet the criteria in section 503(b)(1) of the FD&C Act. 
Therefore, FDA made a scientific determination that there is a 
meaningful difference between the prescription and nonprescription drug 
products because of their different indications, and the prescription 
and nonprescription drug products may be marketed simultaneously 
consistent with section 503(b).
    Another example involves Xyzal (levocetirizine dihydrochloride) 0.5 
mg/milliliter (mL) solution. The prescription product (NDA 022157) was 
approved in 2008 for the relief of symptoms associated with seasonal 
allergic rhinitis (SAR) and perennial allergic rhinitis (PAR), and the 
treatment of uncomplicated skin manifestations of chronic idiopathic 
urticaria (CIU) for patients 6 years of age and older. In 2009, it was 
approved for SAR for patients 2 years of age and older, and PAR and CIU 
in adults and children 6 months of age and older. In 2017, Xyzal 
Allergy 24HR (NDA 209090) was approved for nonprescription use with the 
previously prescription indication of SAR in adults and children 2 
years of age and older. The nonprescription drug product was also 
approved with the PAR indication, but only for adults and children 2 
years of age and older. The younger age range (6 months of age to under 
2 years) remained prescription because the diagnosis of PAR in infants 
and children under the age of 2 years is more complex and requires the 
evaluation of a physician. The indication for CIU for all age ranges 
continues to meet the criteria for prescription use. Thus, the 
meaningful difference between the prescription and nonprescription 
versions of Xyzal (levocetirizine dihydrochloride) for the PAR 
indication is a difference in patient population (i.e., certain age 
groups).
    An ACNU is a condition that must be affirmatively fulfilled by a 
consumer before they can self-select, use, or both self-select and use, 
a nonprescription drug product. Therefore, a consumer will generally 
need to act to fulfill an ACNU, and, as explained further in response 
to Comment 42 below, this distinguishes it from labeling. Similar to 
the different indications and patient population in the above examples 
for Nasonex and Xyzal, an ACNU will be a meaningful difference that 
exists between two drugs that makes the prescription drug product safe 
only under the supervision of a practitioner licensed by law to 
administer the drug and the nonprescription drug product safe for use 
without the supervision of such a practitioner. If an NDA is submitted 
for a nonprescription drug with an ACNU, FDA would only approve it if 
FDA determines that the applicant's studies and other information in 
the application demonstrate the ACNU would make the nonprescription 
drug product safe for use without the supervision of a practitioner 
licensed by law to administer the drug product. However, without the 
ACNU, the drug product would be safe and effective only under the 
supervision of a practitioner licensed by law to administer the drug 
product, and FDA could not approve the drug product as nonprescription.
    (Comment 41) Some commenters argue that FDA's position that an ACNU 
is a meaningful difference ignores the statutory language in section 
503(b) of the FD&C Act, legislative history of the Durham-Humphrey 
Amendments to the FD&C Act, legal precedent, specifically the D.C. 
Circuit's decision in the MiraLAX case, Breckenridge Pharm., Inc. v. 
FDA, 754 Fed. Appx. 1 (D.C. Cir. 2018), and decades of Agency 
precedent. A commenter explains that the Durham-Humphrey Amendments 
amended section 503(b) of the FD&C Act to add the definition for 
prescription drug, which effectively established prescription and 
nonprescription drugs as two separate categories. The commenter further 
explains that legislative history shows that Congress amended the FD&C 
Act to address confusion that arose due to the fact that the same drug 
could be characterized as a prescription drug by one manufacturer and 
as nonprescription by another. The commenter further explains that the 
mutually exclusive nature of the classification of a drug product as 
either prescription or nonprescription is manifest in the statutory 
language. The commenter asserts that if FDA were to collapse the two 
categories for simultaneous marketing of a prescription drug product 
with a nonprescription drug product with an ACNU, it would not only 
contradict the plain-language meaning of the FD&C Act but also cause 
confusion that the Durham-Humphrey Amendments were meant to address. In 
discussing FDA's decision to withdraw approval of ANDA products that 
referenced MiraLAX, PEG-3350, the commenters argue that, in reaching 
its decision that the ANDA products did not have a meaningful 
difference from the RLD product (NDA 02698, MiraLAX (PEG-3350) powder 
for occasional constipation), FDA looked to differences in indication, 
strength, route of administration, dosage form, and patient population, 
but did not look to whether the product had an ACNU (see also Comment 
40).
    (Response 41) As discussed in response to Comments 39 through 40 
above, and discussed further below in responses to Comments 42 through 
43, FDA's position is entirely consistent with, and is in fact the best 
reading of, the statutory language in section 503(b) of the FD&C Act. 
Under section 503(b), the same active ingredient can be simultaneously 
marketed in both a prescription drug product and nonprescription drug 
product if a meaningful difference exists between the two that makes 
the prescription product safe only under the supervision of a 
practitioner licensed by law to administer the drug. FDA disagrees with 
commenters who argue that a

[[Page 105310]]

meaningful difference between two drug products must exist in 
indication, strength, route of administration, dosage form, or patient 
population, and that an ACNU is not a meaningful difference because it 
does not implicate any of these factors.
    Recognizing that an ACNU can be a meaningful difference that allows 
for simultaneous marketing is also consistent with the legislative 
history of the Durham-Humphrey Amendments of 1951 (Pub. L. 82-215, 65 
Stat. 648). Until 1951, the FD&C Act did not contain criteria for 
determining when to limit a drug's approval to prescription use. As a 
result, different manufacturers made different decisions about whether 
to market a drug as prescription or nonprescription. This resulted in 
confusion and uncertainty for pharmacists and consumers about whether 
certain drugs were safe for use without the supervision of a physician. 
To eliminate this confusion and uncertainty, and to protect the public 
health, Congress amended section 503(b) of the FD&C Act with the 
Durham-Humphrey Amendments, which had two primary objectives: (1) to 
protect the public from abuses in the sale of potent prescription 
drugs; and (2) to relieve retail pharmacists and the public from 
burdensome and unnecessary restrictions on the dispensing of drugs that 
are safe for use without the supervision of a physician (see S. Rep. 
No. 946, at 1 (1951), reprinted in 1951 U.S.C.C.A.N. 2454). By 
recognizing that there are circumstances under which an ACNU (e.g., 
restricting access to the drug unless a consumer demonstrates an 
appropriate medical history through a questionnaire) can help ensure 
that a patient can self-select and use a drug safely and effectively 
without the supervision of a practitioner licensed by law to administer 
such drug, this rulemaking advances the second primary objective of 
these amendments. Simultaneous marketing of a prescription drug product 
and a nonprescription drug product with an ACNU that do not have other 
meaningful differences can reduce burdens on access for patients for 
whom a drug is safe and effective for use without supervision of a 
practitioner licensed by law to administer such drug, without causing 
confusion. The ACNU would be a meaningful difference that consumers and 
pharmacists would recognize, along with its associated labeling 
including the ACNU Instructions and Statement, as differentiating the 
product from a potential prescription version of the product.
    FDA's decision to withdraw approval of ANDA products that 
referenced NDA 020698 MiraLAX (PEG-3350) powder for occasional 
constipation, and the D.C. Circuit's decision in Breckenridge Pharm., 
Inc. v. FDA upholding the Agency's position, have no bearing on whether 
an ACNU is a meaningful difference between prescription and 
nonprescription drug products. As a threshold matter, MiraLAX is not a 
nonprescription drug product with an ACNU. Additionally, when FDA made 
its decision, and when Breckenridge Pharm., Inc. v. FDA was decided, 
this regulation had not yet been promulgated. Instead, the court 
focused on whether labeling regarding duration of use could constitute 
a meaningful difference; the court upheld FDA's conclusion that it did 
not in that case, while expressly leaving open the possibility that it 
might in another case (see 754 Fed. Appx. at 4). Accordingly, whether 
an ACNU is an example of a meaningful difference with regard to the 
PEG-3350 products was not relevant to FDA's withdrawal decision for 
MiraLAX and, likewise, was not at issue in Breckenridge Pharm., Inc. v. 
FDA. As discussed further in response to Comment 42 below, as defined 
in this rule, an ACNU cannot consist merely of labeling, even if one 
aspect of it includes labeling, nor is an ACNU ``functionally 
equivalent to labeling.''
    Furthermore, FDA's determination here that an ACNU would constitute 
a meaningful difference is consistent with FDA's approach to the 
MiraLAX proceedings. There, FDA stated: ``In determining whether an Rx 
drug product and an OTC drug product are the same, FDA considers 
whether there are any meaningful differences between the OTC and Rx 
products that would justify the different marketing status of the 
products'' (see 73 FR 63491 at 63492, October 24, 2008). As explained 
in our response to Comment 40, FDA's considered judgment is that an 
ACNU, as defined in this rule, would be such a meaningful difference 
because it would allow a drug product that would otherwise require a 
prescription to be marketed as a nonprescription drug product.
    (Comment 42) One comment argues that an ACNU is labeling or 
``functionally equivalent to labeling'' because it is intended to 
enable an individualized consumer response for the purpose of self-
selection and/or actual use, the same role played by traditional drug 
labeling, and therefore it does not constitute a meaningful difference 
between a prescription drug product and a nonprescription drug product.
    (Response 42) FDA does not agree that an ACNU is labeling or 
``functionally equivalent to labeling,'' or that legal precedent is 
being ignored. Prescription drug labeling is designed to inform 
healthcare practitioners and thus contains more detailed information 
than nonprescription drug labeling. Nonprescription drug labeling is 
designed for consumers. As illustrated in the MiraLAX proceedings in 
Breckenridge Pharm., Inc. v. FDA, we determined that the differences in 
the labeling between the nonprescription drug product and the generic 
prescription drug products that were ``simply . . . due to the 
different audiences (i.e., learned intermediary versus lay consumer) 
and the difference in setting (i.e., use with a physician's supervision 
versus consumer self-directed use)'' were not meaningful differences 
for purposes of section 503(b) of the FD&C Act (see 83 FR 14007). 
However, certain meaningful differences between drugs may be reflected 
in their labeling (e.g., indication or patient population).
    This is consistent with FDA's determination than an ACNU is a 
meaningful difference because an ACNU (as defined in this regulation) 
cannot consist merely of labeling, even if one aspect of it includes 
labeling. A label is the written, printed, or graphic matter on the 
immediate container of the drug product (see section 201(k) of the FD&C 
Act). Labeling is all labels or other written, printed, or graphic 
matter on the drug product or any of its containers or wrappers, or 
accompanying the drug product (see section 201(m) of the FD&C Act). 
Labeling for nonprescription drugs provides information to consumers to 
self-select and use the drug product, and the consumer reads this 
information to self-select and use the drug product.
    In contrast to labeling, an ACNU is a condition that must be 
affirmatively fulfilled by a consumer before they can self-select, use, 
or both self-select and use, a nonprescription drug product. Therefore, 
a consumer will generally need to act to fulfill an ACNU. For example, 
with Drug X (see more information about Drug X, a fictitious 
nonprescription drug product with an ACNU, in the proposed rule (87 FR 
38313 at 38319)), 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. Using a 
consumer's answers to the questions, the underlying program or other 
operating information used by the secure website, not the consumer,

[[Page 105311]]

calculates the risk score for a serious side effect and determines if 
the consumer has an acceptable disease-specific risk score to use Drug 
X and therefore purchase Drug X. As shown in this example, an ACNU may 
include labeling, but the ACNU is not in itself labeling. It is a 
condition that a consumer must affirmatively satisfy, which ensures 
that a drug product can be appropriately selected and used safely and 
effectively without the supervision of a practitioner licensed by law 
to administer such drug.
    FDA disagrees that an ACNU is ``functionally equivalent to 
labeling.'' With previous prescription-to-nonprescription switches that 
have been approved by FDA, including the one at issue in the MiraLAX 
proceedings in Breckenridge Pharm., Inc. v. FDA, the drug product was 
safe for use without the supervision of a practitioner licensed by law 
to administer such drug under section 503(b) of the FD&C Act; it simply 
needed to be labeled to satisfy the requirement for adequate directions 
for use and other labeling requirements for nonprescription marketing 
under the FD&C Act and FDA regulations. On the other hand, for a 
nonprescription drug product approved with an ACNU, FDA has determined 
that labeling alone is insufficient to ensure appropriate self-
selection or appropriate actual use, or both (see generally 21 CFR 
314.56 of this final rule). Therefore, a drug product approved with an 
ACNU could not satisfy the requirement for adequate directions for use 
for a layperson under the FD&C Act and FDA regulations, and would not 
be safe for use without the supervision of a practitioner licensed by 
law to administer such drug. We have provided in this rule an exemption 
from the requirement for adequate directions for use on the condition 
that, among other conditions, the approved ACNU is implemented as 
approved under the application, so that the drug would then become safe 
for use in the nonprescription setting (see 21 CFR 201.130 in this 
final rule).
    With regard to the comment's argument that an ACNU is functionally 
equivalent to labeling because they both ``ensure appropriate self-
selection and use of the OTC product,'' the comment does not explain 
why this is different from other characteristics of a drug that it 
concedes are meaningful differences. In particular, the comment 
``request[s] that the final rule acknowledge and maintain FDA's prior 
position that it will look to indication, strength, route of 
administration, dosage form, and patient population to determine 
whether there are meaningful differences between two products with the 
same active ingredient . . . .'' The comment therefore concedes that 
the indication and patient population can be meaningful differences for 
purposes of simultaneous marketing under section 503(b) of the FD&C 
Act, but does not acknowledge that these conditions, which are only 
reflected in the labeling, also serve to ``ensure appropriate self-
selection and use of the OTC product.'' Such conditions are, in fact, 
critical to appropriate self-selection and use. Because the ACNU would 
similarly provide a difference for the drug that is meaningful, the 
nonprescription drug with an ACNU would be a different drug product 
from a prescription version, even if it does not have other meaningful 
differences for purposes of simultaneous marketing under section 503(b) 
of the FD&C Act.
    (Comment 43) We received a comment that argues that this rule, by 
allowing the simultaneous marketing of the prescription version of the 
drug product and a nonprescription with an ACNU version of the drug 
product, ``indisputably triggers the major questions doctrine because 
it would radically overhaul the OTC drug market and limit consumer 
access to OTC drugs . . . which is undeniably an issue of `vast 
economic and political significance.' '' (quoting West Virginia v. EPA, 
142 S. Ct. 2587, 2605).
    (Response 43) We do not agree that this rule implicates the ``major 
questions doctrine'' because of the provision providing for 
simultaneous marketing. In West Virginia v. EPA, the Supreme Court 
found that, ``to substantially restructure the American energy 
market,'' the `` `claim[ed] to discover in a long-extant statute an 
unheralded power' representing a `transformative expansion in [its] 
regulatory authority,' '' and that the Agency ``located this newfound 
power in the vague language of an `ancillary provision[ ]' of the 
Act.'' 597 U.S. 697, 724 (2022) (citations omitted). The Court further 
found that this ancillary provision ``had rarely been used in the 
preceding decades,'' but was then used ``to adopt a regulatory program 
that Congress had conspicuously and repeatedly declined to enact 
itself.'' Id. Consequently, the Court stated that ``there is every 
reason to `hesitate before concluding that Congress' meant to confer . 
. . the authority'' in question to the EPA and that the case was a 
``major questions case.'' Id. at 724-725. To overcome its hesitation 
and ``skepticism toward EPA's claim,'' the Court stated that ``the 
Government must--under the major questions doctrine--point to `clear 
congressional authorization' to regulate in that manner.'' Id. at 732.
    None of the findings described above in West Virginia v. EPA 
applies to the provision in this rule providing for simultaneous 
marketing of prescription drugs and nonprescription drugs with ACNUs. 
As discussed in the response to Comment 2, Congress has given FDA the 
authority to make scientific determinations about which drugs may be 
marketed as prescription or nonprescription drugs. In addition, section 
503(b)(3) gives FDA the authority to issue regulations to remove the 
prescription-only dispensing requirements from drugs when such 
requirements are not necessary for the protection of the public health. 
FDA's finding that an ACNU would constitute a meaningful difference is 
simply the latest determination in a series of determinations under 
section 503(b) of the FD&C Act regarding whether some difference 
constitutes a meaningful difference for purposes of prescription and 
nonprescription marketing. For example, in 1984, the Agency approved a 
nonprescription ibuprofen product because it had meaningful differences 
from the prescription versions of ibuprofen (see 67 FR 54139 for 
general background related to this regulatory history).
    Likewise, for decades other drug products have been approved as 
nonprescription drug products even though prescription drug products 
contained the same active ingredient (see 70 FR 52051 for some 
examples, including loperamide in a prescription drug product for 
chronic diarrhea and in an OTC drug product for acute diarrhea). In 
2005, FDA noted that such meaningful differences had, up to that time, 
included a difference in indication, strength, route of administration, 
and dosage form. FDA also indicated that it was considering whether a 
difference in patient population could also constitute a meaningful 
difference for purposes of simultaneous marketing (see 70 FR 52050, 
September 1, 2005). Later, in the Federal Register of October 24, 2008 
(73 FR 63491; see also 83 FR 13994), related to the MiraLAX proceeding, 
and in 2013 related to an approval decision for NDA 202211 Oxytrol for 
Women (oxybutynin) extended-release film, 3.9 mg, for the treatment of 
overactive bladder in women, FDA made clear that patient population 
could also be a meaningful difference between a prescription drug 
product and a nonprescription drug product.
    In addition, in 2018, the D.C. Circuit Court of Appeals in 
Breckenridge Pharm, Inc. v. FDA upheld FDA's determination that the 
labeled duration of use for the nonprescription MiraLAX

