105288 Federal Register / Vol. 89, No. 247 / Thursday, December 26, 2024 / Rules and Regulations 

1While 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)). 

2FDA has used the terms ‘‘meaningful 

difference’’ and ‘‘clinically meaningful difference’’ 

interchangeably. Both refer to the same scientific 

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. 

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 selfselection 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, PRAStaff@fda.hhs.gov. 

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. 

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


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determination. See, e.g., 83 FR 13994 (April 2, 

2018) and 87 FR 68702 (November 16, 2022). 

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. 

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 copay 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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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 overthe-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 prescriptiononly 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 selfselection 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/aboutfda/reports-manuals-forms/staffmanual-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 


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3https://www.merriam-webster.com/dictionary/ 

collateral. 

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. 

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 diseasespecific 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-thecounter’’ 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 selfselection 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 

§ 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 pharmacypatient 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 selfselection 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 

§ 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 ‘‘selfselection’’ 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 selfselection or appropriate actual use, or 

both (see, e.g., § 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 § 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 § 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 


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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 ‘‘longaccepted 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 § 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 § 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 ACNUrelated 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 crossreference 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 


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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 

§§ 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 

§§ 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 §§ 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 

(§ 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 

§ 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 selfselection or appropriate actual use, or 

both, by consumers of the 

nonprescription drug product (proposed 

§ 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 selfselection 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 selfselection 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 


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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 selfselection 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 


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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 selfselect 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 selfselection 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 consumerfriendly 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. 


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(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 selfselection 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 lowliteracy 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 selfselection 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 selfselection questionnaire) upon the first 

time purchasing the nonprescription 

drug product with an ACNU and at a 


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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 longterm 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 selfselection). 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 webbased 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 


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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 

§ 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 FDAapproved 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 selfselection 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 

§§ 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 


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4We 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. 

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 selfselection 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 ‘‘technologyneutral.’’ Thus, as stated above, since 

our review is inherently applicationspecific, and because we are specifically 

reviewing and approving how the 

ACNU is operationalized to ensure that 

the ACNU achieves appropriate selfselection, 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 § 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 § 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.’’ 

(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. 


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5We 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. 

(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 

§ 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 §§ 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 § 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 

§ 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 §§ 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 § 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 


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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. 

(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 

§ 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 §§ 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-bycase 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 § 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 


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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 (§ 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 followon 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 


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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 


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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 


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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 


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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 selfdirected 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, 


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calculates the risk score for a serious 

side effect and determines if the 

consumer has an acceptable diseasespecific 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-tononprescription 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 selfselection 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 selfselection 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 


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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 


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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 

(§ 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 (§ 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 FDAregulated 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 


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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 

§§ 201.57 and 201.66 (21 CFR 201.57 

and 201.66), respectively). Labeling for 

nonprescription drug products is 

directed to consumers (see § 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 § 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 § 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 § 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 § 314.81(b)(3)(v) of this final rule. 

We are designating 

§ 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 


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6See 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). 

postmarketing reporting requirements 

for adverse drug experiences (see 

§ 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 § 314.81(b)(3)(v) 

of this final rule and a postmarketing 

report of an adverse drug experience, 

which would be submitted under 

§ 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 

§ 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 

§ 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 § 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 § 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, § 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 

§ 314.81(b)(3)(v) in this final rule to 

align with the terminology used for 

postmarketing reporting requirements 

for adverse drug experiences in 

§ 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., § 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 

§ 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 § 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 § 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. 

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 


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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 diseasespecific 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 § 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 

§ 314.80. In order to clarify that only 

reports of ACNU failures are required to 

be submitted in a postmarketing report 

under § 314.81 and because 

postmarketing reports of adverse 

experiences are currently required 

under § 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 § 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) 

(§ 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 


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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 § 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 (§ 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 (§ 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 § 314.81 because the 

requirement is consistent with the 

timeframe for the submission of certain 

postmarketing reports of adverse drug 

experiences under § 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 FDAapproved 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, 


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which do not specifically refer to a 

current FDA database for submissions 

(see, e.g., § 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 

§ 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 (§ 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 

(§ 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 

§ 314.81). As mentioned earlier, to 

address confusion and be consistent 

with the existing postmarketing 

reporting requirements for adverse drug 

experiences (see § 314.80) and cognizant 

of minimizing burden we are adding 

§ 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 § 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 

§ 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 FDAregulated 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 § 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 

§ 201.130 in this final rule. Specifically, 

we are revising the citation in 21 CFR 

201.67(c) of the final rule from 

‘‘§ 201.130(a)’’ to ‘‘§ 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 quickresponse 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, 


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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 

§ 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 

§ 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 §§ 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 § 201.67(d) for 

clarity. We proposed that the statement 

specified in § 201.130(a)(2) must meet 

all format requirements that are 

specified in § 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 


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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-byproduct 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 onequarter 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 § 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 (§ 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 


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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 selfselection, 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 selfselection 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 

§ 201.130(a)(2) to read as follows: ‘‘The 

statement about the ACNU must be in 

the form and manner required by 

§ 201.67(c).’’ We are redesignating 

proposed 21 CFR 201.130(a)(3) to 

§ 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 § 201.130(b) to 

§ 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 


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must be implemented by the applicant 

in accordance with: (1) key elements of 

the ACNU under § 314.56(c)(1)(iv) or 

(c)(2)(ii) and (2) the operationalization 

of the ACNU under § 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 


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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 ‘‘§ 201.130(a)’’ to 

‘‘paragraphs (c) and (d) of this section 

and § 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 § 3.2(e)) and, 

therefore, be subject to regulatory 

requirements applicable to combination 


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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 


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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-fdaguidance-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. 


