Rule2024-30261
Nonprescription Drug Product With an Additional Condition for Nonprescription Use
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
December 26, 2024
Effective
January 27, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is issuing a final rule to establish requirements for a nonprescription drug product with an additional condition for nonprescription use (ACNU). A nonprescription drug product with an ACNU is a drug product that could be marketed without a prescription if an applicant implements an additional condition to ensure appropriate self-selection or appropriate actual use, or both, by consumers without the supervision of a practitioner licensed by law to administer such drug. The final rule is intended to increase options for applicants to develop and market safe and effective nonprescription drug products and increase consumer access to appropriate, safe, and effective drug products, which could improve public health.
Full Text
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[Federal Register Volume 89, Number 247 (Thursday, December 26, 2024)]
[Rules and Regulations]
[Pages 105288-105331]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-30261]
[[Page 105287]]
Vol. 89
Thursday,
No. 247
December 26, 2024
Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 201 and 314
Nonprescription Drug Product With an Additional Condition for
Nonprescription Use; Final Rule
Federal Register / Vol. 89 , No. 247 / Thursday, December 26, 2024 /
Rules and Regulations
[[Page 105288]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201 and 314
[Docket No. FDA-2021-N-0862]
RIN 0910-AH62
Nonprescription Drug Product With an Additional Condition for
Nonprescription Use
AGENCY: Food and Drug Administration, Department of Health and Human
Services (HHS).
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
issuing a final rule to establish requirements for a nonprescription
drug product with an additional condition for nonprescription use
(ACNU). A nonprescription drug product with an ACNU is a drug product
that could be marketed without a prescription if an applicant
implements an additional condition to ensure appropriate self-selection
or appropriate actual use, or both, by consumers without the
supervision of a practitioner licensed by law to administer such drug.
The final rule is intended to increase options for applicants to
develop and market safe and effective nonprescription drug products and
increase consumer access to appropriate, safe, and effective drug
products, which could improve public health.
DATES: This rule is effective January 27, 2025.
ADDRESSES: For access to the docket to read background documents or
comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the
docket number found in brackets in the heading of this final rule into
the ``Search'' box and follow the prompts, and/or go to the Dockets
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852,
240-402-7500.
FOR FURTHER INFORMATION CONTACT:
With regard to the final rule: Myla Dellupac, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Silver Spring, MD 20993-0002, 301-837-7461.
With regard to the information collection: Amber Sanford, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-8867,
<a href="/cdn-cgi/l/email-protection#9dcdcfdccee9fcfbfbddfbf9fcb3f5f5eeb3faf2eb"><span class="__cf_email__" data-cfemail="2d7d7f6c7e594c4b4b6d4b494c0345455e034a425b">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Final Rule
B. Summary of the Major Provisions of the Final Rule
C. Legal Authority
D. Benefits, Costs, and Transfers
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. Need for the Regulation
B. FDA's Regulatory Framework
C. History of the Rulemaking
D. Summary of Comments to the Proposed Rule
E. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
A. Introduction
B. Description of General Comments and FDA Responses
C. Comments on Applicability and FDA Responses
D. Comments on Definition and FDA Responses
E. Comments on Separate Application Required for a
Nonprescription Drug Product With an ACNU and FDA Responses
F. Comments on Specific Requirements for an Application for a
Nonprescription Drug Product With an ACNU and FDA Responses
G. Comments on Nonprescription and Prescription Approval and
Simultaneous Marketing and FDA Responses
H. Comments on Refusal To Approve an Application With an ACNU
and FDA Response
I. Comments on Other Postmarketing Reports and FDA Responses
J. Comments on General Labeling Requirements and FDA Responses
K. Comments on Format Requirements for Required ACNU Statement
and FDA Responses
L. Comments on Exemption From Adequate Directions for Use and
FDA Responses
M. Comment on Misbranding and FDA Response
N. Miscellaneous Comments and FDA Responses
VI. Effective Date
VII. Economic Analysis of Impacts
A. Introduction
B. Summary of Benefits, Costs, and Transfers
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose of the Final Rule
FDA is finalizing this rule to establish requirements for a
nonprescription drug product with an ACNU. A nonprescription drug
product with an ACNU is a drug product that could be legally marketed
without a prescription if an applicant implements an additional
condition to ensure appropriate self-selection or appropriate actual
use, or both, by consumers without the supervision of a practitioner
licensed by law to administer such drug. Without this rule,
nonprescription drug products are limited to drug products that can be
labeled with sufficient information for consumers to appropriately
self-select and use the drug product without the supervision of a
practitioner licensed by law to administer such drug. For certain drug
products, labeling alone cannot adequately communicate the information
needed for consumers to appropriately self-select or use the drug
product without the supervision of a practitioner licensed by law to
administer such drug. The final rule is intended to increase options
for applicants \1\ to develop and market safe and effective
nonprescription drug products and increase consumer access to
appropriate, safe, and effective drug products, which could improve
public health.
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\1\ While we recognize that in certain circumstances ``sponsor''
is the correct term for the person who would be developing a
nonprescription drug product with an ACNU, we used the term
``applicant'' throughout the final rule for consistency (see the
definition for applicant in 21 CFR 314.3(b) and for sponsor in 21
CFR 312.3(b)).
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B. Summary of the Major Provisions of the Final Rule
This final rule establishes requirements for a nonprescription drug
product with an ACNU, including application, labeling, and
postmarketing reporting requirements. In addition to applicable
existing application requirements, the final rule establishes the
specific requirements for a new drug application (NDA) or abbreviated
new drug application (ANDA) for a nonprescription drug product with an
ACNU. In circumstances where a prescription drug product is already
approved, the rule requires an applicant to submit a separate
application for the approval of a nonprescription drug product with an
ACNU, rather than a supplement to the existing application for the
approved prescription drug product. The final rule establishes specific
labeling requirements, including the content and format of specific
labeling statements. Additionally, the rule requires that an applicant
submit a postmarketing report of an ACNU failure.
The final rule clarifies that an ACNU constitutes a meaningful
difference \2\
[[Page 105289]]
between a prescription drug product and a nonprescription drug product
that makes the nonprescription drug product safe and effective for use
without the supervision of a practitioner licensed by law to administer
such drug; therefore, a prescription drug product and a nonprescription
drug product with an ACNU with the same active ingredient may be
simultaneously marketed even if they do not have meaningful differences
other than the ACNU, such as different indications or strengths.
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\2\ FDA has used the terms ``meaningful difference'' and
``clinically meaningful difference'' interchangeably. Both refer to
the same scientific determination. See, e.g., 83 FR 13994 (April 2,
2018) and 87 FR 68702 (November 16, 2022).
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The final rule specifies that FDA will refuse to approve an
application for a nonprescription drug product with an ACNU if the
application fails to meet applicable requirements.
The final rule exempts a nonprescription drug product with an ACNU
from the requirement to be labeled with adequate directions for use,
provided that certain labeling conditions are met and the ACNU is
implemented by the applicant as approved by FDA.
Finally, the final rule explains certain circumstances in which a
nonprescription drug product with an ACNU would be misbranded.
FDA received many comments supporting the proposed rule's intent to
increase options for applicants to develop and market safe and
effective nonprescription drug products and increase consumer access to
appropriate, safe, and effective drug products. Additionally, we
received comments expressing concerns about certain proposed
requirements and the burden of those requirements for applicants. In
response to several comments expressing concerns about the proposed
postmarketing reporting requirements for nonprescription drug products
with an ACNU, we are revising the proposed requirements to provide
greater clarity for when a postmarketing report of ACNU failure must be
submitted to FDA and to reduce the burden on applicants by decreasing
any potential unnecessary reporting and ensuring consistency with
existing postmarketing reporting requirements. In response to several
comments about the proposed labeling statements on the principal
display panel (PDP) and Drug Facts labeling (DFL), we are revising the
proposed labeling requirements to allow FDA to approve an applicant's
proposed labeling statements that vary somewhat from the labeling
statements in the codified text, under certain circumstances.
Additionally, we are revising the proposed labeling requirements to
allow flexibility for the placement of the labeling statement on the
DFL depending on the purpose of the ACNU.
C. Legal Authority
This final rule, which establishes requirements for a
nonprescription drug product with an ACNU, is authorized by sections
201(n), 502, 503(b), 505, and 701(a) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 321(n), 352, 353(b), 355, and
371(a)).
D. Benefits, Costs, and Transfers
The final rule establishes requirements for a nonprescription drug
product with an ACNU. Compared to traditional nonprescription drug
products, which consumers must be able to self-select and use based on
their labeling, this approved ACNU, in addition to the labeling, will
ensure the appropriate self-selection, the appropriate use, or both of
a nonprescription drug product without the supervision of a
practitioner licensed by law to administer such drug. We expect this
rule will expand consumer access to certain drug products in a
nonprescription setting and increase options for applicants to develop
and market safe and effective nonprescription drug products.
We estimate a reduction in access costs to consumers who could
transfer from a prescription to a nonprescription drug product with an
ACNU. In our analysis, access costs include the time to see a doctor to
obtain a prescription, including waiting time and other transportation
costs. We also include co-pay and out-of-pocket costs in our estimate
of access costs. We compare the baseline access costs to the access
costs under potential scenarios with the final rule to estimate the
potential benefits for each consumer purchase. In this analysis, we use
the costs to obtain candidate prescription-only products as our
baseline access cost. Our primary estimate of reduction in access costs
is $33.62 per consumer per purchase with a range of $0 to $67.23. We
also quantify the value of the potential reduction in the number of
meetings with applicants that will occur during the approval process.
This estimate includes benefits to FDA and industry. Our primary
estimate is $68,773.11 per applicant with a range of $56,332.65 to
$81,763.56. We do not monetize our estimates of benefits over a 10-year
horizon because of the high uncertainty about the number of applicants,
applications, potential approvals, and purchases that might occur; and
consumer preferences to switch drug products. However, we present
estimates in the uncertainty section of this analysis.
Although an applicant will incur the costs to develop and submit an
application for a nonprescription drug product with an ACNU, for this
analysis, we assume that applicants submit applications only when they
believe that the profits from the approval will exceed the costs of the
application. We lack information to monetize these potential profits
and costs over a 10-year horizon.
Monetized costs include a one-time cost of reading and
understanding the rule per interested party in pursuing this path for
their drug products. We do not monetize these estimates for more than
one interested party because of the high uncertainty about the number
of interested parties over this time horizon. The primary estimate
equals $1,156.74 with a range of $533.88 to $1,779.60.
Government-sponsored and commercial insurance payers may experience
cost savings because the availability of nonprescription drug products
with an ACNU may decrease insurance claims and, potentially, future
medical costs. For example, access to drug products under this new
paradigm will allow consumers to treat some medical conditions using
nonprescription drug products with an ACNU without the supervision of a
practitioner licensed by law to administer such drug. We do not
estimate such cost savings due to lack of data.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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ACNU................................... Additional Condition for
Nonprescription Use
ANDA................................... Abbreviated New Drug
Application
DFL.................................... Drug Facts Labeling
FAERS.................................. FDA Adverse Event Reporting
System
FD&C Act............................... Federal Food, Drug, and
Cosmetic Act
FDA.................................... Food and Drug Administration
FTC.................................... Federal Trade Commission
ICSR................................... Individual Case Safety Report
NDA.................................... New Drug Application
NDC.................................... National Drug Code
OMB.................................... Office of Management and Budget
OTC.................................... Over-the-Counter
PDP.................................... Principal Display Panel
RLD.................................... Reference Listed Drug
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[[Page 105290]]
III. Background
A. Need for the Regulation
Nonprescription drug products are important for the treatment of
many conditions and diseases. Unlike prescription drug products,
nonprescription drug products may be accessed and used safely and
effectively by consumers without the supervision of a practitioner
licensed by law to administer such drugs for their intended use. At
present, the majority of nonprescription drug products are intended to
provide temporary relief of minor symptoms or to treat self-limited
conditions and diseases. Nonprescription drug products are usually
available for consumers to purchase at pharmacies, supermarkets, or
other retail locations, and from online retailers.
FDA recognizes the potential benefit of providing consumers with
access to additional types of nonprescription drug products, such as
some drug products that are currently available only by prescription
and that treat certain chronic diseases or conditions. This rule will
increase options for applicants to develop and market safe and
effective nonprescription drug products and increase consumer access to
appropriate, safe, and effective drug products. The availability of
nonprescription drug products with an ACNU may provide public health
benefits by facilitating consumers' ability to care for themselves and
access to appropriate medical treatment. For more information on the
need for regulation, see 87 FR 38313 (June 28, 2022; 2022 proposed
rule).
B. FDA's Regulatory Framework
There are two regulatory pathways to bring a nonprescription drug
product to market in the United States: (1) the over-the-counter (OTC)
drug review process under section 505G of the FD&C Act (21 U.S.C. 355h)
and (2) the new drug application process under section 505 of the FD&C
Act (21 U.S.C. 355). Under the OTC drug review process, a
nonprescription drug product may be marketed without an approved NDA or
ANDA under section 505 of the FD&C Act if the nonprescription drug
product meets the requirements of section 505G of the FD&C Act, and
other applicable requirements in the FD&C Act and implementing
regulations.
FDA approves drugs as either prescription or nonprescription drug
products under section 505 of the FD&C Act. A drug must be dispensed by
prescription when it is not safe for use except under the supervision
of a practitioner licensed by law to administer such drug product
because of its toxicity or other potentiality for harmful effect, or
the method of its use, or the collateral measures necessary to its use
(see section 503(b)(1) of the FD&C Act). If the approved drug does not
meet the criteria for prescription-only dispensing, it may be marketed
as nonprescription. For more on FDA's regulatory framework for
nonprescription drug products, see the 2022 proposed rule entitled
``Nonprescription Drug Product With an Additional Condition for
Nonprescription Use'' (87 FR 38313).
C. History of the Rulemaking
In the 2022 proposed rule, FDA proposed requirements for a
nonprescription drug product with an ACNU, a drug product that could be
marketed without a prescription if an applicant implements an
additional condition to ensure appropriate self-selection or
appropriate actual use, or both, by consumers without the supervision
of a healthcare practitioner. The proposed rule proposed additional
application requirements, labeling requirements, and postmarketing
reporting requirements for a nonprescription drug product with an ACNU.
For more information on the history of rulemaking for the proposed
rule, see 87 FR 38313.
D. Summary of Comments to the Proposed Rule
We received approximately 200 comments. Comments were submitted by
different entities and individuals including private citizens, consumer
groups, trade organizations, pharmaceutical industry, and public
advocacy groups. We received comments on different topics including:
<bullet> General support for or opposition to the proposed rule;
<bullet> The applicability of the proposed rule and whether certain
drug products are appropriate for development as a nonprescription drug
product with an ACNU;
<bullet> The proposed definition of ACNU;
<bullet> The proposed requirements for an application for a
nonprescription drug product with an ACNU, including specific
application requirements such as the submission of a separate
application, labeling, and postmarketing reports;
<bullet> The simultaneous marketing of prescription drug products
and nonprescription drug products with an ACNU; and
<bullet> The role of the pharmacist with a nonprescription drug
product with an ACNU.