[[Page 105312]]

product did not constitute a meaningful difference from the generic 
prescription drugs, and recognized that ``the agency left open the 
possibility that differences in duration of use--in other 
circumstances--could add up to a `meaningful difference.' '' 754 Fed. 
Appx. 1, 4 (citing FDA's publications in the Federal Register related 
to the MiraLAX proceeding, at 83 FR 13994 at 13999 and 73 FR 63491 at 
634913). Thus, whether a difference between a prescription drug product 
and a nonprescription drug product constitutes a meaningful difference 
that permits simultaneous marketing in accordance with section 503(b) 
of the FD&C Act is something FDA has considered and acted upon in 
numerous instances for decades. FDA's determination in this rule that 
an ACNU would constitute the same kind of meaningful difference is 
hardly a ``sweeping assertion of `unprecedented power over American 
industry,' '' as the commenter claims.
    The simultaneous marketing provision in this rule is also unlike 
the Agency actions in ``major questions'' cases because, among other 
things, it does not represent an attempt to ``substantially 
restructure'' a market. All that this provision of the rule will do is 
provide an additional consideration for applicants seeking 
authorization for a product to enter the market. With regard to 
simultaneous marketing of prescription drug products and 
nonprescription drug products, as noted above, there are currently, and 
there have long been, marketed prescription drug products and 
nonprescription drug products that contain the same active ingredient 
because there is some meaningful difference that supports the 
simultaneous marketing of the drug products, and FDA has made 
determinations regarding what constitutes a meaningful difference under 
section 503(b) of the FD&C Act for decades. For this same reason, the 
simultaneous marketing provision in this rule, which simply clarifies 
another difference that the Agency has determined would constitute a 
meaningful difference between prescription and nonprescription drug 
products under section 503(b), does not represent a ``transformative 
expansion in . . . regulatory authority'' that is derived from ``vague 
language of an `ancillary provision[ ]' of the Act.'' In addition, 
inclusion of the simultaneous marketing provision does not create a 
``regulatory program that Congress [has] conspicuously and repeatedly 
declined to enact itself.'' FDA is not aware of any Congressional 
consideration of legislation regarding the marketing of nonprescription 
drugs with ACNUs alongside prescription versions of such drugs.
    The comment also appears to be arguing that the simultaneous 
marketing provision implicates the major questions doctrine because it 
would ``limit consumer access to OTC drugs.'' But any prediction that 
the simultaneous marketing provision would limit consumer access is 
highly speculative. To support this assertion, the comment claims that 
``prescription drug companies may decide not to pursue OTC switch 
opportunities that use an ACNU'' if prescription versions of the drug 
continue to be marketed. Similarly, by way of analogy, one might argue 
that the benefit of statutory exclusivity, such as that provided at 
section 505(j)(5)(F)(iii) of the FD&C Act, would be undermined by FDA's 
rule. However, FDA would disagree with this because as noted below in 
response to Comment 72, an application--including an application for a 
nonprescription drug product with an ACNU--is eligible for exclusivity 
if applicable statutory requirements are met. Further, as noted above, 
the assertion that the ACNU pathway or the benefit of exclusivity would 
be undermined by the rule is speculative, particularly considering the 
evidence showing that roughly 60 percent of purchases for a 
nonprescription drug product are from new consumers who had not 
previously taken the drug before it switched from prescription status, 
suggesting that the potential to attract new-to-therapy consumers for 
nonprescription drug products is substantial (Ref. 13). Moreover, this 
critique is not specific to nonprescription drug products with ACNUs; 
it would also apply to other drug products for which there is a 
meaningful difference that allows simultaneous marketing. Furthermore, 
although we do not anticipate this scenario, even if no applicant 
pursues the development and eventual marketing of a nonprescription 
drug product with an ACNU, ACNU products do not currently exist in the 
marketplace. So, it is not clear how this rule would ``limit consumer 
access to OTC drugs,'' or how that would implicate the major questions 
doctrine. Rather, the final rule is intended to increase options for 
applicants to develop and market safe and effective nonprescription 
drug products and increase consumer access to appropriate, safe, and 
effective drug products, which could improve public health.
    Ultimately, the simultaneous marketing provision in this rule does 
not present one of the ``extraordinary cases that call for a different 
approach'' in statutory interpretation, because it is not one of the 
``cases in which the `history and the breadth of the authority that 
[the agency] has asserted,' and the `economic and political 
significance' of that assertion, provide a `reason to hesitate before 
concluding that Congress' meant to confer such authority.'' 597 U.S. at 
721.
    We also note that in the context of arguing that the major 
questions doctrine applies, this comment further argued that Chevron 
deference would consequently not apply. Since this comment was 
submitted, the Supreme Court decided Loper Bright Enterprises v. 
Raimondo, which overruled Chevron (see 144 S. Ct. 2244 (2024)). 
Therefore, we acknowledge Chevron deference would not apply when 
analyzing the statutory authority for this rule, including the 
simultaneous marketing provision. However, Loper Bright itself 
recognized that ``Congress has often enacted . . . statutes'' that by 
their terms delegate authority to ``exercise a degree of discretion'' 
in ``giv[ing] meaning to a particular statutory term'' or ``fill[ing] 
up the details of a statutory scheme.'' Loper Bright, 144 S. Ct. at 
2263 (cleaned up). Section 503(b)(3) of the FD&C Act, which empowers 
the Secretary to adopt regulations ``remov[ing] drugs subject to 
section 505 from the requirements of paragraph (1) of this subsection 
when such requirements are not necessary for the public health,'' 
delegates just such an authority. As explained in the response to 
comment 2, throughout section 503(b), Congress also more broadly 
delegated FDA the explicit authority to use its scientific judgment to 
determine which drugs should be prescription or nonprescription, within 
the statutory criteria. And as part of its broad authority to approve 
and regulate drug products, including to establish specific regulations 
for drug products, FDA is authorized to determine the conditions under 
which a drug is safe and effective for use without a prescription. See, 
e.g., sections 505, 505G, and 701 of the FD&C Act.
    In any case, we believe this rule represents the best reading of 
the FD&C Act. As explained in the response to comment 39 and in the 
proposed rule, section 503(b) of the FD&C Act allows the same active 
ingredient to be simultaneously marketed in both a prescription drug 
product and nonprescription drug product if a meaningful difference 
exists between the two that makes the prescription product safe only 
under the supervision of a practitioner licensed by law to

[[Page 105313]]

administer the drug (see 87 FR 68702, 87 FR 38313 at 38321, 83 FR 
13994, and 70 FR 52050). Section 503(b)(1)(A) requires a drug to be 
limited to prescription-only status if, because of its toxicity or 
other potentiality for harmful effect, or the method of its use, or the 
collateral measures necessary to its use, it is not safe for use except 
under the supervision of a practitioner licensed by law to administer 
such drug. Conversely, a drug that can be used safely by consumers 
without the supervision of a practitioner licensed by law to administer 
such drug does not require a prescription. Under section 503(b)(1), a 
drug cannot be both prescription and nonprescription at the same time, 
because it cannot be both safe and unsafe for use without the 
supervision of a practitioner licensed by law to administer such drug. 
For the same reason, two drug products with the same active ingredient 
that don't have meaningful differences also can't be simultaneously 
marketed as prescription and nonprescription. However, consistent with 
section 503(b)(1), if there is a meaningful difference between two drug 
products with the same active ingredient that makes one drug product 
safe for use only under the supervision of a practitioner licensed by 
law to administer such drug, while the other drug product is safe for 
use without such supervision, then the two products may be 
simultaneously marketed as prescription and nonprescription drug 
products, respectively.
    In addition, under section 503(b)(4)(B) of the FD&C Act, a drug, 
for which the prescription dispensing provisions of section 503(b)(1) 
do not apply, shall be deemed to be misbranded if at any time prior to 
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. The juxtaposition of 
these two provisions dictates 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. 
However, if there is a meaningful difference between two drug products 
with the same active ingredient that makes one drug product safe for 
use only under the supervision of a practitioner licensed by law to 
administer such drug, then simultaneous marketing of the two products 
is permitted.
    We believe that FDA's longstanding interpretation of section 
503(b), in which a meaningful difference allows prescription and 
nonprescription drug products with the same active ingredient to be 
simultaneously marketed, represents the best reading of that provision. 
A contrary reading would require all ibuprofen products, for example, 
to be restricted to prescription status because some products 
containing ibuprofen meet the prescription drug definition in section 
503(b)(1) of the FD&C Act. Under the Agency's longstanding 
interpretation of section 503(b), however, because the nonprescription 
versions of ibuprofen have meaningful differences from the prescription 
versions, such as different indications and strengths, they are 
different drugs that no longer meet the prescription drug definition 
for purposes of section 503(b). Likewise, a drug that no longer meets 
the prescription drug definition in section 503(b)(1) of the FD&C Act 
because it is approved with an ACNU is a different drug for purposes of 
simultaneous marketing of prescription drugs containing the same active 
ingredient consistent with section 503(b).
    We have already explained in this response how the simultaneous 
marketing provision of this rule simply reflects another determination 
by the Agency regarding whether a particular difference constitutes a 
meaningful difference for purposes of simultaneous marketing of 
prescription and nonprescription drugs with the same active ingredient 
under section 503(b) of the FD&C Act. In our responses to Comments 2 
and 39 through 42, we also explained how this is consistent with FDA's 
statutory authority to make scientific determinations about which drugs 
should be prescription or nonprescription drugs, the legislative 
history of the Durham-Humphrey Amendments, which added section 503(b) 
to the FD&C Act, as well as legal precedent and Agency practice.
    (Comment 44) We received a few comments asserting that simultaneous 
marketing of a prescription drug product and the nonprescription drug 
product with an ACNU could lead to inaccurate case reporting of adverse 
events for the nonprescription drug product with an ACNU. The comments 
describe concerns that reports of adverse events for the prescription 
drug product and the nonprescription drug product with an ACNU could be 
conflated and identification of a true safety signal for a drug product 
may not be detected accurately or could be delayed due to background 
noise.
    (Response 44) We disagree that simultaneous marketing of a 
prescription drug product and a nonprescription drug product with an 
ACNU, where the only meaningful difference between the two drug 
products is the ACNU, could lead to inaccurate case reporting of 
adverse events or delayed identification of a safety signal arising for 
either drug product. An applicant must report adverse drug experience 
information to FDA in compliance with applicable postmarketing 
reporting requirements (Sec.  314.80). Among other information, an 
individual case safety report contains certain identifiable information 
that would be unique to either the prescription drug product or the 
nonprescription drug product with an ACNU, such as application number 
and type, drug product name, national drug code, and lot number (Sec.  
314.80(f)). Therefore, FDA would have information to investigate 
whether the safety signal was associated with a prescription drug 
product, nonprescription drug product with an ACNU, or both.
    Additionally, FDA has robust reporting systems for consumers to 
report adverse drug experiences, complaints, or other issues with FDA-
regulated products, including nonprescription drug products. MedWatch 
is FDA's program for reporting serious adverse drug experiences, 
product quality problems, therapeutic inequivalence/failure, and 
product use errors with human medical products (Ref. 5). Additionally, 
consumers can contact the FDA Consumer Complaint Coordinator for the 
State in which they reside to report adverse drug experiences or other 
problems with FDA-regulated products. FDA's Consumer Complaint 
Coordinators, located in FDA offices, will listen, document a complaint 
about an FDA-regulated product, and follow up as necessary (Ref. 6). As 
with other FDA-regulated products, FDA has experience investigating if 
there is a safety signal with a particular product.
    (Comment 45) We received a few comments opposing simultaneous 
marketing stating that marketing of a prescription drug product and a 
nonprescription drug product with an ACNU may lead to consumer 
confusion because the labeling information for the prescription drug 
product and nonprescription drug product with an ACNU would not be 
identical in content or format.
    (Response 45) We disagree that simultaneous marketing of a 
prescription drug product and a

[[Page 105314]]

nonprescription drug product with an ACNU, where the only meaningful 
difference between the two drug products is the ACNU, would cause 
consumer confusion because of labeling differences between the 
prescription drug product and the nonprescription drug product with an 
ACNU. The commenter did not support its assertion with any evidence. 
There are numerous drug products with the same active ingredient that 
are currently simultaneously marketed as a prescription drug product 
and a nonprescription drug product where there is a meaningful 
difference between the two products. FDA does not have any data to show 
that there is consumer confusion and industry has not previously 
conveyed concerns with these products that are currently simultaneously 
marketed. Generally, labeling for nonprescription drug products and 
prescription drug products are not identical in content and format 
because they are directed to different audiences (primarily consumers 
for nonprescription drug products and healthcare practitioners for 
prescription drug products) to provide the information necessary for 
the safe and effective use of the drug product. Therefore, different 
content and format regulations apply to prescription and 
nonprescription labeling (see generally Sec. Sec.  201.57 and 201.66 
(21 CFR 201.57 and 201.66), respectively). Labeling for nonprescription 
drug products is directed to consumers (see Sec.  201.66). Although 
patient labeling is required for certain prescription drug products 
(see, e.g., 21 CFR part 208), generally, labeling for prescription drug 
products, including the prescribing information (see Sec.  201.57), is 
directed to the healthcare practitioner--not the patient--and a patient 
uses the prescription drug product under the supervision of a 
practitioner licensed by law to administer such drug.

