Federal Register / Vol. 87, No. 123 / Tuesday, June 28, 2022 / Proposed Rules 38313 

are contacted by BEA. Also, a person, or 

their agent, who is contacted by BEA 

about reporting in this survey, either by 

sending them a report form or by 

written inquiry, must respond in writing 

pursuant to this section. This may be 

accomplished by filing the properly 

completed BE–13 report (BE–13A, BE– 

13B, BE–13D, BE–13E, or BE–13 Claim 

for Exemption). 

(b) Who must report. A BE–13 report 

is required of any U.S. business 

enterprise, except certain private funds, 

see exception in item (b.4.), in which: 

(1) A foreign direct investment in the 

United States relationship is created; 

(2) An existing U.S. affiliate of a 

foreign parent establishes a new U.S. 

business enterprise, expands its U.S. 

operations, or acquires a U.S. business 

enterprise, or; 

(3) BEA requests a cost update (Form 

BE–13E) for a U.S. business enterprise 

that previously filed Form BE–13B or 

BE–13D. 

(4) Certain private funds are exempt 

from reporting on the BE–13 survey. If 

a U.S. business enterprise is a private 

fund and does not own, directly or 

indirectly, 10 percent or more of another 

business enterprise that is not also a 

private fund or a holding company, it is 

not required to file any BE–13 report 

except to indicate exemption from the 

survey if contacted by BEA. 

(c) Forms to be filed. Depending on 

the type of investment transaction, U.S. 

affiliates would report their information 

on one of five forms—BE–13A, BE–13B, 

BE–13D, BE–13E, or BE–13 Claim for 

Exemption. 

(1) Form BE–13A—Report for a U.S. 

business enterprise when a foreign 

entity acquires a voting interest 

(directly, or indirectly through an 

existing U.S. affiliate) in that U.S. 

business enterprise including segments, 

operating units, or real estate; and 

(i) The total cost of the acquisition is 

greater than $3 million; and 

(ii) By this acquisition, the foreign 

entity now owns at least 10 percent of 

the voting interest (directly, or 

indirectly through an existing U.S. 

affiliate) in the acquired U.S. business 

enterprise. 

(2) Form BE–13B—Report for a U.S. 

business enterprise when it is 

established by a foreign entity or by an 

existing U.S. affiliate of a foreign parent; 

and 

(i) The expected total cost to establish 

the new U.S. business enterprise is 

greater than $3 million; and 

(ii) The foreign entity owns at least 10 

percent of the voting interest (directly, 

or indirectly through an existing U.S. 

affiliate) in the new U.S. business 

enterprise. 

(3) Form BE–13D—Report for an 

existing U.S. affiliate of a foreign parent 

when it expands its operations to 

include a new facility where business is 

conducted and the expected total cost of 

the expansion is greater than $3 million. 

(4) Form BE–13E—Report for a U.S. 

business enterprise that previously filed 

Form BE–13B or BE–13D. Form BE–13E 

collects updated cost information and 

will be collected annually for three 

years after the year of the establishment 

or expansion of the U.S. business 

enterprise. 

(5) Form BE–13 Claim for 

Exemption—Report for a U.S. business 

enterprise that: 

(i) was contacted by BEA but does not 

meet the requirements for filing Forms 

BE–13A, BE–13B, or BE–13D; or 

(ii) whether or not contacted by BEA, 

met all requirements for filing Forms 

BE–13A, BE–13B, or BE–13D except the 

$3 million reporting threshold. 

(d) Due date. The BE–13 forms are 

due no later than 45 calendar days after 

the acquisition is completed, the new 

U.S. business enterprise is established, 

the expansion is begun, the cost update 

is requested, or a notification letter is 

received from BEA by a U.S. business 

enterprise that does not meet the filing 

requirements for the survey. 

[FR Doc. 2022–13713 Filed 6–27–22; 8:45 am] 

BILLING CODE 3510–06–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 201 and 314 

[Docket No. FDA–2021–N–0862] 

RIN 0910–AH62 

Nonprescription Drug Product With an 

Additional Condition for 

Nonprescription Use 

AGENCY: Food and Drug Administration, 

Department of Health and Human 

Services (HHS). 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is proposing to establish 

requirements for a nonprescription drug 

product with an additional condition for 

nonprescription use (ACNU). The 

proposed rule, if finalized, would 

establish requirements for a 

nonprescription drug product that has 

an ACNU that an applicant must 

implement to ensure appropriate selfselection or appropriate actual use, or 

both, by consumers without the 

supervision of a healthcare practitioner. 

The proposed rule is intended to 

increase options for applicants to 

develop and market safe and effective 

nonprescription drug products, which 

could improve public health by 

broadening the types of nonprescription 

drug products available to consumers. 

DATES: Either electronic or written 

comments on the proposed rule must be 

submitted by October 26, 2022. Submit 

comments (including recommendations) 

on information collection issues under 

the Paperwork Reduction Act of 1995 by 

July 28, 2022. 

ADDRESSES: You may submit comments 

as follows. Please note that late, 

untimely filed comments will not be 

considered. The https://

www.regulations.gov electronic filing 

system will accept comments until 

11:59 p.m. Eastern Time at the end of 

October 26, 2022. Comments received 

by mail/hand delivery/courier (for 

written/paper submissions) will be 

considered timely if they are received 

on or before that date. 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit a comment 

with confidential information that you 

do not wish to be made available to the 

public, submit the comment as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 


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38314 Federal Register / Vol. 87, No. 123 / Tuesday, June 28, 2022 / Proposed Rules 

• For written/paper comments 

submitted to the Dockets Management 

Staff, FDA will post your comment, as 

well as any attachments, except for 

information submitted, marked and 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2021–N–0862 for ‘‘Nonprescription 

Drug Product with an Additional 

Condition for Nonprescription Use.’’ 

Received comments, those filed in a 

timely manner (see ADDRESSES), will be 

placed in the docket and, except for 

those submitted as ‘‘Confidential 

Submissions,’’ publicly viewable at 

https://www.regulations.gov or at the 

Dockets Management Staff between 9 

a.m. and 4 p.m., Monday through 

Friday, 240–402–7500. 

• Confidential Submissions—To 

submit a comment with confidential 

information that you do not wish to be 

made publicly available, submit your 

comments only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ The 

Agency will review this copy, including 

the claimed confidential information, in 

its consideration of comments. The 

second copy, which will have the 

claimed confidential information 

redacted/blacked out, will be available 

for public viewing and posted on 

https://www.regulations.gov. Submit 

both copies to the Dockets Management 

Staff. If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://

www.govinfo.gov/content/pkg/FR-2015- 

09-18/pdf/2015-23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

Submit comments on information 

collection issues under the Paperwork 

Reduction Act of 1995 to the Office of 

Management and Budget (OMB) at 

https://www.reginfo.gov/public/do/ 

PRAMain. Find this particular 

information collection by selecting 

‘‘Currently Under Review—Open for 

Public Comments’’ or by using the 

search function. The title of this 

proposed collection is ‘‘Premarket 

applications, postmarketing reports and 

recordkeeping, and labeling for 

Nonprescription Drug Products With an 

Additional Condition for 

Nonprescription Use.’’ 

FOR FURTHER INFORMATION CONTACT: 

With regard to the proposed rule: 

Chris Wheeler, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, Rm. 3330, 

Silver Spring, MD 20993–0002, 301– 

796–0151, Chris.Wheeler@fda.hhs.gov. 

With regard to the information 

collection: Domini Bean, Office of 

Operations, Food and Drug 

Administration, Three White Flint 

North, 10A–12M, 11601 Landsdown St., 

North Bethesda, MD 20852, 301–796– 

5733, PRAStaff@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Executive Summary 

A. Purpose of the Proposed Rule 

B. Summary of the Major Provisions of the 

Proposed Rule 

C. Legal Authority 

D. Costs and Benefits 

II. Table of Abbreviations/Commonly Used 

Acronyms in This Document 

III. Background 

A. Need for the Regulation 

B. FDA’s Current Regulatory Framework 

C. History of the Rulemaking 

IV. Legal Authority 

V. Description of the Proposed Rule 

A. Applicability 

B. Definitions (Proposed §§ 314.56(a) and 

201.67(b)) 

C. Separate Application Required for a 

Nonprescription Drug Product With an 

ACNU (Proposed § 314.56(b)) 

D. Specific Requirements for an 

Application for a Nonprescription Drug 

Product With an ACNU (Proposed 

§ 314.56(c)) 

E. Nonprescription and Prescription 

Approval and Simultaneous Marketing 

(Proposed § 314.56(d)) 

F. Refusal To Approve an Application 

With an ACNU (Proposed 

§§ 314.125(b)(20) and 314.127(a)(15)) 

G. Other Postmarketing Reports (Proposed 

§ 314.81(b)(3)(v)) 

H. General Labeling Requirements 

(Proposed § 201.67(c)) 

I. Format Requirements for Required 

ACNU Statement (Proposed § 201.67(d)) 

J. Exemption From Adequate Directions for 

Use (Proposed § 201.130) 

K. Misbranding (Proposed § 201.67(e)) 

VI. Proposed Effective Date 

VII. Preliminary Economic Analysis of 

Impacts 

A. Introduction 

B. Summary of Costs and Benefits 

VIII. Analysis of Environmental Impact 

IX. Paperwork Reduction Act of 1995 

X. Federalism 

XI. Consultation and Coordination With 

Indian Tribal Governments 

XII. References 

I. Executive Summary 

A. Purpose of the Proposed Rule 

FDA is proposing to establish 

requirements for a nonprescription drug 

product with an additional condition for 

nonprescription use (ACNU), which is a 

drug product that could be marketed 

without a prescription if an applicant 

implements an additional condition to 

ensure appropriate self-selection or 

appropriate actual use, or both, by 

consumers without the supervision of a 

healthcare practitioner. Currently, 

nonprescription drug products are 

limited to drugs that can be labeled with 

sufficient information for consumers to 

appropriately self-select and use the 

drug product. For certain drug products, 

limitations of labeling present 

challenges for adequate communication 

of information needed for consumers to 

appropriately self-select or use the drug 

product without the supervision of a 

healthcare practitioner. The proposed 

rule is intended to increase options for 

applicants to develop and market safe 

and effective nonprescription drug 

products, which could improve public 

health by broadening the types of 

nonprescription drug products available 

to consumers. 

B. Summary of the Major Provisions of 

the Proposed Rule 

The proposed rule, if finalized, would 

establish requirements for a 

nonprescription drug product with an 

ACNU. The evidentiary standards that 

an application must meet under the 

Federal Food, Drug, and Cosmetic Act 

(FD&C Act) and current FDA regulations 

for demonstrating safety and 

effectiveness would continue to apply to 

nonprescription drug products 

approved with an ACNU. This proposed 

rule would establish additional 

application requirements, labeling 

requirements, and postmarketing 

reporting requirements for a 

nonprescription drug product with an 

ACNU. 

The proposed rule would establish 

the requirements for a new drug 

application (NDA) or abbreviated new 

drug application (ANDA) for a 

nonprescription drug product with an 

ACNU. An applicant would be required 


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to submit a separate application for the 

approval of a nonprescription drug 

product with an ACNU, rather than a 

supplement to an application approved 

as a prescription drug product. In 

addition to applicable existing 

application requirements, NDA 

applicants would also be required to 

describe the ACNU and submit 

information to support the ACNU. 

The proposed rule would clarify that 

an ACNU would constitute a 

meaningful difference between a 

prescription drug product and a 

nonprescription drug product that 

makes the nonprescription drug product 

safe and effective for use without the 

supervision of a healthcare practitioner 

licensed by law to administer the drug. 

For instance, two drug products could 

have the same active ingredient, dosage 

form, strength, route of administration, 

and indication, with one made available 

as a nonprescription drug product with 

an ACNU and the other product made 

available only by prescription. 

The proposed rule would specify that 

FDA would refuse to approve an NDA 

or ANDA for a nonprescription drug 

product with an ACNU if the 

application fails to meet the applicable 

requirements of proposed § 314.56 (21 

CFR 314.56). 

The proposed rule would establish 

postmarketing reporting requirements 

for a nonprescription drug product with 

an ACNU. NDA and ANDA applicants 

would be required to submit a report 

with information concerning any 

incident of failure in the 

implementation of an ACNU, such as a 

consumer gaining access to the drug 

product without fulfilling the ACNU. 

C. Legal Authority 

FDA’s proposal to establish 

requirements for a nonprescription drug 

product with an ACNU is authorized by 

sections 201(n), 502, 503(b), 505, and 

701(a) of the FD&C Act (21 U.S.C. 

321(n), 352, 353(b), 355, and 371(a)). 

D. Costs and Benefits 

The proposed rule, if finalized, would 

establish, for any applicant, the 

requirements for a nonprescription drug 

product with an ACNU. Compared to 

the traditional labeling paradigm of 

nonprescription drug products, this 

approved ACNU in addition to the 

labeling would ensure the appropriate 

self-selection, appropriate use, or both, 

of a drug product. We expect that this 

proposed rule, if finalized, would 

expand consumer access to certain drug 

products in a nonprescription setting. 

Greater access to drug products would 

allow consumers to treat certain medical 

conditions using nonprescription drug 

products with an ACNU without the 

supervision of a healthcare practitioner. 

We estimate a reduction in access costs 

to consumers who could transfer from a 

prescription to a nonprescription drug 

product with an ACNU. Our primary 

estimate for this item is $26.70 with a 

range of $0 to $53.40 per consumer per 

purchase. There may also be cost 

savings associated with a potential 

reduction in the number of repetitive 

meetings between FDA and industry. 