E. General Overview of the Final Rule
FDA considered all comments received on the proposed rule, and in
response, we have made changes for clarity and to reduce the burden on
applicants in meeting certain requirements. The following is a summary
of certain changes from the proposed rule:
<bullet> Revising the postmarketing reporting requirement to
further clarify that a report must be submitted when there is an ACNU
failure, and further explain the meaning of ACNU failure, to enhance
consistency with current processes for the submission of other required
postmarketing reports;
<bullet> Revising the requirements for required labeling statements
on the PDP and DFL to permit applicants to propose revisions to the
content of the required statements under certain circumstances;
<bullet> Revising the placement for the required labeling statement
on the DFL depending on the purpose of the ACNU; and
<bullet> Clarifying certain circumstances when a nonprescription
drug product with an ACNU would be misbranded by providing more detail
about what it means when an ACNU is not implemented by the applicant as
approved by FDA in the application.
IV. Legal Authority
We are issuing this final rule under sections 201(n), 502, 503(b),
505, and 701(a) of the FD&C Act. Section 502(f) of the FD&C Act deems a
drug to be misbranded unless its labeling bears adequate directions for
use and adequate warnings against use in those conditions where its use
may be dangerous to health, as well as adequate warnings against unsafe
dosage or methods or duration of administration or application, in such
manner and form, as are necessary for the protection of users. Section
502(f) also authorizes the issuing of regulations exempting a drug or
device from the requirement to bear adequate directions for use upon a
determination that such directions are not necessary for the protection
of public health.
In addition, section 502(a) of the FD&C Act deems a drug to be
misbranded if its labeling is false or misleading in any particular.
Under section 201(n) of the FD&C Act, in determining whether labeling
is misleading, there shall be taken into account (among other things),
not only representations made or suggested, but also the extent to
which the labeling fails to reveal facts material in the light of such
representations or material with respect to consequences that may
result
[[Page 105291]]
from the use of the drug under the conditions of use prescribed in the
labeling or under usual or customary conditions of use.
In addition, under section 505 of the FD&C Act, FDA will approve an
NDA only if the drug is shown to be both safe and effective for use
under the conditions prescribed, recommended, or suggested in the
proposed labeling for the drug. See section 505(c)(1) and (d) of the
FD&C Act. If, for example, on the basis of information submitted as
part of the NDA or on the basis of any other information before the
Agency with respect to such drug, there is insufficient information to
determine whether such drug is safe for use under such conditions, the
Agency will not approve the drug. Section 505(j) of the FD&C Act
describes the requirements for ANDAs. In particular, section
505(j)(2)(A) specifies the information that must be included in an
ANDA, and section 505(j)(4) describes the approval standard for an
ANDA.
In addition, section 503(b) of the FD&C Act contains provisions
requiring that a drug product be dispensed by prescription when it is
not safe for use except under the supervision of a practitioner
licensed by law to administer such drug product because of toxicity or
other potentiality for harmful effect, or the method of the drug
product's use, or the collateral measures necessary to the drug
product's use (see section 503(b)(1) of the FD&C Act). If a drug
product does not require a prescription under these provisions, it can
be marketed as nonprescription. Section 503(b) gives authority for the
Secretary, which is delegated to FDA, to make certain decisions
regarding a drug's applicable category (see, e.g., section 503(b)(1)
and (b)(3); see also the FDA Staff Manual Guide 1410.10 (Delegations of
Authority to the Commissioner of Food and Dugs), available at <a href="https://www.fda.gov/about-fda/reports-manuals-forms/staff-manual-guides">https://www.fda.gov/about-fda/reports-manuals-forms/staff-manual-guides</a>.).
Finally, section 701(a) of the FD&C Act authorizes FDA to issue
regulations for the efficient enforcement of the FD&C Act.
V. Comments on the Proposed Rule and FDA Response
A. Introduction
We received approximately 200 comment letters on the proposed rule
by the close of the comment period, each containing one or more
comments on one or more issues. We received comments from entities and
individuals including private citizens, consumer groups, trade
organizations, pharmaceutical industry, and public advocacy groups. The
120-day comment period was extended by an additional 30 days based on
requests from members of the public.
We describe and respond to the comments in sections V.B through V.N
of this document. We have numbered each comment to help distinguish
between different comments. We have grouped similar comments together
under the same number, and in some cases, we have separated different
issues discussed in the same comment and designated them as distinct
comments for purposes of our responses. The number assigned to each
comment or comment topic is purely for organizational purposes and does
not signify the comment's value or importance or the order in which
comments were received.
B. Description of General Comments and FDA Responses
We received many general comments supporting and opposing the
purpose, necessity, and appropriateness of the proposed rule. In the
following paragraphs, we discuss and respond to these general comments.
We did not make any changes to the final rule based on consideration of
these general comments.
(Comment 1) Many comments generally support the proposed rule
because it could broaden the types of nonprescription drug products
available to consumers. For example, these commenters believe the
proposed rule has the potential to improve consumer access, improve
consumer autonomy, expand the market for companies, address
undertreatment of many common and chronic conditions in the United
States, and reduce the number of routine visits to a healthcare
practitioner.
(Response 1) We appreciate the general support. The rule is
intended to increase options for applicants to develop and market safe
and effective nonprescription drug products and increase consumer
access to appropriate, safe, and effective drug products, which could
improve public health.
(Comment 2) We received a comment recommending that Congress, in
conjunction with State boards of pharmacy, State health departments,
and State/national pharmacist associations, is better positioned to
increase options for the development and marketing of safe and
effective nonprescription drug products through legislative changes, as
compared to FDA acting through regulatory changes. The same comment
sought clarity on whether FDA has the legal authority to approve
nonprescription drug products with ACNUs that restrict distribution and
sales of the drug product.
(Response 2) As part of the statutory framework for regulation of
drug products, Congress recognized the need for specific considerations
and requirements for prescription drugs. As explained further in the
response to comment 41, Congress amended section 503(b) of the FD&C Act
in 1951 to reduce confusion and uncertainty in the market as to when a
drug is safe for use without the supervision of a practitioner licensed
by law to administer such drug, as well as to remove unnecessary
restrictions on dispensing, and to protect public health from abuses in
the sale of potent prescription drugs. Several provisions of the FD&C
Act, including section 503(b), demonstrate that Congress envisioned
that FDA would determine which drugs must be dispensed only upon a
prescription and which drugs would not require a prescription. For
example, section 503(b)(1) of the FD&C Act states, in relevant part,
that a drug intended for human use that, ``because of its toxicity or
other potentiality for harmful effect, or the method of its use, or the
collateral measures necessary to its use, is not safe for use except
under the supervision of a practitioner licensed by law to administer
such drug,'' must be limited to prescription use. That section
authorizes FDA, in approving an application under section 505 of the
FD&C Act, to require the supervision of a practitioner licensed by law
to administer such a drug. Conversely, FDA may approve drugs that do
not fall within section 503(b)(1) of the FD&C Act for nonprescription
use. In addition, section 503(b)(3) of the FD&C Act authorizes FDA to
issue regulations to remove the prescription-only dispensing
requirements from drugs when such requirements are not necessary for
the protection of the public health. Congress explicitly delegated FDA
authority to use its scientific judgement to determine which drugs
should be prescription or nonprescription, within the statutory
criteria.
Further, section 503(b)(1)(A) of the FD&C Act specifies certain
identified features of a drug, such as its ``toxicity or other
potentiality for harmful effect, or the method of its use, or the
collateral measures necessary for its use,'' that are relevant to the
determination of prescription or nonprescription status. The statute
only states these factors in describing the prescription drug category,
while leaving the nonprescription drug category described in opposition
to the prescription
[[Page 105292]]
category. See section 503(b)(4)(A) and (B) (separately prescribing
labeling requirements for ``[a] drug that is subject to [section
503(b)(1)]'' and, by contrast, ``[a] drug to which [section 503(b)(1)]
does not apply''). However, these factors are not unique to
prescription drugs; all drugs have a ``method of . . . use,'' all or
nearly all drugs have some level of ``toxicity or other potentiality
for harmful effect,'' and many drugs require at least some ``collateral
measures'' for safe use. Merriam-Webster defines the adjective
``collateral'' to mean, among other things, ``accompanying as secondary
or subordinate. . .[and/or] serving to support or reinforce.'' \3\ Thus
the key distinction in the statute between prescription and
nonprescription drugs is not that certain drugs have these factors
while others do not; rather prescription drugs are those that, when
considering these factors, are not safe for use except under the
supervision of a practitioner licensed by law to administer such a
drug.
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\3\ <a href="https://www.merriam-webster.com/dictionary/collateral">https://www.merriam-webster.com/dictionary/collateral</a>.
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Features of a drug that qualify as ``collateral measures'' vary
from drug to drug, and can include, for example, things which a
layperson, because of their lack of education, training, and
experience, cannot do to safely manage the disease. These include, but
are not limited to, taking a proper history, doing a physical exam,
ordering appropriate laboratory tests, having a knowledge of the
relevant diseases, integrating the results of the history, exam, and
tests with this knowledge, making a diagnosis, designing a treatment
plan, and carrying the plan through with proper continuing evaluation.
If the collateral measures necessary for safe use of the drug require
the supervision of a practitioner licensed by law to administer such
drug, section 503(b)(1)(A) requires that it can only be dispensed
pursuant to a prescription.
This rule recognizes that drugs approved with certain types of
collateral measures do not require supervision of a practitioner
licensed by law to administer such drug. Some such measures may be
things that used to require a practitioner's direct involvement, but
that no longer require such supervision because of the availability of
technological advancements. For example, with Drug X (see more
information about Drug X, a fictitious nonprescription drug product
with an ACNU, in the proposed rule (87 FR 38313 at 38319)), the ACNU
requires all consumers to complete a questionnaire located on a secure
website created by the applicant to determine whether Drug X is
appropriate for the consumer. Using a consumer's answers to the
questions, the underlying program or other operating information used
by the secure website, not the consumer, calculates the risk score for
a serious side effect and determines if the consumer has an acceptable
disease-specific risk score to use Drug X and therefore purchase Drug
X.
This type of collateral measure could also be accomplished through
the direct involvement of a practitioner licensed by law to administer
such drug, as the practitioner integrates their knowledge of the
patient with their knowledge of the disease and the drug--but now, in
certain cases, this has the potential to be done without a
practitioner's direct involvement because of the availability of
technology that can conduct the necessary evaluation. By carefully
evaluating whether such advancements in collateral measures mean that
the drug ``is not safe for use except under the supervision of a
practitioner licensed by law to administer such drug . . .'', section
503(b)(1)(A) for the FD&C Act (emphasis added), FDA is implementing the
statute's direction to limit the burdens of dispensing drugs by
prescription to only those drugs for which they are truly necessary.
More generally, as part of its broad authority to approve and
regulate drug products, including to establish specific regulations for
drug products, FDA is authorized to determine the conditions under
which a drug is safe and effective for use without a prescription,
including a determination that an ACNU is needed where labeling alone
will not suffice (see, e.g., sections 505, 505G, and 701 of the FD&C
Act). Until now, FDA's approval of nonprescription drug products has
been limited to those that can be labeled with sufficient information
for consumers to appropriately self-select and use the drug product.
These nonprescription drug products are generally available ``over-the-
counter'' (e.g., on a retail shelf). However, nothing in the FD&C Act
compels nonprescription drug products to be limited in this way, nor
does the FD&C Act dictate a particular manner in which a
nonprescription drug must be made available to consumers.
For certain drug products, labeling alone may not adequately
communicate the information needed for consumers to appropriately self-
select or use the drug product, but consumers may still be able to use
the product safely and effectively without the supervision of a
practitioner licensed by law to administer such drug under certain
conditions. Nonprescription drug products approved with ACNUs have an
additional condition of use, beyond labeling, that allows consumers to
appropriately self-select or use the drug product without the
supervision of a practitioner licensed by law to administer such drug.
Thus, a nonprescription drug product with an ACNU, although not an
``over-the-counter'' drug product, is a nonprescription drug product
under section 503(b) of the FD&C Act, because, when approved with an
ACNU, it is safe and effective for consumers to use without the
supervision of a practitioner licensed by law to administer such drug.
Additionally, FDA disagrees with this comment's suggestion that
legislative change is needed to authorize this rule. As explained
above, FDA has adequate statutory authority to issue this rule. See
also the responses to comments 39 through 43 below. FDA has long
determined which drug products are ones that consumers can
appropriately self-select or use without the supervision of a
practitioner licensed by law to administer such drug, and under what
conditions, and these determinations are squarely within FDA's
scientific expertise and authority under the FD&C Act. Additionally,
FDA has engaged the public in various ways throughout the development
of this rule. For example, FDA held a public hearing and participated
in a series of workshops convened by the Engelberg Center for Health
Care Reform at the Brookings Institution (Brookings Institution) to
solicit public input on expanding the approval of nonprescription drug
products. FDA used stakeholder input from the public hearing and the
workshops to develop the 2022 proposed rule (see 87 FR 38313). FDA also
carefully considered public comments in developing the final rule.
(Comment 3) We received many comments on the role of a pharmacist
in relation to nonprescription drug products with ACNUs. One comment
suggests that nonprescription drug products with ACNUs be available
only from State-licensed pharmacies, where there is a licensed
pharmacist available to assist consumers. Many of these comments
suggest that FDA require nonprescription drug products with ACNUs to be
sold only after consultation with a pharmacist. The comments assert
that pharmacists should: (1) assist with determining whether a
nonprescription drug product with an ACNU is appropriate for the
consumer; (2) ensure consumer fulfillment of the ACNU; and (3) provide
a stopgap for consumer
[[Page 105293]]
questions or concerns regarding the benefits and risks of the
nonprescription drug product with an ACNU.
Additionally, we received many comments about the practice of
pharmacy or medicine that are outside the scope for this rulemaking,
including comments about reimbursement for pharmacist professional
services, increased prescribing authority for pharmacists, pharmacy
recordkeeping, documentation of nonprescription drug products in
profiles for the consumer or drug history data repositories, State laws
about sales of nonprescription drug products, and legal liability for
pharmacists.
(Response 3) FDA disagrees that a nonprescription drug product with
an ACNU should be available only from State-licensed pharmacies, where
there is a licensed pharmacist available to assist consumers, or sold
only after consultation with a pharmacist. The purpose of this rule is
to increase options for applicants to develop and market safe and
effective nonprescription drug products, which in turn may increase
consumer access to appropriate, safe, and effective drug products. FDA
recognizes the potential benefit of providing consumers with access to
additional types of nonprescription drug products, such as some drug
products that are currently available only by prescription and that
treat chronic diseases or conditions. Nonprescription drug products are
generally available for consumers to purchase at such as pharmacies,
supermarkets, or other retail locations, and from online retailers. FDA
anticipates that nonprescription drug products with an ACNU would be
sold similarly. FDA recognizes the potential benefit of providing
consumers with appropriate access to nonprescription drug products. As
long as consumers can fulfill the ACNU, limiting the locations in which
nonprescription drug products with an ACNU can be sold, or requiring
consultation with a healthcare professional (i.e., a pharmacist), when
not necessary for safe and effective use of the drug product, would
limit consumer access to appropriate, safe, and effective drug
products, which would unnecessarily undermine these public health
benefits of this rule.
Such a system also would be inconsistent with this final rule,
which pertains to nonprescription drug products. Section 503(b) of the
FD&C Act requires that a drug product be dispensed by prescription when
it is not safe for use except under the supervision of a practitioner
licensed by law to administer such drug because of toxicity or other
potentiality for harmful effect, or the method of the drug product's
use, or the collateral measures necessary to the drug product's use
(see section 503(b)(1) of the FD&C Act). If an approved drug product
does not meet the criteria for prescription-only dispensing, it may be
marketed as nonprescription (see 87 FR 38313 at 38316).
C. Comments on Applicability and FDA Responses
We proposed requirements for NDAs and ANDAs for nonprescription
drug products with ACNUs (see proposed 21 CFR 201.67, 201.130, 314.56,
314.81, 314.125, and 314.127). In the following paragraphs, we discuss
comments on the applicability of the rule. After consideration of
public comments received, we are finalizing our proposals without
change.