H. Comments on Refusal To Approve an Application With an ACNU and FDA 
Response

    FDA specified in the proposed rule that we would refuse to approve 
an application for a nonprescription drug product with an ACNU if FDA 
has determined the application failed to meet the requirements 
specified in proposed 21 CFR 314.56 applicable to NDAs (proposed 21 CFR 
314.125(b)(20)) or ANDAs (proposed 21 CFR 314.127(a)(15)). In the 
following paragraphs, we discuss the comments on this proposal. After 
consideration of public comments received, we are finalizing our 
proposals without change.
    (Comment 46) We received a few comments supporting the provision. 
One comment explains that this provision is important because it alerts 
applicants to the requirements for a nonprescription drug product with 
an ACNU and explains FDA's action if the application does not comply 
with the requirements. We received one comment requesting that FDA 
include language in the rule to explain that FDA would not approve a 
nonprescription drug product with an ACNU if it has not been shown that 
the ACNU is necessary because the commenter believes this specific 
reason for rejecting an application is somewhat unusual.
    (Response 46) An application for a nonprescription drug product 
with an ACNU must meet all applicable requirements for an application 
in addition to the specific requirements for a nonprescription drug 
product with an ACNU in Sec.  314.56 in this final rule. FDA is 
including in the rule when FDA would refuse to approve an application 
for a nonprescription drug product with an ACNU. In addition to the 
other reasons for refusing to approve an application previously 
established at 21 CFR 314.125 and 314.127, we are establishing at 21 
CFR 314.125(b)(20) and 314.127(a)(15) in this final rule, that we would 
refuse to approve an application for a nonprescription drug product 
with an ACNU if FDA determined the application failed to meet the 
applicable requirements in 21 CFR 314.56. For example, if an 
application for a nonprescription drug product with an ACNU fails to 
include a statement regarding the necessity of the ACNU (21 CFR 
314.56(b)(1)(ii) in this final rule) or include adequate data or other 
information that demonstrates the necessity of the ACNU to ensure 
appropriate self-selection or appropriate actual use, or both (21 CFR 
314.56(b)(1)(v) in this final rule), FDA would not approve the 
application.

I. Comments on Other Postmarketing Reports and FDA Responses

    We proposed to require a new postmarketing report for 
nonprescription drug products with ACNUs. We proposed that applicants 
must report to FDA information concerning any incident of failure in 
the implementation of an ACNU using the FDA Adverse Event Reporting 
System (FAERS) (proposed 21 CFR 314.81(b)(3)(v)). In the following 
paragraphs, we discuss comments on this proposed requirement.
    After considering the comments, which we discuss below, we are 
making clarifying changes to the requirement because of significant 
commenter confusion as to when a postmarketing report should be 
submitted to FDA and concerns about duplicative reporting requirements. 
We are replacing the title ``Report of failure in the implementation of 
an additional condition for nonprescription use'' with ``Report of 
additional condition of nonprescription use (ACNU) failure for a 
nonprescription drug product with an ACNU'' in the heading. We are 
replacing the phrases ``when a failure in the implementation of an 
additional condition for nonprescription use (ACNU) for a 
nonprescription drug product occurs'' and ``report of a failure in 
implementation of an ACNU'' with ``report of an ACNU failure'' 
throughout 21 CFR 314.81(b)(3)(v) of the final rule. We are designating 
21 CFR 314.81(b)(3)(v)(A) and adding the subtitle ``ACNU failure'' 
followed by the explanation that an ACNU failure occurs upon either of 
the following events: (1) a failure associated with the implementation 
of the key elements of the ACNU under 21 CFR 314.56(c)(1)(iv) or 
(c)(2)(ii)) or (2) a failure associated with the operationalization of 
an ACNU under 21 CFR 314.56(c)(1)(vii) or (c)(2)(iii), as approved by 
FDA in the application (21 CFR 314.81(b)(3)(v)(A) in this final rule). 
To address confusion about applicant responsibilities in connection 
with ACNU failure reporting requirements and to be consistent with 
certain existing postmarketing reporting requirements for adverse drug 
experiences (see Sec.  314.80), we are adding 21 CFR 
314.81(b)(3)(v)(B), stating that the applicant must develop written 
procedures for the surveillance, receipt, evaluation, and reporting of 
ACNU failures to FDA. We note that FDA has described its intention to 
issue a proposed rule that, among other things, would modernize 
postmarketing safety reporting requirements for human drug and 
biological products and require application holders for drug products 
and certain biological products to establish and maintain a 
pharmacovigilance quality system (see Regulation Identifier Number 
0910-AI61 on Fall 2023 Unified Agenda of Regulatory and Deregulatory 
Actions). In that proposed rule, FDA intends to provide notice and an 
opportunity for comment on any proposed changes that, if finalized, may 
affect the requirements in Sec.  314.81(b)(3)(v) of this final rule.
    We are designating Sec.  314.81(b)(3)(v)(C) and adding the subtitle 
``Report of ACNU failure'' followed by information about the report of 
ACNU failure. To address commenter confusion that a report of an ACNU 
failure is duplicative of existing

[[Page 105315]]

postmarketing reporting requirements for adverse drug experiences (see 
Sec.  314.80), we are removing the clause ``that may cause or lead to 
inappropriate medication use or consumer harm'' from the explanation of 
an event that triggers the submission of a report of an ACNU failure 
because an ACNU failure may still occur even if such failure does not 
cause or lead to inappropriate medication use or consumer harm. In 
addition, we are removing the clause stating that a report must be 
submitted, ``whether or not the failure is associated with an adverse 
event,'' to avoid confusion between a report of an ACNU failure 
submitted under Sec.  314.81(b)(3)(v) of this final rule and a 
postmarketing report of an adverse drug experience, which would be 
submitted under Sec.  314.80. To reduce burden and further address 
commenter confusion, we are clarifying that if an applicant receives or 
otherwise obtains information regarding an adverse drug experience 
associated with an ACNU failure before the submission of a report of an 
ACNU failure, a single individual case safety report must be submitted 
to FDA that describes both the adverse drug experience and the 
associated ACNU failure. To clarify the term ``supplement,'' and not to 
confuse with a supplement to an approved application, we are revising 
the phrase ``must supplement the report'' to ``submit a follow-up 
report to the previously submitted report,'' and ``the supplement must 
include'' to ``the follow-up report must include.''
    We are designating the content of the report of ACNU failure to 
Sec.  314.81(b)(3)(v)(D) in this final rule and adding the subheading 
``Content of Report of ACNU failure.'' We are revising the subheading 
in Sec.  314.81(b)(3)(v)(A)(2) from ``Additional information, if 
known.'' to ``Additional Information if available to the applicant.'' 
for clarity. In order to reduce burden on industry by having 
consistency with current processes for ICSR submissions, we are also 
revising the requirement for the content of an ACNU report to include 
the additional information, if available to the applicant, as a dataset 
in a structured manner instead of a narrative summary (see proposed 
Sec.  314.81(b)(3)(v)(A)(2)(iv) and (v)). Therefore, while the 
additional information is consistent with the proposed rule, we are 
separating the additional information into separate provisions 
consistent with current practices for reporting structure beginning at 
Sec.  314.84(b)(3)(v)(D)(2)(iv) in this final rule (21 CFR 
314.81(b)(3)(v)(D)(2)(iv) through (x) in this final rule). Among other 
requirements, Sec.  314.84(b)(3)(v)(D)(2)(iv) in this final rule 
requires the use of ACNU failure terms. The applicant may use, for 
example, a MedDRA (Medical Dictionary for Regulatory Activities) term 
or the verbatim phrasing used by the reporter as the ACNU failure term. 
Additionally, new MedDRA terms have been added to describe certain ACNU 
failures.
    We are also making nonsubstantive changes to align with existing 
postmarketing reporting requirements. We are replacing ``adverse 
event'' with ``adverse drug experience'' throughout Sec.  
314.81(b)(3)(v) in this final rule to align with the terminology used 
for postmarketing reporting requirements for adverse drug experiences 
in Sec.  314.80. Although reports of an ACNU failure will be submitted 
to FAERS, we have removed specific mention of FAERS from the rule to 
align with existing postmarketing reporting requirements which do not 
specifically refer to an FDA database for submissions (see, e.g., Sec.  
314.80). Therefore, in addition to the reasons stated in the previous 
paragraphs, we are omitting the following sentence from the regulation: 
``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.'' (as 
stated in proposed Sec.  314.81(b)(3)(v)). We are also removing the 
phrase ``to FAERS'' throughout the section.
    We are also making the following clarifying revisions on our own 
initiative in Sec.  314.81(b)(3)(v): (1) replacing the word 
``submitter'' with ``applicant,'' (2) replacing ``obtains'' with 
``receives or otherwise obtains,'' (3) removing the word ``as'' before 
the clause ``required in Sec.  314.80(f),'' and making corresponding 
grammatical changes in sentences (e.g., revising an ``a'' to ``an'' due 
to sentence revisions).
    (Comment 47) We received many comments that support FDA's proposal 
to require postmarketing reports for an ACNU failure. We received many 
comments that support robust postmarketing surveillance for 
nonprescription drug products with ACNUs for FDA to monitor the drug 
products. One comment recommends that if an applicant does not comply 
with the reporting requirement, the applicant must market its drug 
product as a prescription drug product and cannot market its drug 
product as a nonprescription drug product with an ACNU.
    (Response 47) FDA agrees that postmarketing reports of an ACNU 
failure are an important part of FDA surveillance to ensure that 
consumers are appropriately accessing the nonprescription drug product 
with the ACNU as approved by FDA. If an applicant does not comply with 
the requirements for postmarketing reports, the applicant may be 
subject to an FDA enforcement action for failure to submit required 
postmarketing reports (see section 301(e) of the FD&C Act (21 U.S.C. 
331(e)); see also section 505(e) of the FD&C Act).
    (Comment 48) We received a few comments asserting that the 
requirement for a report of an ACNU failure exceeds FDA's statutory 
authority, particularly where no adverse event occurred.
    (Response 48) We disagree that FDA lacks authority to require 
postmarketing reports of ACNU failures, including when they are not 
associated with particular adverse drug experiences.\6\ Section 
505(k)(1) of the FD&C Act authorizes FDA to require such reporting. 
Specifically, section 505(k)(1) requires reports ``of data relating to 
clinical experience and other data or information'' as FDA prescribes 
by regulation, ``on the basis of a finding that such . . . reports are 
necessary in order to enable [FDA] to determine, or facilitate a 
determination, whether there is or may be ground'' for withdrawing 
approval of an application.
---------------------------------------------------------------------------

    \6\ See 21 CFR 314.80(a), (defining adverse drug experience as 
``any adverse event associated with the use of a drug in humans, 
whether or not considered drug related'' including the following:, 
An adverse event occurring in the course of the use of the drug in 
professional practice; an adverse event occurring from drug overdose 
whether accidental or intentional; an adverse event occurring from 
drug abuse; an adverse event occurring from drug withdrawal; and any 
failure of expected pharmacological action).
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    When describing the kinds of data or information that FDA may 
require to be reported, section 505(k)(1) of the FD&C Act does not 
expressly refer to adverse drug experiences, and instead refers to a 
broader category of ``data relating to clinical experience and other 
data or information.'' In contrast, in other parts of the FD&C Act, the 
statute does expressly use the term ``adverse drug experience,'' see, 
e.g., sections 505(k)(3) and 505-1, underscoring that ``data relating 
to clinical experience and other data or information'' means something 
distinct from data or information relating to ``adverse drug 
experiences.'' Indeed, consistent with the statutory text, FDA has long 
interpreted ``data relating to clinical experience and other data or 
information,'' as described in section 505(k)(1) of the FD&C Act, as

[[Page 105316]]