Our primary estimate is $55,469 per 

applicant with a range of $45,260 to 

$66,174. Government and private 

insurance payers may also experience 

cost savings because the availability of 

nonprescription drug products with an 

ACNU may decrease future medical 

costs and the number of submitted 

insurance claims. In addition, we 

assume that applicants would submit 

applications when they believe that the 

profits from a potential approval would 

exceed the costs of the application. We 

lack information to monetize these 

potential profits and costs. We do not 

monetize our estimates of benefits over 

a 10-year horizon because of the high 

uncertainty about the number of 

applicants, applications, potential 

approvals, the number of purchases that 

might occur, and consumer preferences 

to switch products. For details, see the 

Preliminary Regulatory Impact Analysis 

(PRIA), the Uncertainty and Sensitivity 

section, as well as the Appendix of the 

same document. 

Monetized costs include a one-time 

cost of reading and understanding the 

rule for those applicants potentially 

interested in submitting applications for 

their nonprescription drug products 

with an ACNU. Our primary estimate of 

these costs equals $821 with a range of 

$379 and $1,264 using a 7-percent 

discount rate annualized over a ten-year 

horizon. 

II. Table of Abbreviations/Commonly 

Used Acronyms in This Document 

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. 

ICSR ................................................................................................................................................ Individual Case Safety Report. 

NDA ................................................................................................................................................. New Drug Application. 

NDC ................................................................................................................................................. National Drug Code. 

OMB ................................................................................................................................................ Office of Management and Budget. 

OTC ................................................................................................................................................. Over-the-Counter. 

PDP ................................................................................................................................................. Principal Display Panel. 

RLD ................................................................................................................................................. Reference Listed Drug. 

III. Background 

A. Need for the Regulation 

Nonprescription drug products are 

important for the treatment of many 

conditions and diseases, although at 

present most nonprescription drug 

products are intended to provide 

temporary relief of minor symptoms or 

self-diagnosable, self-limited conditions 

and diseases, rather than chronic 

diseases. Unlike prescription drug 

products, nonprescription drug 

products may be accessed and used 

safely and effectively by consumers 

without the supervision of a healthcare 

practitioner when certain conditions are 

met. Currently, nonprescription drug 

products are limited to drugs that can be 

labeled with sufficient information to 

enable consumers to appropriately selfselect and use the drug product without 

the supervision of a healthcare 

practitioner. Self-selection is the 

decision consumers make to use or not 

to use a drug product based on reading 

the information on the drug product 

labeling and applying knowledge of 

their personal medical history (Ref. 1). 

Nonprescription drug products are 

usually available for consumers to 

purchase at pharmacies, supermarkets, 


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or other retail locations, and from online 

retailers. 

FDA recognizes the potential benefit 

of providing consumers with access to 

additional types of nonprescription drug 

products, such as some drug products 

that are currently available only by 

prescription and that treat chronic 

diseases or conditions. However, there 

are certain drug products that an 

applicant may seek to market on a 

nonprescription basis where labeling 

alone cannot adequately communicate 

the information needed for consumers 

to appropriately self-select, use, or both 

self-select and use the drug product 

safely and effectively without the 

supervision of a healthcare practitioner. 

The proposed rule has the potential to 

broaden the types of drug products that 

FDA could approve as nonprescription. 

Under the proposed rule, when labeling 

alone is not sufficient to ensure that the 

consumer can appropriately self-select 

or appropriately actually use, or both, a 

drug product correctly in a 

nonprescription setting, an applicant 

may submit an application proposing an 

ACNU that a consumer must 

successfully fulfill to obtain the 

nonprescription drug product with an 

ACNU. For example, an applicant may 

submit an application for a 

nonprescription drug product with an 

ACNU that enables a consumer to treat 

a chronic condition that currently does 

not have a nonprescription treatment. 

The availability of nonprescription drug 

products with an ACNU may provide 

public health benefits by facilitating 

consumers’ self-care and autonomy over 

their medical treatment (Ref. 2). 

B. FDA’s Current Regulatory Framework 

There are two regulatory pathways to 

bring a nonprescription drug product to 

market in the United States: (1) the 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. Under the OTC drug 

review process, a nonprescription drug 

product may be marketed without an 

approved NDA or ANDA under section 

505 of the FD&C Act if the 

nonprescription drug product meets the 

requirements of section 505G of the 

FD&C Act, and other applicable 

requirements. 

FDA approves drugs as either 

prescription or nonprescription drug 

products under section 505 of the FD&C 

Act. A drug must be dispensed by 

prescription when it is not safe for use 

except under the supervision of a 

healthcare practitioner licensed by law 

to administer such drug product 

because of its toxicity or other 

potentiality for harmful effect, or the 

method of its use, or the collateral 

measures necessary to its use (see 

section 503(b)(1) of the FD&C Act). If the 

approved drug does not meet the criteria 

for prescription-only dispensing, it may 

be marketed as nonprescription. 

Section 503(b)(4)(B) of the FD&C Act 

provides that a drug product to which 

the prescription provisions of the FD&C 

Act do not apply (i.e., a nonprescription 

drug product) will be deemed to be 

misbranded if at any time before 

dispensing, the label of the drug bears 

the ‘‘Rx only’’ symbol. Read together 

with section 503(b)(4)(A) of the FD&C 

Act, which requires prescription drug 

products to bear the ‘‘Rx only’’ symbol, 

this effectively means that absent a 

meaningful difference between the 

products, simultaneous marketing of 

two drug products with the same active 

ingredient as both a prescription and a 

nonprescription drug would result in 

one of the two products being 

misbranded. Examples of meaningful 

differences that can make a prescription 

drug product safe and effective only 

under the supervision of a healthcare 

practitioner licensed by law to 

administer such drug include the 

indication, strength, route of 

administration, dosage form, or patient 

population (see 83 FR 13994 at 13995, 

April 2, 2018; see also 70 FR 52050, 

September 1, 2005). 

An applicant may submit an NDA for 

a nonprescription drug product using 

the pathways described in section 

505(b)(1) or (2) of the FD&C Act to 

market a new drug product. A 505(b)(1) 

NDA includes full reports of 

investigations to demonstrate that the 

proposed drug product is safe and 

effective under the conditions 

prescribed, recommended, or suggested 

in its proposed labeling (see sections 

505(d) and (b)(1) of the FD&C Act). 

Thus, an NDA for a nonprescription 

drug product must include, among other 

things, information to demonstrate that 

consumers can appropriately self-select 

and use the proposed drug product 

safely and effectively without the 

supervision of a healthcare practitioner. 

An NDA submitted under section 

505(b)(2) of the FD&C Act also includes 

information to demonstrate that the 

proposed drug product is safe and 

effective under the conditions 

prescribed, recommended, or suggested 

in its proposed labeling, but at least 

some of the information required for 

approval comes from studies not 

conducted by or for the applicant and 

for which the applicant has not obtained 

a right of reference or use (21 U.S.C. 

355(b)(2)). 

Applicants may submit an ANDA 

using the pathway described in section 

505(j) of the FD&C Act for a drug 

product that is a generic version of a 

previously approved drug product. An 

ANDA for a nonprescription drug 

product generally references a 

nonprescription drug product 

previously approved under section 

505(c) of the FD&C Act (known as the 

RLD) and relies on the Agency’s finding 

that the RLD is safe and effective. An 

ANDA generally must contain 

information to show that the proposed 

generic product (1) is the same as the 

RLD with respect to the active 

ingredient(s), conditions of use, route of 

administration, dosage form, strength, 

labeling (with certain permissible 

differences) and (2) is bioequivalent to 

the RLD. The procedures and 

requirements for the submission and 

approval of NDAs, ANDAs, and 

supplements to those applications are 

provided in part 314 (21 CFR part 314). 

Generally, nonprescription drug 

products must be labeled with adequate 

directions for use so the consumer: (1) 

can use the drug product safely and for 

the purposes for which it is intended 

and (2) make an appropriate selfselection decision and appropriately use 

the nonprescription drug product (see 

section 502(f)(1) of the FD&C Act and 

§ 201.5 (21 CFR 201.5)). Consumer 

studies can help demonstrate that the 

requirement for adequate directions for 

use is met. These studies may include 

label comprehension studies (Ref. 3), 

self-selection studies (Ref. 1), actual-use 

studies, and other human factors 

studies. 

Nonprescription drug products must 

also comply with applicable labeling 

requirements under part 201 (21 CFR 

part 201), including the format and 

content requirements for OTC drug 

product labeling under § 201.66. 

Labeling created to satisfy the 

requirements in § 201.66 is commonly 

referred to as the Drug Facts labeling 

(DFL). The DFL is intended to enable 

consumers to appropriately self-select 

and use the nonprescription drug 

product safely and effectively. In 

addition to the DFL, FDA may approve 

additional labeling for nonprescription 

drug products. 

C. History of the Rulemaking 

FDA has received a number of 

inquiries from stakeholders about 

whether applications may be submitted 

for nonprescription drug products with 

one or more additional conditions that 

consumers must fulfill to ensure that the 

drug product is safe and effective for 

nonprescription use. As explained in 

detail below, FDA held a public hearing 


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and participated in a series of 

workshops convened by the Engelberg 

Center for Health Care Reform at the 

Brookings Institution (Brookings 

Institution) to solicit public input on 

expanding the approval of 

nonprescription drug products. FDA 

used stakeholder input from the public 

hearing and the workshops to develop 

the proposed rule. 

1. FDA 2012 Public Hearing 

In the Federal Register of February 

28, 2012 (77 FR 12059), FDA announced 

a public hearing under part 15 (21 CFR 

part 15) entitled ‘‘Using Innovative 

Technologies and Other Conditions of 

Safe Use to Expand Which Drug 

Products Can Be Considered 

Nonprescription’’ (2012 public hearing). 

FDA held this public hearing on March 

22 and 23, 2012, to: (1) seek input from 

interested stakeholders on a potential 

new paradigm where FDA would 

approve certain drug products for 

nonprescription use with certain 

conditions specific to a drug product 

that would otherwise require a 

prescription and (2) obtain information 

and comments on the feasibility of this 

paradigm and its potential benefits and 

costs. As part of the public hearing, FDA 

requested information and public 

comment on the types of technology 

that could be used; the types of 

conditions of safe use; and the potential 

impacts on pharmacies, consumers, and 

healthcare practitioners, as well as other 

issues that might arise under the 

paradigm. FDA received comments from 

various stakeholders, including 

consumers, private industry, healthcare 

professional associations, academic 

institutions, and patient advocacy 

organizations, on a broad range of topics 

such as: (1) access to care, (2) 

medication nonadherence, (3) 

practitioner oversight, (4) potential 

effect on healthcare and healthcare 

costs, (5) potential impact on medical 

conditions or diseases, (6) use of 

diagnostic aids and technologies as 

possible conditions of safe use, and (7) 

potential barriers to successful 

implementation and adoption (see 

Docket No. FDA–2012–N–0171). 

2. Brookings Institution Workshops 

The Brookings Institution convened a 

series of three expert workshops, based 

on a cooperative agreement with FDA, 

to seek stakeholder feedback on 

practical considerations for the 

development of a new paradigm focused 

on developing innovative approaches 

for consumers to self-select 

nonprescription drug products 

appropriately and maintain their safe 

and effective use and to explore 

potential practical strategies. 

Participants included a diverse set of 

stakeholders from both public and 

private sectors, including FDA and 

other Government agencies, healthcare 

professional associations, trade 

associations, technology developers, 

pharmaceutical manufacturers, 

healthcare professionals, academic 

institutions, retail pharmacy 

representatives, and patient advocacy 

organizations. 

On November 8, 2012, the Brookings 

Institution convened the first expert 

workshop, ‘‘Nonprescription 

Medications With Conditions of Safe 

Use as a Novel Solution for 

Undertreated Diseases or Conditions.’’ 

This workshop explored issues and 

practical considerations for the 

development of this new paradigm (Ref. 

4). 

On May 9, 2013, the Brookings 

Institution held the second expert 

workshop, ‘‘Innovative Technologies 

and Nonprescription Medications: 

Addressing Undertreated Diseases and 

Conditions Through Technology 

Enabled Self-Care.’’ This workshop 

explored the potential for innovative 

technologies to facilitate safe and 

effective use of nonprescription drug 

products (Ref. 5). 

On November 4, 2013, the Brookings 

Institution held the final expert 

workshop, ‘‘Exploring Implications of 

the Nonprescription Drug Safe Use 

Regulatory Expansion Initiative on 

Reimbursement and Access.’’ This 

workshop focused on assessing this 

paradigm’s potential impact on 

consumer access and reimbursement 

(Ref. 6). 

3. Innovative Approaches for 

Nonprescription Drug Products; Draft 

Guidance for Industry 

In the Federal Register of July 18, 

2018 (83 FR 33938), FDA published a 

notice of availability of a draft guidance 

entitled ‘‘Innovative Approaches for 

Nonprescription Drug Products’’ and 

established Docket No. FDA–2018–D– 

2281. This draft guidance describes two 

innovative approaches that may be 

useful for applicants to consider in 

cases where the DFL alone is not 

sufficient to ensure that a drug product 

can be used safely and effectively in a 

nonprescription setting. These 

approaches include the development of 

labeling in addition to the DFL and the 

implementation of additional conditions 

so that consumers can appropriately 

self-select and use the product. 

IV. Legal Authority 

FDA’s proposal to establish 

requirements for a nonprescription drug 

product with an ACNU is authorized by 

sections 201(n), 502, 503(b), 505, and 

701(a) of the FD&C Act (21 U.S.C. 

321(n), 352, 353(b), 355, and 371(a)). 

Section 502(f) of the FD&C Act deems a 

drug to be misbranded unless its 

labeling bears adequate directions for 

use and adequate warnings against use 

in those conditions where its use may 

be dangerous to health, as well as 

adequate warnings against unsafe 

dosage or methods or duration of 

administration or application, in such 

manner and form, as are necessary for 

the protection of users. Section 502(f) 

also authorizes the promulgation of 

regulations exempting a drug or device 

from the requirement to bear adequate 

directions for use upon a determination 

that such directions are not necessary 

for the protection of public health. 