(Comment 4) We received several comments on how the rule will be
applied to already marketed drug products. We received a comment
asserting that an ACNU cannot be retroactively required for a
nonprescription drug product that FDA has already approved without an
ACNU. However, the comment requests FDA make clear in the final rule
that FDA has the authority to revisit the approval of a nonprescription
drug product when information emerges in the postmarketing setting
regarding the safety and efficacy of the nonprescription drug product.
Further, we received a comment that FDA approval of a nonprescription
drug product with an ACNU should not become the ``temporary stopping
ground'' for every drug moving from prescription to nonprescription
status.
(Response 4) We do not intend, as a result of this rule, to revisit
nonprescription drug products marketed under approved applications. The
approval of an application for a nonprescription drug product prior to
the finalization of this rule was based on FDA's finding, in part, that
labeling alone is sufficient for the drug product to be used safely and
effectively by consumers. Under this rule, such a finding by FDA would
obviate the need for the approved nonprescription drug product to have
an ACNU in order for the drug product to be used safely and
effectively. In addition, we do not think that FDA approval of a
nonprescription drug product with an ACNU will generally become a
``temporary stopping ground'' as a step toward nonprescription approval
without an ACNU (i.e., the applicant would regularly propose to remove
the ACNU after approval) because the applicant would have demonstrated
and FDA would have determined that labeling, alone, was insufficient to
ensure appropriate self-selection or appropriate actual use, or both.
We agree that FDA has authority to address safety and efficacy
concerns observed for an approved drug product in the postmarketing
setting, including existing authority under the FD&C Act and current
regulations to withdraw approval of an application in certain
circumstances (see section 505(e) of the FD&C Act and 21 CFR 314.150).
This includes withdrawal of an approval of an application for a
nonprescription drug product with or without an ACNU for safety or
efficacy concerns. In certain situations, if FDA withdraws approval of
an application for a nonprescription drug product due to the emergence
of a safety issue with regard to appropriate self-selection or actual
use of the drug product, the applicant could submit a new application
for the product as a nonprescription drug product with an ACNU to
ensure appropriate self-selection or actual use, as appropriate.
(Comment 5) We received over 100 comments recommending that
specific drug products be available as nonprescription (e.g.,
antibiotics) or that specific drug products not be made available as
nonprescription (e.g., albuterol inhaler). The majority of these
comments recommend that oral contraceptives should be available as
nonprescription. We also received one comment advocating FDA use the
rule to increase access to naloxone. These comments did not discuss
whether ACNUs would be appropriate for these drug products if available
as nonprescription.
Additionally, we received a few comments discussing the
appropriateness of approving nonprescription drug products with ACNUs
for certain general types of drug products. We received one comment
recommending FDA only approve a nonprescription drug product with an
ACNU if it has a low risk for misuse. We received a few comments
expressing concerns about the appropriateness of nonprescription drug
products with ACNUs for the treatment of chronic conditions and
asserting that consumers may not be able to appropriately manage
chronic health conditions without the communication and supervision by
a healthcare practitioner. We also received a comment discussing that
FDA may have unintentionally implied that a drug product to treat
chronic conditions or intended for long-term use must have an ACNU to
be available as nonprescription. We received several comments
expressing concern about the approval of a nonprescription drug
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product with an ACNU that has potentially harmful interactions and
recommending that the ACNU needs to include information on possible
interactions (e.g., drug-drug interactions, questions about diet,
vitamins, complementary and alternative medicine, and other
nonprescription drug products) to avoid potential life-threatening
adverse drug experiences.
(Response 5) We disagree that we need to clarify the rule to
address comments regarding approval of specific drug products or
categories of drug products or restrict the types of drug products that
FDA may consider for approval as a nonprescription drug product with an
ACNU. FDA considers the specifics of each application during its
review, including the potential risk for misuse of the drug product. As
long as the application meets the existing evidentiary standards under
the FD&C Act and current FDA regulations to demonstrate the safety and
effectiveness of the drug product, and the drug product does not meet
the criteria for prescription-only dispensing (see section 503(b)(1) of
the FD&C Act), FDA may approve the application as nonprescription. FDA
has the authority to approve a nonprescription drug product intended
for a chronic disease or condition, or for long-term use, that meets
the existing evidentiary standards and FDA regulations. In fact, FDA
has approved nonprescription drug products for chronic diseases or
conditions, or for long-term use, based on FDA's finding, in part, that
labeling alone is sufficient for the drug product to be used safely and
effectively by consumers. For example, on January 25, 2013, FDA
approved NDA 202211 Oxytrol for Women (oxybutynin) extended-release
film, 3.9 milligrams (mg), for the treatment of overactive bladder in
women. When relevant, the applicant must ensure consumers understand
information on potential interactions to safely and effectively use a
nonprescription drug product with an ACNU. Further, consistent with the
existing requirements for all nonprescription drug products, an
applicant of a nonprescription drug product with an ACNU must include
specific warnings, including all major drug-drug and drug-food
interaction warnings in the DFL (see Sec. 201.66(c)(5)(v) (21 CFR
201.66(c)(5)(v))).
We appreciate the public's interest in advocating for specific drug
products or types of drug products to be approved or not be approved
for nonprescription use, such as oral contraceptives and naloxone. Of
note, on July 13, 2023, FDA approved supplemental NDA 017031 for Opill
(norgestrel) tablet, 0.075 mg, as a nonprescription daily oral
contraceptive to prevent pregnancy. On March 29, 2023, FDA approved
supplemental NDA 208411 for Narcan (naloxone hydrochloride) nasal
spray, 4 mg, for nonprescription use to reverse the effects of a life-
threatening opioid emergency. Additionally, on July 28, 2023, FDA
approved NDA 217722 for RiVive (naloxone hydrochloride) nasal spray, 3
mg, for nonprescription use for emergency treatment of opioid overdose
in adults and children. Based on FDA's review under relevant statutory
and regulatory standards for approval, FDA determined the labeling for
these drug products was sufficient to ensure consumers' appropriate
self-selection and use of the products without the supervision of a
practitioner licensed by law to administer such drug.
(Comment 6) We received several comments asking FDA to clarify when
an applicant should propose an ACNU for a nonprescription drug product.
We received a comment that asserts that the definition of an ACNU
should be limited to those conditions that are most feasible to
implement at the pharmacy-patient level and suggests that FDA provide a
finite list of additional conditions that would be applied to real-
world situations. We received several comments asking FDA to provide
examples when labeling is inherently insufficient for appropriate self-
selection or actual use, if these examples exist, or examples of
specific drug products that FDA considers as possible candidates for
approval.
(Response 6) We decline to establish such inflexible limits on when
an ACNU should be proposed. The rule is intended to increase options
for an applicant to develop and market safe and effective
nonprescription drug products and increase consumer access to
appropriate, safe, and effective drug products. The rule is
intentionally flexible, mindful that technologies evolve and ACNUs may
be developed for many different nonprescription drug products. FDA
placing limits on the types of conditions that can be proposed or the
creation of a finite list of additional conditions is not warranted and
may unnecessarily restrict the type and number of drug products that
could be marketed nonprescription, contrary to the intent of this rule.
We expect applicants may submit applications for nonprescription
drug products with ACNUs for a wide range of indications, including for
drug products intended to treat both acute and chronic diseases.
However, FDA cannot predetermine the full range of indications for
which nonprescription drug products with ACNUs could be approved, nor
can the Agency predetermine that all proposed nonprescription drug
products with ACNUs for a given indication would be safe and effective,
because FDA considers the specifics of each application during its
review. Further, we cannot provide a general list or guideline of when
labeling alone is insufficient to ensure appropriate self-selection or
appropriate actual use, or both, because the determination of when
labeling is insufficient is made for a specific nonprescription drug
product based upon the data or other information that the applicant
submits to FDA as part of an application.
D. Comments on Definition and FDA Responses
We proposed to establish a definition for additional condition for
nonprescription use (ACNU) (see proposed 21 CFR 201.67(b)(1) and
314.56(a)(1)). As proposed, an ACNU means one or more FDA-approved
conditions that an applicant of a nonprescription drug product must
implement to ensure consumers' appropriate self-selection or
appropriate actual use, or both, of the nonprescription drug product
without the supervision of a healthcare practitioner if the applicant
demonstrates and FDA determines that labeling alone is insufficient to
ensure appropriate self-selection or appropriate actual use, or both.
As an example, an ACNU for appropriate self-selection could be a
questionnaire that consumers are required to complete on a secure
website or mobile application created by the applicant to determine
whether the drug product is appropriate for the consumer. The
questionnaire would contain a series of questions that the consumer
answers. The underlying program or other operating information used by
the secure website or mobile application would determine if the drug is
appropriate for the consumer based on these responses. If the drug is
indeed appropriate for the consumer, the consumer could then access and
purchase the drug product. For a more specific example, see the
proposed rule (87 FR 38313 at 38319), in which we discuss Drug X, a
fictitious nonprescription drug product with an ACNU.
In the following paragraphs, we discuss comments on the proposed
definition. After consideration of public comments received, we are
finalizing our proposal with revisions for consistency with the wording
in section 503(b) of the FD&C Act. Therefore, we
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are revising the phrase ``of a healthcare practitioner'' to ``of a
practitioner licensed by law to administer such drug.''
(Comment 7) We received one comment supporting FDA's proposed
definition of an ACNU because it provides sufficient flexibility for
the applicant to develop and tailor the ACNU to a specific drug
product.
(Response 7) We agree that the proposed definition of ACNU is
sufficiently broad, as was intended, to give applicants flexibility
regarding the types of additional conditions that may be proposed and
how those conditions can be implemented (87 FR 38313 at 38318). This
flexibility will allow applicants to consider the unique benefit and
risk considerations for a particular drug product while developing an
ACNU to ensure consumers' appropriate self-selection or appropriate
actual use, or both, of the drug product.
(Comment 8) We also received several comments disagreeing with
FDA's proposed definition of ACNU. Some comments disagree with the use
of the term ``ensure'' in the definition and recommend FDA revise the
definition to replace the term ``ensure'' with ``enable.'' The comments
assert that the term ``ensure'' implies that any risk to consumers from
the nonprescription drug product with an ACNU has been eliminated even
though all drug products have residual risk regardless of any
mitigation steps taken. We received one comment asserting that the
proposed definition is vague and suggesting that FDA provide a
definition of ``appropriate actual use'' and ``appropriate self-
selection.''
(Response 8) We disagree with replacing the term ``ensure'' with
``enable'' in the definition. The Merriam-Webster dictionary defines
``ensure'' as ``to make sure, certain, or safe.'' The Merriam-Webster
dictionary defines ``enable'' as ``to make possible, practical, or easy
or to provide with the means or opportunity.'' The term ``ensure''
reflects a greater level of certainty that is consistent with FDA's
approval standards. All drug products, including nonprescription drug
products, have risks. As part of our regulatory decision-making
process, we conduct a structured benefit-risk assessment to facilitate
the balanced consideration of benefits and risks (see, e.g., section
505(d) of the FD&C Act and Sec. 314.50 (21 CFR 314.50)). Nothing in
the rule affects this benefit-risk assessment for an application for a
nonprescription drug product with an ACNU.
FDA disagrees that specifically defining ``appropriate actual use''
and ``appropriate self-selection'' is necessary for nonprescription
drug products with an ACNU. The terms ``actual use'' and ``self-
selection'' are used in the context of all nonprescription drug
products. In general, applicants of nonprescription drug products
conduct consumer studies such as label comprehension studies, self-
selection studies, actual use studies, and human factors studies to
help demonstrate that consumers can correctly self-select and correctly
use the drug products (see also 87 FR 38313 at 38316). FDA has defined
``self-selection'' in FDA guidance for industry (Ref. 1 and 87 FR 38313
at 38315).
(Comment 9) Several comments recommend FDA revise the proposed
definition to make clear that applicants, not FDA, should determine
when an ACNU is necessary. The comments assert that the applicant
should have the ability to evaluate the need for an ACNU and propose
the use of an ACNU without seeking prior agreement from FDA.
(Response 9) We disagree with revising the definition to permit the
applicant, not FDA, to make the final determination on the necessity of
the ACNU. To approve a drug product, FDA must determine whether the
specific application meets the applicable statutory and regulatory
requirements. FDA will not require a nonprescription drug product to
have an ACNU if the drug product can be used safely and effectively by
consumers, without the supervision of a practitioner licensed by law to
administer such drug, based on labeling alone. Requiring unnecessary
ACNUs would be inconsistent with the goal of this rulemaking, which is
to increase consumer access to safe and effective nonprescription drug
products.
While applicants are not required to meet with FDA prior to the
submission of an application for a nonprescription drug product with an
ACNU, we encourage applicants to meet with FDA to discuss their drug
development plans and seek feedback, including whether an ACNU may be
necessary. However, it is during FDA's review of an application that
FDA must determine whether the application meets the applicable
statutory and regulatory requirements, including whether the applicant
demonstrates the necessity of the ACNU to ensure appropriate self-
selection or appropriate actual use, or both (see, e.g., Sec.
314.56(c)(1)(v)) in order to approve the nonprescription drug product
with an ACNU.
E. Comments on Separate Application Required for a Nonprescription Drug
Product With an ACNU and FDA Responses
We proposed that an applicant must submit a separate application
for a nonprescription drug product with an ACNU (proposed 21 CFR
314.56(b)). For cases where there is an approved prescription drug
product, we proposed that initial approval for a nonprescription drug
product with an ACNU cannot be obtained through a supplement to the
approved application for prescription use of the drug product.
In the following paragraphs, we discuss comments on this proposed
requirement. After consideration of public comments received, we are
finalizing our proposal with a clarifying revision to explain that this
provision supersedes Sec. 310.200(b) (21 CFR 310.200(b)) with regard
to nonprescription drug products with an ACNU. To clarify and avoid
ambiguity, we are adding the clause ``Notwithstanding Sec.
310.200(b)'' to the beginning of the first sentence in 21 CFR
314.56(b).
(Comment 10) We received a few comments supporting the proposed
requirement for the submission of a separate application for a
nonprescription drug product with an ACNU because it would improve
consumer options. Additionally, a commenter asserted that the proposed
requirement increases equity and access to drug products. We also
received several comments opposing this proposed requirement and
asserting that an applicant should be allowed to submit a supplement to
an approved prescription application rather than a separate
application. One comment asserts that an applicant should not be
required to submit a separate application simply because the ACNU is
part of a development program, especially where the formulation is
similar to the approved prescription application. We received a comment
requesting FDA remove the proposed requirement and, instead, address
the issue on a case-by-case basis to determine the circumstances when
it would be appropriate for an applicant to seek approval of a
nonprescription drug product with an ACNU by submitting a supplement.
The comment argues that the proposed requirement for a separate
application is inconsistent with the FDA guidance for industry from
December 2004 ``Submitting Separate Marketing Applications and Clinical
Data for Purposes of Assessing User Fees'' (available at <a href="https://www.fda.gov/media/72397/download">https://www.fda.gov/media/72397/download</a>) and FDA
[[Page 105296]]
practices, which, according to the comment, contemplate that labeling
changes may be the subject of a supplement. In addition, some comments
assert that requiring a separate application would disincentivize
innovation and limit utilization of the ACNU pathway because the
separate application would allow for the potential continued marketing
of generic prescription drugs that would compete with the
nonprescription drug with an ACNU. The commenters assert that
incorporating an ACNU into a development program for a nonprescription
drug product is expected to increase the overall costs and time in
developing the nonprescription drug product. The commenters explain
that there is typically a limited period of marketing exclusivity when
a new nonprescription drug product is approved, a ``long-accepted means
of incentivizing'' applicants to undertake such investment. Therefore,
the commenters argue that potential continued simultaneous marketing of
a generic prescription drug product that could compete with the
nonprescription drug product with an ACNU would render any marketing
exclusivity moot.