covering a broader set of information than solely adverse drug 
experiences. For example, under 21 CFR 314.81(b), implementing section 
505(k)(1) of the FD&C Act, applicants are required to report other 
kinds of information, regardless of whether the information is 
associated with adverse drug experiences, such as ``information 
concerning any incident that causes the drug product or its labeling to 
be mistaken for, or applied to, another article,'' ``a summary of new 
information from the previous year that might affect safety, 
effectiveness, or labeling of the drug product,'' and ``distribution 
data.''
    Additionally, like these other kinds of information, even when 
there is no adverse drug experience that is clearly associated with an 
ACNU failure, ACNU failures generally would have a bearing on whether 
the Agency may consider withdrawal proceedings pursuant to section 
505(e) of the FD&C Act. For example, under section 505(e), the Agency 
may withdraw approval of an application if certain new information 
shows that a drug is not safe for use under the conditions of use upon 
the basis of which the application was approved. If the applicant does 
not ensure that the ACNU is implemented and operationalized as approved 
by FDA in the application, then the drug may no longer be considered 
safe and effective for use in the nonprescription setting. In such a 
case, FDA may consider withdrawing an application, if, for example, an 
applicant fails to take appropriate corrective action to prevent 
reoccurrence of an ACNU failure of the same nature.
    More specifically, because a nonprescription drug product with an 
ACNU must only be made available to consumers who fulfill the ACNU for 
whom it is appropriate, ACNU failures are relevant to understanding the 
safety and effectiveness of the drug. With an ACNU failure, an adverse 
drug experience may very well occur even if there are no reported 
adverse drug experiences associated with a particular ACNU failure. The 
ACNU failure could be an indication that the method of implementing or 
operationalizing the ACNU is flawed, which may result in the drug 
product not being made available to consumers for whom it is 
appropriate and, in other instances, may result in the drug product 
being made available to consumers for whom it is not appropriate. For 
example, with Drug X (see more information about Drug X, a fictitious 
nonprescription drug product with an ACNU, in the proposed rule (87 FR 
38313 at 38319)), 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 consumer 
answers the series of questions in the questionnaire and the underlying 
program or other operating information used by the secure website 
calculates the risk score for a serious side effect and determines if 
the consumer has an acceptable disease-specific risk score to use Drug 
X and therefore purchase Drug X. A software failure that results in a 
miscalculation of the risk score would be an ACNU failure even if the 
failure did not provide the consumer with access to drug product 
because such failure in calculating the risk score could similarly 
provide consumers access to the drug product for whom it is not 
appropriate. FDA and applicants have an interest in understanding the 
ACNU failures and mitigating the risk of reoccurrence of an ACNU 
failure because ACNU failures could result in adverse drug experiences 
or lead to the drug product being made available to consumers that 
should not be taking the drug product for various reasons.
    (Comment 49) We also received several comments that oppose the 
proposed postmarketing reporting requirement for a nonprescription drug 
product with an ACNU as ``overly broad,'' ``unnecessary'', or 
``excessive burdensome.'' Those comments request that FDA revise or 
remove the requirement to report an ACNU failure. The comments contend 
that a nonprescription drug product with an ACNU would already be 
subject to the same postmarketing reporting requirements for adverse 
drug experiences in Sec.  314.80 and, if applicable, 21 CFR part 803 
for medical devices. The comments assert that the postmarketing 
reporting requirement for ACNU failures could require the submission of 
a very large number of postmarketing reports and will place undue 
resource demands on both applicants and FDA. Several comments suggest 
revisions in how FDA defines a failure in implementation of an ACNU to 
narrow the scope of the reporting requirement. A few of these comments 
suggest that the submission of a report should be limited to an ACNU 
failure that results in an adverse event or that is likely to result in 
an adverse event. A few comments suggest that what they consider 
nonsignificant failures (e.g., ACNU failures with no adverse events) 
should be captured and investigated under an applicant's existing 
complaint handling processing instead of under a postmarketing 
reporting requirement.
    (Response 49) After consideration of comments received, FDA is 
revising the requirement to report ACNU failures for clarity and to 
decrease any potential duplicative reporting. We are clarifying the 
events that would result in the submission of a report of an ACNU 
failure to make clear that these reports are not duplicative of the 
applicable regulatory requirement for the submission of postmarketing 
reports of adverse drug experiences under Sec.  314.80. In order to 
clarify that only reports of ACNU failures are required to be submitted 
in a postmarketing report under Sec.  314.81 and because postmarketing 
reports of adverse experiences are currently required under Sec.  
314.80, we are removing language that: (1) a report of an ACNU failure 
should be submitted if the failure may cause or lead to inappropriate 
medication use or consumer harm and (2) a report must be submitted to 
FAERS whether or not the failure in implementation of the ACNU is 
associated with an adverse event. We clarify that a report of an ACNU 
failure must be submitted to FDA when an event occurs that differs from 
the following, as approved by FDA in the application including: (1) a 
failure associated with the implementation of one or more of the key 
elements of an ACNU under Sec.  314.56(c)(1)(iv) or (c)(2)(ii) or (2) a 
failure associated with operationalization of the ACNU under 21 CFR 
314.56(c)(1)(vii) or (c)(2)(iii) (Sec.  314.81(b)(3)(v) in this final 
rule). A nonprescription drug product with an ACNU that includes a 
device constituent part is also subject to combination product 
reporting requirements, including malfunction reporting (see 21 CFR 
803.50 and part 4) for an event involving the device constituent part.
    For the reasons explained in response to Comment 48, we disagree 
that reports of ACNU failure should only be submitted for ACNU failures 
that result in an adverse event or that is likely to result in an 
adverse event.
    (Comment 50) We received a comment suggesting that the proposed 
postmarketing reporting provision would require reports about a wide 
range of technological failures, including routine and quickly resolved 
technological failures (e.g., broken kiosks or credit card readers, 
disruptions at a retailer, or temporarily inaccessible websites or 
mobile applications).
    (Response 50) Reports of ACNU failures may need to be submitted for 
various types of technological failures. However, the specific 
circumstances of the technological failure would

[[Page 105317]]

determine whether it constitutes an ACNU failure. We are revising the 
rule to clarify the events that would be considered ACNU failures. We 
further clarify that a report of an ACNU failure must be submitted to 
FDA when there is an event that occurs that differs from how FDA 
approved the nonprescription drug product with an ACNU: (1) a failure 
associated with the implementation of the key elements of an ACNU under 
Sec.  314.56(c)(1)(iv) or (c)(2)(ii), as approved by FDA in the 
application or (2) a failure associated with operationalization of an 
ACNU under 21 CFR 314.56(c)(1)(vii) or (c)(2)(iii), as approved by FDA 
in the application (Sec.  314.81(b)(3)(v) in this final rule).
    (Comment 51) One comment states that frequent reporting of 
``problems'' to FDA also might stigmatize nonprescription drug products 
with ACNUs, as some observers may incorrectly equate any reported 
problem with a threat to someone's health.
    (Response 51) We interpret the comment about ``frequent reporting 
of problems'' to mean frequent reporting of ACNU failures and disagree. 
FDA has a public health interest in receiving reports of ACNU failures 
because the FDA-approved ACNU ensures consumers' appropriate self-
selection or appropriate actual use, or both, of the nonprescription 
drug product without the supervision of a practitioner licensed by law 
to administer such drug. FDA and applicants have an interest in 
understanding the ACNU failures and mitigating the risk of reoccurrence 
of an ACNU failure because ACNU failures could result in adverse drug 
experiences or lead to the drug product being made available to 
consumers that should not be taking the drug product for various 
reasons, even if the initial failure did not.
    (Comment 52) We received a comment expressing concerns that the 
proposed rule requires immediate reporting regardless of the nature of 
the failure and will require a significant change to pharmacovigilance 
programs with limited benefit.
    (Response 52) As explained in our responses to Comments 49-50, FDA 
clarified the events that would result in the submission of a report of 
an ACNU failure. The applicant must submit the report of an ACNU 
failure as soon as possible but no later than 15 calendar days from the 
date when the applicant has acquired the minimum dataset for an ACNU 
failure (Sec.  314.81(b)(3)(v)(E) of this final rule). We disagree that 
applicants will need to make significant changes to pharmacovigilance 
programs in order to comply with the timeframe for submitting a report 
of an ACNU failure under Sec.  314.81 because the requirement is 
consistent with the timeframe for the submission of certain 
postmarketing reports of adverse drug experiences under Sec.  314.80. 
Therefore, applicants will generally already have systems in place that 
could be adapted to facilitate the reporting of ACNU failures. FDA has 
a public health interest in receiving reports of ACNU failures 
expeditiously because the FDA-approved ACNU ensures consumers' 
appropriate self-selection or appropriate actual use, or both, of the 
nonprescription drug product without the supervision of a practitioner 
licensed by law to administer such drug. Further, as explained 
previously, FDA and applicants have an interest in understanding the 
ACNU failures and working to mitigate the risk of recurrence of an ACNU 
failure.
    (Comment 53) We received several comments on the burden and 
benefits of submitting individual reports to FDA for each individual 
ACNU failure encountered by a consumer resulting from the same cause of 
failure, as opposed to a single, consolidated report for all such 
failures. We received several comments supporting a single, 
consolidated report to reduce the reporting burden on applicants. We 
received a few comments that recommend FDA consider the nature of the 
failure or clinical outcome of the failure (i.e., a risk-based 
approach) to determine whether individual or consolidated reporting is 
appropriate. We received one comment recommending consolidated 
reporting whereby reports would be submitted at intervals less than 5 
days apart or when the particular error occurs after a certain number 
of times because applicants may not have the capacity to submit 
individual reports for every occurrence of a particular technical 
malfunction or error. Another comment urges FDA to consider 
consolidated reporting for ACNU failures that the comment characterized 
as unrelated to safety and effectiveness (such as a computer system 
failure). Finally, we received a comment that requests FDA consider 
implementing a more streamlined reporting procedure for nonprescription 
drug products with ACNUs similar to CDRH's Voluntary Malfunction 
Summary Reporting (VMSR) program for medical devices.
    (Response 53) As explained in our responses to Comments 49-50, FDA 
clarified the events that would result in the submission of a report of 
an ACNU failure as not all issues related to an ACNU are ACNU failures. 
FDA specifically sought comment on the burden and benefits of 
submitting an individual report to FDA for each ACNU failure 
encountered by a consumer resulting from the same cause of failure, as 
opposed to a single, consolidated report for such failures. Given the 
possibility for numerous reasons for an ACNU failure depending on the 
particular circumstances, FDA believes that individual reporting for 
ACNU failures would provide more specific information to facilitate an 
understanding of ACNU failures, their causes, and their outcomes. 
Therefore, we disagree with submitting a single, consolidated report of 
an ACNU failure resulting from the same cause of failure.
    The VMSR program (see 83 FR 40973, August 17, 2018) is a voluntary 
program intended to streamline reporting of device malfunctions in 
certain situations based on FDA experience with summary reporting 
programs, key findings from CDRH's pilot program for the submission of 
Medical Device Reports (MDRs) in summary format on a quarterly basis, 
and other information summarized in the 2017 proposal for the VMSR 
program (see 82 FR 60922, December 26, 2017). Therefore, we disagree 
with implementing a reporting procedure for nonprescription drug 
products with ACNUs similar to the VMSR program because we do not have 
findings on which to base a streamlined approach. To decrease any 
potential duplicative reporting burden by applicants, we clarified the 
events that would result in the submission of a report of an ACNU 
failure to FDA.
    (Comment 54) We received a few comments questioning whether FAERS 
is an appropriate database for collecting reports of ACNU failures. One 
comment specifically raises a concern about whether FAERS is 
appropriate to collect reports of technological failures, considering 
that FAERS currently focuses on adverse events and product defects and 
quality. The comment further asks FDA to clarify any changes that would 
be required to the reporting forms to accommodate ACNU failures. A few 
comments also question whether the clinical reviewers of FAERS reports 
have the expertise to evaluate reports of technological problems and 
the attempted remedies.
    (Response 54) FAERS is the database currently designed to support 
FDA's postmarketing safety surveillance program for drugs and certain 
biological products and can currently accommodate reports of ACNU 
failures. Although reports of an ACNU failure will currently be 
submitted to FAERS, we have removed specific mention of FAERS from the 
rule to align with other postmarketing reporting regulations,

[[Page 105318]]

which do not specifically refer to a current FDA database for 
submissions (see, e.g., Sec.  314.80).
    The informatic structure of the FAERS database aligns with the 
International Council for Harmonisation guidance for industry entitled 
``E2B(R3) Electronic Transmission of Individual Case Safety Reports 
(ICSRs) Implementation Guide--Data Elements and Message Specification'' 
(available at https://www.fda.gov/media/81904/download).
    FDA reviewers are trained to evaluate reports of technological 
problems and the attempted remedies. Center for Drug Evaluation and 
Research (CDER) reviewers may consult CDRH reviewers, when appropriate, 
to address any issues regarding technology related to an ACNU.
    (Comment 55) We received one comment suggesting that pharmacies or 
sellers would be required to report and record ACNU failures thereby 
placing a tremendous burden on the pharmacies or sellers.
    (Response 55) We disagree. While a pharmacist or other individual 
may voluntarily submit a report of an ACNU failure to FDA's reporting 
systems such as Medwatch (Ref. 5), the rule requires the applicant of 
the nonprescription drug product with an ACNU to submit reports of an 
ACNU failure (see Sec.  314.81(b)(3)(v) in this final rule). Therefore, 
unless they are applicants for the relevant drug product, pharmacies 
and sellers are not required under the rule to report ACNU failures.
    (Comment 56) We received a comment seeking clarification on whether 
FDA expects an applicant to implement remediation for every ACNU 
failure. The comment further states that an applicant should determine 
when remediation should be implemented based on its safety assessment 
and that the remedial action taken to address the ACNU failure depends 
on the type of failure and the consequence of the failure.
    (Response 56) If there is an ACNU failure, an event has occurred 
that is not consistent with FDA's approval of the nonprescription drug 
product with an ACNU in one or both of two ways: (1) a failure 
associated with the implementation of the key elements of an ACNU under 
21 CFR 314.56(c)(1)(iv) or (c)(2)(ii) or (2) a failure associated with 
operationalization of the ACNU under 21 CFR 314.56(c)(1)(vii) or 
(c)(2)(iii), as approved by FDA in the application (Sec.  
314.81(b)(3)(v) in this final rule). The applicant must explain the 
remedial action initiated or completed and the corrective action to 
prevent ACNU failures of the same nature in the future (Sec.  
314.81(b)(3)(v)(A)(2)(v) in this final rule).
    (Comment 57) We received a comment requesting that FDA provide 
guidance on how often applicants should monitor a nonprescription drug 
product with an ACNU.
    (Response 57) We understand the need for additional clarity here. 
In the proposed rule, we stated that, ``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'' (87 FR 38313 at 38322). The proposed rule also proposed that 
the report must 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 (87 FR 38313 at 38323 and proposed Sec.  
314.81). As mentioned earlier, to address confusion and be consistent 
with the existing postmarketing reporting requirements for adverse drug 
experiences (see Sec.  314.80) and cognizant of minimizing burden we 
are adding Sec.  314.81(b)(3)(v)(B), stating that the applicant must 
develop written procedures for the surveillance, receipt, evaluation, 
and reporting of ACNU failures to FDA. This gives applicants 
flexibility to develop procedures specific to the drug product and 
potentially align with any written procedures already established with 
respect to Sec.  314.80 to help minimize burden. We anticipate that 
applicants could adapt any written procedures for surveillance, 
receipt, evaluation, and reporting of postmarketing adverse drug 
experiences as already required under Sec.  314.80 to also include 
instances of an ACNU failure.
    (Comment 58) We received a comment that recommends FDA create a 
consumer-friendly website and telephone number for consumers to report 
issues with a nonprescription drug product with an ACNU.
    (Response 58) FDA already has reporting systems for consumers to 
report adverse drug experiences, complaints, or other issues with FDA-
regulated products, including nonprescription drug products. MedWatch 
is the FDA's program for reporting serious adverse drug experiences, 
product quality problems, therapeutic inequivalence/failure, and 
product use errors with human medical products (Ref. 5). Additionally, 
consumers can contact the FDA Consumer Complaint Coordinator for the 
State in which they reside to report adverse drug experiences or other 
problems with FDA-regulated products. FDA's Consumer Complaint 
Coordinators, located in FDA offices, will listen, document a complaint 
about an FDA-regulated product, and follow up as necessary (Ref. 6). 
Therefore, we disagree that FDA needs to create an additional consumer-
friendly website and telephone number for consumers to report issues 
specific for a nonprescription drug product with an ACNU.