We are proposing to add an 

exemption for human nonprescription 

drug products approved with an ACNU 

from the requirement in section 

502(f)(1) of the FD&C Act for drug 

products to have labeling that provides 

adequate directions for use (see 

proposed § 201.130). When labeling 

alone cannot provide adequate 

directions for use for a human 

nonprescription drug product, FDA may 

approve the nonprescription drug 

product with an ACNU under proposed 

§ 314.56. 

In addition, section 502(a) of the 

FD&C Act deems a drug to be 

misbranded if its labeling is false or 

misleading in any particular. Under 

section 201(n) of the FD&C Act, in 

determining whether labeling is 

misleading, there shall be taken into 

account (among other things), not only 

representations made or suggested but 

also the extent to which the labeling 

fails to reveal facts material in the light 

of such representations or material with 

respect to consequences that may result 

from the use of the drug under the 

conditions of use prescribed in the 

labeling or under usual or customary 

conditions of use. 

In addition, under section 505 of the 

FD&C Act, FDA will approve an NDA 

only if the drug is shown to be both safe 

and effective for use under the 

conditions prescribed, recommended, or 

suggested in the proposed labeling for 

the product. See section 505(c)(1) and 

(d) of the FD&C Act. If, for example, on 

the basis of information submitted as 

part of the application or on the basis of 

any other information before the Agency 

with respect to such drug, there is 

insufficient information to determine 

whether such drug is safe for use under 

such conditions, the Agency will not 

approve the drug. Section 505(j) of the 

FD&C Act describes the requirements 


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for ANDAs. In particular, section 

505(j)(2)(A) specifies the information 

that must be included in an ANDA, and 

section 505(j)(4) describes the approval 

standard for an ANDA. 

In addition, section 503(b) of the 

FD&C Act contains provisions regarding 

the marketing of a drug as either a 

prescription drug product or a 

nonprescription drug product. 

Finally, section 701(a) of the FD&C 

Act authorizes FDA to issue regulations 

for the efficient enforcement of the 

FD&C Act. 

V. Description of the Proposed Rule 

We are proposing to add § 314.56 to 

part 314, subpart B, to establish 

additional application requirements for 

a nonprescription drug product with an 

ACNU under an NDA or an ANDA. The 

evidentiary standards that an NDA for a 

nonprescription drug product must 

meet under the FD&C Act and current 

FDA regulations to demonstrate the 

safety and effectiveness of the drug 

product would apply to a 

nonprescription drug product approved 

with an ACNU. An ANDA referencing a 

nonprescription drug product with an 

ACNU previously approved under an 

NDA may rely on FDA’s finding that the 

listed drug product is safe and effective 

for use under the conditions described 

in the labeling. We are proposing to add 

§ 314.125(b)(20) to part 314, subpart D, 

to specify that FDA would refuse to 

approve an NDA for a nonprescription 

drug product with an ACNU that does 

not meet the applicable requirements 

established in § 314.56. We are also 

proposing to add § 314.127(a)(15) to part 

314, subpart D, to specify that FDA 

would refuse to approve an ANDA for 

a nonprescription drug product with an 

ACNU that does not meet the applicable 

requirements established in § 314.56. 

We are proposing to add 

§ 314.81(b)(3)(v) to part 314, subpart B, 

to establish postmarketing reporting 

requirements for a nonprescription drug 

product with an ACNU. We are also 

proposing to add § 201.67 to part 201, 

subpart C, to establish labeling 

requirements for a nonprescription drug 

product with an ACNU. We are 

proposing to add § 201.130 to part 201, 

subpart D, to establish an exemption 

from the statutory requirement for 

adequate directions for use for a 

nonprescription drug product with an 

ACNU. The proposed rule is intended to 

increase options for applicants to 

develop and market safe and effective 

nonprescription drug products, which 

could improve public health by 

broadening the types of nonprescription 

drug products available to consumers. 

For example, FDA may approve a 

nonprescription drug product with an 

ACNU to treat a chronic condition that 

currently does not have nonprescription 

treatments. 

A detailed description of each 

proposed section is provided in sections 

V.A through V.K of this document. 

A. Applicability 

The proposed rule would apply to 

NDAs and ANDAs for nonprescription 

drug products with an ACNU (see 

proposed §§ 314.56, 314.81, 314.125, 

314.127, 201.67, and 201.130). 

Nonprescription drug products 

currently marketed under an approved 

application do not need an ACNU to 

ensure appropriate self-selection and 

appropriate actual use because FDA 

previously determined that labeling 

alone is sufficient for these drugs to be 

used safely and effectively without a 

prescription. The proposed rule would 

not apply to nonprescription drugs 

marketed under section 505G of the 

FD&C Act. Therefore, a requestor (as 

defined in section 505G(q)(3) of the 

FD&C Act) cannot submit a request 

under section 505G(b) of the FD&C Act 

for a nonprescription drug product with 

an ACNU. 

B. Definitions (Proposed §§ 314.56(a) 

and 201.67(b)) 

We are proposing to define the term 

‘‘additional condition for 

nonprescription use’’ (ACNU) as one or 

more FDA-approved conditions that an 

applicant of a nonprescription drug 

product must implement to ensure 

consumers’ appropriate self-selection or 

appropriate actual use, or both, of the 

nonprescription drug product without 

the supervision of a healthcare 

practitioner if the applicant 

demonstrates and FDA determines that 

labeling alone is insufficient to ensure 

appropriate self-selection or appropriate 

actual use, or both (see proposed 

§§ 314.56(a) and 201.67(b)). If the ACNU 

is intended to address appropriate selfselection only, the labeling must enable 

appropriate actual use of the 

nonprescription drug product by 

consumers. Alternatively, if the ACNU 

is intended to address appropriate 

actual use only, the labeling must 

enable consumers to appropriately selfselect the nonprescription drug product. 

The proposed definition for an ACNU 

is intentionally broad to give applicants 

flexibility regarding the types of 

additional conditions applicants may 

propose and how those additional 

conditions can be implemented. For 

example, an applicant could propose an 

ACNU that requires a consumer, in 

order to purchase the nonprescription 

drug product, to respond with specific 

answers to a set of questions on a selfselection test available by either a 

mobile application or an automated 

telephone response system. An 

applicant may also propose that before 

purchasing the nonprescription drug 

product with an ACNU, a consumer be 

required to view labeling (for example, 

text or images in a video), that describes 

how to appropriately use the 

nonprescription drug product and to 

respond to questions to confirm 

understanding. 

C. Separate Application Required for a 

Nonprescription Drug Product With an 

ACNU (Proposed § 314.56(b)) 

The proposed rule would not require 

a nonprescription drug product with an 

ACNU to be first marketed as a 

prescription drug product. However, in 

cases where there is an approved 

prescription drug product, the proposed 

rule would establish the requirement 

that a nonprescription drug product 

with an ACNU cannot be approved 

through a supplement to the approved 

prescription application. Rather, an 

applicant must submit a separate 

application for a nonprescription drug 

product with an ACNU. Although a 

separate application would be required, 

an applicant may cross reference 

information in its approved NDA for the 

prescription product and would not 

need to duplicate studies already 

conducted for and submitted in its NDA 

for the prescription product. As 

explained in Section III.B., a different 

applicant may submit an NDA under 

section 505(b)(2) of the FD&C Act, 

where at least some of the information 

required for approval comes from 

studies not conducted by or for the 

applicant and for which the applicant 

has not obtained a right of reference or 

use. This is provided the 505(b)(2) 

applicant establishes that the relied 

upon NDA or literature is relevant to its 

nonprescription drug product with an 

ACNU and its application includes 

support for any differences between the 

applicant’s proposed drug product and 

the listed drug on which the applicant 

is relying to demonstrate the safety and 

effectiveness of the proposed 

nonprescription drug product with an 

ACNU. 

As explained in section V.E of this 

document, the approved prescription 

drug product and the approved 

nonprescription drug product with an 

ACNU are two different products and 

could be simultaneously marketed. 

Requiring a separate application for 

the nonprescription drug product with 

an ACNU would enable continued 

marketing of the prescription product 

under the original NDA and would 


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allow it to serve as an RLD for ANDAs 

for the prescription product. Continued 

access to the prescription drug product, 

along with availability of the 

nonprescription drug product approved 

with an ACNU, would ensure greater 

access to needed drugs by providing 

flexibility in how to obtain them. For 

example, if a nonprescription drug 

product approved with an ACNU is 

available through a kiosk in a pharmacy, 

patients who do not live near a 

pharmacy with such a kiosk may find it 

easier to obtain the drug through a 

prescription. 

Additionally, patients who prefer to 

continue interacting with their 

healthcare providers and obtain the 

drug by prescription would have that 

option. Patients who had not previously 

used the drug may also feel more 

comfortable initiating treatment and 

obtaining the drug with the involvement 

of their healthcare providers. While 

FDA would generally expect any 

technology that is used to operationalize 

an ACNU to be easily usable to the 

majority of consumers, there may be 

some consumers who may not be 

comfortable using such technology. 

Continued availability of the 

prescription drug product would 

provide greater flexibility in obtaining 

the drug and enable these patients to 

continue their care without potential 

interruption. 

An applicant seeking an initial 

approval of an ANDA to market a 

nonprescription drug product with an 

ACNU may submit an ANDA 

referencing a nonprescription drug 

product with an ACNU previously 

approved under an NDA and may rely 

on FDA’s finding that the RLD is safe 

and effective. This ANDA would also be 

required to have a separate application 

from an existing ANDA approved as a 

prescription drug product. Because the 

RLD nonprescription drug product with 

an ACNU would have a separate NDA 

from the NDA approved as a 

prescription drug product, the ANDA 

would be using a different NDA as its 

RLD from the RLD for the ANDA for the 

prescription product. Section 

505(j)(2)(D) of the FD&C Act prohibits 

an applicant from amending or 

supplementing its ANDA to rely on a 

different listed drug from the listed drug 

identified in the ANDA submitted to 

FDA. 

An applicant may submit an 

amendment, supplement, or annual 

report to an application for a 

nonprescription drug product with an 

ACNU, consistent with FDA regulations 

(§§ 314.60, 314.96, 314.70, and 314.97). 

An applicant seeking to make changes 

to an NDA or ANDA submitted for a 

nonprescription drug product with an 

ACNU that is under review by FDA 

would submit an amendment to the 

application to request a change 

(§§ 314.60 and 314.96). An applicant 

seeking to make changes to an FDAapproved NDA or ANDA for a 

nonprescription drug product with an 

ACNU would submit a supplement to 

the approved NDA or ANDA (§§ 314.70 

and 314.97). 

D. Specific Requirements for an 

Application for a Nonprescription Drug 

Product With an ACNU (Proposed 

§ 314.56(c)) 

The proposed rule would establish 

the specific NDA and ANDA 

requirements for a nonprescription drug 

product with an ACNU (see proposed 

§ 314.56(c)). 

1. New Drug Application 

In addition to applicable existing 

application requirements, NDA 

applicants would also be required to 

describe the ACNU and submit 

information to support the ACNU. 

Specifically, the proposed rule would 

require that an NDA for a 

nonprescription drug product with an 

ACNU must, when fulfilling the content 

and format requirements under § 314.50, 

include the following information about 

the ACNU in the application: (1) a 

statement regarding the purpose of the 

ACNU (i.e., appropriate self-selection or 

appropriate actual use, or both, by 

consumers of the nonprescription drug 

product without the supervision of a 

healthcare practitioner) (see proposed 

§ 314.56(c)(1)(i)); (2) a statement of the 

necessity of the ACNU (see proposed 

§ 314.56(c)(1)(ii)); (3) a description of 

how the ACNU ensures appropriate selfselection or appropriate actual use, or 

both (see proposed § 314.56(c)(1)(iii)); 

(4) a description of the key elements of 

the ACNU (see proposed 

§ 314.56(c)(1)(iv)); (5) adequate data or 

other information that demonstrate the 

necessity of the ACNU to ensure 

appropriate self-selection or appropriate 

actual use, or both (see proposed 

§ 314.56(c)(1)(v)); (6) adequate data or 

other information that demonstrate the 

effect of the ACNU on the appropriate 

self-selection or appropriate actual use, 

or both (see proposed § 314.56(c)(1)(vi)); 

and (7) a description of the specific way 

the ACNU is operationalized (see 

proposed § 314.56(c)(1)(vii)). The first 

four requirements for the ACNU in the 

application (see proposed 

§ 314.56(c)(1)(i) through (iv)) and the 

last requirement for the ACNU in the 

application (see proposed 

§ 314.56(c)(1)(vii) provide statements, 

including explanations, descriptions, 

and justifications, about the ACNU; the 

remaining requirements for the ACNU 

in the application (see proposed 

§ 314.56(c)(1)(v) through (vi)) provide 

data or other information to support 

these statements. Each of these seven 

requirements for the ACNU to be 

included in the application are further 

described in this section. 

We are providing an example of one 

fictitious nonprescription drug product 

with an ACNU, Drug X, to provide a 

simplified illustration of a product that 

may potentially be considered under 

this proposed regulatory framework. We 

will use Drug X to explain examples of 

information that the applicant would 

submit in the NDA for a nonprescription 

drug product with an ACNU. This is 

only one type of example; many other 

types of ACNUs for nonprescription 

drug products could be possible. 

Drug X is proposed as a 

nonprescription drug product indicated 

for the treatment of symptom Y in 

adults who have a disease-specific risk 

score below the threshold for 

developing serious side effect E when 

taking Drug X. As part of the 

nonprescription development program, 

the applicant conducted robust selfselection and label comprehension 

studies. The results of the self-selection 

and label comprehension studies 

demonstrated that consumers cannot 

appropriately self-select Drug X with 

labeling alone. FDA acknowledges these 

self-selection and label comprehension 

studies were well designed and 

conducted and concurs that consumers 

cannot self-select Drug X with labeling 

alone. Results of the self-selection and 

label comprehension studies show that, 

although consumers recognize that they 

have symptom Y, they cannot 

appropriately calculate their diseasespecific risk score for side effect E. 