(Response 10) We disagree with removing the requirement for the
submission of a separate application. This requirement is essential to
achieving the key policy goal of increasing consumer access to
appropriate drug products. In cases where there is an approved
prescription drug product, this requirement creates a pathway for the
simultaneous marketing of the prescription drug product, along with the
nonprescription drug product with an ACNU. While many consumers will
benefit from the availability of nonprescription drug products with
ACNUs, FDA also recognizes that some may not be able to access the
nonprescription drug product with an ACNU. For example, a consumer may
not be able to access the technology that operationalizes the ACNU.
Therefore, continued availability of the prescription drug product
along with the nonprescription drug product with an ACNU promotes the
greatest access to needed drug products.
We are also clarifying that a separate application must be
submitted for a nonprescription drug product with an ACNU
notwithstanding Sec. 310.200, which states that an interested person
may submit a supplement to an approved new drug application to propose
to exempt a drug from the prescription-dispensing requirements of
section 503(b)(1)(B) of the FD&C Act. Under Sec. 310.200(b),
applicants may continue to submit a supplement to switch a drug from
prescription to nonprescription status if the nonprescription drug
product would not have an ACNU and the resulting approved application
would only address the nonprescription drug product. Nonprescription
drug products without ACNUs do not implicate the same issues regarding
continued consumer access to appropriate drug products, because they
are generally available to consumers and do not have additional
conditions of approval that restrict consumer access.
Additionally, we do not agree that the proposed separate
application requirement is inconsistent with existing FDA guidance. The
guidance entitled ``Submitting Separate Marketing Applications and
Clinical Data for Purposes of Assessing User Fees'' did not contemplate
and, therefore, did not address the submission of an application for a
nonprescription drug product with an ACNU. Therefore, the guidance is
not relevant to the question of whether a separate application or a
supplement is appropriate for such a product. Furthermore, the guidance
document merely provides FDA's recommendations on submission of certain
applications to FDA. The guidance document does not set forth any
requirements, and the recommendations therein are not binding on FDA or
applicants.
We also do not agree that requiring a separate application would
necessarily disincentivize innovation and limit utilization of the ACNU
pathway. This assertion is speculative and does not outweigh the
potential benefits from requiring a separate application, which would
increase consumer access to appropriate drug products. We acknowledge
that the cost to develop a nonprescription drug product with an ACNU is
higher than a nonprescription drug product without an ACNU. The
Appendix of the Regulatory Impact Analysis estimates that the core
development cost of a nonprescription drug product is $31.1 million
while the estimated cost to develop cost of a nonprescription drug
product with an ACNU is $47.3 million, an estimated markup of $16.2
million for ACNU-related development. However, as noted in section I.C.
of the Regulatory Impact Analysis, evidence shows that roughly 60
percent of purchases for a nonprescription drug product are from new-
to-therapy consumers who had not previously taken the drug before it
switched from prescription status, suggesting that the potential to
attract new-to-therapy consumers for nonprescription drug products is
substantial (Ref. 13). Further, section V.B. of the Regulatory Impact
Analysis estimates that every year nonprescription drug manufacturers
get $112.02 million of additional revenue from switching a drug to
nonprescription status (Ref. 13), which also indicates there will be
incentives for drug manufacturers to innovate and use the ACNU pathway.
We disagree that simultaneous marketing would reduce or render moot the
benefit of any statutory exclusivity that may be associated with a
nonprescription drug product. For example, three-year new clinical
investigation exclusivity (e.g., section 505(c)(3)(E)(iii) and
(j)(5)(F)(iii) of the FD&C Act) rewards an applicant for sponsoring or
conducting additional studies on previously approved drug products
containing an active moiety that has been previously approved, and an
NDA applicant for a nonprescription drug product with an ACNU could be
eligible for such exclusivity, provided the relevant statutory
requirements are met. We discuss the issue of ``market exclusivity'' or
``statutory exclusivity'' for nonprescription drug products with an
ACNU further in our responses to Comments 36 and 72.
(Comment 11) Several comments express concerns that submitting an
application is more burdensome than submitting a supplement. Although
another comment acknowledges FDA's explanation that applicants can
cross-reference information in an approved application, the comment
asserts that the applicant would be required to pay a new application
user fee, even though the commenter believes that FDA's review would be
less resource-intensive compared to other NDAs.
(Response 11) We acknowledge that submitting a separate application
may be more burdensome than submitting a supplement to the approved
prescription drug application; however, an applicant may cross-
reference information from its approved NDA for the prescription drug
product and would not need to duplicate studies already conducted for
and submitted in its NDA for the prescription drug product (87 FR 38313
at 38318). While we acknowledge that a new application user fee will be
required, we disagree that FDA's review of an application for a
nonprescription drug product with an ACNU is less resource intensive
for the Agency compared to other NDAs. As required for other NDAs, the
application must include data and information from studies to support
the safety and efficacy of the drug product as nonprescription as well
as meet the additional specific requirements for a
[[Page 105297]]
nonprescription drug product with an ACNU (see 21 CFR 314.56(c) in this
final rule). Generally, these requirements would include the submission
of newly generated data and information that FDA would not have
previously reviewed, including but not limited to, label comprehension
studies, self-selection studies, actual use studies, and human factors
studies to demonstrate both the necessity and the effect of the ACNU.
In some cases, device information may also be submitted. Additionally,
FDA's review of an application for a nonprescription drug product with
an ACNU will typically involve many offices in the Center for Drug
Evaluation and Research, and in some instances, consults to other
Centers within FDA.
(Comment 12) We also received one comment requesting that FDA
establish a process for the applicant to revise or remove an approved
ACNU for a nonprescription drug product with an ACNU. The comment notes
that an ACNU should not be expected to remain unchanged or permanent.
(Response 12) We disagree that we need to establish a new, separate
process specific for making post approval changes to an application for
a nonprescription drug product with an ACNU. An applicant may propose
revisions to an approved application for a nonprescription drug product
with an ACNU by submitting a supplement and may describe certain
changes in the annual report, consistent with our current regulations
for making changes to an FDA-approved application (see Sec. Sec.
314.70, 314.81, 314.97, and 314.98 (21 CFR 314.70, 314.81, 314.97, and
314.98)). An applicant seeking to make changes to an NDA or ANDA
submitted for a nonprescription drug product with an ACNU that is under
review by FDA would submit an amendment to the application to request a
change (see Sec. Sec. 314.60 and 314.96 (21 CFR 314.60 and 314.96)).
An applicant seeking to make changes to an FDA-approved NDA or ANDA for
a nonprescription drug product with an ACNU would submit a supplement
to the approved NDA or ANDA (see Sec. Sec. 314.70 and 314.97) (87 FR
38313 at 38319).
F. Comments on Specific Requirements for an Application for a
Nonprescription Drug Product With an ACNU and FDA Responses
We proposed to establish specific NDA and ANDA requirements for a
nonprescription drug product with an ACNU (proposed 21 CFR 314.56(c)).
After consideration of public comments received, we are finalizing
these proposals with a few editorial modifications to provide clarity.
The changes are described below in sections V.F.1. and V.F.2.
1. NDA
In addition to existing content and format requirements for an NDA
(Sec. 314.50), FDA proposed specific requirements for an NDA for a
nonprescription drug product with an ACNU. We discuss the specific
requirements in the following paragraphs.
a. Statement regarding the purpose of the ACNU. We proposed to
require the applicant to provide a statement regarding the purpose of
the ACNU: ensure appropriate self-selection or appropriate actual use,
or both, by consumers of the nonprescription drug product with an ACNU
without the supervision of a practitioner licensed by law to administer
such drug (proposed Sec. 314.56(c)(1)(i)). We received no comment
specifically regarding this proposed requirement. We are finalizing our
proposal with a few editorial modifications to provide greater clarity.
We are revising the sentence to add the word ``whether'' after the
phrase ``A statement regarding. . . .'' We are also removing the colon
after ``ACNU'' and replacing it with the phrase ``is to.''.
b. Statement of necessity of the ACNU. We proposed to require the
applicant explain why the ACNU is necessary to ensure appropriate self-
selection or appropriate actual use, or both, by consumers of the
nonprescription drug product (proposed Sec. 314.56(c)(1)(ii)). We
received no comment regarding this proposed requirement, and we are
finalizing it without change.
c. Description of how the ACNU ensures appropriate self-selection
or appropriate actual use, or both. We proposed to require the
applicant describe how the ACNU will ensure appropriate self-selection
or appropriate actual use, or both, by consumers (proposed 21 CFR
314.56(c)(1)(iii)). After consideration of public comments received, we
are finalizing our proposal without change.
(Comment 13) We received a few comments asserting that the proposed
rule lacks clarity on how often an ACNU must be fulfilled by consumers.
A few commenters question if the consumer would be required to fulfill
an ACNU each time the consumer repurchases the drug product, which
would be burdensome, particularly if the drug product is indicated for
a chronic condition. One comment recommends that FDA require the
application to include information on how the consumer would repurchase
a nonprescription drug product with an ACNU.
(Response 13) There is not one standard for the frequency in which
an ACNU must be fulfilled by the consumer; this will be determined on a
case-by-case basis as we consider the specifics of each application for
a nonprescription drug product with an ACNU during our review. As
finalized in this final rule, we require that the application include a
description of how the ACNU ensures appropriate self-selection or
appropriate actual use, or both (21 CFR 314.56(c)(1)(iii) in this final
rule), and describe the additional condition(s) implemented and the
criteria by which the consumer would successfully fulfill the ACNU,
including a description of the specific actions to be taken by a
consumer as part of the description of key elements of the ACNU (21 CFR
314.56(c)(1)(iv) in this final rule). Therefore, the application may
include information describing how a consumer would make subsequent
purchases of the nonprescription drug product with an ACNU, if
appropriate. For example, an applicant may explain that a consumer
would fulfill an ACNU (e.g., complete a self-selection questionnaire)
upon the first time purchasing the nonprescription drug product with an
ACNU and at a specific time interval (e.g., every 3 months) in order to
repurchase the drug product.
d. Description of the key elements of the ACNU. We proposed to
require the applicant to include a description of the key elements of
the ACNU, including: the additional condition implemented by the
applicant to be fulfilled by the consumer to obtain the nonprescription
drug product with an ACNU; the labeling specifically associated with
the ACNU; and the criteria by which the consumer would successfully
fulfill the ACNU, including a description of the specific actions to be
taken by a consumer or required responses to be provided by a consumer
(see proposed 21 CFR 314.56(c)(1)(iv)). We received no comment
regarding this proposed requirement. We are making an editorial
modification for clarity. We are adding the introductory clause: ``Key
elements of the ACNU'' to better explain the required information and
to allow for ease of reference to discuss the requirement.
e. Adequate data or other information that demonstrate the
necessity of the ACNU to ensure appropriate self-selection or
appropriate actual use, or both. We proposed to require an applicant to
include adequate data or other information that demonstrate the
necessity of the ACNU to ensure
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appropriate self-selection or appropriate actual use, or both (proposed
21 CFR 314.56(c)(1)(v)). After consideration of public comments
received, we are finalizing our proposal without change.
FDA believes that the requirement for demonstrating that the ACNU
is necessary, as reflected in the ACNU definition and in 21 CFR
314.56(c)(1)(v), and as determined by FDA, is necessary to fulfill the
key goals of this rulemaking. The key goals are to: (1) increase
options for applicants to develop and market safe and effective
nonprescription drug products, which would broaden the types of
nonprescription drug products available to consumers and (2) increase
consumer access to appropriate, safe, and effective drug products, by
providing for the availability of prescription versions of
nonprescription drug products approved with ACNUs, both of which in
turn could improve public health (see the discussion in this section
F.1.e.). Allowing a product to be approved as a nonprescription drug
product with an ACNU, when the ACNU is not necessary, would not
increase options for applicants to develop and market safe and
effective nonprescription drug products because they could already be
marketed as a nonprescription drug product without an ACNU. Approving a
nonprescription drug product with an ACNU that is not necessary also
would not necessarily increase consumer access because, although this
rule has the potential to provide consumers with access to additional
types of nonprescription drug products, FDA recognizes that ACNUs
necessarily restrict consumer access, which is appropriate when they
are needed to ensure appropriate self-selection or appropriate actual
use, or both. However, nonprescription drug products without ACNUs do
not necessarily implicate the same issues regarding continued consumer
access to drug products because they are generally available to
consumers and do not have additional conditions of approval that
restrict consumer access. Therefore, if the definition in 21 CFR
201.67(b)(1) and 314.56(a)(1), or the provision at 21 CFR
314.56(c)(1)(v), is stayed or determined to be invalid or
unenforceable, the entire rule should be invalidated.
(Comment 14) We received several comments requesting that FDA
provide further guidance on the meaning of ``adequate data'' as it
pertains to demonstrating the necessity of the ACNU and the effect of
the ACNU. FDA received one comment stating the proposed rule does not
address the types of consumer studies that would be needed to provide
adequate data. A few comments assert that FDA should not limit adequate
data to prospective consumer behavior studies if other sources
referenced by the applicant are reliable and fit for purpose.
(Response 14) Consistent with our proposal, the applicant must
conduct or reference adequate testing to show that labeling alone would
not support the safe and effective use of the nonprescription drug
product (87 FR 38313 at 38320 and 21 CFR 314.56(c)(1)(vi) in this final
rule). Further, the applicant must submit data that show that consumers
appropriately self-select or actually use the drug product, or both,
safely and effectively using the ACNU. To clarify, adequate data need
to be relevant to the specific application and need to be interpretable
for FDA to evaluate the scientific finding. The types of data that can
be submitted are not limited. Applicants can submit data from consumer
studies such as label comprehension studies, self-selection studies,
actual use studies, and human factors studies (87 FR 38313 at 38315) to
demonstrate the necessity of the ACNU and the effect of the ACNU. The
specific types of consumer studies an applicant would conduct depends
on the development program for the particular nonprescription drug
product with an ACNU.
FDA has issued guidances on some types of consumer studies (Refs.
1, 2, and 3). We may provide advice (e.g., specific verbal or written
feedback) to applicants on adequate data or other information that
demonstrate the necessity and effect of the ACNU in the context of a
pending or proposed application, as appropriate. Additionally,
applicants can request to meet with FDA staff to discuss questions that
arise during the development of a nonprescription drug product with an
ACNU. FDA may consider issuing guidance in the future to address
general considerations that may arise and are applicable to all
applicants developing nonprescription drug products with an ACNU.
(Comment 15) We received many comments asserting that FDA should
remove the proposed requirement that the applicant must develop or
reference adequate data to demonstrate that labeling is insufficient
for safe and effective use of a nonprescription drug product. We
received many comments expressing concerns that, before developing an
ACNU, an applicant must first generate data from a failed labeling
study (i.e., fail first) and FDA must then agree with the applicant's
assessment that labeling alone is insufficient. Several comments state
that the fail-first concept would put the onus on the applicant to
prove a negative, rather than developing the key self-selection or use
question(s) that trigger the need for an ACNU. One comment asserts that
the rigidity of trying to prove a negative is inconsistent with
scientific methods in developing a label. A few comments assert that it
can become apparent for a variety of reasons that labeling is not
adequate throughout the development program. Although the comments note
that applicants can utilize meetings with FDA during the development
program to obtain alignment, many commenters believe that applicants
should have the ability to evaluate the necessity of an ACNU without
seeking prior agreement with FDA.