J. Comments on General Labeling Requirements and FDA Responses

    We proposed to require that a nonprescription drug product with an 
ACNU must comply with all applicable regulatory requirements for 
nonprescription drug products under part 201 (21 CFR part 201), 
including the format and content of nonprescription drug product 
labeling under Sec.  201.66 and the statements specified in proposed 21 
CFR 201.130(a) (proposed 21 CFR 201.67(c)). In the following 
paragraphs, we discuss the comments on these requirements. After 
consideration of public comments received, we are finalizing our 
proposals with modifications for clarity and consistency with revisions 
made to Sec.  201.130 in this final rule. Specifically, we are revising 
the citation in 21 CFR 201.67(c) of the final rule from ``Sec.  
201.130(a)'' to ``Sec.  201.130(a) and (b).''
    (Comment 59) We received several comments supporting the proposed 
labeling requirements because the labeling will help consumers use 
nonprescription drug products with ACNUs safely and effectively. 
However, a few comments express concerns about whether consumers 
possess the capacity to obtain, process, and understand the basic 
health information needed to make an appropriate health decision using 
the labeling for nonprescription drug products with ACNUs. A few 
comments discuss accessibility of labeling for nonprescription drug 
products with an ACNU, and one comment recommends that labeling should 
be made available to consumers in multiple languages using a quick-
response code (commonly referred to as a QR code) on the labeling. 
Another comment requests that FDA develop criteria to ensure 
accessibility of labeling for nonprescription drug products with ACNUs.
    (Response 59) We understand commenters' concerns that some 
consumers may have difficulty using the labeling for a nonprescription 
drug product with an ACNU. However, consistent with the development of 
nonprescription drug products,

[[Page 105319]]

applicants of nonprescription drug products with ACNUs may be required 
to conduct consumer studies which can help demonstrate that the 
requirement for adequate directions for use is met (87 FR 38313 at 
38316). These studies may include label comprehension studies, self-
selection studies, actual use studies, and other human factors studies 
(87 FR 38313 at 38316). FDA has issued guidances on certain types of 
consumer studies (Refs. 1 to 3). Because nonprescription drug products 
with an ACNU, like other nonprescription drug products, will be used by 
consumers from the general population without supervision of a 
practitioner licensed by law to administer such drug, applicants are 
expected to include a wide range of subjects in consumer studies. 
Specifically, in self-selection studies, exclusion criteria should be 
minimal (e.g., inability to read and understand English) (Ref. 2). In 
label comprehension studies, applicants should include an adequate 
number of subjects in self-selection studies who have limited literacy 
skills. The proportion of low-literacy subjects in the study sample 
should be representative of the proportion of adults in the United 
States with low literacy skills based on available national data (Ref. 
1).
    FDA acknowledges the benefits of having translated drug information 
for individuals with limited English proficiency. FDA's current 
regulations require that all words, statements, and other information 
required by or under authority of the FD&C Act appear on the label or 
labeling in the English language, with limited exceptions (see Sec.  
201.15(c)). In the case of articles distributed solely in the 
Commonwealth of Puerto Rico or in a Territory where the predominant 
language is one other than English, the predominant language may be 
substituted for English. In addition to English, an applicant may 
provide consumers with labeling in other languages; however, applicants 
(and not FDA) must ensure the translation of the labeling is accurate 
and complete. FDA strongly encourages applicants to work with retailers 
and other organizations to ensure that a nonprescription drug product 
with an ACNU is accessible to individuals with limited English 
proficiency. To the extent an applicant, retailer, or other 
organization receives Federal financial assistance from the U.S. 
Department of Health and Human Services (HHS), they are required to 
take reasonable steps to provide meaningful access to their programs 
and activities by individuals with limited English proficiency under 
Title VI of the Civil Rights Act of 1964 and its implementing 
regulations (42 U.S.C. 2000d, et seq.; 45 CFR part 80; see also section 
1557 of the Affordable Care Act, 42 U.S.C. 18116, which provides 
similar protections as those under Title VI in health programs and 
activities receiving Federal financial assistance).
    We note that we considered requiring that the label include 
additional information for consumers such as information that the drug 
may also be available as a prescription drug product. We ultimately 
rejected that idea, however; the purpose of applicable labeling 
requirements for nonprescription drug products and the specific 
labeling requirements for nonprescription drug products with an ACNU is 
to provide consumers with the information that they need to self-select 
and use the drug product in the nonprescription setting, not to inform 
them of other treatment options. However, while FDA would not require 
this information on the labeling of the nonprescription drug product, 
the applicant may choose to engage in promotional communications for 
both the approved prescription and nonprescription drug products.
    (Comment 60) We received one comment that requests FDA clarify the 
standards for permissible labeling differences between an RLD and an 
ANDA nonprescription drug product with an ACNU that is operationalized 
differently from the RLD to increase the viability of the ACNU pathway 
for generic drug products.
    (Response 60) We disagree with the need to clarify permissible 
labeling differences specific to an RLD and an ANDA nonprescription 
drug product with an ACNU because the rule does not change the 
standards for permissible labeling differences between an RLD and an 
ANDA. 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 section 505(j)(2)(A) and (j)(4) of the FD&C Act and 
Sec. Sec.  314.94(a)(8)(iv) and 314.127(a)(7)). Any permissible 
labeling difference would be determined on a case-by-case basis as we 
consider the specifics of each application for a nonprescription drug 
product with an ACNU during our review.
    (Comment 61) We received a comment that the proposed labeling 
requirements of 21 CFR 201.67(c) do not impose any incentive or 
requirement for consumers to read the information provided by the 
applicant before accessing and fulfilling the ACNU. The comment 
suggests that consumers could access the information on the provided 
website, disregard the information, and fulfill the ACNU without having 
the requisite knowledge to make an informed decision.
    (Response 61) While FDA acknowledges that we cannot require a 
consumer to read labeling, the applicant must describe how the ACNU 
will ensure appropriate self-selection or appropriate actual use, or 
both, by consumers (21 CFR 314.56(c)(1)(iii) in this final rule) and 
submit adequate data or other 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 (21 
CFR 314.56(c)(1)(vi) in this final rule).

K. Comments on Format Requirements for Required ACNU Statement and FDA 
Responses

    We proposed to require that the ACNU Statement specified in 
proposed 21 CFR 201.130(a)(2) meet specific format requirements 
(proposed 21 CFR 201.67(d)). In the following paragraphs, we discuss 
the comments on this proposed requirement. After consideration of 
public comments received, we are finalizing our proposal with 
modifications for consistency with changes made to 21 CFR 201.130 and 
elsewhere in this final rule. We are finalizing the proposed title of 
the requirement, ``Format requirements for required ACNU statement'' 
with minor revision to read as follows: ``Format requirements for the 
required statement about the ACNU.'' We are replacing the word 
``statement'' with the phrase ``statement about the ACNU'' in all 
instances throughout Sec.  201.67(d) for clarity. We proposed that the 
statement specified in Sec.  201.130(a)(2) must meet all format 
requirements that are specified in Sec.  201.67(d). However, due to 
revisions in the regulation's text, we are revising the citation of 21 
CFR 201.130(a)(2) to 21 CFR 201.130(b)(1).
    (Comment 62) We received one comment in support of the proposed 
format requirement that the ACNU Statement specified in proposed 21 CFR 
201.130(a)(2) appear in a yellow background banner. However, several 
comments oppose the proposed format requirement that the statement 
about the ACNU appear in boldface and black type in a yellow background 
banner. Several comments state that the proposed format requirements: 
(1) are overly prescriptive, (2) may not achieve

[[Page 105320]]

the desired visibility in all cases, and (3) do not appropriately 
consider a drug product's unique trade dress. One comment argued that 
while there are benefits of highlighting the statement to increase 
attention to it, too much highlighted information could reduce 
attention to other important elements on the PDP. Many comments state 
that the format of the statement about the ACNU should be determined on 
a product-by-product basis. A few comments recommend that FDA allow 
flexibility in the font type, color of the font, and highlight color 
that fits the requirement of prominence and the proposed trade dress 
consistent with the format requirements in 21 CFR 201.66(d)(3).
    (Response 62) We disagree with revising the format requirements for 
the statement about the ACNU. While we understand concerns from some 
commenters that the formatting of the statement may visually conflict 
with trade dress, the distinctive formatting (e.g., boldface and black 
type in a yellow background banner) of the statement is necessary for 
consistency across all nonprescription drug products with ACNUs. Having 
standardized format and content on labeling is consistent with FDA 
practice and regulations, where possible (see generally 21 CFR part 
201). Consistency in the format and content of the statement about the 
ACNU is important so that consumers become familiar with the statement 
and can easily identify the drug product as a nonprescription drug 
product with an ACNU, not a traditional nonprescription drug product 
that can be purchased without fulfilling an ACNU. We want consumers to 
know that there is something different about an ACNU drug product and 
for consumers and other persons to understand that these drug products 
are not suitable for all individuals and should only be used after 
fulfilling the ACNU. This statement is to provide immediate notice to 
consumers and for other people who may have access to the drug product 
purchased by the consumer (e.g., household members, visitors to the 
consumer's house) but did not fulfill the ACNU. This drug may not be 
right for that person and using the drug product without fulfilling the 
ACNU could put the person at risk for side effects and medication 
errors. Thus, the format requirements for the statement are intended to 
help ensure the safe and effective use of nonprescription drug products 
with ACNUs.
    (Comment 63) A few comments oppose the proposed font size 
requirement asserting the font size is exceptionally large given the 
variability of package sizes. One comment suggests that the proposed 
font size requirements result in the statement consuming a significant 
portion of the PDP, from one-quarter to one-third of the PDP, at a 
minimum. One comment recommends permitting the use of a smaller font 
size when the required minimum font size is not feasible due to the 
package size (e.g., convenience or small size packaging).
    (Response 63) FDA disagrees that the required font size is 
exceptionally large. Published references recommend a larger font size, 
such as 12-point sans serif to improve readability (Refs. 7 and 8). A 
larger font size will help ensure consumers can identify a 
nonprescription drug product with an ACNU and read the statement that 
alerts consumers that the drug product is not suitable for all 
individuals and should only be used after fulfilling the ACNU. As 
required in existing regulations for nonprescription drug product 
labeling, the PDP must be large enough to accommodate all the mandatory 
label information required to be placed on the PDP with clarity and 
conspicuousness and without obscuring designs, vignettes, or crowding 
(see Sec.  201.60). Applicants can reduce the font size of the trade or 
proprietary name of the nonprescription drug product with an ACNU, if 
one exists, and promotional material to allow room for the statement 
about the ACNU. We believe an applicant should generally be able to 
include the statement on the PDP as specified in the rule without 
having to increase the package size. However, we also proposed an 
exception--an applicant may request an exception to the minimum font 
size requirement for containers where its size would render compliance 
with the requirement impractical (Sec.  201.67(d)(5) in this final 
rule).

L. Comments on Exemption From Adequate Directions for Use and FDA 
Responses

    We proposed to 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, we 
proposed 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 
21 CFR 201.130(a) and the ACNU is implemented by the applicant as 
approved by FDA in the application (proposed 21 CFR 201.130). We 
proposed to require that the following statement appear as the first 
direction under the heading ``Directions'' in the labeling, as required 
in 21 CFR 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.'' (Proposed 21 CFR 201.130(a)(1)) We 
also proposed to 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.'' (Proposed 21 CFR 201.130(a)(2)) We proposed that this 
statement must meet the specific format requirements as specified in 
proposed 21 CFR 201.67(d). We also proposed that the labeling of the 
drug must comply with other applicable labeling requirements for 
nonprescription drug products under part 201, including the format and 
content requirements for nonprescription drug product labeling under 21 
CFR 201.66 (proposed 21 CFR 201.130(a)(3)). Lastly, we proposed to 
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 87 FR 
38313 at 38324 and proposed 21 CFR 201.130(b)).
    In the following paragraphs, we discuss the comments on this 
requirement. After consideration of public comments received, we are 
finalizing our proposals with modifications as discussed. After 
considering comments, as discussed below, we are adding flexibility to 
the labeling requirements regarding instructions for the ACNU and the 
statement about the ACNU (21 CFR 201.130(a) and (b) in this final 
rule). These requirements, as revised based on comments we received, 
provide flexibility for applicants to better convey information to 
consumers for a particular nonprescription drug product with an ACNU. 
FDA feels strongly that the content of required labeling in 21 CFR 
201.130(a)(1) and (b)(1) in this final rule should generally be 
consistent across all nonprescription drug products with ACNUs. 
Consistency in the content of the labeling is important to help 
consumers understand (including the original purchaser and persons 
other than the original purchaser) that these nonprescription drug 
products are not

[[Page 105321]]

suitable for all individuals and should be only used after fulfilling 
the ACNU. Consistency assists consumers in understanding the ACNU that 
the consumer must fulfill and where to find additional information. 
Consistency in the labeling can reduce consumer confusion about 
nonprescription drug products with an ACNU because the labeling will 
become familiar to consumers and promote recognition that a 
nonprescription drug product has an ACNU. However, we recognize that in 
certain situations, revisions to the required labeling may be 
appropriate for a drug product due to the specifics of the drug product 
or the ANCU. Therefore, we are revising the requirement to allow FDA to 
approve an NDA applicant's revisions to the labeling specified in 21 
CFR 201.130(a)(1) and (b)(1) in this final rule when the revisions are 
appropriate for a specific drug product and the applicant supports the 
revisions with adequate data or other information that demonstrates 
sufficient consumer understanding of the revised labeling. Because FDA 
believes that consistency in the content of the required labeling is 
important FDA does not intend to approve revisions to the labeling that 
are minor in nature, do not address a specific aspect of the particular 
drug product or ACNU, or are inconsistent with the labeling for similar 
nonprescription drug products with ACNUs in the same therapeutic 
category. For example, if FDA has approved an NDA for Drug X as a 
nonprescription drug product with an ACNU for condition A and in 
therapeutic category B with the ACNU Statement in 21 CFR 
201.130(b)(1)(i), FDA would generally expect to approve an NDA for a 
nonprescription drug product with an ACNU for Drug Y also for condition 
A and in therapeutic category B with the same ACNU Statement as Drug X 
(i.e., the ACNU Statement in 21 CFR 201.130(b)(1)(i) in this final 
rule).
    FDA is also adding flexibility by requiring the location of the 
instructions for the ACNU specified in 21 CFR 201.130(a)(1) in this 
final rule to either appear under the ``Use'' or ``Uses'' heading or 
the ``Directions'' heading, depending on the purpose of the ACNU, to 
better inform consumers of the reason that the ACNU needs to be 
fulfilled (21 CFR 201.130(a)(2) in this final rule).
    To accommodate the revisions, we had to make changes to the 
structure of the regulatory text. We are adding ``(ACNU)'' to the 
header in 21 CFR 201.130 in this final rule. We are deleting the clause 
``in paragraphs (a) and (b) of this section are met'' in the 
introductory text. We are revising 21 CFR 201.130(a) completely in this 
final rule to explain the required instructions for the ACNU. The 
introductory text at 21 CFR 201.130(a) in this final rule now states: 
``The label of the drug must include instructions for the ACNU as 
follows:''. We are also completely revising 21 CFR 201.130(a)(1) 
introductory text in this final rule to read ``Content of instructions 
for the ACNU must either be:'' in order to accommodate revisions that 
the applicant may propose to the instructions for the ACNU. We are also 
moving the language of the instructions for the ACNU from 21 CFR 
201.130(a)(1) as proposed to 21 CFR 201.130(a)(1)(i). Therefore, the 
ACNU instructions in 21 CFR 201.130(a)(1)(i) will read as follows: 
``[T]o 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''. Additionally, we are adding alternative ACNU 
instructions in 21 CFR 201.130(a)(1)(ii) to read ``FDA may approve an 
NDA applicant's revisions to the ACNU Instructions when the revisions 
are appropriate for a specific drug product and the applicant supports 
the revisions with adequate data or other information that demonstrate 
sufficient consumer understanding of the revised statement.'' We are 
deleting the clause in proposed 21 CFR 201.130(a)(1) ``The statement 
must be followed by the other information required in 21 CFR 
201.66(c)(6)'' as it was redundant after the revisions to the final 
rule. We are adding 21 CFR 201.130(a)(2) introductory text for clarity 
and to provide the location of the instructions, which will read ``The 
locations of instructions for the ACNU are as follows:''. We are adding 
flexibility to the placement of the statement by adding 21 CFR 
201.130(a)(2)(i) through (iii) in this final rule (previously proposed 
in 21 CFR 201.130(a)(1)). We are adding 21 CFR 201.130(a)(2)(i), 
stating that if the purpose of the ACNU is for self-selection, the 
instructions for the ACNU must appear under the ``Use'' or ``Uses'' 
heading required in 21 CFR 201.66(c)(4) as the first statement, 
followed by the other information required in 21 CFR 201.66(c)(4). We 
are also adding 21 CFR 201.130(a)(2)(ii) in the final rule, stating 
that if the purpose of the ACNU is for actual use, the instructions for 
the ACNU must appear under the ``Directions'' heading required in 21 
CFR 201.66(c)(6) as the first direction, followed by the other 
information required in 21 CFR 201.66(c)(6), which is consistent with 
the location of the statement on the labeling as proposed. We are 
adding 21 CFR 201.130(a)(2)(iii) in the final rule, stating that if the 
purpose of the ACNU is for both self-selection and actual use, the 
instructions for the ACNU must appear under the ``Use'' or ``Uses'' 
heading as the first statement, followed by the other information 
required in 21 CFR 201.66(c)(4) and may also appear under the 
``Directions'' heading as the first direction, followed by the other 
information required in 21 CFR 201.66(c)(6).
    Additionally to further accommodate the added flexibility, we are 
revising 21 CFR 201.130(b) introductory text in this final rule to 
state that the label of the drug must include a statement about the 
ACNU. We are also adding 21 CFR 201.130(b)(1) to read ``Content of the 
statement about the ACNU must either be:'' We are adding 21 CFR 
201.130(b)(1)(i) to include the language of the statement in proposed 
21 CFR 201.130(a)(2) as follows: ``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''. We are also adding 21 CFR 201.130(b)(1)(ii), stating 
that FDA may approve an NDA applicant's revisions to the ACNU Statement 
when revisions are appropriate for a specific drug product and the 
applicant supports the revisions with adequate data or other 
information that demonstrate sufficient consumer understanding of the 
revised statement. We are adding 21 CFR 201.130(b)(2) in this final 
rule to include information consistent with the format information 
proposed in Sec.  201.130(a)(2) to read as follows: ``The statement 
about the ACNU must be in the form and manner required by Sec.  
201.67(c).'' We are redesignating proposed 21 CFR 201.130(a)(3) to 
Sec.  201.130(c) of this final rule with minor editorial changes to 
revise ``Complies'' to ``The labeling of the drug must comply'' for 
clarity. We are redesignating proposed Sec.  201.130(b) to Sec.  
201.130(d) in this final rule with minor editorial revisions to revise 
``The additional condition for nonprescription use'' to ``ACNU.'' 
Furthermore, we are also making revisions for consistency with 
revisions to 21 CFR 201.67(e) and 314.81(b)(3)(v) in this final rule to 
provide clarity on implementation of an ACNU by revising ``under the 
conditions set forth in the approved application.'' to state that the 
ACNU