Therefore, the applicant proposes an 

ACNU for Drug X to ensure consumers’ 

appropriate self-selection and now seeks 

approval of Drug X as a nonprescription 

drug product with an ACNU. The ACNU 

requires all consumers to complete a 

questionnaire located on a secure 

website created by the applicant to 

determine whether Drug X is 

appropriate for the consumer. The 

questionnaire has a series of questions 

that the consumer answers. The 

underlying program or other operating 

information used by the secure website 

calculates the risk score for serious side 

effect E using the consumer’s answers 

and determines if the consumer has an 

acceptable disease-specific risk score to 

use Drug X. A consumer with an 

acceptable risk score can then either: (1) 

purchase Drug X on the applicant’s 

secure website or (2) purchase Drug X 


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at a retail site specified by the applicant 

after presenting a barcoded voucher that 

can be printed or downloaded onto the 

consumer’s mobile device from the 

applicant’s secure website. 

a. Statement regarding the purpose of 

the ACNU. The proposed rule would 

require the applicant to provide a 

statement regarding the purpose of the 

ACNU (see proposed § 314.56(c)(1)(i)). 

This statement would indicate whether 

the ACNU is intended for: (1) 

appropriate self-selection, (2) 

appropriate actual use, or (3) both. For 

example, the purpose of the ACNU for 

Drug X is to ensure appropriate selfselection by consumers. 

b. Statement of the necessity of the 

ACNU. The proposed rule would 

require the applicant to explain why the 

ACNU is necessary to ensure 

appropriate self-selection or appropriate 

actual use, or both, by consumers of the 

nonprescription drug product (see 

proposed § 314.56(c)(1)(ii)). The 

applicant must explain why labeling 

alone cannot be sufficient for the 

purposes of meeting the approval 

requirements for a nonprescription drug 

product. The applicant may include a 

summary of the adequate data or other 

information that is submitted as part of 

an application for a nonprescription 

drug product with an ACNU, pursuant 

to proposed § 314.56(c)(1)(v), to explain 

why labeling alone cannot be sufficient. 

c. Description of how the ACNU 

ensures appropriate self-selection or 

appropriate actual use, or both. The 

proposed rule would require the 

applicant to describe how the ACNU 

will ensure appropriate self-selection or 

appropriate actual use, or both, by 

consumers (see proposed 

§ 314.56(c)(1)(iii)). For example, with 

Drug X, the applicant would describe 

that the ACNU requires a consumer to 

complete a questionnaire, located on a 

website, created by the applicant, that 

would assist in calculating a consumer’s 

risk score for developing serious side 

effect E. This questionnaire would 

determine whether Drug X is 

appropriate for the consumer. The 

applicant may be expected, among other 

things, to justify the appropriateness of 

the self-selection questions, including 

the criteria and/or considerations used 

in calculating the risk score for a 

particular consumer. This may include 

a description of the algorithm in the 

underlying program or other operating 

information used by the website that 

calculates the risk score for serious side 

effect E to determine if the consumer 

has an acceptable risk score to use Drug 

X. The applicant would also describe 

how a consumer with an acceptable risk 

score can then purchase Drug X. 

d. Description of key elements of the 

ACNU. The proposed rule would 

require the applicant to describe the key 

elements of the ACNU (see proposed 

§ 314.56(c)(1)(iv)). The description of 

the key elements must include: (1) the 

additional condition(s) implemented by 

the applicant to be fulfilled by the 

consumer to be able to obtain or use the 

nonprescription drug product with an 

ACNU, (2) the labeling specifically 

associated with the ACNU, and (3) the 

criteria by which the consumer would 

successfully fulfill the ACNU, including 

a description of the specific actions to 

be taken by a consumer or required 

responses to be provided by a consumer. 

Labeling specifically associated with the 

ACNU should be annotated with each 

specific element of the ACNU. All 

labeling, including labeling specifically 

associated with the ACNU, should be 

provided in editable documents 

whenever possible. For example, 

labeling specifically associated with 

Drug X would include the carton and 

container annotated with the elements 

specific to the ACNU. All questions in 

the questionnaire would be submitted as 

labeling. The applicant for Drug X 

would describe the criteria by which the 

consumer would fulfill the ACNU 

including the questions and all potential 

consumer responses that would 

determine that Drug X was appropriate 

or not appropriate for the consumer. 

e. Adequate data or other information 

that demonstrates the necessity of the 

ACNU to ensure appropriate selfselection or appropriate actual use, or 

both. The proposed rule would require 

an applicant to include data or other 

information that demonstrates the 

necessity of the ACNU to ensure 

appropriate self-selection or appropriate 

actual use, or both (see proposed 

§ 314.56(c)(1)(v)). To do so, the 

applicant must conduct or reference 

adequate testing to show that labeling 

alone would not support the safe and 

effective use of the nonprescription drug 

product. For example, the applicant of 

Drug X would submit adequate data 

from robust self-selection studies and 

label comprehension studies that 

demonstrate that consumers could not 

appropriately self-select Drug X with 

labeling alone. 

Alternatively, the applicant can 

submit information explaining the 

necessity of the ACNU for appropriate 

self-selection or appropriate actual use, 

or both, when FDA has previously 

signaled that labeling alone is not 

sufficient to ensure appropriate selfselection or appropriate actual use, or 

both. For example, this might apply if 

FDA has previously approved multiple 

nonprescription drug products for the 

same indication with a similar ACNU. 

The applicant is encouraged to discuss 

its drug development plans with FDA if 

the applicant has questions about 

whether an ACNU would be 

appropriate. 

f. Adequate data or other information 

that demonstrates the effect of the 

ACNU on the appropriate self-selection 

or appropriate actual use, or both. The 

applicant must also submit adequate 

data or information that demonstrates 

the effect of the ACNU on the 

appropriate self-selection or appropriate 

actual use, or both, by the consumer of 

the nonprescription drug product (see 

proposed § 314.56(c)(1)(vi)). The data 

must show that consumers can 

appropriately self-select or use the drug 

product safely and effectively, or both, 

with the ACNU. For example, the 

applicant of Drug X would submit 

adequate data from robust self-selection 

studies that demonstrate that consumers 

could appropriately self-select Drug X 

with the ACNU. 

g. Description of how the applicant 

will operationalize the ACNU. The 

proposed rule would require that the 

applicant describe the specific way the 

ACNU is operationalized (see proposed 

§ 314.56(c)(1)(vii)). While it is important 

for FDA to understand how the ACNU 

is operationalized because this is part of 

achieving appropriate self-selection or 

use, the specific way an ACNU is 

operationalized is not a key element of 

the ACNU. The purpose of the ACNU is 

to enable self-selection and appropriate 

use without the oversight of a healthcare 

practitioner. The ACNU can be 

operationalized in different ways 

provided it reliably meets the objective. 

Alternatives to the way the ACNU is 

operationalized in the previous 

example, which involves administration 

of a questionnaire using a website, 

might include: (1) administering the 

questionnaire using a display screen at 

a pharmacy kiosk, (2) administering the 

questionnaire using a mobile 

application, and (3) administering the 

questionnaire using an automated 

telephone response system. These 

examples differ in the way the ACNU is 

operationalized (i.e., how the 

questionnaire is being administered), 

but the key elements (including the 

questions in the questionnaire and 

responses that ensure appropriate selfselection) remain the same. FDA seeks 

comment on any unique issues that 

might arise for retailers or consumers 

based on the way the applicant 

operationalizes the ACNU in the 

previous examples, e.g., in a store kiosk, 

online, or otherwise. 

h. Additional considerations. If an 

NDA applicant submits an application 


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for a nonprescription drug product with 

an ACNU that proposes to use certain 

technologies, but FDA determines that 

labeling alone is sufficient to enable 

appropriate self-selection and 

appropriate actual use, FDA would 

refuse to approve the application for the 

nonprescription drug product with the 

ACNU (see proposed §§ 314.125(b)(20) 

and 314.127(a)(15)). However, FDA may 

approve an application for a 

nonprescription drug product with 

technologies that do not meet the 

definition of an ACNU. In cases where 

FDA determines that labeling alone is 

sufficient to enable appropriate selfselection and appropriate actual use, the 

labeling statements specifically required 

for a nonprescription drug product with 

an ACNU under this proposed rule (see 

proposed § 201.130) must not appear on 

the drug product labeling. 

2. Abbreviated New Drug Application 

Applicants may submit an ANDA 

referencing a listed drug that has been 

approved with an ACNU under section 

505(c) of the FD&C Act and rely on 

FDA’s previous finding that the RLD is 

safe and effective. The proposed rule 

would require that an ANDA for a 

nonprescription drug product with an 

ACNU must, when fulfilling the content 

and format requirements under § 314.94: 

(1) state the purpose of the ACNU (the 

same purpose as the ACNU for the 

RLD), (2) include information 

demonstrating that the key elements of 

the proposed ACNU are the same as the 

key elements of the ACNU for its RLD, 

and (3) include information on the way 

the ANDA applicant intends to 

operationalize the proposed ACNU. If 

an applicant believes the ACNU is 

operationalized in the same way as the 

RLD (e.g., both use a mobile 

application), the ANDA must include 

information demonstrating the 

operationalization of the ACNU is the 

same as the RLD. If the ANDA proposes 

a different way to operationalize the 

proposed ACNU, the ANDA must 

include information to show that this 

different operationalization of the 

proposed ACNU achieves the same 

purpose as the ACNU for its RLD and 

the differences from the RLD are 

otherwise acceptable in an ANDA (see 

proposed § 314.56(c)(2)). As with all 

ANDAs, an ANDA for a nonprescription 

drug product with an ACNU also would 

be expected to be pharmaceutically 

equivalent and bioequivalent to its RLD 

and to have the same clinical effect and 

safety profile as its RLD when 

administered to patients under the 

conditions specified in the labeling. 

Information concerning the purpose of 

the reference product’s ACNU and the 

description of the key elements should 

be available in the approval letter for the 

reference product or in the publicly 

available approval package. 

The labeling for the ANDA drug 

product must be the same as the 

labeling for its RLD at the time of the 

ANDA’s approval, except for changes 

required because of differences 

approved under a petition filed under 

§ 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) and 314.127(a)(7)). 

a. Statement regarding the purpose of 

the ACNU. As part of the submission, an 

ANDA applicant would state the 

purpose of the ACNU (the same purpose 

as the ACNU for the RLD) (see proposed 

§ 314.56(c)(2)(i)). Although an ANDA 

must state the purpose of the ACNU, an 

ANDA would not be required to include 

the explanation of the necessity for the 

ACNU or how the ACNU would ensure 

appropriate self-selection, appropriate 

actual use, or both. As a general matter, 

the ANDA would rely on FDA’s findings 

of safety and effectiveness for an RLD 

with an ACNU. 

b. Description of key elements of the 

ACNU. An ANDA applicant would also 

provide information to show that the 

key elements of the proposed ACNU are 

the same as the key elements of the 

ACNU approved for its RLD (see 

proposed § 314.56(c)(2)(ii)). 

c. Description of how the applicant 

will operationalize the ACNU. An 

ANDA applicant would include 

information on how the ACNU would 

be operationalized. The proposed rule 

would allow ANDA applicants to 

operationalize its ACNU in a different 

way from its RLD. For instance, an 

ANDA applicant may consider 

proposing to make available on the 

internet a self-selection aid for its 

nonprescription drug product with an 

ACNU, whereas the self-selection aid for 

its RLD is made available at a physical 

retail store via an electronic display. 

Consistent with section 505(j) of the 

FD&C Act and our general approach to 

ANDAs, an ANDA would have a variety 

of ways to achieve the same purpose as 

the ACNU for its RLD. The ANDA 

would contain information to support 

that the way in which it is 

operationalized, as proposed, achieves 

the same purpose as the ACNU for its 

RLD and the differences from the RLD 

are otherwise acceptable in an ANDA 

(see proposed § 314.56(c)(2)(iii)). As 

with all ANDAs, an ANDA for a 

nonprescription drug product with an 

ACNU also would be expected to be 

pharmaceutically equivalent and 

bioequivalent to its RLD and have the 

same clinical effect and safety profile as 

its RLD when administered to patients 

under the conditions specified in the 

labeling. 

FDA requests comment on the 

proposal to allow potential permissible 

differences between the NDA and the 

ANDA in the ways to operationalize the 

ACNU and how an applicant would 

demonstrate that the ACNU for the 

ANDA achieves the same purpose as the 

ACNU for its RLD. 

As stated earlier in this proposed rule, 

the specific ways to operationalize the 

ACNU are not considered key elements 

of the ACNU and otherwise are not 

considered a condition of use of the 

drug product. For example, to the extent 

NDA applicants operationalize their 

ACNUs using proprietary means, ANDA 

applicants can use different ways than 

their RLD for operationalizing the 

ACNU (provided that the purpose of the 

ACNU is achieved through the same key 

elements). 

Although FDA plays a ministerial role 

in listing patents in the publication 

‘‘Approved Drug Products with 

Therapeutic Equivalence Evaluations’’ 

(commonly known as the Orange Book), 

FDA seeks comment on whether patents 

claiming aspects of the ACNU for the 

nonprescription drug product may be 

submitted for listing consistent with 

§ 314.53 and section 505(b)(1)(A)(viii) 

and (c)(2) of the FD&C Act. FDA seeks 

comments on this topic and other issues 

FDA should consider in implementing 

this proposal that will help avoid 

unnecessarily delaying the entry of 

ANDA nonprescription drug products 

with an ACNU to the drug market. 