(Response 15) We disagree with removing the requirement that the
applicant must provide adequate data or other information to show that
labeling alone would not support the safe and effective use of the
nonprescription drug product and disagree that the requirement is
inconsistent with the methods of developing labeling for
nonprescription drug products. An ACNU cannot be proposed merely to
provide consumers with additional information when the labeling could
be sufficient to ensure appropriate self-selection or actual use or
both. In such case, the use of an ACNU can present potential barriers
for another applicant developing a nonprescription drug product. We
cannot make a determination about whether labeling alone is
insufficient without adequate data or other information. While the data
or other information will typically come from consumer testing or by
reference, it does not necessarily need to come from a failed labeling
study. Further, the necessity for adequate data or other information,
which typically comes from consumer testing or by reference is
consistent with FDA's approval requirements for all nonprescription
drug products. For a nonprescription drug product, the applicant
develops and optimizes the labeling using an iterative process and
conducts consumer studies (e.g., label comprehension studies, self-
selection studies, actual use studies, and human factors studies) to
demonstrate whether consumers appropriately self-select and use the
drug product using labeling alone. In certain circumstances, an ACNU
may only be required for appropriate self-selection or appropriate
actual use, but not both, of the nonprescription drug product. For
example, if the applicant demonstrates that labeling alone is
insufficient to ensure appropriate self-selection (but
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not appropriate actual use) of the nonprescription drug product and
proposes an ACNU for self-selection, the applicant must still conduct
consumer studies to demonstrate that consumers will appropriately use
the drug product based on labeling, alone. In addition to reflecting
the reality of developing a nonprescription drug product, this policy
is also intended to help ensure consumers can access nonprescription
drug products without barriers or hurdles to access that are
unnecessary when that drug product could be approved as nonprescription
without an ACNU.
We encourage applicants to meet with FDA to discuss their drug
development plans and seek advice. However, these meetings are not
required; applicants that view these meetings as unnecessary are not
required to have them.
(Comment 16) We received a few comments recommending that FDA
clarify when an applicant can submit ``other information'' explaining
the necessity of the ACNU. One comment recommends FDA define the
criteria for when an applicant can submit ``other information''; for
example, situations that require additional tests, lab values, or other
ancillary values or measurements as part of self-selection or actual
use; literature; and medical practice guidelines. One comment
recommends that FDA clarify how FDA will signal to an applicant when
labeling alone is insufficient because clear communication with FDA
will allow the applicant to proceed in its development program.
(Response 16) FDA disagrees with providing criteria in the rule for
when an applicant can submit ``other information'' to demonstrate the
necessity of the ACNU. Because this determination is specific to the
circumstances surrounding each individual drug development program, FDA
does not think specifying such criteria in the rule would be feasible
and may instead unnecessarily limit the options available to applicants
for development program designs.
An applicant may be able to submit information explaining the
necessity of the ACNU for appropriate self-selection or appropriate
actual use, or both, when FDA has previously signaled that labeling
alone is not sufficient to ensure appropriate self-selection or
appropriate actual use, or both. For example, this might apply if FDA
has previously approved multiple nonprescription drug products for the
same indication with a similar ACNU. FDA is available to meet with
applicants to discuss drug development plans, which can include
discussing questions about when ``other information'' can demonstrate
the necessity of the ACNU. FDA encourages applicants to discuss their
drug development plans with FDA and seek advice.
(Comment 17) We received a few comments suggesting that FDA revise
the rule to permit the submission of adequate data or other information
that demonstrate ``the rationale for use of an ACNU,'' rather than
adequate data or other information that demonstrate ``the necessity of
the ACNU.'' Another comment also asserts that the results of the self-
selection and label comprehension studies or other adequate data or
information should justify, rather than demonstrate, that consumers
cannot appropriately self-select the drug product with labeling alone.
(Response 17) While this rule has the potential to provide
consumers with access to additional types of nonprescription drug
products, FDA recognizes that nonprescription drug products without
ACNUs do not necessarily implicate the same issues regarding continued
consumer access to appropriate drug products, because they are
generally available to consumers and do not have additional conditions
of approval that restrict consumer access. Therefore, we disagree with
the commenters' assertions because providing adequate data or other
information that simply provides a rationale or justification for the
use of an ACNU is a lower threshold. A lower threshold may result in an
applicant submitting an application for a nonprescription drug product
with an ACNU even when an ACNU is not necessary to ensure consumers'
appropriate self-selection or appropriate actual use or both (i.e.,
labeling was sufficient to ensure appropriate self-selection or actual
use or both). Consistent with the rigorous scientific data necessary
for an application to meet the evidentiary standards under the FD&C Act
and current FDA regulations for demonstrating safety and effectiveness,
we expect the applicant to provide adequate data or other information
that demonstrates the necessity of the ACNU.
(Comment 18) We received a few comments recommending that FDA
provide a streamlined process for demonstrating the necessity of an
ACNU because, in certain instances, the need for an ACNU may be obvious
and requiring data may delay drug product development. One comment
requests that FDA clarify--in situations where the need for an ACNU is
uncertain--that applicants may streamline the drug development process
by running simultaneous trials that test the effectiveness of labeling
both with and without an ACNU.
(Response 18) FDA disagrees with providing a streamlined process
applicable to all applications. Because each development program is
unique, establishing a ``streamlined'' process and standards that
applicants must follow as part of the development program may be overly
restrictive. FDA acknowledges that applicants may choose to conduct
simultaneous trials to demonstrate the necessity of the ACNU and the
effect of the ACNU. However, because the results of the studies needed
to demonstrate the necessity of the ACNU could affect the studies
needed to demonstrate the effect of the ACNU, conducting simultaneous
studies may result in the need to conduct additional trials. In
general, FDA recommends the development program for a nonprescription
drug product with an ACNU proceed in a stepwise approach. The
development of labeling for all nonprescription drug products,
including a nonprescription drug product with an ACNU, is an iterative
process that may depend upon testing and retesting as the label evolves
(Ref. 1). The applicant should begin by creating the complete labeling
for the drug product that includes consumer-friendly language for all
directions, warnings, and precautions, that is consistent with the
available prescription labeling, in cases where there is an approved
prescription drug product. FDA expects that the applicant will then
optimize the labeling using an iterative process and conduct or
reference adequate testing (e.g., label comprehension studies, self-
selection studies, actual use studies, and human factors studies) to
determine if consumer comprehension can be improved to the point where
labeling is sufficient for appropriate self-selection or appropriate
actual use, or both, without an ACNU. If the conducted or referenced
consumer studies demonstrate the necessity for an ACNU, information
that is part of the ACNU may need to be aligned with the optimized
label. In addition, when it is necessary to conduct pivotal actual use
trials, an optimized label is needed before proceeding because
consumers will need to refer to the label for use instructions after
the point of purchase (e.g., throughout the trial), and the study may
be invalid if there are subsequent substantive changes to the labeling.
Because each development program is different, we encourage the
applicant to discuss its drug development plans with FDA.
[[Page 105300]]
(Comment 19) We received one comment questioning whether applicants
should assume that the statutory standard for approving an NDA applies
to NDAs for nonprescription drug products with ACNUs (e.g., two phase 3
clinical trials to demonstrate safety and effectiveness).
(Response 19) Yes, the statutory standard that an application for a
nonprescription drug product must meet under the FD&C Act and current
FDA regulations to demonstrate the safety and effectiveness of the drug
product would apply to a nonprescription drug product with an ACNU just
as they apply to any other NDAs and ANDAs (see section 505(b)(1) or (2)
and (j) of the FD&C Act). For example, an NDA for a nonprescription
drug product with an ACNU must demonstrate the proposed drug product's
safety and effectiveness. Therefore, the NDA must include full reports
of investigations to demonstrate that the proposed drug product is safe
and effective under the conditions prescribed, recommended, or
suggested in its proposed labeling (e.g., phase 3 clinical trials or
cross reference information in its approved NDA for the prescription
product, where applicable (see section 505(d) and (b) of the FD&C Act).
f. Adequate data or other information that demonstrate the effect
of the ACNU to ensure appropriate self-selection or appropriate actual
use, or both. We proposed to require the applicant to submit adequate
data or information that demonstrates the effect of the ACNU on the
appropriate self-selection or appropriate actual use, or both, by the
consumer of the nonprescription drug product (proposed 21 CFR
314.56(c)(1)(vi)). After consideration of public comments received, we
are finalizing our proposal without change.
(Comment 20) A comment recommends that health literacy be a
significant factor in determining adequate data or other information
that demonstrates the effect of the ACNU.
(Response 20) FDA understands this comment to be suggesting that
health literacy be considered when enrolling study participants. An
application for a nonprescription drug product with an ACNU must
include adequate data or information that demonstrates the effect of
the ACNU on the appropriate self-selection or appropriate actual use,
or both, by the consumer of the nonprescription drug product (21 CFR
314.56(c)(1)(vi)). The data must show that consumers appropriately
self-select or use the drug product safely and effectively, or both,
with the ACNU. Because a nonprescription drug product with an ACNU,
like other nonprescription drug products, would be used by consumers
from the general population without the supervision of a practitioner
licensed by law to administer such drug, an applicant is expected to
include a wide range of subjects in consumer studies. Specifically, in
self-selection studies, exclusion criteria should be minimal (e.g.,
excluding only those who cannot read and understand English) (Ref. 2).
While FDA does not have specific recommendations on enrolling subjects
with varying levels of health literacy, applicants should include an
adequate number of subjects who have limited literacy skills in their
consumer studies. The proportion of low-literacy subjects in the study
sample should be representative of the proportion of adults in the
United States with low-literacy skills based on available national data
(Ref. 1) to help ensure that the study population is representative of
the population that may use the nonprescription drug product.
g. Description of the specific way the ACNU is operationalized. We
proposed to require that the applicant describe the specific way the
ACNU is operationalized (proposed 21 CFR 314.56(c)(1)(vii)). We stated
that while it is important for FDA to understand how the ACNU is
operationalized because this is part of achieving appropriate self-
selection or use, the specific way an ACNU is operationalized is not a
key element of the ACNU (87 FR 38313 at 38320) (see 21 CFR
314.56(c)(1)(iv) of this final rule regarding key elements of the
ACNU). The purpose of the ACNU is to ensure appropriate self-selection,
or appropriate actual use, or both by consumers of the nonprescription
drug product with an ACNU without the supervision of a practitioner
licensed by law to administer such drug (21 CFR 314.56(c)(1)(i) of this
final rule). The ACNU can be operationalized in different ways provided
it reliably meets the objective. In the following paragraphs, we
discuss and respond to comments on this requirement. After
consideration of public comments received, we are finalizing the
proposal with editorial modifications for clarity. We are adding the
introductory clause: ``Operationalization of the ACNU'' for clarity and
to allow for ease of reference to discuss the requirement. We are
revising the word ``way'' to ``way(s)'' to add clarity because an
application may include more than one way to operationalize the ACNU.
(Comment 21) We received a few comments that support FDA's position
that an ACNU can be operationalized in different ways as long as it
reliably meets its objective. Specifically, one comment supports the
flexibility in how an ACNU may be operationalized given that the
technologies used may change over time. One comment requests that FDA
clarify its expectation for the description of how the applicant will
operationalize the ACNU.
(Response 21) We appreciate commenters' support and firmly believe
that the ACNU can be operationalized in different ways provided it
reliably meets the objective. The applicant should describe the
specific way the ACNU is operationalized so that we can understand how
the ACNU is ensuring appropriate self-selection or appropriate actual
use, or both. Because each development program is different, we
encourage the applicant to discuss its drug development plans with FDA.
Additionally, FDA may consider issuing guidance in the future to
address general considerations that may arise and are applicable to all
applicants developing nonprescription drug products with an ACNU, or to
address new technology, if appropriate.
(Comment 22) We received a few comments that request that FDA add
language to the rule clarifying that ACNUs must be operationalized in
ways that do not restrict the sale of a nonprescription drug product
with an ACNU so that the ACNU does not become a barrier to long-term
use of a drug product.
(Response 22) We do not think that additional language needs to be
added to the rule to address this comment. Because the ACNU is
necessary to ensure appropriate self-selection or appropriate actual
use, or both, by consumers of the drug product, the nonprescription
drug product with an ACNU must only be made available to the consumer
after the ACNU has been fulfilled by the consumer. However, in the case
of long-term use of a nonprescription drug product with an ACNU where
there is the need to repurchase the drug product, there is not one
standard for the frequency in which an ACNU must be fulfilled by the
consumer; this will be determined on a case-by-case basis as we
consider the specifics of each application for a nonprescription drug
product with an ACNU during our review. Therefore, the application may
include information describing how a consumer would make subsequent
purchases of the nonprescription drug product, if appropriate. For
example, an applicant may explain that a consumer would fulfill an ACNU
(e.g., complete a self-selection questionnaire) upon the first time
purchasing the nonprescription drug product with an ACNU and at a
[[Page 105301]]
specific time interval (e.g., every 3 months) when repurchasing the
drug product.
(Comment 23) Several comments suggest that the operationalization
of an ACNU may have potential implications on access, health equity,
privacy, and ultimately health outcomes. A few comments state that
applicants should consider how to prevent or mitigate potential access
issues for older adults, people with disabilities, people in long-term
care facilities, incarcerated persons, and for people with limited
English proficiency, health literacy, or digital literacy. One comment
recommends that FDA require the applicant to describe considerations of
ease of use, health equity, access, and privacy in deciding how to
operationalize the ACNU. Some comments suggest that applicants should
implement more than one way of operationalizing an ACNU to accommodate
various health and digital literacy or comfort levels to ensure
equitable access. One comment recommends that FDA clarify that
applicants and FDA will abide by existing and future Federal, State,
and local protections against discrimination in designing, approving,
and implementing ACNUs such as the Federal Americans with Disabilities
Act and section 1557 of the Affordable Care Act, which prohibits
discrimination based on race, color, national origin, sex, age, or
disability in any health program administered by the Department of
Health and Human Services.
(Response 23) We acknowledge and understand the concerns and
emphasize the importance of access to appropriate drug products. FDA
recognizes the potential benefit of providing consumers with access to
additional types of nonprescription drug products and the rule has the
potential to broaden the types of drug products that FDA could approve
as nonprescription (87 FR 38313 at 38316). As discussed in Response 20,
because a nonprescription drug product with an ACNU, like other
nonprescription drug products, would be used by consumers from the
general population without the supervision of a practitioner licensed
by law to administer such drug, an applicant is expected to include a
wide range of subjects in consumer studies. While FDA does not have
specific recommendations for enrolling subjects with varying levels of
health literacy, applicants should include an adequate number of
subjects who have limited literacy skills in their consumer studies
(including human factors validation studies of the user interface) to
help ensure that the study population is representative of the
population that may use ACNU for the nonprescription drug product. As
discussed further in our response to Comment 59, FDA acknowledges the
benefits of having translated drug information for individuals with
limited English proficiency. FDA strongly encourages applicants to work
with retailers and other organizations to ensure that a nonprescription
drug product with an ACNU is accessible to individuals with limited
English proficiency. Additionally, FDA recognizes that in certain
situations, an individual may need assistance in fulfilling an ACNU.
Therefore, FDA acknowledges the possibility an individual other than
the intended user might be the person who fulfills the ACNU and obtains
the drug product. For example, a caregiver may fulfill the ACNU on
behalf of a child or an older adult.