[[Page 105322]]

must be implemented by the applicant in accordance with: (1) key 
elements of the ACNU under Sec.  314.56(c)(1)(iv) or (c)(2)(ii) and (2) 
the operationalization of the ACNU under Sec.  314.56(c)(1)(vii) or 
(c)(2)(iii), as approved by FDA in the application.
    (Comment 64) A few comments oppose the placement of the proposed 
statement of instructions for the ACNU specified in proposed 21 CFR 
201.130(a)(1) in the DFL under the ``Directions'' heading because the 
placement of the statement should distinguish between an ACNU that is 
necessary for appropriate self-selection, appropriate actual use, or 
both. For example, one comment recommends that the labeling statement 
should appear under the ``Use'' heading in the DFL to alert consumers 
that they will need to fulfill an ACNU for the listed use(s) rather 
than under the ``Directions'' heading because information under the 
``Directions'' heading is more closely associated with how consumers 
should take a product after the consumer determines whether the 
nonprescription drug product with an ACNU is appropriate for the 
consumer to use.
    (Response 64) We agree with the concerns about the standardized 
placement of the statement in the DFL under the heading ``Directions.'' 
Therefore, FDA is revising the rule to require the labeling statement 
to either appear under the ``Use'' or ``Uses'' heading or the 
``Directions'' heading, depending on the purpose of the ACNU, to better 
inform consumers of the reason that the ACNU needs to be fulfilled. 
Therefore, we are revising the requirement at 21 CFR 201.130(a)(2) in 
this final rule to require that if the purpose of the ACNU is to ensure 
appropriate self-selection, the labeling statement must appear under 
the ``Use'' or ``Uses'' heading as the first statement, followed by the 
other information required in 21 CFR 201.66(c)(4) (21 CFR 
201.130(a)(2)(i) in this final rule); if the purpose of the ACNU is to 
ensure appropriate actual use, the labeling statement must appear under 
the ``Directions'' heading as the first direction, followed by the 
other information required in 21 CFR 201.66(c)(6) (21 CFR 
201.130(a)(2)(ii) in this final rule); or if the ACNU is for both self-
selection and actual use, the statement must appear under the ``Use'' 
or ``Uses'' heading as the first statement, followed by the other 
information required in 21 CFR 201.66(c)(4) and may also appear under 
the ``Directions'' heading as the first direction, followed by the 
other information required in 21 CFR 201.66(c)(6) (21 CFR 
201.130(a)(2)(iii) in this final rule).
    (Comment 65) Several comments support the use of standardized 
statements in proposed 21 CFR 201.130(a)(1) and (2) to communicate the 
presence of an ACNU clearly and prominently for a nonprescription drug 
product to consumers, especially because fulfillment of an ACNU will be 
a completely new behavior for consumers. However, many comments oppose 
the standardized wording of the proposed labeling statement specified 
in proposed 21 CFR 201.130(a)(1) and (2) for being unnecessarily 
specific and restrictive. Many comments suggest the proposed labeling 
statements are too lengthy, not consumer-friendly and should be 
significantly streamlined. Many comments recommend that FDA's proposed 
language should be an example or template to help guide applicants 
during their development programs to allow for flexibility to convey 
specific information about a particular ACNU. A few comments state that 
the proposed wording for the required labeling statement in proposed 21 
CFR 201.130(a)(2) is only appropriate for an ACNU necessary to ensure 
appropriate self-selection, but not an ACNU necessary to ensure 
appropriate actual use. We received one comment providing results of a 
small qualitative research study assessing consumer understanding of 
the proposed labeling statement specified in proposed 21 CFR 
201.130(a)(2); the study suggested poor understanding of the 
statement's intended purpose. A few comments suggest FDA consider 
requiring a validated symbol or simple, universal flag in lieu of the 
proposed ACNU Statement. Several comments recommend that the content of 
the proposed required labeling statement be determined on a product-by-
product basis. For example, a comment recommends that a stronger 
labeling statement be used on nonprescription drug products with ACNUs 
that have the potential for more adverse events.
    (Response 65) FDA believes that consistency in the content of the 
required labeling is important to alert consumers and decrease 
confusion (see discussion above). However, we recognize that in certain 
situations, revisions to the required labeling may be appropriate for a 
drug product to convey specific information for a particular 
nonprescription drug product with an ACNU. Therefore, we are revising 
the requirements at 21 CFR 201.130(a)(1)(ii) and (b)(1)(ii) in this 
final rule to permit FDA to approve an NDA applicant's revisions to the 
required labeling when the revisions are appropriate for a specific 
drug product and the applicant supports the revisions with adequate 
data or other information that demonstrate sufficient consumer 
understanding of the revised statement. For example, the NDA applicant 
would submit adequate data from robust label comprehension studies that 
demonstrate consumers understand the revised labeling statement(s). 
Additionally, while we reviewed the qualitative research study that was 
submitted, the study was small and did not provide usable data with 
which to assess or revise the required labeling.
    (Comment 66) One comment supports the proposed exemption from 
adequate directions for use for nonprescription drug products with an 
ACNU provided the following information is adequately described and 
provided to consumers at the point of purchase: (1) name and 
description of the drug product, (2) dosage form, dosage, route of 
administration, and duration of drug therapy, (3) special directions 
and precautions for preparation, administration, and use by the 
consumer, (4) common severe side effects or adverse effects or 
interactions and therapeutic contraindications that may be encountered, 
(5) techniques for self-monitoring of drug therapy, (6) proper storage, 
and (7) action to be taken in the event of an erroneous dose (e.g., a 
missed dose or a double dose).
    (Response 66) Existing statutory and regulatory requirements ensure 
that the information discussed in the comment would be included on the 
labeling of the nonprescription drug product with an ACNU, if relevant 
for the drug product. Consistent with section 502(c) of the FD&C Act, 
approved labeling for a nonprescription drug product with an ACNU would 
need to be available to consumers under the customary conditions of 
purchase and use of the product. Nonprescription drug products, 
including nonprescription drug products with ACNUs, must comply with 
applicable labeling requirements under part 201, including the format 
and content requirements for the DFL (see 21 CFR 201.66).
    (Comment 67) A few comments discuss the need for exemption from the 
labeling requirements in part 201. One comment recommends that FDA 
amend proposed 21 CFR 201.130(a)(3) by adding the following sentence at 
the end of the paragraph: ``This requirement would not apply when an 
exemption has been granted or approved.'' One comment states that 
because nonprescription drug products may be sold in convenience or 
small pack sizes, there may be limited space for the required statement 
provided at

[[Page 105323]]

proposed 21 CFR 201.130(a)(1). The comment recommends that the rule 
include an exemption for nonprescription drug products with an ACNU 
when the container is too small to bear all of the required 
information, similar to the exemption in 21 CFR 201.10(h)(2)(i) through 
(iv).
    (Response 67) We disagree with revising the rule to provide a 
waiver or an exemption for nonprescription drug products with an ACNU 
from the applicable labeling requirements in part 201. The required 
labeling in 21 CFR 201.130(a)(1) and (b)(1) of this final rule are 
important for consumers to appropriately self-select or appropriately 
use the nonprescription drug product with an ACNU because it informs 
consumers where the additional condition would be found and explains 
the additional condition that the consumer must fulfill. The statement 
about the ACNU also alerts consumers that the drug product is not 
suitable for all individuals and should only be used after fulfilling 
the ACNU. Further, a nonprescription drug product with an ACNU must 
comply with all applicable labeling requirements for nonprescription 
drug products, including the DFL requirements under 21 CFR 201.66.

M. Comment on Misbranding and FDA Response

    We proposed an exemption for a nonprescription drug product with an 
ACNU from the requirement for adequate directions for use in section 
502(f)(1) of the FD&C Act, if the product contains the labeling 
specified in proposed 21 CFR 201.130(a) and the ACNU is implemented by 
the applicant as approved by FDA in the application (see proposed 21 
CFR 201.67(e)). In the following paragraphs, we discuss a comment on 
this proposal. After consideration of the public comment received, as 
discussed below, we are finalizing our proposal with modifications for 
consistency with revisions made elsewhere to the rule. We are revising 
21 CFR 201.67(e)(1) from ``It is made available without the labeling'' 
to ``It does not comply with the labeling requirements'' for clarity. 
We are revising the citation in 21 CFR 201.67(e)(1) from ``Sec.  
201.130(a)'' to ``paragraphs (c) and (d) of this section and Sec.  
201.130(a) through (c)'' for clarity and completeness. We are also 
making revisions to 21 CFR 201.67(e)(2) for clarity and consistency 
with revisions to 21 CFR 201.130(d) and 314.81(b)(3)(v) in this final 
rule by revising ``as approved by FDA in the application'' to state 
that the ACNU is not implemented by the applicant in accordance with 
the following, as approved by FDA in the application: (1) the key 
elements of the ACNU under 21 CFR 314.56(c)(1)(iv) for NDAs or 21 CFR 
314.56(c)(2)(ii) for ANDAs or (2) the operationalization of the ACNU 
under 21 CFR 314.56(c)(1)(vii) for NDAs or 21 CFR 314.56(c)(2)(iii) for 
ANDAs.
    (Comment 68) We received one comment seeking clarity on what it 
means when an ACNU is not implemented by the applicant as approved by 
FDA in the application. The comment questions whether implementation of 
the ACNU means to make the ACNU available, or whether implementation 
includes the steps the pharmacy/seller must take to ensure the ACNU was 
fulfilled.
    (Response 68) We understand the commenter's need for clarity and 
are revising the misbranding provision accordingly. Specifically, we 
are revising 21 CFR 201.67(e)(2) in this final rule, consistent with 
the revisions in 21 CFR 201.130(d) in this final rule, to state that a 
nonprescription drug product with an ACNU is misbranded when the ACNU 
is not implemented by the applicant in accordance with: (1) the key 
elements of the ACNU under 21 CFR 314.56(c)(1)(iv) or (c)(2)(ii) or (2) 
the operationalization of the ACNU under in 21 CFR 314.56(c)(1)(vii) or 
(c)(2)(iii), as approved by FDA in the application.