E. Nonprescription and Prescription 

Approval and Simultaneous Marketing 

(Proposed § 314.56(d)) 

FDA has interpreted the language in 

section 503(b)(4) of the FD&C Act to 

allow simultaneous marketing of drug 

products with the same active 

ingredient as prescription and 

nonprescription if some meaningful 

difference, such as indication, strength, 

route of administration, dosage form, or 

patient population, exists between the 

drug products that makes the 

prescription product safe and effective 

only under the supervision of a 

healthcare practitioner licensed by law 

to administer the drug (see 83 FR 13994, 

April 2, 2018; see also 70 FR 52050, 

September 1, 2005). Section 503(b)(1) of 

the FD&C Act requires a drug which: (1) 

because of its toxicity or other 

potentiality for harmful effect, or the 

method of its use, or the collateral 

measures necessary to its use, is not safe 

for use except under the supervision of 


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a practitioner licensed by law to 

dispense such drug or (2) is limited by 

an approved application under section 

505 of the FD&C Act to use under the 

professional supervision of a 

practitioner licensed by law to 

administer such drug, to be dispensed 

only upon prescription of a practitioner 

licensed to administer such drug. Under 

section 503(b)(4)(B) of the FD&C Act, a 

drug, for which the prescription 

dispensing provisions of section 

503(b)(1) of the FD&C Act do not apply, 

shall be deemed to be misbranded if at 

any time before dispensing, the label of 

the drug bears the ‘‘Rx only’’ symbol. 

Likewise, under section 503(b)(4)(A), 

drugs that are subject to the prescription 

dispensing provisions of section 

503(b)(1) must bear the ‘‘Rx only’’ 

symbol, or else they are misbranded. 

This effectively means that, absent a 

meaningful difference between the 

products, simultaneous marketing of 

two drug products with the same active 

ingredient as both a prescription and a 

nonprescription drug product would 

result in one of the two products being 

misbranded. 

Under this proposed rule, the 

additional condition(s) that allow a 

nonprescription drug product to be 

safely used without the supervision of a 

healthcare practitioner would be a 

meaningful difference between the 

prescription drug product and the 

nonprescription drug product with an 

ACNU. Therefore, under the proposed 

rule, a prescription drug product and a 

nonprescription drug product with an 

ACNU that contain the same active 

ingredient can be simultaneously 

marketed even if they do not have other 

meaningful differences, such as 

different indications or strengths (see 

proposed § 314.56(d)). 

The proposed rule would require 

applicants seeking approval for the first 

time of an NDA for a nonprescription 

drug product with an ACNU to submit 

a separate NDA, rather than a 

supplement to an approved NDA (see 

proposed § 314.56(b)). The approval of a 

separate NDA would permit 

simultaneous marketing and access to 

the drug as both a prescription drug 

product and a nonprescription drug 

product with an ACNU. Consistent with 

FDA’s goal of increasing options for 

applicants to develop and market safe 

and effective drugs for consumers, this 

proposed rule would enable continued 

access to the drug product as a 

prescription drug product, while also 

extending access to the drug product in 

the nonprescription setting with the 

ACNU. Even if the application holder of 

the NDA for the prescription drug 

product decides to discontinue 

marketing of the NDA for the 

prescription drug product, generic 

versions of the prescription drug 

product would be eligible for approval 

relying on the discontinued NDA for the 

prescription product as an RLD, so long 

as FDA determines that the NDA for the 

prescription product was not 

discontinued for reasons of safety or 

effectiveness (see § 314.161). 

F. Refusal To Approve an Application 

With an ACNU (Proposed 

§§ 314.125(b)(20) and 314.127(a)(15)) 

The proposed rule would specify that 

FDA would refuse to approve an NDA 

for a nonprescription drug product with 

an ACNU if FDA has determined the 

NDA failed to meet the requirements in 

§ 314.56 applicable to NDAs (see 

proposed § 314.125(b)(20)). Similarly, 

the proposed rule would specify that 

FDA would refuse to approve an ANDA 

for a nonprescription drug product with 

an ACNU that fails to meet the 

requirements in § 314.56 applicable to 

ANDAs (see proposed § 314.127(a)(15)). 

In addition to other reasons cited in 

§ 314.125 or § 314.127, FDA would 

refuse to approve an application for a 

nonprescription drug product with an 

ACNU if FDA has determined that the 

applicant failed to demonstrate that 

labeling is insufficient to ensure 

consumers’ appropriate self-selection or 

appropriate actual use, or both, of the 

nonprescription drug product without 

the supervision of a healthcare 

practitioner or if the applicant failed to 

demonstrate that its proposed ACNU is 

adequate to ensure appropriate selfselection or appropriate actual use, or 

both, by consumers without the 

supervision of a healthcare practitioner. 

We also note that under current 

§ 314.125(b)(8), FDA may refuse to 

approve an NDA if the drug product’s 

proposed labeling does not comply with 

the requirements for labels and labeling 

in part 201. This authority would permit 

FDA to refuse to approve an NDA with 

an ACNU if the labeling does not 

comply with labeling requirements 

specific to such NDAs, such as proposed 

§§ 201.67 and 201.130. Similarly, under 

current § 314.127(a)(7), FDA will refuse 

to approve an ANDA if its labeling is 

not the same as the labeling of its RLD, 

with certain permitted exceptions. 

Thus, FDA may refuse to approve an 

ANDA with an ACNU if its proposed 

labeling does not comply with labeling 

requirements specific to 

nonprescription products with an 

ACNU, such as proposed §§ 201.67 and 

201.130. 

G. Other Postmarketing Reports 

(Proposed § 314.81(b)(3)(v)) 

The proposed rule would require 

NDA and ANDA applicants to report to 

FDA information concerning any 

incident of failure in the 

implementation of an ACNU using the 

FDA Adverse Event Reporting System 

(FAERS) (see proposed 

§ 314.81(b)(3)(v)). A failure in 

implementation of an ACNU would 

include any event that results from a 

deviation in an applicant’s 

implementation of the ACNU that may 

cause or lead to inappropriate 

medication use or consumer harm, such 

as a consumer gaining access to the drug 

product without fulfilling all necessary 

conditions for the nonprescription drug 

product with an ACNU. A failure in 

implementation of an ACNU must be 

reported by the applicant whether or not 

the failure is associated with an adverse 

event. To meet these reporting 

requirements, applicants will likely 

need quality assurance systems in place 

to capture instances where failures in 

implementation of an ACNU occur. A 

failure in implementation of an ACNU 

includes the following circumstances: 

(1) the consumer accessed or used the 

drug product without successfully 

fulfilling the ACNU, (2) the consumer 

successfully fulfilled the ACNU but 

could not access or appropriately use 

the drug product in the nonprescription 

setting, or (3) the consumer was unable 

to make an attempt to fulfill the ACNU 

due to systematic, technological, or 

mechanical errors in the 

implementation of the ACNU. For 

example, for the fictitious 

nonprescription drug product with an 

ACNU Drug X (as discussed in section 

V.D of this document), a report would 

be required to be submitted to FDA if 

the consumer with an acceptable risk 

score, was unable to purchase Drug X on 

the applicant’s website or receive a 

voucher from the applicant’s website in 

order to purchase Drug X at a retail site 

specified by the applicant. Failure to 

access the drug product could result in 

the consumer missing doses of the drug 

product. 

The applicant must submit a single 

report (an individual case safety report 

(ICSR) of an adverse event) describing 

both the failure in implementation of an 

ACNU and an associated adverse event 

when both occur and the applicant is 

aware of both before submitting a report. 

If the applicant determines that a failure 

of implementation of an ACNU occurred 

that is associated with a previously 

submitted ICSR of an adverse event, a 

followup report must be submitted to 

FAERS using the same unique 


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identification number as the original 

ICSR of an adverse event and must 

include the information concerning the 

failure in implementation of an ACNU 

as required by proposed 

§ 314.81(b)(3)(v)(A). If the applicant 

receives information of an adverse event 

associated with a previously submitted 

report in FAERS of a failure in 

implementation of an ACNU, a followup 

report must be submitted to FAERS as 

an ICSR of an adverse event. Such 

followup report must use the same 

unique identification number as the 

original report in FAERS of a failure in 

implementation of an ACNU and must 

include the information concerning the 

adverse event as required in § 314.80(f). 

A report to FAERS for a failure in 

implementation of an ACNU would be 

submitted when the applicant has at 

least the minimum dataset for a failure 

in implementation, which includes the 

following three elements: (1) an 

identifiable reporter, (2) the drug 

product name, and (3) a description of 

the failure in implementation of the 

ACNU. The proposed rule would 

require the report to include certain 

information that the applicant is aware 

of about the drug product and the initial 

reporter, as well as a narrative summary 

of the failure in implementation of an 

ACNU and a description of the action 

initiated or completed to address the 

failure in implementation of an ACNU. 

The applicant would be required to 

submit a report for each failure in 

implementation of an ACNU as soon as 

possible but no later than 15 calendar 

days from the date when the applicant 

has acquired the minimum dataset for a 

report of a failure in implementation of 

an ACNU. Additionally, if an applicant 

obtains or otherwise receives any new 

information about previously submitted 

reports about the failure in 

implementation of an ACNU, the 

applicant would be required to 

investigate the new information, assess 

the relationship or impact of the new 

information on the initial report, and 

submit followup reports as soon as 

possible but no later than 15 calendar 

days after obtaining the new 

information. Proposed 

§ 314.81(b)(3)(v)(C) would require the 

report to be submitted to FDA in an 

electronic format that FDA can process, 

review, and archive unless a waiver has 

been requested and granted. To better 

enable FDA to assess compliance with 

reporting requirements and to facilitate 

FDA’s inspection of related records, we 

are proposing to require an applicant to 

maintain for a period of 10 years the 

records of all reports of failures in 

implementations of an ACNU and 

associated adverse events known to the 

applicant (proposed 

§ 314.81(b)(3)(v)(D)). 

FDA seeks specific comment on the 

burden and benefits of submitting an 

individual report to FDA for each 

individual failure in implementation of 

an ACNU encountered by a consumer 

resulting from the same cause of failure, 

as opposed to a single, consolidated 

report for all such failures. For example, 

there could be a situation where an 

ACNU involves administration of a 

questionnaire using a pharmacy kiosk, 

and the kiosk screen malfunctions, 

preventing multiple consumers from 

fulfilling the ACNU because they cannot 

complete the questionnaire on the kiosk 

screen. We are seeking comment on the 

benefits and burdens in this type of 

situation of submitting individual 

reports for each consumer affected by 

the malfunction versus one single, 

consolidated report for all consumers 

affected. 

H. General Labeling Requirements 

(Proposed § 201.67(c)) 

The proposed rule would clarify that 

a nonprescription drug product with an 

ACNU must comply with all applicable 

regulatory requirements for 

nonprescription drug products, 

including those under part 201. 

Specifically, the applicant must comply 

with the existing content and format 

requirements for nonprescription drug 

products in § 201.66, known as the DFL 

(see proposed § 201.67(c)(1)). As 

required in § 201.66(c)(6), the labeling 

for all nonprescription drug products 

must contain directions for use under 

the heading ‘‘Directions.’’ The proposed 

rule would require the labeling for all 

nonprescription drug products 

approved with an ACNU to include the 

following statement, as specified in 

proposed § 201.130(a)(1), as the first 

statement under the heading 

‘‘Directions’’: ‘‘To check if this drug is 

safe for you, go to [insert where or how 

consumers can find information about 

the ACNU; for example, applicant’s 

website, applicant’s phone number, or 

specific retail location] and [insert 

action to be taken by consumer]. Do not 

take this drug without completing this 

step.’’ This initial statement would be 

followed by the other required 

information in § 201.66(c)(6). This 

proposed statement would alert 

consumers that the nonprescription 

drug product with an ACNU has a 

requirement that must be fulfilled to 

ensure safe and effective use. The 

proposed statement would further 

remind the original purchaser and alert 

persons other than the original 

purchaser that the product is not 

suitable for all individuals and that 

consumers should carefully examine 

any labeling accompanying the 

nonprescription product with an ACNU 

before using the product. 

As stated previously, FDA may 

currently approve labeling for 

nonprescription drug products in 

addition to the DFL, and this would 

continue if the proposed rule is 

finalized (see proposed § 201.67(c)(2)). 

For example, FDA could approve 

information leaflets or other documents 

contained inside the carton or container 

for a nonprescription drug product, 

including for a nonprescription drug 

product with an ACNU. 

A list of questions to be answered by 

the consumer in a self-selection aid 

could be labeling necessary to 

effectively implement the ACNU. All 

labels and other written, printed, or 

graphic matter that are necessary to 

effectively implement the ACNU (e.g., 

questions associated with a selfselection aid) would be considered to 

accompany the nonprescription drug 

product and, therefore, would meet the 

definition of labeling under the FD&C 

Act. 

Approved labeling for a 

nonprescription drug product with an 

ACNU must be available to consumers 

at the time of purchase and use as 

required in section 502(c) of the FD&C 

Act. In general, we believe that the 

applicant should describe in their 

application the process for ensuring 

consumers have access to the approved 

labeling prior to fulfilling the ACNU. 

I. Format Requirements for Required 

ACNU Statement (Proposed § 201.67(d)) 

The proposed rule would require that 

the statement specified in 

§ 201.130(a)(2) meet specific format 

requirements (see proposed § 201.67(d)). 

This statement must be visible to 

consumers at the time of purchase and 

use. Additionally, the statement would 

alert persons that may have access to the 

drug product (e.g., family members in 

the purchaser’s home), including the 

individual who originally purchased the 

product, that these nonprescription drug 

products are not suitable for all 

individuals and should only be used 

after fulfilling the ACNU. The proposed 

rule would require that the statement 

appear on the principal display panel 

(see § 201.60) and the immediate 

container surface that the consumer is 

most likely to view when seeking 

information about the drug product (see 

proposed § 201.67(d)(1)). If the 

immediate container is a bottle, the 

statement must appear on the surface 

that the consumer would most likely 

consider to be the front of the bottle. If 


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the immediate container is a blister 

card, the statement must appear on the 

blister card surface that the consumer 

would most likely view when removing 

the drug product from the blister card. 