We disagree with revising the requirement regarding the specific
way the ACNU is operationalized because the requirement is
intentionally broad to allow applicants significant flexibility
regarding how the ACNU can be operationalized, mindful that
technologies evolve and ACNUs may be developed for many different
nonprescription drug products. The flexibility in this requirement will
allow applicants to develop an ACNU appropriate for the specific drug
product while taking into consideration a diverse group of consumers
who may use the drug product if approved. While FDA will not require an
applicant to operationalize an ACNU in more than one way, an applicant
may submit and FDA may approve an application that includes more than
one way to operationalize an ACNU for a particular nonprescription drug
product with an ACNU provided that the ways the ACNU is operationalized
reliably meets the objective (e.g., appropriate self-selection). For
example, an ACNU that includes the administration of a questionnaire as
a key element might operationalize the ACNU by administering the
questionnaire using a website and might alternatively operationalize
the ACNU by administering the questionnaire using a mobile application
or an automated telephone response system (see also 87 FR 38313 at
38320).
Additionally, continued availability of the prescription drug
product, if one is approved, along with the availability of the
nonprescription drug product with an ACNU, will promote greater access
to needed drugs by providing flexibility in how people can obtain them.
Patients can continue interacting with their healthcare practitioner
and obtain the drug by prescription, or choose to purchase a
nonprescription drug product with an ACNU after fulfilling the ACNU, if
appropriate (21 CFR 314.56(b) and see also 87 FR 38313 at 38319).
We agree that FDA and applicants must comply with all applicable
statutory and regulatory requirements, including Federal, State, and
local protections against discrimination. However, FDA does not provide
guidance on how to comply with any legal obligations stemming from a
source outside of the statutes and regulations that FDA administers. To
the extent the comments summarized here also pertain to privacy
considerations, those portions of the comments are addressed in our
response to Comment 70.
(Comment 24) We received a comment expressing concern that remote,
technological access to fulfill an ACNU for a nonprescription drug
product may not ensure that the individual fulfilling the ACNU is in
fact the consumer.
(Response 24) FDA acknowledges the possibility that an individual
other than the intended user might be the person who fulfills the ACNU
and obtains the drug product. In some cases, this might be acceptable.
For example, a caregiver may fulfill the ACNU on behalf of a child or
an older adult. However, in other cases, an individual might attempt to
misrepresent themself as the intended user to inappropriately access
the nonprescription drug product with an ACNU. FDA expects applicants
to mitigate this by incorporating safeguards against such attempts. For
example, an applicant may consider bot detection, unique user
identification, requirements for affirmation of truthfulness, or other
methods.
(Comment 25) We received a few comments requesting guidance on the
use of technology. We received a comment recommending that when
operationalization of an ACNU is based on software (e.g., via a kiosk
or web-based application), the software should be considered a key
element of the ACNU. Further, the comment suggests that because the
software is being used to direct access, the software should be
regulated as a device and the quality assurance system should meet part
4 (21 CFR part 4) for combination products.
(Response 25) We disagree that software should be considered a key
element of the ACNU. The applicant must describe the specific way the
ACNU is operationalized (see 21 CFR 314.56(c)(1)(vii)). While it is
important for FDA to understand how the ACNU
[[Page 105302]]
is operationalized because this is part of achieving appropriate self-
selection or use, the specific way an ACNU is operationalized is not a
key element of the ACNU. The purpose of the ACNU is to ensure
appropriate self-selection, appropriate actual use, or both, of the
drug product without the oversight of a healthcare practitioner. The
ACNU can be operationalized in different ways provided it reliably
meets the objective (87 FR 38313 at 38320). However, any technology,
including software, used to operationalize the ACNU must comply with
relevant requirements. FDA considers a software function that meets the
definition of a device in section 201(h) of the FD&C Act and does not
meet the criteria under section 520(o) of the FD&C Act to be a device
software function. Software used to operationalize an ACNU that meets
the definition of a device and is not otherwise excluded from that
definition will generally be regulated as such. Consistent with FDA's
approach to other device software functions, we recommend that
applicants of such software consult the policies and recommendations
set forth in FDA's guidance documents, such as FDA's ``Policy for
Device Software Functions and Mobile Medical Applications'' (Ref. 4).
FDA acknowledges that certain nonprescription drug products with ACNUs
may be considered drug-device combination products as defined in Sec.
3.2(e) (21 CFR 3.2(e)).
(Comment 26) We received one comment asserting that an applicant
must ensure that safeguards are in place to deny access to the
nonprescription drug product with an ACNU if a technology failure in
the operationalization of the ACNU occurs and the ACNU cannot be
completed. The comment also suggests that FDA could allow a
manufacturer's representative, a pharmacist, or a pharmacy technician
to be able to administer a questionnaire to consumers in the event that
the technology fails (e.g., kiosks or online portals are not working).
(Response 26) We agree that the applicant must ensure that
consumers cannot access the nonprescription drug product with an ACNU
without fulfilling the ACNU. ``Additional condition for nonprescription
use'' (ACNU) is defined as one or more FDA-approved conditions that an
applicant of a nonprescription drug product must implement to ensure
consumers' appropriate self-selection or appropriate actual use, or
both, of the nonprescription drug product without the supervision of a
practitioner licensed by law to administer such drug if the applicant
demonstrates and FDA determines that labeling alone is insufficient to
ensure appropriate self-selection or appropriate actual use, or both
(21 CFR 314.56(a) and 201.67(b) of this final rule). The requirement
that the applicant describe the specific way the ACNU is
operationalized is intentionally broad to allow significant flexibility
regarding how the ACNU can be operationalized (21 CFR 314.56(c)(1)(vii)
of this final rule). An applicant may submit, and FDA may approve, more
than one way to operationalize an ACNU, which could also increase
consumers' ability to access the drug product with an ACNU if one way
the ACNU is operationalized fails. There is no requirement that an ACNU
be operationalized using particular technology.
(Comment 27) We received a few comments recommending that FDA
provide clarity about the process and information needed for an
applicant to update how an approved ACNU is operationalized. One
comment seeks clarity on the process an applicant would use to notify
FDA when software upgrades and technology updates are needed for the
ACNU. The comment suggests most technical changes and software upgrades
should be submitted in the applicant's annual report. However, the
comment suggests if the change is expected to result in a substantive
change in how a consumer interacts with the ACNU, impacts the drug
product's intended use, significantly improves safety and effectiveness
of the ACNU, impacts risk controls, or increases risk to consumers,
then the applicant would be expected to seek prior approval from FDA
before proceeding with the change. The comment further states that the
principles outlined in the existing Center for Devices and Radiological
Health (CDRH) guidances, including the guidance for industry and FDA
staff from October 2017, entitled ``Deciding When to Submit a 510(k)
for a Software Change to an Existing Device'' (available at <a href="https://www.fda.gov/media/99785/download">https://www.fda.gov/media/99785/download</a>), should apply to applicants that may
need to make technical or software changes. The comment requests FDA
issue new guidance advising applicants how to inform FDA of the changes
needed when the ACNU does not involve software.
(Response 27) An applicant of an approved NDA or ANDA for a
nonprescription drug product with an ACNU must follow the same
requirements as holders of other approved NDAs and ANDAs to make
changes to a drug product. This means that an applicant must propose
revisions to an approved application for a nonprescription drug product
with an ACNU by submitting a supplement, or, if applicable, by
describing changes in an annual report, consistent with our current
regulations for making changes to an FDA-approved application (see
Sec. Sec. 314.70, 314.81, 314.97, and 314.98). FDA may consider
issuing guidance in the future to address general considerations that
may arise applicable to all applicants on changes to the
operationalization of, or software or technology associated with, an
ACNU, if appropriate.
(Comment 28) FDA sought comment on any unique retail issues that
might arise for retailers or consumers based on the way the applicant
operationalizes the ACNU. We received two comments asking FDA to
clarify whether consumers who satisfy the ACNU for the reference listed
drug (RLD) (i.e., branded drug product) could purchase the generic
product. These two comments noted that this question may arise, for
example, if a retailer does not currently have in stock the specific
nonprescription drug product with an ACNU for which the ACNU was
fulfilled, or a consumer fulfills the ACNU for the RLD but prefers to
purchase the generic version. We received a comment that states FDA
should only approve technology-neutral ACNUs and limit the
proliferation of excessive proprietary platforms. We received a few
comments asserting that if each applicant uses its own mechanism to
provide a nonprescription drug product with an ACNU, pharmacies and
other retailers may be unable to accommodate the many different
mechanisms.
(Response 28) We acknowledge and appreciate the retail concerns
expressed in the comments. During the development program of a
nonprescription drug product with an ACNU, we encourage applicants to
consider the feasibility of the specific way the ACNU is
operationalized and the potential impact on retailers so as not to
impede consumer access.
As our review is inherently application-specific, we expect a
consumer seeking a particular nonprescription drug product with an ACNU
will fulfill the ACNU as operationalized for that specific product.
Accordingly, in general, consumers could not purchase the generic drug
product without fulfilling the ACNU as operationalized for the generic
drug product. FDA will review and approve NDAs and ANDAs for
nonprescription drug products with an ACNU consistent with applicable
requirements, which includes
[[Page 105303]]
consideration and review of, the statement of purpose of the ACNU, key
elements of the ACNU, and the way(s) the ACNU is operationalized, as
finalized in this rule at 21 CFR 314.56(c)(2). FDA must review and
understand how the ACNU is operationalized to ensure that the ACNU
achieves appropriate self-selection or use. As noted above, while it is
important for FDA to understand how the ACNU is operationalized because
this is part of achieving appropriate self-selection or use, the
specific way an ACNU is operationalized is not a key element of the
ACNU. The purpose of the ACNU is to ensure appropriate self-selection,
appropriate actual use, or both, of the drug product without the
supervision of a practitioner licensed by law to administer such drug,
and the ACNU can be operationalized in different ways provided it
reliably meets the objective (see also 87 FR 38313 at 38320). (See our
response to Comment 25 and section V.F.g. of this document.) The
regulations are intentionally broad and provide applicants significant
flexibility in determining the specific way the ACNU may be
operationalized, and FDA will not require an ACNU to use any specific
technology or be ``technology-neutral.'' Thus, as stated above, since
our review is inherently application-specific, and because we are
specifically reviewing and approving how the ACNU is operationalized to
ensure that the ACNU achieves appropriate self-selection, appropriate
actual use, or both, we expect a consumer seeking a particular
nonprescription drug product with an ACNU will fulfill the ACNU as
operationalized for that specific product. Also, even if a generic
applicant operationalizes the ACNU in a different way (e.g., uses a
different technology) than its RLD, the purpose and key elements of the
ACNU must be the same between RLD and generic drug. As a result, we
expect that a consumer who can fulfill the brand drug's ACNU would also
be able to fulfill the generic drug's ACNU.
In addition to the content and format requirements under Sec.
314.94, FDA proposed specific requirements for an ANDA for a
nonprescription drug product with an ACNU (proposed 21 CFR
314.56(c)(2)). We are making a few editorial modifications to the
proposed requirement. The first editorial modification is adding the
word ``include'' at the end of the introductory statement for ease of
reading, and other changes are described below in section V.F.2. In the
following paragraphs, we discuss a general comment on the topic of
ANDAs as a whole prior to discussing each of the specific requirements.
h. General comment on ANDAs.
(Comment 29) We received one comment that asserts that when there
are significant differences in efficacy or side effect profiles between
the RLD nonprescription drug product with an ACNU and an ANDA
nonprescription drug product with an ACNU, such discrepancies should be
addressed in the ANDA. The comment further asserts that different
formulations should require a separate process which might not require
a de novo application but would be more rigorous than an ANDA, which
could include additional pharmacokinetic data and evidence
demonstrating that consumers can safely use the drug product.
(Response 29) We disagree with the comment. To be approved, an ANDA
for a nonprescription drug product with an ACNU must meet the standards
specified in section 505(j) of the FD&C Act and relevant FDA
regulations (see part 314, subpart C (21 CFR part 314, subpart C)) (see
also 87 FR 38313 at 38318), as is true for any other ANDA. These
standards do not change as a result of this final rule. For example,
consistent with all ANDAs (other than ANDAs with differences approved
under a petition filed under Sec. 314.93), an ANDA for a
nonprescription drug product with an ACNU must contain information to
show that the drug product is pharmaceutically equivalent and
bioequivalent to its RLD, and thus is expected to have the same
clinical effect and safety profile as its RLD when used under the
conditions specified in the labeling (see 87 FR 38313 at 38321).
i. Statement regarding the purpose of the ACNU. We proposed to
require an ANDA applicant state the purpose of the ACNU (proposed 21
CFR 314.56(c)(2)(i)). We explained that as part of the submission, an
ANDA applicant would state the purpose of the ACNU (the same purpose as
the ACNU for the RLD) (87 FR 38313 at 38321). The heading in the
preamble of the proposed rule was entitled, ``Statement regarding the
purpose of the ACNU'' while both the preamble discussion and proposed
codified text used the slightly different wording, ``state the purpose
of the ACNU'' (see 87 FR 38313 at 38321 and 38330, respectively).
We received no comment regarding this proposed requirement, and we
are finalizing it with editorial modifications for clarity and
consistency. We are making a modification by revising the wording from
``State the purpose of the ACNU'' to ``A statement regarding whether
the purpose of the ACNU is to ensure appropriate self-selection or
appropriate actual use, or both, by consumers of the nonprescription
drug product with an ACNU without the supervision of a practitioner
licensed by law to administer such drug, which must be the same as the
purpose of the ACNU for its reference listed drug (RLD)'' for
consistency and to capture the requirement more clearly. This
modification clarifies that the ACNU for the ANDA must have the same
purpose as the ACNU for the RLD, consistent with the discussion in the
proposed rule (87 FR 38313 at 38321). This modification also makes the
language consistent with the requirement for NDAs for a nonprescription
drug product with an ACNU (see 87 FR 38313 at 38320 and 21 CFR
314.56(c)(1)(i) in this final rule).
j. Information demonstrating that the key elements of the ACNU are
the same as the key elements of the ACNU for its RLD.\4\ We proposed to
require an ANDA applicant include information demonstrating that the
key elements of the proposed ACNU are the same as the key elements of
the ACNU for its reference listed drug (RLD) (proposed 21 CFR
314.56(c)(2)(ii)). After consideration of public comment received, we
are finalizing the proposal with only minor editorial modifications to
provide greater clarity. We are revising the heading at 21 CFR
314.56(c)(2)(ii) to remove the word ``include'' since we moved
``include'' to be the last word of the introductory sentence under the
broader heading at 21 CFR 314.56(c)(2) for ease of reading as discussed
previously. We also shortened ``reference listed drug'' to ``RLD.''
---------------------------------------------------------------------------
\4\ We note that the heading for this section was ``Description
of key elements of the ACNU'' in the proposed rule (87 FR 38313 at
38321). Nonsubstantive edits made here in this final rule for
increased clarity.
---------------------------------------------------------------------------
(Comment 30) We received a few comments that specifically support
the requirement that an ANDA demonstrate that the key elements of the
ACNU are the same as the key elements of the ACNU for its RLD. We also
received a comment that suggests FDA reconsider what it defines as the
key elements of the ACNU and provide more flexibility than the rule
already provides for differences in how an ACNU is implemented by the
RLD and ANDA applicants. The commenter further states that it does not
believe that if the purpose of the ACNU is to ensure adequate self-
selection by screening out consumers with certain conditions, that
purpose can only be achieved through a single set of questions and
responses that might be proprietary to the RLD.