N. Miscellaneous Comments and FDA Responses

    We received other relevant comments on the proposed rule, but not 
specific to a requirement. In the following paragraphs, we discuss and 
respond to these comments. After considering these comments, we are not 
making any changes as a result of these comments.
    (Comment 69) We received several comments requesting that FDA 
advise applicants on where the specific NDA and ANDA requirements for a 
nonprescription drug product with an ACNU should be included in the 
existing structure of an application (e.g., in which module(s) should 
information be placed).
    (Response 69) Consistent with applications for nonprescription drug 
products, an application for a nonprescription drug product with an 
ACNU must be submitted electronically (see section 745A(a) of the FD&C 
Act) in electronic common technical document (eCTD) format. eCTD is the 
standard format for submitting applications, amendments, supplements, 
and certain reports to FDA's Center for Drug Evaluation and Research 
(CDER) and Center for Biologics Evaluation and Research. Generally, the 
eCTD format consists of five modules. FDA issues guidances related to 
eCTD, which are applicable to nonprescription drug products with ACNUs 
(Ref. 9). We may provide guidance specific for applications for 
nonprescription drug products with ACNUs in the future as appropriate. 
Additionally, an applicant can request to meet with FDA staff to 
discuss questions that arise during the development of a 
nonprescription drug product with an ACNU, including in which module(s) 
specific information should be placed.
    (Comment 70) We received a comment that requests FDA require 
applicants to protect any consumer data that may have been collected 
via an ACNU.
    (Response 70) It is unclear what kinds of data are the focus of the 
comment. Although FDA does not provide guidance on how to comply with 
any legal obligations stemming from a source outside of the statutes 
and regulations that FDA administers, FDA generally expects that 
applicants will comply with applicable statutory and regulatory 
requirements related to protecting consumer information, including 
health information and consumer data (e.g., purchasing history). 
Additionally, FDA has resources on a web page entitled ``Digital Health 
Policy Navigator,'' which includes information on privacy and is 
available on FDA's website at https://www.fda.gov/, which based on our 
understanding of the comment, addresses the commenter's concerns.
    (Comment 71) We received a few comments stating that the proposed 
rule lacks clarity on the criteria that FDA will use to determine when 
a nonprescription drug product with an ACNU is a combination product 
because of the inclusion of a component that is deemed to be a medical 
device. The comments request that FDA issue a companion guidance to 
explain the criteria that will be used to determine whether a 
nonprescription drug product with an ACNU is a combination product. The 
comments also request that FDA confirm that when a nonprescription drug 
product with an ACNU is considered a combination product, CDER will 
continue to be the lead review center if the primary mode of action is 
attributed to the drug component, which aligns with current practices.
    (Response 71) In some cases, a nonprescription drug product with an 
ACNU may be comprised of a drug constituent part and a device 
constituent part (see Sec.  3.2(e)) and, therefore, be subject to 
regulatory requirements applicable to combination

[[Page 105324]]

products (see, e.g., part 4). FDA would continue to follow existing 
regulatory requirements to determine whether a nonprescription drug 
product with an ACNU is a drug or a combination product. Under 21 CFR 
3.4, the center that leads the premarket review and regulation of a 
combination product is determined by the product's primary mode of 
action (i.e., the single mode of action of a combination product that 
provides the most important therapeutic action). Because FDA expects 
that nonprescription drug products with an ACNU that are combination 
products generally will have a drug primary mode of action, FDA expects 
CDER would be the lead center for the review. We encourage applicants 
to utilize FDA resources on combination products (Ref. 10). We also 
encourage applicants to engage with FDA during the drug development 
process for a nonprescription drug product with an ACNU, including 
regarding questions about how their product is classified.
    (Comment 72) FDA received a comment that the proposed rule does not 
discuss whether an NDA for a nonprescription drug product with an ACNU 
would be eligible for 3-year, new clinical investigation exclusivity, 
or whether an ANDA for a nonprescription drug product with an ACNU and 
containing a paragraph IV certification could give rise to 180-day 
exclusivity even if the RLD was originally approved as a prescription 
drug product. The comment requests that FDA address these issues in the 
final rule.
    (Response 72) FDA declines to address these exclusivity comments in 
the final rule, as this rulemaking does not propose any changes or 
considerations regarding exclusivity. An NDA or ANDA holder, including 
an NDA or ANDA holder for a nonprescription drug product with an ACNU, 
is eligible for exclusivity if applicable statutory requirements are 
met (see, e.g., section 505(c)(3)(E)(iii), (j)(5)(B)(iv), and 
(j)(5)(F)(iii) of the FD&C Act) (see also 21 CFR 314.108). As explained 
in our response to Comment 36, FDA proposed significant flexibility in 
the types of ACNUs that may be developed, as well as how those ACNUs 
may be operationalized. Given this flexibility, and that eligibility 
for statutory exclusivity (such as, 3-year new clinical investigation 
exclusivity for an NDA) depends on the facts of each application, FDA 
is unable to predict potential eligibility for statutory exclusivity 
for nonprescription drug products with an ACNU across the board.
    (Comment 73) We received a comment stating that the proposed rule 
does not mention whether FDA or the Federal Trade Commission (FTC) will 
oversee the advertisement of nonprescription drug products with ACNUs.
    (Response 73) Consistent with the memorandum of understanding 
between FTC and FDA, FTC has primary responsibility with respect to the 
regulation of the truth or falsity of all advertising of 
nonprescription drug products, which would include nonprescription drug 
products with ACNUs (Ref. 11). FDA has primary responsibility with 
respect to regulating the labeling of nonprescription drug products.
    (Comment 74) We received a comment that strongly encourages FDA to 
implement educational campaigns geared toward consumers, retailers, and 
healthcare professionals to explain the differences between 
prescription drug products, nonprescription drug products, and 
nonprescription drug products with ACNUs. The comment further states 
that members of the Nonprescription Drugs Advisory Committee will also 
need training about how they should evaluate applications that propose 
an ACNU.
    (Response 74) We will provide robust communication to inform the 
public about the final rule. We will have specific communications 
tailored to interested parties, including consumers, retailer, and 
healthcare providers. We will also have specific communication and 
educational information for members of FDA advisory committees, should 
an advisory committee be necessary for a specific application for a 
nonprescription drug product with an ACNU. FDA will especially focus 
communication and education for consumers both about the final rule and 
in the future should FDA approve a nonprescription drug product with an 
ACNU.
    (Comment 75) We received a comment requesting that FDA create a 
public registry of all approved nonprescription drug products with 
ACNUs, including all data and information about the ACNU and the 
purpose of the ACNU.
    (Response 75) FDA agrees with including approved nonprescription 
drug products with an ACNU, including relevant information about the 
approval, in a database. FDA has an existing public database of 
approved drug products entitled ``Drugs@FDA'' available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. FDA issues approval 
letters that are publicly available for all drug product approvals. 
Consistent with FDA approval for all drug products, upon approval of a 
nonprescription drug product with an ACNU, FDA will issue an approval 
letter for a nonprescription drug product with an ACNU that includes, 
among other things, a statement that the drug product requires an ACNU 
and the key elements of the ACNU. Information about the approved 
nonprescription drug product with an ACNU will also be available in 
FDA's database of approved drug products at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Additionally, FDA 
communicates certain nonprescription drug product approvals on our 
website (see Ref. 12), and we intend to consider a similar process to 
communicate approvals of nonprescription drug products with an ACNU.
    (Comment 76) We received a comment requesting that FDA either 
clarify how it will enforce the requirement that a nonprescription drug 
product with an ACNU not be made available to consumers unless the ACNU 
is fulfilled, or require the applicant to submit procedures to ensure 
that requirement is met.
    (Response 76) The burden is on the applicant to implement the ACNU 
as approved by FDA in the application and to ensure that the drug 
product is not made available to consumers unless the ACNU is 
fulfilled. A nonprescription drug product with an ACNU that is made 
available to a consumer without the ACNU being fulfilled by the 
consumer would be misbranded (21 CFR 201.67(e) in this final rule). 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 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 with an ACNU would be an 
unapproved new drug product if it is made available to consumers 
without an 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 into interstate commerce an unapproved new drug 
(87 FR 38313 at 38325). FDA may pursue enforcement action against 
applicants who violate the FD&C Act.
    (Comment 77) We received a few comments requesting further 
clarification of certain topics (e.g., submission requirements and 
labeling) through guidance documents. We also received a comment 
requesting that FDA provide clear and timely input on

[[Page 105325]]

the development program for a nonprescription drug product with an ACNU 
throughout the development process.
    (Response 77) We encourage applicants to read existing applicable 
FDA guidance documents by searching for relevant topics on our website 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. For example, search ``nonprescription'' to find 
relevant guidances on labeling specific for nonprescription drug 
products. Additionally, FDA may consider issuing guidance in the future 
to address general considerations that may arise and are applicable to 
all applicants developing nonprescription drug products with an ACNU. 
We encourage applicants to meet with FDA to discuss their drug 
development plans and seek advice.
    (Comment 78) We received a comment encouraging FDA to explain how 
it intends to address any application proposing an ACNU for a 
nonprescription drug product that was submitted for approval before the 
proposed rule is finalized.
    (Response 78) Once the rule is in effect, FDA may approve 
applications for nonprescription drug products that meet the relevant 
standard, regardless of whether such applications were submitted before 
or after the rule was in effect.

VI. Effective Date

    This rule is effective January 27, 2025.

VII. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, Executive Order 14094, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), the Congressional Review 
Act/Small Business Regulatory Enforcement Fairness Act (5 U.S.C. 801, 
Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4).
    Executive Orders 12866, 13563, and 14094 direct us to assess all 
benefits, costs, and transfers 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). Rules are ``significant'' under Executive Order 12866, 
section 3(f)(1) (as amended by Executive Order 14094) if they ``have an 
annual effect on the economy of $200 million or more (adjusted every 3 
years by the Administrator of [the Office of Information and Regulatory 
Affairs (OIRA)] for changes in gross domestic product); or adversely 
affect in a material way the economy, a sector of the economy, 
productivity, competition, jobs, the environment, public health or 
safety, or State, local, territorial, or tribal governments or 
communities.'' OIRA has determined that this final rule is not a 
significant regulatory action under Executive Order 12866, section 
3(f)(1).
    Because this rule is not likely to result in an annual effect on 
the economy of $100 million or more or meets other criteria specified 
in the Congressional Review Act/Small Business Regulatory Enforcement 
Fairness Act, OIRA has determined that this rule does not fall within 
the scope of 5 U.S.C. 804(2).
    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 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 0.12 percent of the gross receipts of 
very small applicants. Therefore, we certify that the final rule will 
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 estimates of 
anticipated impacts, before issuing ``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 $183 
million, using the most current (2023) Implicit Price Deflator for the 
Gross Domestic Product. This final rule will not result in an 
expenditure in any year that meets or exceeds this amount.

B. Summary of Benefits, Costs, and Transfers

    The final rule will establish requirements for a nonprescription 
drug product with an ACNU. Compared to traditional nonprescription drug 
products, which consumers must be able to self-select and use based on 
labeling, alone, an approved ACNU, in addition to the labeling, will 
ensure the appropriate self-selection, the appropriate use, or both of 
a nonprescription drug product without the supervision of a 
practitioner licensed by law to administer such drug. We expect this 
rule will expand consumer access to certain drug products in a 
nonprescription setting and increase options for applicants to develop 
and market safe and effective nonprescription drug products.
    Table 1 shows our quantified benefits. We estimate a reduction in 
access costs to consumers who could transfer from a prescription drug 
product to a nonprescription drug product with an ACNU. Our primary 
estimate for this item is $33.62 per consumer per purchase with a range 
of $0 to $67.23. We also quantify the value of the potential reduction 
in the number of repetitive meetings with applicants that will occur 
during the approval process. For example, potential applicants have 
requested additional meetings with us for each development program to 
discuss this topic; these types of individual meetings are time-
consuming and use Agency resources. Multiple potential applicants have 
been asking the same types of questions, creating repetitiveness and 
inefficiencies. Because the rule addresses these and other questions, 
we anticipate that the rule will reduce or eliminate this burden for 
potential applicants and us. Our primary estimate is $68,773.11 per 
applicant with a range of $56,332.65 to $81,763.56. 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, and purchases that might occur; and consumer preferences to 
switch products. However, we present estimates in the uncertainty 
section of this analysis.
    Although an applicant will incur the costs to develop and apply for 
a nonprescription drug product with an ACNU, for this analysis, we 
assume that applicants submit applications only when they believe that 
the profits from the approval will exceed the costs of the application. 
We lack information to monetize these potential profits and costs over 
a 10-year horizon.
    Monetized costs include a one-time cost of reading and 
understanding the rule for those potentially interested in pursuing 
this path for their drug products. We do not monetize these estimates 
for more than one interested party because of the high uncertainty 
about the number of interested parties over this time horizon. The 
primary estimate equals $1,156.74 with a range of $533.88 to $1,779.60.

[[Page 105326]]

    Government-sponsored and commercial insurance payers may experience 
cost savings because the availability of nonprescription drug products 
with an ACNU may decrease insurance claims and, potentially, future 
medical costs. For example, access to drug products under this new 
paradigm will allow consumers to treat medical conditions using 
nonprescription drug products with ACNUs without the supervision of a 
practitioner licensed by law to administer such drug. We do not 
estimate such cost savings due to lack of data.

                                    Table 1--Summary of Benefits, Costs, and Distributional Effects of the Final Rule
                                                                 [Millions 2023 dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                           Units
                                          Primary       Low        High    ------------------------------------
               Category                  estimate    estimate    estimate      Year      Discount     Period                      Notes
                                                                              dollars    rate (%)     covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized ($millions/
     year)
    Annualized Quantified.............  ..........  ..........  ..........        2023  ..........  ..........  Quantified reduction in access costs per
                                                                                                                 consumer purchase range from $0.0 to
                                                                                                                 $67.23, and a primary estimate of
                                                                                                                 $33.62.
                                                                                  2023  ..........  ..........  Quantified reduction in meetings between
                                                                                                                 FDA and applicants range from
                                                                                                                 $56,332.65 to $81,763.56 per applicant,
                                                                                                                 and a primary estimate of $68,773.11.
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized........................        $0.0        $0.0        $0.0        2023           7    10 years  The reading and understanding one-time
                                                                                                                 costs primary estimate is $1,156.74 and
                                                                                                                 ranges from $533.88 to $1,779.60 per
                                                                                                                 interested party.
    Monetized ($millions/year)........        $0.0        $0.0        $0.0        2023           3    10 years
    Annualized
    Quantified
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Qualitative.......................  Interested firms will incur costs to develop and submit applications
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal...........................  ..........  ..........  ..........  ..........           7
    Annualized Monetized ($millions/    ..........  ..........  ..........  ..........           3
     year).
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
                                       -----------------------------------------------------------------------------------------------------------------
    Other.............................  ..........  ..........  ..........  ..........           7
    Annualized Monetized ($millions/    ..........  ..........  ..........  ..........           3
     year).
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:                                  Potential
                                                                                  cost
                                                                            savings to
                                                                            government
                                                                                   and
                                                                            commercial
                                                                              insurers
                                                                                    if
                                                                              coverage
                                                                               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 range from 0.04 percent to 0.12 percent of gross receipts.
    Wages: No estimated effect.
    Growth: No estimated effect.
--------------------------------------------------------------------------------------------------------------------------------------------------------

    We have developed a Final Economic Analysis of Impacts that 
assesses the impacts of the final rule. The full analysis of economic 
impacts is available in the docket for this final rule (Ref. 13) and at 
https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.

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 final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The title, 
description, and respondent description of the information collection 
provisions are shown in the following paragraphs with an estimate of 
the annual reporting and recordkeeping 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.
    Title: Premarket applications, postmarketing reports and

[[Page 105327]]

recordkeeping, and labeling for Nonprescription Drug Products With an 
Additional Condition for Nonprescription Use--OMB Control Numbers 0910-
0001 and 0910-0340--Revision.
    Description: The final 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 product with an ACNU; (2) for ACNU failure 
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.
    In the proposed rule, we sought comments on this analysis. We did 
not receive any comments that were specific to our numeric hour burden 
estimates. However, we received numerous comments on the provisions of 
the proposed rule having to do with proposed requirements for 
applications, postmarketing reports, and labeling. This final rule 
contains comment summaries and responses for these comments in section 
V. E and F, and I through M. Additionally, we received comments that 
the preliminary regulatory impact analysis does not adequately account 
for the costs of quality assurance systems or implementing the 
reporting requirements. We understand concerns about the potential 
costs of establishing and maintaining quality assurance systems. 
However, due to the uncertainty about the nature of ACNU failures that 
could occur, the likelihood, the number, and the cost, any estimate 
would be characterized by a substantial degree of uncertainty.
    FDA estimates the burden of existing information collection 0910-
0001 will be increased by the information collections in this rule this 
information collection as follows:

NDA and ANDA Submissions

               Table 2--Estimated Annual Reporting Burden Increase; OMB Control No. 0910-0001 \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
    Activity; 21 CFR part 314        Number of     responses per   Total annual    per response     Total Hours
                                    respondents     respondent       responses        (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 an ACNU
 failure; Sec.   314.81.........
    Total.......................  ..............  ..............             156  ..............           7,920
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating or maintenance costs associated with the information collection.