If the blister card contains more than 

one blister unit, the statement would 

not need to be included on each blister 

unit of a blister card. However, the 

statement must remain intact and be 

readable on the blister card when the 

drug product is removed from each 

blister unit. 

The proposed rule would require that 

the statement be prominently presented 

in boldface and black type in a yellow 

background banner (see proposed 

§ 201.67(d)(2) and (3)). No other 

information or statement may be 

included in the yellow background 

banner. The hue of the yellow color in 

the background banner must be a shade 

that provides a high contrast with the 

black type of the statement. The font 

size of the statement would be at least 

25 percent as large as the font size of the 

largest printed words on the container 

surface that the consumer would most 

likely view when seeking information 

about the drug product; in no case could 

the font size be smaller than 12 point 

type (1 point = 0.0138 inches) (see 

proposed § 201.67(d)(4)). For containers 

where the size would render 

compliance with this requirement 

impractical, the applicant would be able 

to request an exception to the minimum 

font size requirement (see proposed 

§ 201.67(d)(5)). However, FDA would 

not determine an exception is warranted 

if the statement is not prominent in 

relation to other elements on the 

container surface containing the 

statement. 

J. Exemption From Adequate Directions 

for Use (Proposed § 201.130) 

Consistent with the proposed 

definition of ACNU, a drug product can 

only be approved with an ACNU if the 

applicant demonstrates and FDA 

determines that labeling alone is 

insufficient to ensure appropriate selfselection or appropriate actual use, or 

both. Therefore, it is not possible for 

these products to be labeled with 

adequate directions for use under 

section 502(f)(1) of the FD&C Act, as 

defined in § 201.5. The proposed rule 

would exempt a nonprescription drug 

product with an ACNU from the 

statutory requirement to be labeled with 

adequate directions for use, provided 

that certain conditions are met. 

Specifically, a nonprescription drug 

product approved with an ACNU under 

section 505(c) or (j) of the FD&C Act 

would be exempt from section 502(f)(1) 

if the product contains the labeling 

required under proposed § 201.130(a) 

and the ACNU is implemented by the 

applicant as approved by FDA in the 

application (see proposed § 201.130). 

FDA is proposing this exemption to the 

requirement for adequate directions for 

use for a nonprescription drug product 

with an ACNU because we have 

determined that the labeling and the 

ACNU are sufficient to ensure 

consumers’ appropriate self-selection 

and actual use of the nonprescription 

product without the supervision of a 

healthcare practitioner. Therefore, 

adequate directions for use, as required 

by section 502(f)(1) of the FD&C Act and 

§ 201.5, would not be necessary for the 

protection of the public health. 

The proposed rule would require that 

the following statement appear as the 

first direction under the heading 

‘‘Directions’’ in the labeling, as required 

in § 201.66(c)(6): ‘‘To check if this drug 

is safe for you, go to [insert where or 

how consumers can find information 

about the ACNU; for example, 

applicant’s website, phone number, or 

specific retail location] and [insert 

action to be taken by consumer]. Do not 

take this drug without completing this 

step.’’ (See proposed § 201.130(a)(1).) 

The applicant would include 

information to inform consumers where 

the additional condition would be 

found and explain the additional 

condition that the consumer must 

fulfill. For example, ‘‘To check if this 

drug is safe for you, go to 

www.XYZCompany.com and take the 

self-selection questionnaire. Do not take 

this drug without completing this step.’’ 

The statement would be followed by the 

other information required in 

§ 201.66(c)(6). FDA is specifically 

seeking comment on the content of the 

statements and the ability of these 

statements to sufficiently inform 

consumers that the product is a 

nonprescription drug product with an 

ACNU and how consumers would fulfill 

the ACNU. 

The proposed rule would also require 

that the following statement appear on 

the immediate container label and, if 

one exists, the outside container or 

wrapper of the retail package: ‘‘You 

must complete an extra step to see if 

this drug is safe for you before you use 

it. Do not take this drug without 

completing this step. See the Drug Facts 

labeling for more information.’’ (See 

proposed § 201.130(a)(2).) This 

statement must meet the specific format 

requirements as specified in proposed 

§ 201.67(d). The statement would 

remind the original purchaser and alert 

persons other than the original 

purchaser that these nonprescription 

drug products are not suitable for all 

individuals and should only be used 

after fulfilling the ACNU. FDA is 

specifically seeking comment on 

whether this statement would 

sufficiently alert consumers that this 

product is a nonprescription drug 

product with an ACNU. 

The proposed rule would require the 

ACNU to be implemented by the 

applicant under the conditions set forth 

in the approved application for the 

nonprescription drug product with an 

ACNU to be exempt from the 

requirement to be labeled with adequate 

directions for use (see proposed 

§ 201.130(b)). 

K. Misbranding (Proposed § 201.67(e)) 

As noted immediately above, the 

proposed rule would exempt a 

nonprescription drug product with an 

ACNU from the requirement to be 

labeled with adequate directions for use 

under section 502(f)(1) of the FD&C Act, 

provided that certain conditions are met 

(see proposed § 201.130). If a 

nonprescription drug product with an 

ACNU is made available to consumers 

without the labeling specified in 

proposed § 201.130(a) or the ACNU is 

not implemented by the applicant as 

approved by FDA in the application, the 

drug product would be misbranded 

under section 502(f)(1) of the FD&C Act 

(see proposed § 201.67(e)). 

As discussed in sections V.H and V.I 

of this document, the proposed rule 

would include specific labeling 

requirements for a nonprescription drug 

product with an ACNU. If the 

nonprescription drug product with an 

ACNU is made available to consumers 

without the specific required labeling, 

the product would also be misbranded 

under section 502(a) of the FD&C Act, 

which provides that a drug’s labeling 

must not be false or misleading in any 

particular (see proposed § 201.67(e)). 

Under section 201(n) of the FD&C Act, 

in determining whether labeling is 

misleading, there shall be taken into 

account (among other things), not only 

representations made or suggested but 

also the extent to which the labeling 

fails to reveal facts material in the light 

of such representations or material with 

respect to consequences that may result 

from the use of the drug under the 

conditions of use prescribed in the 

labeling or under usual or customary 

conditions of use. The required labeling 

statements described in proposed 

§ 201.130(a) are intended to inform 

consumers that the product is a 

nonprescription drug product with an 

ACNU; to instruct consumers on how to 

fulfill the ACNU; and to remind the 

original purchaser (and alert persons 

other than the original purchaser) that 


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the nonprescription drug product is not 

suitable for all individuals and should 

only be used after fulfilling the ACNU. 

Thus, failure of a nonprescription drug 

product approved with an ACNU to bear 

the required labeling statements 

described in proposed § 201.130(a) 

would constitute a failure to reveal 

material facts about the product or with 

respect to consequences that might 

result from its use and would misbrand 

the product. 

In addition, a nonprescription drug 

product with an ACNU could be 

misbranded under other provisions of 

section 502 of the FD&C Act. For 

example, in certain circumstances, such 

a drug may be misbranded under 

section 502(j) if the product does not 

meet the requirements of this proposed 

rule. 

Under the proposed rule, a 

nonprescription drug product with an 

ACNU must only be made available to 

the consumer after the ACNU has been 

fulfilled by the consumer. It is a 

prohibited act under section 301(a) of 

the FD&C Act to introduce or deliver for 

introduction into interstate commerce 

any drug that is misbranded (21 U.S.C. 

331(a)). It is also a prohibited act under 

section 301(k) of the FD&C Act to do 

any act with respect to a drug if such act 

is done while such drug is held for sale 

after shipment in interstate commerce 

and results in the drug being 

misbranded. 

Additionally, a nonprescription drug 

product approved with an ACNU would 

be an unapproved new drug if it is made 

available to consumers without the 

ACNU. With certain limited exceptions 

not relevant here, it is a violation of 

sections 301(d) and 505(a) of the FD&C 

Act to introduce or deliver for 

introduction into interstate commerce 

an unapproved new drug. 

VI. Proposed Effective Date 

We propose that a final rule based on 

this proposed rule become effective 60 

days after the date the final rule 

publishes in the Federal Register. 

VII. Preliminary Economic Analysis of 

Impacts 

A. Introduction 

We have examined the impacts of the 

proposed rule under Executive Order 

12866, Executive Order 13563, the 

Regulatory Flexibility Act (5 U.S.C. 

601–612), and the Unfunded Mandates 

Reform Act of 1995 (Pub. L. 104–4). 

Executive Orders 12866 and 13563 

direct us to assess all costs and benefits 

of available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). This 

proposed rule has been designated by 

the Office of Information and Regulatory 

Affairs as a significant regulatory action 

as defined by Executive Order 12866. 

The Regulatory Flexibility Act 

requires us to analyze regulatory options 

that would minimize any significant 

impact of a rule on small entities. This 

rule would establish the requirements 

for a nonprescription drug product with 

an ACNU. We cannot anticipate the 

number of applicants that would submit 

applications or the types of drug 

products that would be covered under 

such applications. However, we 

estimate the costs for any applicant to 

read and understand the rule would 

likely range between 0.04 percent and 

0.14 percent of the gross receipts of very 

small applicants. Therefore, we propose 

to certify that the proposed rule, if 

finalized, would not have a significant 

economic impact on a substantial 

number of small entities. 

The Unfunded Mandates Reform Act 

of 1995 (section 202(a)) requires us to 

prepare a written statement, which 

includes an assessment of anticipated 

costs and benefits, before proposing 

‘‘any rule that includes any Federal 

mandate that may result in the 

expenditure by State, local, and tribal 

governments, in the aggregate, or by the 

private sector, of $100,000,000 or more 

(adjusted annually for inflation) in any 

one year.’’ The current threshold after 

adjustment for inflation is $165 million, 

using the most current (2021) Implicit 

Price Deflator for the Gross Domestic 

Product. This proposed rule would not 

result in an expenditure in any year that 

meets or exceeds this amount. 

B. Summary of Costs and Benefits 

The proposed rule, if finalized, would 

establish the requirements for a 

nonprescription drug product with an 

ACNU. Compared to the traditional 

labeling paradigm of nonprescription 

drug products, this approved ACNU in 

addition to the labeling would ensure 

the appropriate self-selection, 

appropriate use, or both, of a drug 

product. We expect this rule could 

expand consumer access to certain drug 

products in a nonprescription setting. 

Table 1 shows our quantified benefits. 

We estimate a reduction in access costs 

to consumers who could transfer from a 

prescription to a nonprescription drug 

product with an ACNU. Our primary 

estimate for this item is $26.70 with a 

range of $0 to $53.40 per consumer per 

purchase. We also quantify the value of 

the potential reduction in the number of 

repetitive meetings with sponsors that 

the rule could eliminate, which occur 

during the approval process. This 

estimate includes benefits to FDA and 

industry. Our primary estimate is 

$55,469 per applicant with a range of 

$45,260 to $66,174. We do not monetize 

our estimates of benefits over a 10-year 

horizon because of the high uncertainty 

about number of applicants, 

applications, potential approvals, the 

number of purchases that might occur, 

and consumer preferences to switch 

products but present estimates in the 

uncertainty section of the full 

preliminary analysis of economic 

impacts. 

Although an applicant would incur 

the development and postmarketing, 

including reporting of failure in the 

implementation of the ACNU and 

recordkeeping costs, we assume that 

applicants submit applications when 

they believe that their expected profits 

from the approval will exceed the costs 

of the application. We present a range 

of these potential development and 

postmarketing costs in the appendix of 

the complete economic analysis. 

However, we lack information to 

monetize these costs over a 10-year 

horizon and request comment or data on 

these potential costs. 

Monetized costs include a one-time 

cost of reading and understanding the 

rule. Using a 7-percent discount rate, 

the primary estimate, annualized over a 

10-year horizon, equals $821 with a 

range of $379 to $1,264. These 

annualized costs are the same using a 3- 

percent discount rate. 

Government and private insurance 

payers may experience positive transfers 

because consumers may decrease future 

medical costs and the number of 

submitted insurance claims. Earlier 

access to drug products would allow 

consumers to treat medical conditions 

using nonprescription drug products 

with an ACNU without the supervision 

of a healthcare practitioner. 


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TABLE 1—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(%) 

Period 

covered 

Benefits: 

Annualized Monetized $millions/year. 

Annualized Quantified ......................................... .................. .................. .................. 2018 .................. .................. Quantified reduction in access costs per consumer 

purchase range from $0.0 

to $53.40, and a primary 

estimate of $26.70. 

2018 .................. .................. Quantified reduction in 

meetings between FDA 

and applicants range from 

$45,260 to $66,174 per 

applicant, and a primary 

estimate of $55,469. 

Qualitative. 

Costs: 

Annualized ........................................................... $0.0 $0.0 $0.0 2018 7 10 years ... Reading and understanding

one-time costs. 

Monetized $millions/year ..................................... $0.0 $0.0 $0.0 2018 3 10 years.

Annualized. 

Quantified. 

Qualitative ........................................................... .................. .................. .................. .................. .................. .................. Affected firms would incur 

costs to develop and submit applications. 

Transfers: 

Federal ................................................................ .................. .................. .................. .................. 7 

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

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

Other ...................................................................

Annualized Monetized $millions/year ..................

.................. .................. .................. .................. 7 

3 

From/To ............................................................... From: To: Potential benefits to government and private payors if 

access 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 would range from 0.04 percent to 0.14 percent of gross receipts. 

Wages: No estimated effect. 

Growth: No estimated effect. 