[[Page 105304]]
(Response 30) We appreciate the comments supporting the requirement
that an ANDA demonstrate that the key elements of the proposed ACNU are
the same as the key elements of the ACNU for its RLD. We disagree that
FDA should reconsider what it defines as the key elements of the ACNU
and provide more flexibility for differences in how an ACNU is
implemented by the RLD and ANDA applicants.
Based on existing statutory and regulatory requirements for ANDAs,
applicants may submit an ANDA referencing a listed drug (including a
listed drug that has been approved with an ACNU) under section 505(c)
of the FD&C Act and rely on FDA's previous finding that the RLD is safe
and effective (see 87 FR 38313 at 38321). Because FDA is approving the
description of the key elements of the ACNU for the NDA (see 21 CFR
314.56(c)(1)(iv)), which includes the criteria by which the consumer
would successfully fulfill the ACNU, including a description of the
specific actions to be taken by a consumer or required responses to be
provided by a consumer), which are necessary for the safe and effective
use of the nonprescription drug product with the ACNU, and because the
ANDA is relying upon FDA's previous finding that the RLD is safe and
effective, the ANDA must demonstrate that the key elements of the
proposed ACNU are the same as the key elements of the ACNU approved for
its RLD. The labeling for the ANDA drug product must be the same as the
labeling for its RLD at the time of the ANDA's approval, except for
changes required because of differences approved under a petition filed
under Sec. 314.93 or because the drug product for which an ANDA is
submitted and the RLD are produced or distributed by different
manufacturers (see sections 505(j)(2)(A) and (j)(4) of the FD&C Act and
Sec. Sec. 314.94(a)(8)(iv) and 314.127(a)(7)). Generally, we
anticipate that the ANDA applicant would use the same questions and
responses as the RLD in its labeling.
Lastly, consistent with 505(j) of the FD&C Act and our general
approach to ANDAs, we are providing flexibility in how an ANDA
applicant can operationalize its ACNU in a different way from its RLD
(87 FR 38313 at 38321). The ANDA would contain information to support
that the way in which the ACNU is operationalized achieves the same
purpose as the ACNU for its RLD, and the differences from the RLD are
otherwise acceptable in an ANDA (87 FR 38313 at 38321).
(Comment 31) We received a few comments that express concern about
the complexities of consumer selection of ANDAs. A comment expresses
concerns that allowable differences between the RLD and ANDA(s) for a
nonprescription drug product with an ACNU could lead to increased
consumer confusion and limit the ability of consumers to transition to
a generic drug product, which could undermine the cost-saving potential
that accompanies generic drug products. Another comment states that
generic drug product applicants may conceivably be able to devise a
completely novel ACNU that achieves substantially the same result as
the ACNU for the RLD, which could cause consumer confusion. A few
comments assert that consumers who have become accustomed to fulfilling
an ACNU for a nonprescription drug product may be hesitant to change to
a generic drug product if the ACNU varies too drastically from the RLD.
One comment requests FDA clarify that all similar drug products that
require an ACNU for nonprescription use will be subject to the same
ACNU to limit consumer confusion and asserts that such a clarification
could aid in retailers' ability to stock multiple nonprescription drug
products with an ACNU.
(Response 31) While we agree that the rule permits an ANDA
applicant to operationalize its ACNU in a different way from its RLD,
we disagree that this rule permits the ANDA applicant to devise a
completely novel ACNU. An ANDA for a nonprescription drug product with
an ACNU must meet the evidentiary standards under the FD&C Act and FDA
regulations for approval of an ANDA (see 87 FR 38313 at 38318). This
final rule does not affect the applicability of these standards. As
with all ANDAs (other than ANDAs with differences approved under a
petition filed under Sec. 314.93), an ANDA for a nonprescription drug
product with an ACNU must contain information to show that the drug is
pharmaceutically equivalent and bioequivalent to its RLD, and thus is
expected to have the same clinical effect and safety profile as its RLD
when used under the conditions specified in the labeling. Applicants
submitting an ANDA referencing a listed drug that has been approved
with an ACNU under section 505(c) of the FD&C Act are relying on FDA's
previous finding that the RLD is safe and effective. Therefore, because
FDA would have previously approved the description of the key elements
of the ACNU for the NDA, which are necessary for the safe and effective
use of the nonprescription drug product with the ACNU, and the ANDA is
relying upon FDA's previous finding that the RLD is safe and effective,
the ANDA must demonstrate that the purpose and key elements of the
proposed ACNU are the same as the purpose and key elements of the ACNU
approved for its RLD (see 21 CFR 314.56(c)(2)(i) and (ii) of this final
rule). As noted, the requirement provides flexibility for ANDAs in how
the applicant operationalizes the ACNU. The rule requires that the ANDA
contain information to support that the way in which the ACNU is
operationalized achieves the same purpose as the ACNU for its RLD, and
to show that differences from the RLD are otherwise acceptable in an
ANDA. Moreover, the labeling for the ANDA drug product must be the same
as the labeling for its RLD at the time of the ANDA's approval, except
for changes required because of differences approved under a petition
filed under Sec. 314.93 or because the drug product for which an ANDA
is submitted and the RLD are produced or distributed by different
manufacturers (see section 505(j)(2)(A) and (j)(4) of the FD&C Act and
Sec. Sec. 314.94(a)(8)(iv) and 314.127(a)(7)).
Therefore, while we appreciate concerns that consumers may be
hesitant to use a generic drug product with an ACNU that is
operationalized differently from the RLD, we disagree that the
differences between the RLD and the ANDA would be so great as to impede
consumers' consideration of using a generic nonprescription drug
product with an ACNU.
(Comment 32) We received a comment that recommends FDA require an
ANDA include information demonstrating that the key elements of the
ACNU are ``equivalent to'' the key elements of the ACNU for its RLD,
rather than ``the same as'' the key elements of the ACNU for its RLD.
(Response 32) We disagree. The use of the term ``same as'' is
consistent with current regulations applicable to ANDAs. For example,
when determining the appropriateness of an ANDA, the term ``same as''
generally means identical in active ingredient(s), dosage form,
strength, route of administration, and conditions of use (see Sec.
314.92(a)(1) (21 CFR 314.92(a)(1))).
k. Information on the way the ACNU would be operationalized.\5\ We
proposed to require that an ANDA applicant include information on the
way the ACNU would be operationalized, as follows. If an
[[Page 105305]]
applicant believes the ACNU is operationalized in the same way as the
RLD, include information demonstrating that the ACNU is operationalized
in the same way as the RLD. If a different way to operationalize the
proposed ACNU is used, include information to show that this different
way to operationalize the proposed ACNU achieves the same purpose as
the ACNU for its RLD and that the differences from the RLD are
otherwise acceptable in an ANDA (proposed 21 CFR 314.56(c)(2)(iii)).
After consideration of public comments received, we are finalizing the
proposal with editorial modifications for clarity. We revised the
heading at 21 CFR 314.56(c)(2)(iii) to remove the word ``include.'' As
previously discussed in section V.F.2., we moved ``include'' to be the
last word of the introductory sentence under the broader section, 21
CFR 314.56(c)(2), for ease of reading. We are adding the introductory
clause: ``Operationalization of the ACNU:'' to the first sentence of
the requirement for clarity and to allow for ease of reference to
discuss the requirement. We are revising ``include information on the
way the ACNU would be operationalized'' of the first sentence to ``a
description of the specific way(s) the ACNU is operationalized'' for
consistency with the NDA requirement in 21 CFR 314.56(b)(1)(vii) of
this final rule. We are revising the word ``way'' to ``way(s)'' to add
clarity because an application may include more than one way to
operationalize the ACNU.
---------------------------------------------------------------------------
\5\ We note that the heading for this section was ``Description
of how the applicant will operationalize the ACNU'' in the proposed
rule (87 FR 38313 at 38321). Nonsubstantive edits made here in this
final rule for increased clarity.
---------------------------------------------------------------------------
(Comment 33) We received a comment asserting that FDA's proposed
rule incorrectly suggested that ACNUs are not ``conditions of use''
under section 505(j) of the FD&C Act. The comment states that although
the proposed rule contends that ``the specific ways to operationalize
the ACNU are not considered key elements of the ACNU and otherwise are
not considered a condition of use of the drug product,'' the proposed
rule does not provide a basis for distinguishing an ACNU from other
labeling elements that qualify as ``conditions of use.''
(Response 33) We agree with the comment that an ACNU is a
``condition of use'' under section 505(j) of the FD&C Act, and we
appreciate the opportunity to clarify, as relevant to section 505(j),
the differences between the ACNU and the way(s) the ACNU is
operationalized.
An ANDA for a nonprescription drug product with an ACNU must meet
the standards specified under section 505(j) of the FD&C Act and
applicable FDA regulations for approval of an ANDA. This final rule
does not affect the applicability of these standards, as noted in our
responses to Comments 29 and 31. Under section 505(j), an ANDA
applicant can rely on FDA's previous finding that the RLD is safe and
effective so long as the ANDA applicant demonstrates that the proposed
drug product and the RLD are the same with respect to active
ingredient(s), conditions of use, dosage form, route of administration,
strength, and, with certain exceptions, labeling. (An ANDA must also
include sufficient information to demonstrate that the proposed product
is bioequivalent to the RLD and that the ANDA meets the approval
requirements relating to chemistry, manufacturing, and controls. See
sections 505(j)(2)(A) and (4) of the FD&C Act.) This means that for an
RLD with an ACNU, FDA would have previously approved the NDA with the
description of the key elements of the ACNU (including the additional
condition implemented by the applicant to be fulfilled by the consumer,
the labeling specifically associated with the ACNU, and the criteria by
which the consumer would successfully fulfill the ACNU) as necessary
for the safe and effective use of the nonprescription drug product with
the ACNU (see 21 CFR 314.56(c)(1)(i) through (vii)). This also means
that for an ANDA--which relies upon FDA's previous finding that the RLD
is safe and effective--the ANDA must demonstrate that the purpose and
key elements of the proposed ACNU are the same as the purpose and key
elements of the ACNU approved for its RLD (see 21 CFR 314.56(c)(2)(i)
and (ii) of this final rule) as part of meeting section 505(j)'s
requirements for sameness (see section 505(j)(2)(A)(ii) of the FD&C
Act).
However, an ANDA generally is not required to be the same as the
listed drug it references in all respects (see section 505(j)(2)(A)).
For example, a generic drug generally can differ from its RLD in
certain respects, such as with regard to device configuration or with
respect to inactive ingredients. As explained in response to Comment
31, this rule intentionally provides the ANDA applicant flexibility to
operationalize its ACNU in a different way from its RLD, as long as the
ANDA applicant is able to show that it achieves the same purpose as the
ACNU for its RLD and that any differences from the RLD are otherwise
acceptable in an ANDA. Moreover, the labeling for the ANDA drug product
must be the same as the labeling for its RLD at the time of the ANDA's
approval, except for changes required because of differences approved
under a petition filed under Sec. 314.93 or because the drug product
for which an ANDA is submitted and the RLD are produced or distributed
by different manufacturers (see section 505(j)(2)(A) and (j)(4) of the
FD&C Act and Sec. Sec. 314.94(a)(8)(iv) and 314.127(a)(7)).
Differences in operationalization between an ANDA and its RLD, and
differences in labeling that stem from those differences in operational
design, may be permissible; the extent to which such differences affect
the approvability of a proposed ANDA will be evaluated on a case-by-
case basis. See section 505(j)(2)(A)(v) and (j)(4)(B) of the FD&C Act.
We would expect an ANDA that meets the statutory and regulatory
sameness requirements for an ANDA, and that operationalizes the ACNU in
a different way than the RLD yet achieves the same purpose as the ACNU
for its RLD, to be as safe and effective as its RLD.
(Comment 34) We received a comment that recommends that when an
ANDA applicant proposes a different way to operationalize the ACNU, the
applicant is required to include information to show that this
different way to operationalize the proposed ACNU achieves ``an
equivalent'' purpose as the ACNU for its RLD, rather than ``the same''
purpose as the ACNU for its RLD.
(Response 34) We disagree. The use of the term ``same as'' is
consistent with section 505(j) of the FD&C Act and current regulations
applicable to ANDAs. For example, when determining the appropriateness
of an ANDA, the term ``same as'' generally means identical in active
ingredient(s), dosage form, strength, route of administration, and
conditions of use (see Sec. 314.92(a)(1)).
(Comment 35) We received a few comments that encourage FDA to
consider the use of shared system ACNUs between the RLD and ANDA
applicants. One comment encourages FDA to establish processes to have
ANDA applicants use the same ACNU as the RLD to maintain consistency,
similar to the use of shared risk evaluation and mitigation strategy
(REMS) programs by generic and brand manufacturers. Another comment
states that use of shared system ACNUs could facilitate implementation
of the systems in pharmacies and other points of sale and provide a
simpler ACNU experience for consumers; however, the comment further
states that FDA should not require the use of shared system ACNUs
because they could be used to block generic competition.
(Response 35) FDA disagrees with the comment that FDA should
encourage ANDA applicants to use a shared system to operationalize the
ACNU. While ANDA applicants are required to
[[Page 105306]]
demonstrate that the purpose and key elements of the ACNU are the same
as that of the ACNU for the RLD, we intentionally proposed a broad
requirement to allow significant flexibility regarding how the ACNU can
be operationalized. An ANDA applicant may operationalize its ACNU in a
different way from its RLD so long as it achieves the same purpose as
the ACNU for its RLD and that the differences from the RLD are
otherwise acceptable in an ANDA (Sec. 314.56(c)(2)(iii) of this final
rule). Requiring a shared system to operationalize the ACNU would limit
the ability of the ANDA applicant to operationalize the ACNU in a
different manner than the RLD.
(Comment 36) We received a few comments that state that patents
claiming aspects of an ACNU for a nonprescription drug product should
be eligible for patent listing in FDA's publication ``Approved Drug
Products With Therapeutic Equivalence Evaluations'' (commonly known as
the Orange Book) if they meet the criteria outlined in the FD&C Act and
FDA's patent listing regulations. One comment states that the statute,
which was amended by the Orange Book Transparency Act (Pub. L. 116-290,
134 Stat. 4889 (2021)), and existing regulations already identify the
factors that govern whether an ACNU-related patent must be listed.
Another comment asserts that the ACNU itself should be given the same
full purview of patent protection afforded in the ANDA drug review
process and require the follow-on applicant to consider and certify as
to the NDA holder's patents. The comment further states that this would
serve to put the original ACNU applicant on notice and allow them to
take any necessary action regarding potential patent infringement
before the follow-on nonprescription drug product with an ACNU comes to
market. A separate comment discusses patentability of the ACNU and
recommends that an ACNU be afforded similar intellectual patent
protection as the drug formulation but only as it relates to drug
products indicated to treat a specific condition or symptom. The
comment further states that such protection is not advisable for the
operationalization of the ACNU because it is unlikely that a
sufficiently broad array of possibilities exists to operationalize
ACNUs to justify any periods of market exclusivity.
FDA also received a comment recommending that patents claiming
aspects of an ACNU for the nonprescription drug product should not be
submitted for listing because allowing patents claiming aspects of the
ACNU to be listed in the Orange Book would allow a patent holder to try
to delay FDA approval of an ANDA for a nonprescription drug product
with an ACNU.
(Response 36) We appreciate the comments received in response to
our request for comments on whether patents claiming aspects of the
ACNU for the nonprescription drug product may be submitted consistent
with applicable laws and regulations. To the extent the comments opined
on whether an ACNU should be subject to patent protection, FDA notes
that questions of patentability are overseen by the U.S. Patent and
Trademark Office, and not FDA.