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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] 

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(%) 

Period 

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/year) ................ .................. .................. .................. .................. 3 

From/To ............................................................... From: To: 

Other .................................................................... .................. .................. .................. .................. 7 

Annualized Monetized ($millions/year) ................ .................. .................. .................. .................. 3 

From/To ............................................................... From: To: Potential cost savings to 

government and commercial insurers if coverage 

cost of medications 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/regulatoryimpact-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 


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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

Activity; 21 CFR part 314 Number of 

respondents 

Number of 

responses 

per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

(hours) 

Total Hours 

Submission of separate application for nonprescription 

drug product with an ACNU (§ 314.56(b) and (c)) ........... 6 1 6 320 1,920 

Other postmarketing reports; submission of each individual 

consumer affected by an ACNU failure; § 314.81 ........... 6 25 150 40 6,000 

Total .............................................................................. ........................ ........................ 156 ........................ 7,920 

1There 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 §§ 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 

§ 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

Activity; 21 CFR part 314 Number of 

respondents 

Number of 

responses 

per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

(hours) 

Total hours 

Requirements for reports of ACNU failure for a nonprescription drug product with an ACNU 

(§ 314.81(b)(3)(v)(D)) ........................................................ 6 25 150 8 1,200 

1There 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 


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TABLE 4—THIRD-PARTY DISCLOSURE BURDEN; THIRD-PARTY DISCLOSURE BURDEN; OMB CONTROL NO. 0910–0340 1

Activity; 21 CFR part 201, subpart C Number of 

respondents 

Number of 

responses 

per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total hours 

Disclosure of information on the principal display panel or 

within Drug Facts Labeling; § 201.66 (including) statements specified in § 201.130(a)(1) and (2) ...................... 6 1 6 15 90 

ACNU Statement; (§ 201.67) ............................................... 6 1 6 9 54 

Total .............................................................................. ........................ ........................ 12 ........................ 144 

1There 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 

(§§ 201.61 and 201.62) which appear on 

the principal display panel (PDP) 

(defined by § 201.60), and the Drug 

Facts labeling (DFL) requirements of 

§ 201.66, as part of which the 

respondents must also include (where 

applicable) labeling to satisfy sodium, 

calcium, magnesium, and potassium 

labeling requirements (§§ 201.64, 

201.70, 201.71, and 201.72), and the 

statements required by § 201.130(a)(1) 

and (2). These products may also have 

additional labeling beyond the DFL 

requirements (§ 201.67(c)(2)). 

Estimating six respondents will 

expend 1 hour annually to comply with 

PDP and DFL labeling requirements 

under § 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, ‘‘SelfSelection 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-andadverse-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_/http://

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/wpcontent/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/recommendContainer

Labeling.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. 


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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/domesticmous/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-drugevaluation-and-research-cder/prescriptionover-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 

■ 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. 

■ 2. Add § 201.67 to subpart C to read 

as follows: 

§ 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 selfselection 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 § 201.66 and the statements 

specified in § 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 § 201.66. 

(d) Format requirements for the 

required statement about the ACNU. 

The statement about the ACNU 

specified in § 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 § 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 § 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 § 314.56(c)(1)(iv) of this chapter 

for NDAs or § 314.56(c)(2)(ii) of this 

chapter for ANDAs; or 

(ii) The operationalization of the 

ACNU under § 314.56(c)(1)(vii) of this 

chapter for NDAs or § 314.56(c)(2)(iii) of 

this chapter for ANDAs. 

■ 3. Add § 201.130 to subpart D to read 

as follows: 

§ 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 

§ 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 


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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 

§ 201.66(c)(4) as the first statement, 

followed by the other information 

required in § 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 

§ 201.66(c)(6) as the first direction, 

followed by the other information 

required in § 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 § 201.66(c)(4) 

and may also appear under the 

‘‘Directions’’ heading as the first 

direction, followed by the other 

information required in § 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 § 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 § 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 § 314.56(c)(1)(iv) of this chapter 

for NDAs or § 314.56(c)(2)(ii) of this 

chapter for ANDAs; and 

(2) The operationalization of the 

ACNU under § 314.56(c)(1)(vii) of this 

chapter for NDAs or § 314.56(c)(2)(iii) of 

this chapter for ANDAs. 

PART 314—APPLICATIONS FOR FDA 

APPROVAL TO MARKET A NEW DRUG 

■ 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. 

■ 5. Add § 314.56 to subpart B to read 

as follows: 

§ 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 selfselection or appropriate actual use, or 

both. 

(2) [Reserved] 

(b) Separate application required for 

a nonprescription drug product with an 

ACNU. Notwithstanding § 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 § 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 selfselection 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 § 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 


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

■ 6. Amend § 314.81 by adding 

paragraph (b)(3)(v) to read as follows: 

§ 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 § 314.56(c)(1)(iv) or 

(c)(2)(ii); or 

(2) A failure associated with the 

operationalization of an ACNU under 

§ 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 § 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 § 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 

§ 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 § 314.90 or § 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. 

* * * * * 

■ 7. Amend § 314.125 by adding 

paragraph (b)(20) to read as follows: 

§ 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 

§ 314.56, if FDA has determined the 

application failed to meet the 

requirements in § 314.56 applicable to 

NDAs. 

* * * * * 

■ 8. Amend § 314.127 by adding 

paragraph (a)(15) to read as follows: 

§ 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 § 314.56, if FDA has 

determined the application failed to 

meet the requirements in § 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 


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