We have developed a comprehensive 

Preliminary Economic Analysis of 

Impacts that assesses the impacts of the 

proposed rule. The full preliminary 

analysis of economic impacts is 

available in the docket for this proposed 

rule (Ref. 7) and at https://www.fda.gov/ 

about-fda/reports/economic-impactanalyses-fda-regulations. 

VIII. Analysis of Environmental Impact 

We have determined under 21 CFR 

25.30(h) and (k) that this action is of a 

type that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

IX. Paperwork Reduction Act of 1995 

This proposed rule contains 

information collection provisions that 

are subject to review by OMB under the 

Paperwork Reduction Act of 1995 (44 

U.S.C. 3501–3521). A description of 

these provisions is given in the 

Description section below, with an 

estimate of the annual reporting, 

recordkeeping, and third-party 

disclosure burden. Included in the 

estimate is the time for reviewing 

instructions, searching existing data 

sources, gathering and maintaining the 

data needed, and completing and 

reviewing each collection of 

information. 

FDA invites comments on these 

topics: (1) whether the proposed 

collection of information is necessary 

for the proper performance of FDA’s 

functions, including whether the 

information will have practical utility; 

(2) the accuracy of FDA’s estimate of the 

burden of the proposed collection of 

information, including the validity of 

the methodology and assumptions used; 

(3) ways to enhance the quality, utility, 

and clarity of the information to be 

collected; and (4) ways to minimize the 

burden of the collection of information 

on respondents, including through the 

use of automated collection techniques, 

when appropriate, and other forms of 

information technology. 

Title: Premarket applications, 

postmarketing reports and 

recordkeeping, and labeling for 

Nonprescription Drug Products With an 

Additional Condition for 

Nonprescription Use. 

Description: We are revising 

requirements applicable to NDA and 

ANDA applicants of nonprescription 

drug products with an ACNU 

(collectively, respondents). If finalized, 

the proposed rule will modify 

information collections applicable to 

regulations in part 314 governing new 

and abbreviated new drug application 

submissions and drug labeling 

provisions in part 201 pertaining to 

nonprescription drug products. 

Description of Respondents: The 

respondents are: (1) for NDA and ANDA 


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submissions, an applicant who submits 

an NDA (including a 505(b)(2) 

application) or an ANDA under part 314 

to obtain FDA approval of a 

nonprescription drug with an ACNU; (2) 

for failure of implementation of an 

ACNU reporting and recordkeeping, any 

person who holds an approved NDA 

(including a 505(b)(2) application) or an 

approved ANDA that includes an 

ACNU; and (3) for labeling, any person 

who holds an approved NDA (including 

a 505(b)(2) application) or an approved 

ANDA that includes an ACNU. 

We estimate the burden of the 

information collection as follows: 

TABLE 2—ESTIMATED ANNUAL REPORTING BURDEN; OMB CONTROL NO. 0910–00011

Information collection activity; 21 CFR part 314 

(application for FDA approval to market a new drug) 

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 a failure in implementation of an 

ACNU; § 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. 

NDA and ANDA Submissions 

Based on our experience with 

information collection associated with 

current NDA and ANDA submissions, 

we estimate six applications for a 

nonprescription drug product with an 

ACNU will be submitted annually by six 

respondents. Based on Broad Agency 

Announcement proposals that set forth 

the number of hours anticipated to 

produce study reports for submission to 

us, we assume it will take an average of 

320 hours per application for both NDA 

and ANDA applicants to prepare and 

submit the information required for 

applications for nonprescription drugs 

with an ACNU (in addition to meeting 

the general NDA or ANDA requirements 

under §§ 314.50 and 314.94, already 

approved in OMB control number 0910– 

0001). 

Reports of a Failure in Implementation 

of an ACNU 

We estimate six respondents will each 

submit 25 reports to FDA for an 

individual failure in implementation of 

an ACNU under § 314.81(b)(3)(v). We 

assume an average of 40 hours per 

response for each applicant, for a total 

of 6,000 hours annually. As noted in the 

preamble of the proposed rule, we are 

also soliciting comments on the 

alternative reporting mechanism 

requiring the applicant to submit a 

single, consolidated report for all 

consumers affected by the same failure 

in implementation of an ACNU rather 

than a report for each individual 

impacted by the same failure in 

implementation of an ACNU. If that 

alternative is implemented in the final 

rule, we estimate that the number of 

reports per respondent would be 

reduced from 25 annual responses per 

respondent to 1 per year per respondent. 

TABLE 3—ESTIMATED ANNUAL RECORDKEEPING BURDEN; OMB CONTROL NO. 0910–0001 1

Information collection; 21 CFR part 314 (applications for 

FDA approval to market a new drug) 

Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

(hours) 

Total hours 

Requirements for failures in implementation of an ACNU; 

§ 314.81 ............................................................................ 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. 

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

Information collection activity; 21 CFR part 201, subpart C 

(format and content requirements for over-the-counter 

drug product labeling) 

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)) .................................. 6 1 6 15 90 

Additional ACNU labeling—§ 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. 


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Labeling for Nonprescription Drugs With 

an ACNU 

Based on our experience with NDA 

and ANDA submissions, we estimate six 

respondents will each submit an 

application for a nonprescription drug 

product with an ACNU, each becoming 

subject to all nonprescription labeling 

regulations in (21 CFR part 201, subpart 

C). This includes the requirements for 

statements of identity and net contents 

(§§ 201.61 and 201.62) which appear on 

the principal display panel (PDP) 

(defined by § 201.60); 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 proposed to be 

required by § 201.130(a)(1). (The 

proposed requirement in § 201.130(a)(2) 

to place a specified ACNU statement on 

the product PDP is not included in the 

definition of collection of information 

under the PRA and is therefore not 

subject to review and approval by OMB. 

See 5 CFR 1320.3(c)(2). These products 

may also have additional labeling 

beyond the DFL requirements 

(§ 201.67(c)(2)). 

Estimating six respondents will each 

have one new, approved drug that must 

comply with PDP and DFL labeling 

requirements, including statements 

specified in § 201.130(a)(1), and 

assuming compliance with these 

disclosures will require 15 hours per 

drug, we calculate a total of 90 hours 

annually. Additionally, we estimate six 

respondents will each have one new 

nonprescription drug product approved 

with an ACNU that contains additional 

labeling requirements, for a total of six 

annual responses. Based on our 

experience with nonprescription 

labeling requirements, we assume an 

average burden per response of 9 hours, 

for a total of 54 hours annually. 

To ensure that comments on this 

information collection are received, 

OMB recommends that written 

comments be submitted through 

reginfo.gov (see ADDRESSES). All 

comments should be identified with the 

title of the information collection. 

In compliance with the Paperwork 

Reduction Act of 1995 (44 U.S.C. 

3407(d)), we have submitted the 

information collection provisions of this 

proposed rule to OMB for review. These 

information collection requirements 

will not be effective until FDA 

publishes a final rule, OMB approves 

the information collection requirements, 

and the rule goes into effect. FDA will 

announce OMB approval of these 

requirements in the Federal Register. 

X. Federalism 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. We 

have determined that this proposed rule 

does not contain policies that have 

substantial direct effects on the States, 

on the relationship between the 

National Government and the States, or 

on the distribution of power and 

responsibilities among the various 

levels of government. Accordingly, we 

conclude that the rule does not contain 

policies that have federalism 

implications as defined in the Executive 

order and, consequently, a federalism 

summary impact statement is not 

required. 

XI. Consultation and Coordination With 

Indian Tribal Governments 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13175. We 

have tentatively determined that the 

rule does not contain policies that 

would have a substantial direct effect on 

one or more Indian Tribes, on the 

relationship between the Federal 

Government and Indian Tribes, or on 

the distribution of power and 

responsibilities between the Federal 

Government and Indian Tribes. The 

Agency solicits comments from tribal 

officials on any potential impact on 

Indian Tribes from this proposed action. 

XII. References 

The following references are on 

display at the Dockets Management Staff 

(see ADDRESSES) and are available for 

viewing by interested persons between 

9 a.m. and 4 p.m., Monday through 

Friday; they also are available 

electronically at https://

www.regulations.gov. FDA has verified 

the website addresses, as of the date this 

document publishes in the Federal 

Register, but websites are subject to 

change over time. 

1. FDA, Guidance for Industry, ‘‘SelfSelection Studies for Nonprescription 

Drug Products,’’ April 2013 (available at 

https://www.fda.gov/drugs/guidancecompliance-regulatory-information/ 

guidances-drugs). 

2. Chang J., A. Lizer, I. Patel, et al., 

‘‘Prescription to Over-the-Counter 

Switches in the United States,’’ Journal 

of Research in Pharmacy Practice, vol. 

5(3), pp. 149–154, doi:10.4103/2279– 

042X.185706. Available at: https://

www.jrpp.net/text.asp?2016/5/3/149/ 

185706. 

3. FDA, Guidance for Industry, ‘‘Label 

Comprehension Studies for 

Nonprescription Drug Products,’’ August 

2010 (available at https://www.fda.gov/ 

drugs/guidance-compliance-regulatoryinformation/guidances-drugs). 

4. Engelberg Center for Health Care Reform 

at the Brookings Institution, ‘‘Expert 

Workshop: Nonprescription Medications 

With Conditions of Safe Use as a Novel 

Solution for Undertreated Diseases or 

Conditions,’’ November 8, 2012 

(available at https://www.brookings.edu/ 

events/nonprescription-medicationswith-conditions-of-safe-use-as-a-novelsolution-for-undertreated-diseases-orconditions), accessed July 30, 2021. 

5. Engelberg Center for Health Care Reform 

at the Brookings Institution, ‘‘Expert 

Workshop: Innovative Technologies and 

Nonprescription Medications: 

Addressing Undertreated Diseases and 

Conditions through Technology Enabled 

Self-Care,’’ May 9, 2013 (available at 

https://www.brookings.edu/events/ 

innovative-technologies-andnonprescription-medications-addressingundertreated-diseases-and-conditionsthrough-technology-enabled-self-care), 

accessed July 30, 2021. 

6. Engelberg Center for Health Care Reform 

at the Brookings Institution, ‘‘Expert 

Workshop: Exploring Implications of the 

Nonprescription Drug Safe Use 

Regulatory Expansion (NSURE) Initiative 

on Reimbursement and Access,’’ 

November 4, 2013 (available at https://

www.brookings.edu/events/exploringimplications-of-the-nonprescriptiondrug-safe-use-regulatory-expansionnsure-initiative-on-reimbursement-andaccess), accessed July 30, 2021. 

7. FDA, Preliminary Regulatory Impact 

Analysis; Initial Regulatory Flexibility 

Analysis; Unfunded Mandates Reform 

Act Analysis, Nonprescription Drug 

Product With an Additional Condition 

for Nonprescription Use; Proposed Rule 

(available at http://www.fda.gov/ 

AboutFDA/ReportsManualsForms/ 

Reports/EconomicAnalyses/default.htm). 

List of Subjects 

21 CFR Part 201 

Drugs, Labeling, Reporting and 

recordkeeping requirements. 

21 CFR Part 314 

Administrative practice and 

procedure, Confidential business 

information, Drugs, Reporting and 

recordkeeping requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, and under 

authority delegated to the Commissioner 

of Food and Drugs, we propose that 21 

CFR parts 201 and 314 be amended as 

follows: 

PART 201—LABELING 

■ 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. 


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■ 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 healthcare 

practitioner if the applicant 

demonstrates and FDA determines that 

labeling alone is insufficient to ensure 

appropriate self-selection or appropriate 

actual use, or both. 

(2) [Reserved] 

(c) General labeling requirements. (1) 

A nonprescription drug product with an 

ACNU must comply with applicable 

labeling requirements for 

nonprescription drug products under 

this part, including the format and 

content requirements for 

nonprescription drug product labeling 

under § 201.66 and the statements 

specified in § 201.130(a). 

(2) A nonprescription drug product 

with an ACNU may also be approved 

with additional labeling that 

supplements the format and content 

requirements for nonprescription drug 

product labeling under § 201.66. 

(d) Format requirements for required 

ACNU statement. The statement 

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

all format requirements as follows: 

(1) The statement 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 must 

appear on the surface that the consumer 

is most likely to consider the front of the 

bottle. If the immediate container is a 

blister card (including a card that 

contains more than one blister unit), the 

statement must appear on the blister 

card surface that the consumer would 

most likely view when removing the 

drug product from the blister card. If the 

blister card contains more than one 

blister unit (e.g., perforated blister card 

where individual blister units can be 

separated from one another), the 

statement does not need to be included 

on each blister unit of a blister card. 

However, the statement must remain 

intact and be readable on the blister 

card when the drug product is removed 

from each blister unit. 

(2) The statement must appear in 

boldface and black type. 

(3) The statement must appear in a 

yellow background banner. No other 

information or statements may be 

included within the yellow background 

banner. 

(4) The statement must be in one of 

the following font sizes, whichever is 

greater: 

(i) At least 25 percent as large as the 

font size of the largest printed words on 

the principal display panel and 

immediate container; or 

(ii) At least 12 point font (1 point = 

0.0138 inches). 

(5) An applicant may request an 

exception to the minimum font size 

requirement specified in paragraph 

(d)(4) of this section for containers 

where its size would render compliance 

with this requirement impractical. FDA 

may allow such an exception upon 

request by an applicant if FDA 

determines an exception is warranted. 

(e) Misbranding. A nonprescription 

drug product with an ACNU is 

misbranded under section 502 of the 

Federal Food, Drug, and Cosmetic Act 

(21 U.S.C. 352) if— 

(1) It is made available without the 

labeling specified in § 201.130(a); or 

(2) The ACNU is not implemented by 

the applicant as approved by FDA in the 

application. 

■ 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. 