    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. 
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 drug products 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). The 320 hours would include scientific studies and 
experimentation such as developing new technology to aid consumers in 
self-selection, advancing statistical methods for analyzing complex 
data, developing innovative clinical trial designs, or research on new 
drug delivery systems for both NDA and ANDA applications.

Reports of ACNU Failure

    We estimate six respondents will submit 25 reports each to FDA for 
an individual ACNU failure 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.

                  Table 3--Estimated Annual Recordkeeping Burden; OMB Control No. 0910-0001 \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
    Activity; 21 CFR part 314        Number of     responses per   Total annual    per response     Total hours
                                    respondents     respondent       responses        (hours)
----------------------------------------------------------------------------------------------------------------
Requirements for reports of ACNU               6              25             150               8           1,200
 failure for a nonprescription
 drug product with an ACNU (Sec.
   314.81(b)(3)(v)(D))..........
----------------------------------------------------------------------------------------------------------------
\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.
    FDA estimates the burden of existing information collection 0910-
0340 will be increased by the information collections in this rule, as 
follows:

Labeling for Nonprescription Drugs with an ACNU

[[Page 105328]]



      Table 4--Third-Party Disclosure Burden; Third-Party Disclosure Burden; OMB Control No. 0910-0340 \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
   Activity; 21 CFR part 201,        Number of     responses per   Total annual   Average burden    Total hours
            subpart C               respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
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) and (2)..........
ACNU Statement; (Sec.   201.67).               6               1               6               9              54
----------------------------------------------------------------------------------------------------------------
    Total.......................  ..............  ..............              12  ..............             144
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    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, including 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), and 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 required by Sec.  
201.130(a)(1) and (2). These products may also have additional labeling 
beyond the DFL requirements (Sec.  201.67(c)(2)).
    Estimating six respondents will expend 1 hour annually to comply 
with PDP and DFL labeling requirements under Sec.  201.67(c)(1), and 
assuming each disclosure will require 15 hours, we calculate a total of 
90 hours annually. Additionally, we estimate six respondents will each 
submit one application for a nonprescription drug product 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.
    The information collection provisions in this final rule have been 
submitted to OMB for review as required by section 3507(d) of the 
Paperwork Reduction Act of 1995.
    Before the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. We have determined that the 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 rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects 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. Accordingly, we 
conclude that the rule does not contain policies that have Tribal 
implications as defined in the Executive order and, consequently, a 
Tribal summary impact statement is not required.

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 are also 
available electronically at https://www.regulations.gov/. Although FDA 
verified the website addresses in this document, please note that 
websites are subject to change over time.

    1. FDA, Guidance for Industry, ``Label Comprehension Studies for 
Nonprescription Drug Products,'' August 2010 (available at https://www.fda.gov/media/75626/download).
    2. FDA, Guidance for Industry, ``Self-Selection Studies for 
Nonprescription Drug Products,'' April 2013 (available at https://www.fda.gov/media/81141/download).
    3. FDA, Guidance for Industry, ``Application of Human Factors 
Engineering Principles for Combination Products: Questions and 
Answers,'' September 2023 (available at https://www.fda.gov/media/171855/download).
    4. FDA, Guidance for Industry and FDA Staff, ``Policy for Device 
Software Functions and Mobile Medical Applications,'' September 2013 
(updated September 2019 and September 2022) (available at https://www.fda.gov/media/80958/download).
    5. FDA, Medwatch: The FDA Safety Information and Adverse Event 
Reporting Program, (available at https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program). Accessed November 27, 2023.
    6. FDA, Consumer Complaint Coordinators, web page, (available at 
https://www.fda.gov/safety/report-problem-fda/consumer-complaint-coordinators). Accessed November 27, 2023.
    7. National Patient Safety Agency, ``Information Design for 
Patient Safety: A Guide to the Graphic Design of Medication 
Packaging,'' 2nd edition, 2007 (available at https://webarchive.nationalarchives.gov.uk/ukgwa/20080727044055mp_/https://www.npsa.nhs.uk/EasySiteWeb/GatewayLink.aspx?alId=5599); National 
Patient Safety Agency, ``Design for Patient Safety: A Guide to 
Labelling and Packaging of Injectable Medicines,'' 1st edition, 2008 
(available at https://www.intmedsafe.net/wp-content/uploads/2014/01/0592_InjectablesBookV9_Web1.pdf).
    8. United States Pharmacopeia, Recommendations to the Safe 
Medication Use Expert Committee by the Health Literacy and 
Prescription Container Labeling Advisory Panel, May and November 
2009, posted April 2010 (available at https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/recommendContainerLabeling.pdf).
    9. FDA, eCTD Resources, web page (available at https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-resources). Accessed November 27, 2023.

[[Page 105329]]

    10. FDA, Combination Products, web page (available at https://www.fda.gov/combination-products). November 27, 2023.
    11. Memorandum of Understanding Between the Federal Trade 
Commission and the Food and Drug Administration Concerning the 
Exchange of Information (FDA-225-71-8003), April 1971 (available at 
https://www.fda.gov/about-fda/domestic-mous/mou-225-71-8003). 
Accessed November 27, 2023.
    12. FDA, Prescription to Over-the-Counter (OTC) Switch List, web 
page (available at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/prescription-over-counter-otc-switch-list). Accessed November 27, 2023.
    13. FDA, Final Regulatory Impact Analysis; Final Regulatory 
Flexibility Analysis; Unfunded Mandates Reform Act Analysis, 
Nonprescription Drug Product With an Additional Condition for 
Nonprescription Use; Final Rule (available at https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria).

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, 21 CFR 
parts 201 and 314 are 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 practitioner licensed by law 
to administer such drug, 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) and 
(b).
    (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 the required statement about the ACNU. 
The statement about the ACNU specified in Sec.  201.130(b)(1) must meet 
all format requirements as follows:
    (1) The statement about the ACNU 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 
about the ACNU 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 about the ACNU 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 about 
the ACNU does not need to be included on each blister unit of a blister 
card. However, the statement about the ACNU must remain intact and be 
readable on the blister card when the drug product is removed from each 
blister unit.
    (2) The statement about the ACNU must appear in boldface and black 
type.
    (3) The statement about the ACNU must appear in a yellow background 
banner. No other information or statements may be included within the 
yellow background banner.
    (4) The statement about the ACNU 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 does not comply with the labeling requirements specified in 
paragraphs (c) and (d) of this section and Sec.  201.130(a) through 
(c); or
    (2) The ACNU is not implemented by the applicant in accordance with 
the following, as approved by FDA in the application:
    (i) The key elements of the ACNU under Sec.  314.56(c)(1)(iv) of 
this chapter for NDAs or Sec.  314.56(c)(2)(ii) of this chapter for 
ANDAs; or
    (ii) The operationalization of the ACNU under Sec.  
314.56(c)(1)(vii) of this chapter for NDAs or Sec.  314.56(c)(2)(iii) 
of this chapter for ANDAs.

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 (ACNU).

    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)(1) is exempt from section 502(f)(1) only if 
all the following conditions are met:
    (a) The label of the drug must include instructions for the ACNU as 
follows:
    (1) Content of instructions for the ACNU must either be:
    (i) ACNU Instructions, which read as follows: ``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''; or
    (ii) Alternative ACNU Instructions: FDA may approve an NDA 
applicant's revisions to the ACNU Instructions when the revisions are 
appropriate for a specific drug product and the applicant supports the 
revisions with adequate data or other information that

[[Page 105330]]

demonstrate sufficient consumer understanding of the revised statement.
    (2) The locations of instructions for the ACNU are as follows:
    (i) If the purpose of the ACNU is for self-selection, the 
instructions for the ACNU must appear under the ``Use'' or ``Uses'' 
heading required in Sec.  201.66(c)(4) as the first statement, followed 
by the other information required in Sec.  201.66(c)(4);
    (ii) If the purpose of the ACNU is for actual use, the instructions 
for the ACNU must appear under the ``Directions'' heading required in 
Sec.  201.66(c)(6) as the first direction, followed by the other 
information required in Sec.  201.66(c)(6); or
    (iii) If the purpose of the ACNU is for both self-selection and 
actual use, the instructions for the ACNU must appear under the ``Use'' 
or ``Uses'' heading as the first statement, followed by the other 
information required in Sec.  201.66(c)(4) and may also appear under 
the ``Directions'' heading as the first direction, followed by the 
other information required in Sec.  201.66(c)(6).
    (b) The label of the drug must include a statement about the ACNU 
as follows:
    (1) The content of the statement about the ACNU must either be:
    (i) The ACNU Statement, which reads as follows: ``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''; or
    (ii) An Alternative ACNU Statement: FDA may approve an NDA 
applicant's revisions to the ACNU Statement when the revisions are 
appropriate for a specific drug product and the applicant supports the 
revisions with adequate data or other information that demonstrate 
sufficient consumer understanding of the revised statement.
    (2) The statement about the ACNU must be in the form and manner 
required by Sec.  201.67(c).
    (c) The labeling of the drug must comply 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.
    (d) The ACNU must be implemented by the applicant in accordance 
with the following, as approved by FDA in the application:
    (1) The key elements of the ACNU under Sec.  314.56(c)(1)(iv) of 
this chapter for NDAs or Sec.  314.56(c)(2)(ii) of this chapter for 
ANDAs; and
    (2) The operationalization of the ACNU under Sec.  
314.56(c)(1)(vii) of this chapter for NDAs or Sec.  314.56(c)(2)(iii) 
of this chapter for ANDAs.

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 practitioner licensed by law 
to administer such drug 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. Notwithstanding Sec.  310.200(b) of this chapter, 
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 whether the purpose of the ACNU is to 
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 practitioner licensed by law to administer such 
drug;
    (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(s) 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 include:
    (i) A statement regarding whether the purpose of the ACNU is to 
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 practitioner licensed by law to administer such 
drug, which must be the same as the purpose of the ACNU for its 
reference listed drug (RLD);
    (ii) Information demonstrating that the key elements of the ACNU 
are the same as the key elements of the ACNU for its RLD; and
    (iii) A description of the specific way(s) the ACNU is 
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 drug 
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

[[Page 105331]]

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 such 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 an additional condition for nonprescription use 
(ACNU) failure for a nonprescription drug product with an ACNU--(A) 
ACNU failure. An ACNU failure occurs upon either of the following 
events:
    (1) A failure associated with the implementation of a key element 
of an ACNU under Sec.  314.56(c)(1)(iv) or (c)(2)(ii); or
    (2) A failure associated with the operationalization of an ACNU 
under Sec.  314.56(c)(1)(vii) or (c)(2)(iii).
    (B) Review of ACNU failure. The applicant must develop written 
procedures for the surveillance, receipt, evaluation, and reporting of 
ACNU failures to FDA.
    (C) Report of ACNU failure. If an applicant receives or otherwise 
obtains information regarding an adverse drug experience associated 
with an ACNU failure before the submission of a report of an ACNU 
failure, an applicant must submit a report in the form of an individual 
case safety report (ICSR) that describes both the adverse drug 
experience and the associated ACNU failure. The ICSR must contain the 
information required in Sec.  314.80(f) and paragraph (b)(3)(v)(A) of 
this section. If a previously submitted report of ACNU failure reports 
only an ACNU failure or if a previously submitted ICSR reports only an 
adverse drug experience, and the applicant subsequently receives or 
otherwise obtains information regarding an associated adverse drug 
experience or associated ACNU failure, the applicant must submit a 
follow up report to the previously submitted report with the new 
information. The follow-up report must include the information required 
in Sec.  314.80(f) or paragraph (b)(3)(v)(A) of this section, as 
applicable.
    (D) Content of Report of ACNU failure. The report of an ACNU 
failure must include the following:
    (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 ACNU failure.
    (2) Additional information if available to the applicant. 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 follow-up report(s), if 
applicable.
    (iv) ACNU failure term(s).
    (v) Date of ACNU failure (or best estimate).
    (vi) Date the ACNU failure was reported to the applicant.
    (vii) Location of the ACNU failure, including business name and 
contact information.
    (viii) Concise narrative summary of the ACNU failure including 
whether any of the following circumstances occurred: the consumer 
accessed or used the drug product without successfully fulfilling the 
ACNU; the consumer successfully fulfilled the ACNU but could not access 
or use the drug product; or the consumer was unable to make an attempt 
to fulfill the ACNU.
    (ix) Description of the remedial action initiated or completed to 
address the ACNU failure, including the type of remedial action 
initiated or completed (for example, repair, replace, recall, 
inspection, modification, or adjustment).
    (x) Description of the corrective action to prevent reoccurrence of 
an ACNU failure of the same nature.
    (E) Submission. (1) The applicant must submit the report of an ACNU 
failure as soon as possible but no later than 15 calendar days from the 
date when the applicant has acquired the minimum dataset for an ACNU 
failure.
    (2) The applicant must also investigate any new information it 
receives or otherwise obtains about a previously submitted report of an 
ACNU failure and assess the relationship or impact of the new 
information on the initial report. The applicant must submit any 
follow-up report of an ACNU failure as soon as possible but no later 
than 15 calendar days after obtaining the new information.
    (F) Electronic format for submissions. (1) The report of an ACNU 
failure must be submitted to FDA in accordance with Sec.  314.80(g).
    (2) An applicant may request, in writing, a waiver of the 
requirements in paragraph (b)(3)(v)(F)(1) of this section in accordance 
with Sec.  314.90 or Sec.  314.99.
    (G) Recordkeeping. The applicant must maintain for a period of 10 
years, the records of all reports of ACNU failures and associated 
adverse drug experiences known to the applicant, including raw data and 
any correspondence relating to a report of an ACNU failure.
* * * * *

0
7. Amend Sec.  314.125 by adding paragraph (b)(20) to read as follows:


Sec.  314.125  Refusal to approve an NDA.

* * * * *
    (b) * * *
    (20) For an NDA for a nonprescription drug product with an 
additional condition for nonprescription use under Sec.  314.56, if FDA 
has determined the application failed to meet the requirements in Sec.  
314.56 applicable to NDAs.
* * * * *

0
8. Amend Sec.  314.127 by adding paragraph (a)(15) to read as follows:


Sec.  314.127  Refusal to approve an ANDA.

    (a) * * *
    (15) For an ANDA for a nonprescription drug product with an 
additional condition for nonprescription use under Sec.  314.56, if FDA 
has determined the application failed to meet the requirements in Sec.  
314.56 applicable to ANDAs.
* * * * *

    Dated: December 13, 2024.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2024-30261 Filed 12-23-24; 8:45 am]
BILLING CODE 4164-01-P