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) is exempt from section 

502(f)(1) if all the following conditions 

in paragraphs (a) and (b) of this section 

are met: 

(a) The label of the drug: 

(1) Bears, as the first direction under 

the ‘‘Directions’’ heading required in 

§ 201.66(c)(6), the statement ‘‘To check 

if this drug is safe for you, go to [insert 

where or how consumers can find 

information about the ACNU; for 

example, applicant’s website, 

applicant’s phone number, or specific 

retail location] and [insert action to be 

taken by consumer]. Do not take this 

drug without completing this step.’’ The 

statement must be followed by the other 

information required in § 201.66(c)(6). 

(2) Bears, in the form and manner 

required by § 201.67(d), the statement 

‘‘You must complete an extra step to see 

if this drug is safe for you before you use 

it. Do not take this drug without 

completing this step. See the Drug Facts 

labeling for more information.’’ 

(3) Complies with other applicable 

labeling requirements for 

nonprescription drug products under 

this part, including the format and 

content requirements for 

nonprescription drug product labeling 

under § 201.66. 

(b) The additional condition for 

nonprescription use is implemented by 

the applicant under the conditions set 

forth in the approved application. 

PART 314—APPLICATIONS FOR FDA 

APPROVAL TO MARKET A NEW DRUG 

■ 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 healthcare 

practitioner if an applicant 

demonstrates and FDA determines that 

labeling alone is insufficient to ensure 

appropriate self-selection or appropriate 

actual use, or both. 

(2) [Reserved] 

(b) Separate application required for 

a nonprescription drug product with an 

ACNU. An applicant must submit a 

separate application for a 

nonprescription drug product with an 

ACNU. Initial approval for a 

nonprescription drug product with an 

ACNU cannot be obtained through a 

supplement to an approved application. 

(c) Specific requirements for an 

application for a nonprescription drug 

product with an ACNU. The applicant 

must submit an application that 

complies with the following 

requirements: 

(1) New drug application (NDA). 

When fulfilling the content and format 

requirements under § 314.50, an NDA 

for a nonprescription drug product with 

an ACNU must include— 


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38330 Federal Register / Vol. 87, No. 123 / Tuesday, June 28, 2022 / Proposed Rules 

(i) A statement regarding the purpose 

of the ACNU: ensure appropriate selfselection or appropriate actual use, or 

both, by consumers of the 

nonprescription drug product with an 

ACNU without the supervision of a 

healthcare practitioner; 

(ii) A statement regarding the 

necessity of the ACNU; 

(iii) A description of how the ACNU 

ensures appropriate self-selection or 

appropriate actual use, or both; 

(iv) A description of the key elements 

of the ACNU, including: 

(A) The additional condition 

implemented by the applicant to be 

fulfilled by the consumer to obtain the 

nonprescription drug product with an 

ACNU; 

(B) The labeling specifically 

associated with the ACNU; and 

(C) The criteria by which the 

consumer would successfully fulfill the 

ACNU, including a description of the 

specific actions to be taken by a 

consumer or required responses to be 

provided by a consumer; 

(v) Adequate data or other 

information that demonstrates the 

necessity of the ACNU to ensure 

appropriate self-selection or appropriate 

actual use, or both; 

(vi) Adequate data or other 

information that demonstrates the effect 

of the ACNU on the appropriate selfselection or appropriate actual use, or 

both; and 

(vii) A description of the specific way 

the ACNU is operationalized. 

(2) Abbreviated new drug application 

(ANDA). When fulfilling the content 

and format requirements under § 314.94, 

an ANDA for a nonprescription drug 

product with an ACNU must— 

(i) State the purpose of the ACNU; 

(ii) Include information 

demonstrating that the key elements of 

the proposed ACNU are the same as the 

key elements of the ACNU for its 

reference listed drug (RLD); and 

(iii) Include information on the way 

the ACNU would be operationalized. If 

an applicant believes the ACNU is 

operationalized in the same way as the 

RLD, include information demonstrating 

that the ACNU is operationalized in the 

same way as the RLD. If a different way 

to operationalize the proposed ACNU is 

used, include information to show that 

this different way to operationalize the 

proposed ACNU achieves the same 

purpose as the ACNU for its RLD and 

that the differences from the RLD are 

otherwise acceptable in an ANDA. 

(d) Simultaneous marketing of 

nonprescription and prescription 

products. An ACNU constitutes a 

meaningful difference between a 

nonprescription drug product and a 

prescription drug product, such that a 

prescription drug product and a 

nonprescription drug product with an 

ACNU may be simultaneously marketed 

even if there is not another meaningful 

difference between the two products 

that makes the nonprescription drug 

product safe and effective for use 

without the supervision of a healthcare 

practitioner licensed by law to 

administer the drug (e.g., a different 

active ingredient, indication, strength, 

route of administration, dosage form, or 

patient population). 

■ 6. Amend § 314.81 by adding 

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

§ 314.81 Other postmarketing reports. 

* * * * * 

(b) * * * 

(3) * * * 

(v) Report of failure in the 

implementation of an additional 

condition for nonprescription use. The 

applicant must submit a report when a 

failure in the implementation of an 

additional condition for nonprescription 

use (ACNU) for a nonprescription drug 

product occurs. A report of a failure in 

implementation of an ACNU includes 

any event that results from a deviation 

in an applicant’s implementation of the 

ACNU that may cause or lead to 

inappropriate medication use or 

consumer harm. All failures in 

implementation of an ACNU must be 

reported to the FDA Adverse Event 

Reporting System (FAERS), whether or 

not the failure in implementation of an 

ACNU is associated with an adverse 

event. If an applicant becomes aware of 

both a failure in implementation of an 

ACNU and an associated adverse event 

before the submission to FAERS, a 

single individual case safety report 

(ICSR) that describes both the failure in 

implementation of an ACNU and the 

associated adverse event must be 

submitted and must contain the 

information as required in § 314.80(f) 

and paragraph (b)(3)(v)(A) of this 

section. If a previously submitted report 

to FAERS describes only a failure in 

implementation of an ACNU or a 

previously submitted ICSR reports only 

an adverse event, and the submitter 

subsequently becomes aware of an 

associated adverse event or associated 

failure in implementation of an ACNU, 

the submitter must supplement the 

original report to FAERS with the new 

information. The supplement must 

include the information required in 

§ 314.80(f) or paragraph (b)(3)(v)(A) of 

this section, as applicable. 

(A) Content. The report must include 

the following for a failure in 

implementation of an ACNU: 

(1) Required information. The name, 

address, email, and telephone number 

of the applicant; an identifiable reporter; 

the drug product name; and the 

description of the failure in 

implementation of the ACNU. 

(2) Additional information, if known. 

In addition, the report must include the 

following information, if known: 

(i) Drug product strength; National 

Drug Code (NDC); lot number; and NDA 

or ANDA number. 

(ii) Initial reporter information 

including name, address, and telephone 

number of the initial reporter. 

(iii) Unique case identification 

number, which must be the same in the 

initial report and any subsequent 

followup report(s). 

(iv) Narrative summary of failure in 

implementation of an ACNU, including 

the date of failure in implementation of 

an ACNU (or best estimate); the date the 

failure in implementation of an ACNU 

was reported to applicant; the location 

of failure in implementation of an 

ACNU, including business name and 

contact information; and 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; and 

(v) The remedial action taken or 

completed to address the failure in 

implementation of an ACNU, including 

the type of remedial action initiated or 

completed (for example, repair, replace, 

recall, inspection, modification, or 

adjustment) and a description of how 

the applicant will prevent failures of the 

same nature in the future. 

(B) Submission. (1) The applicant 

must submit the report for each failure 

in implementation of an ACNU as soon 

as possible but no later than 15 calendar 

days from the date when the applicant 

has acquired the minimum dataset for a 

failure in implementation of an ACNU. 

(2) The applicant must also 

investigate any new information it 

obtains or otherwise receives about 

previously submitted reports and assess 

the relationship or impact of the new 

information on the initial report. The 

applicant must submit followup reports 

as soon as possible but no later than 15 

calendar days after obtaining the new 

information. 

(C) Electronic format for submissions. 

(1) The report 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)(C)(1) of this section 

in accordance with § 314.90 or § 314.99. 


khammond on DSKJM1Z7X2PROD with PROPOSALS
Federal Register / Vol. 87, No. 123 / Tuesday, June 28, 2022 / Proposed Rules 38331 

(D) Recordkeeping. The applicant 

must maintain for a period of 10 years, 

the records of all reports of failures in 

implementation of an ACNU and 

associated adverse events known to the 

applicant, including raw data and any 

correspondence relating to a report of a 

failure in implementation of an ACNU. 

* * * * * 

■ 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: June 15, 2022. 

Robert M. Califf, 

Commissioner of Food and Drugs. 

[FR Doc. 2022–13309 Filed 6–27–22; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF THE TREASURY 

Internal Revenue Service 

26 CFR Part 20 

[REG–130975–08] 

RIN 1545–BI11 

Guidance Under Section 2053 

Regarding Deduction for Interest 

Expense and Amounts Paid Under a 

Personal Guarantee, Certain 

Substantiation Requirements, and 

Applicability of Present Value 

Concepts 

AGENCY: Internal Revenue Service (IRS), 

Treasury. 

ACTION: Notice of proposed rulemaking 

and notice of public hearing. 

SUMMARY: This document proposes to 

amend existing regulations issued under 

section 2053 of the Internal Revenue 

Code (Code). The proposed regulations 

provide guidance on the proper use of 

present-value principles in determining 

the amount deductible by an estate for 

funeral expenses, administration 

expenses, and certain claims against the 

estate. In addition, the proposed 

regulations provide guidance on the 

deductibility of interest expense 

accruing on tax and penalties owed by 

an estate, and interest expense accruing 

on certain loan obligations incurred by 

an estate. The proposed regulations also 

amend and clarify the requirements for 

substantiating the value of a claim 

against an estate that is deductible in 

certain cases. Finally, the proposed 

regulations provide guidance on the 

deductibility of amounts paid under a 

decedent’s personal guarantee. The 

proposed regulations will affect estates 

of decedents seeking to deduct funeral 

expenses, administration expenses, and/ 

or certain claims against the estate 

under section 2053. This document also 

provides a notice of a public hearing on 

these proposed regulations. 

DATES: Electronic or written comments 

must be received by September 26, 

2022. The public hearing is being held 

by teleconference on October 12, 2022, 

at 10 a.m. EST. Requests to speak and 

outlines of topics to be discussed at the 

public hearing must be received by 

September 26, 2022. If no outlines are 

received by September 26, 2022, the 

public hearing will be cancelled. 

Requests to attend the public hearing 

must be received by 5:00 p.m. EST on 

October 7, 2022. The telephonic hearing 

will be made accessible to people with 

disabilities. Requests for special 

assistance during the telephonic hearing 

must be received by October 6, 2022. 

ADDRESSES: Commenters are strongly 

encouraged to submit public comments 

electronically. Submit electronic 

submissions via the Federal 

eRulemaking Portal at 

www.regulations.gov (indicate IRS and 

REG–130975–08). Once submitted to the 

Federal eRulemaking Portal, comments 

cannot be edited or withdrawn. The IRS 

expects to have limited personnel 

available to process comments that are 

submitted on paper through the mail. 

The IRS will publish any comments 

submitted electronically, and to the 

extent practicable, comments submitted 

on paper to the public docket. Send 

paper submissions to CC:PA:LPD:PR 

(REG–130975–08), Room 5205, Internal 

Revenue Service, P.O. Box 7604, Ben 

Franklin Station, Washington, DC 

20044. 

For those requesting to speak during 

the hearing, send an outline of topic 

submissions electronically via the 

Federal eRulemaking Portal at 

www.regulations.gov (indicate IRS and 

REG–130975–08). 

Individuals who want to testify (by 

telephone) at the public hearing must 

send an email to publichearings@irs.gov 

to receive the telephone number and 

access code for the hearing. The subject 

line of the email must contain the 

regulation number REG–130975–08 and 

the word TESTIFY. For example, the 

subject line may say: Request to 

TESTIFY at Hearing for REG–130975– 

08. The email should include a copy of 

the speaker’s public comments and 

outline of topics. Individuals who want 

to attend (by telephone) the public 

hearing must also send an email to 

publichearings@irs.gov to receive the 

telephone number and access code for 

the hearing. The subject line of the 

email must contain the regulation 

number REG–130975–08 and the word 

ATTEND. For example, the subject line 

may say: Request to ATTEND Hearing 

for REG–130975–08. To request special 

assistance during the telephonic 

hearing, contact the Publications and 

Regulations Branch of the Office of 

Associate Chief Counsel (Procedure and 

Administration) by sending an email to 

publichearings@irs.gov (preferred) or by 

telephone at (202) 317–5177 (not a tollfree number). 

FOR FURTHER INFORMATION CONTACT: 

Concerning the proposed regulations, 

Karlene Lesho or Melissa Liquerman at 

(202) 317–6859; concerning the 

submission of comments, the hearing, or 

to be placed on the building access list 

to attend the hearing, Regina Johnson at 

(202) 317–6901 (not toll-free numbers) 

or by sending an email to 

publichearings@irs.gov. 

SUPPLEMENTARY INFORMATION: 

Background and Explanation of 

Provisions 

I. Overview 

This document contains proposed 

amendments to the Estate Tax 

Regulations (26 CFR part 20) under 

section 2053. 

Section 2001(a) imposes a tax on the 

transfer of the taxable estate of every 

decedent who was at death a citizen or 

resident of the United States. Section 

2051 defines the taxable estate as the 

value of the gross estate less the 

deductions provided for in sections 

2053 through 2058. Section 2031(a) 

describes the value of the gross estate of 

the decedent as including the value at 

the time of the decedent’s death of all 

property, real or personal, tangible or 

intangible, wherever situated. 

Under section 2053(a), for Federal 

estate tax purposes, the value of the 


khammond on DSKJM1Z7X2PROD with PROPOSALS