As a general matter, any applicant who submits an NDA must submit
applicable patent information to FDA. Such submission of patent
information must be consistent with section 505(b)(1)(A)(viii) and
(c)(2) of the FD&C Act and 21 CFR 314.53, and a patent must not be
submitted for listing unless the patent claims the drug that is the
subject of the application and is a drug substance (active ingredient)
patent or drug product (formulation or composition) patent, or claims a
method of using the drug described in the drug's approved labeling. In
turn, a 505(b)(2) or ANDA applicant must provide an appropriate patent
certification or statement with respect to each such patent. The status
of each patent listed for the listed drug(s) relied upon or reference
listed drug, and the relevant patent certification or statement, must
be considered in determining the timing of the approval of a 505(b)(2)
or ANDA application.
Taking into consideration patent certification and other
requirements that might serve as potential barriers to ANDA applicants
developing nonprescription drug products, we proposed significant
flexibility in the rule to allow an ANDA applicant to operationalize
its ACNU in a different way from its RLD. As described throughout this
rule (e.g., Responses 5, 6, and 7), this rule gives applicants
flexibility regarding the types of ACNUs that may be developed, as well
as how those ACNUs may be operationalized. Given this flexibility, and
without knowing what patents an RLD application holder may ultimately
have with respect to a nonprescription drug product with an ACNU (as
noted above, the U.S. Patent and Trademark Office oversees
determinations of patentability), FDA is unable to predict the patent
issues that may be relevant to nonprescription drug products with an
ACNU. However, we reiterate that in all cases, submission of patent
information must be consistent with section 505(b)(1)(A)(viii) and
(c)(2) of the FD&C Act and 21 CFR 314.53, and a patent must not be
submitted for listing unless the patent claims the drug that is the
subject of the application and is a drug substance (active ingredient)
patent or drug product (formulation or composition) patent, or claims a
method of using the drug described in the drug's approved labeling.
To the extent the comments summarized here about ``market
exclusivity'' also pertain to statutory exclusivity, those portions of
the comments are addressed in our response to Comment 72.
G. Comments on Nonprescription and Prescription Approval and
Simultaneous Marketing and FDA Response
We proposed to establish that because the ACNU allows the
nonprescription drug product to be used safely and effectively without
the supervision of a practitioner licensed by law to administer such
drug, the ACNU is a meaningful difference between the prescription drug
product and the nonprescription drug product with an ACNU. Therefore, a
prescription drug product and a nonprescription drug product with an
ACNU that contain the same active ingredient can be simultaneously
marketed even if they do not have other meaningful differences, such as
different indications or strengths (proposed 21 CFR 314.56(d)).
After consideration of public comments received, we are finalizing
our proposal with an editorial correction. We are making an editorial
correction to the proposed heading in 21 CFR 314.56(d), ``Simultaneous
marketing of nonprescription and prescription products,'' by adding the
word ``drug'' such that it now more accurately states, ``Simultaneous
marketing of nonprescription and prescription drug products''.
FDA believes that the requirement for submission of a separate
application (21 CFR 314.56(b)) and the simultaneous marketing provision
(21 CFR 314.56(d)) are necessary to fulfill the key goals of this
rulemaking, which are to: (1) increase options for applicants to
develop and market safe and effective nonprescription drug products,
which would broaden the types of nonprescription drug products
available to consumers and (2) increase consumer access to appropriate,
safe, and effective drug products, by providing for the availability of
prescription versions of nonprescription drug products approved with
ACNUs, both of which in
[[Page 105307]]
turn could improve public health. If either of those requirements in
the final rule is stayed or determined to be invalid or unenforceable,
the remaining provisions of the rule should no longer continue in
effect because the rule would not meet FDA's objectives. Without the
requirement to submit a separate application, an applicant could submit
a supplemental application to switch the status of an approved
prescription drug product to a nonprescription drug product with an
ACNU. If such a supplemental ``switch'' application were approved for
an RLD, prescription ANDAs that reference the RLD would be required to
submit supplemental applications to switch their drug products from
prescription to nonprescription with an ACNU. This would potentially
remove all the prescription drug products from the market. If a
consumer who had been using a prescription drug product is unable to
obtain it once it became available only as a nonprescription drug
product with an ACNU (e.g., because the person lacks access to the
relevant technology), the consumer would lose access to the drug.
Similarly, consumers who prefer to interact with their healthcare
practitioners and obtain the drug by prescription may be less likely to
continue the treatment with a nonprescription drug product with an
ACNU. These outcomes would be contrary to FDA's intent for the rule.
Therefore, if 21 CFR 314.56(b) or (d) is stayed or determined to be
invalid or unenforceable, the entire rule should be invalidated.
(Comment 37) Many comments support the simultaneous marketing of
the same drug as a prescription drug product and a nonprescription drug
product with an ACNU. One comment supports simultaneous marketing to
increase equitable access to safe and effective drug products and
expand consumer choice. Another comment expresses support for FDA
clarifying that an ACNU is a meaningful difference and asserts that
there has not been clear understanding to date as to what ``meaningful
difference'' means. We also received a comment requesting that FDA
require the applicant to have a marketed prescription version of the
same drug product at the same time as a marketed nonprescription drug
product with an ACNU. However, we received a few comments that disagree
with simultaneous marketing and assert that it does not improve or
otherwise affect opportunities for consumer access. These commenters
assert that simultaneous marketing would inadvertently create a less
competitive marketplace by failing to incentivize investment in the
process of switching prescription drug products to nonprescription
status and, consequently, fail to realize the public health benefits
associated with the introduction of novel nonprescription drug
products. These commenters also assert that simultaneous marketing is
not necessary because the applicant could choose to initiate
discussions with FDA about possible options for product access for
persons who cannot or choose not to fulfill the ACNU or a consumer
would be able to speak to their healthcare practitioner about treatment
options if they cannot fulfill the ACNU.
(Response 37) As discussed in section V.G. of this document, we
agree that simultaneous marketing could increase consumer access.
Continued access to the prescription drug product, along with the
availability of the nonprescription drug product with an ACNU, allows
greater access to needed drugs by providing flexibility in how to
obtain them. The consumer may obtain a nonprescription drug product
with an ACNU however it is operationalized or continue to interact with
their healthcare practitioner and obtain the approved prescription drug
product, if appropriate (see also 87 FR 38313 at 38319).
As discussed in our response to Comment 10, we disagree that
simultaneous marketing is not necessary to promote greater access to
drug products or that simultaneous marketing would disincentivize
development of a nonprescription drug product with an ACNU. FDA
recognizes that some consumers may not be able to access the
nonprescription drug product with an ACNU. While we agree, as discussed
in our response to comment 23, that the applicant may operationalize an
ACNU in more than one way, there are consumers that the drug product
would not be appropriate for in the nonprescription setting, but the
drug product would be an appropriate use when under the supervision of
a practitioner licensed by law to administer such drug. If there is not
simultaneous marketing of the prescription drug product and
nonprescription drug product with the ACNU, the prescription drug
product would no longer be able to be marketed, which would eliminate
the prescription drug product as a treatment option for health care
practitioners to prescribe for patients. Therefore, continued
availability of the prescription drug product along with the
nonprescription drug product with an ACNU promotes the greatest access
to needed drug products in both the prescription and nonprescription
settings.
We disagree with the recommendations to revise the rule to require
that the applicant market both a prescription version of the drug
product and a nonprescription with an ACNU version of the drug product.
A nonprescription drug product with an ACNU is not required to first be
marketed as a prescription drug product. If the application for a
nonprescription drug product with an ACNU meets the evidentiary
standards under the FD&C Act and current FDA regulations to demonstrate
the safety and effectiveness of the drug product in the nonprescription
setting, then FDA could approve the application even if there is not a
marketed prescription version.
(Comment 38) We received a comment that many stakeholders have
misconceptions about a nonprescription drug product with an ACNU,
including the view that nonprescription drug products with ACNUs are a
third class of drugs or ``an expansion of dual status.'' The commenter
states that FDA can address these misconceptions by changing the
terminology from ``simultaneous marketing'' to ``simultaneous access.''
(Response 38) We clarify that the rule does not establish a third
class of drug products for purposes of section 503(b) of the FD&C Act.
FDA approves drugs as either prescription or nonprescription drug
products under section 505 of the FD&C Act. The rule is intended to
increase options for applicants to develop and market safe and
effective nonprescription drug products. Also, we interpret the comment
about ``dual status'' to refer to simultaneous marketing of
prescription and nonprescription drugs. While we recognize that there
may be various misconceptions about what constitutes meaningful
differences between prescription and nonprescription drug products, we
disagree that changing the terminology in this rule from ``simultaneous
marketing'' to ``simultaneous access'' will reduce any confusion that
may exist. Based on our experience with industry, the term does not
currently cause confusion. FDA has consistently used the term
``simultaneous marketing'' to explain FDA's interpretation of the
language in section 503(b) of the FD&C Act to allow the same active
ingredient to be simultaneously marketed in both a prescription drug
product and nonprescription drug product if a meaningful difference
exists between the two that makes the prescription product safe only
under the supervision
[[Page 105308]]
of a practitioner licensed by law to administer such drug (see 87 FR
38313 at 38321, 83 FR 13994, April 2, 2018, and 70 FR 52050, September
1, 2005). Changing this long-used term may introduce new confusion.
(Comment 39) We received comments that agree that FDA has the legal
authority under the FD&C Act to allow the simultaneous marketing of
products with the same active ingredient as both a prescription drug
product and a nonprescription drug product if there is a meaningful
difference between the two drug products.
(Response 39) We agree with the comments that the FD&C Act permits
the simultaneous marketing of a prescription drug product and a
nonprescription drug product where a meaningful difference exists
between the two that makes the prescription product safe only under the
supervision of a practitioner licensed by law to administer such drug.
As noted in the proposed rule, under section 503(b) of the FD&C
Act, the same active ingredient can be simultaneously marketed in both
a prescription drug product and nonprescription drug product if a
meaningful difference exists between the two that makes the
prescription product safe only under the supervision of a practitioner
licensed by law to administer such drug (see 87 FR 68702, 87 FR 38313
at 38321, 83 FR 13994, and 70 FR 52050). Section 503(b)(1)(A) requires
a drug to be limited to prescription-only status if, because of its
toxicity or other potentiality for harmful effect, or the method of its
use, or the collateral measures necessary to its use, it is not safe
for use except under the supervision of a practitioner licensed by law
to administer such drug. Conversely, a drug that can be used safely by
consumers without the supervision of a practitioner licensed by law to
administer such drug does not require a prescription. Under section
503(b)(1), a drug cannot be both prescription and nonprescription at
the same time, because it cannot be both safe and unsafe for use
without the supervision of a practitioner licensed by law to administer
such drug. For the same reason, two drug products with the same active
ingredient that don't have meaningful differences also can't be
simultaneously marketed as prescription and nonprescription. However,
consistent with section 503(b)(1), if there is a meaningful difference
(e.g. indication, strength, route of administration, dosage form, or
patient population) between two drug products with the same active
ingredient that makes one drug product safe for use only under the
supervision of a practitioner licensed by law to administer such drug,
while the other drug product is safe for use without such supervision,
then the two products may be simultaneously marketed as prescription
and nonprescription drug products, respectively. (See also the
discussion on meaningful difference in our response to Comment 40).
In addition, under section 503(b)(4)(B) of the FD&C Act, a drug for
which the prescription dispensing provisions of section 503(b)(1) do
not apply shall be deemed to be misbranded if at any time prior to
dispensing, the label of the drug bears the ``Rx only'' symbol.
Likewise, under section 503(b)(4)(A), drugs that are subject to the
prescription dispensing provisions of section 503(b)(1) must bear the
``Rx only'' symbol, or else they are misbranded. This effectively means
that, absent a meaningful difference between them, simultaneous
marketing of two drug products with the same active ingredient as both
prescription and nonprescription drug products would result in one of
the two products being misbranded. However, if there is a meaningful
difference between two drug products with the same active ingredient
that makes one drug product safe for use only under the supervision of
a practitioner licensed by law to administer such drug, then
simultaneous marketing of the two products is permitted. See also the
responses to Comment 2 and Comments 40 through 43, below.
(Comment 40) Some commenters contend that an ACNU is not a
meaningful difference for purposes of simultaneous marketing of
prescription and nonprescription drugs under section 503(b) of the FD&C
Act (see also Comments 41-43 and FDA responses). Specifically, the
comments argue that a meaningful difference between two drug products
must exist in indication, strength, route of administration, dosage
form, or patient population. The commenters assert that a switch to
nonprescription status may be accompanied by one of these meaningful
changes in addition to an ACNU, but the ACNU itself does not establish
such a difference. The commenters specifically cite FDA's decision to
withdraw ANDA drug products that referenced the prescription NDA
020698, MiraLAX Powder (polyethylene glycol (PEG)-3350) powder for
occasional constipation because FDA approved a full switch of NDA 02698
from prescription to nonprescription marketing. The commenters assert
that FDA found that while there were differences in labeling, FDA looks
to differences in indication, strength, route of administration, dosage
form, [and] patient population to determine whether there is a
meaningful difference between the two products. Therefore, the
commenters assert that the mere presence of an ACNU does not implicate
any of these factors.
(Response 40) FDA disagrees with these comments. FDA's considered
judgment, based on the Agency's scientific and technical expertise, is
that an ACNU would in fact constitute a meaningful difference between a
prescription drug product and a nonprescription drug product with an
ACNU, even if they do not have other meaningful differences, such as
different indications or strengths. While we have previously provided
some examples of what may constitute a meaningful difference, such as
indication, strength, route of administration, dosage form, or patient
population (see 83 FR 13994 and 70 FR 52050), we have not created a
finite list of what may constitute a meaningful difference and will
continue to make determinations of ``meaningful difference'' as
appropriate.
In circumstances where the applicant would like to market a
previously approved prescription drug product as nonprescription, the
applicant must demonstrate that the proposed nonprescription drug
product does not meet the criteria in section 503(b)(1) of the FD&C
Act. FDA evaluates the data submitted by the applicant and makes a
scientific determination about whether consumers can use the drug
product safely and effectively without the supervision of a
practitioner licensed by law to administer such drug, and therefore the
drug product can be approved as nonprescription. When FDA determines
that, based on the data, a proposed nonprescription drug product does
not meet the criteria in section 503(b)(1) of the FD&C Act, the Agency
may also make a scientific determination regarding whether there is a
meaningful difference between the nonprescription drug product and a
prescription drug product that contains the same active ingredient. If
there is no meaningful difference between the products, then the
product marketed as a prescription drug product would no longer meet
the criteria for prescription drugs in section 503(b)(1) and would need
to switch to nonprescription status. For example, with NDA 020698,
MiraLAX (PEG-3350) powder for occasional constipation, FDA made a
scientific determination that there are no meaningful differences
between the prescription and nonprescription drug
[[Page 105309]]
products. In that scenario, the following were the same for the
prescription and the nonprescription drug product: the active
ingredient (PEG-3350), dosage form (powder for solution), strength (17
gram (g) dose in 4 to 8 ounces of liquid), route of administration
(oral), indications (constipation), and patient population (17 years of
age or older). As discussed in the response to Comment 41, in
Breckenridge Pharm., Inc. v. FDA, 754 Fed. Appx. 1 (D.C. Cir. 2018),
the U.S. Court of Appeals for the D.C. Circuit found no error in FDA's
determination that differences in the duration of use between the
prescription and nonprescription PEG-3350 products were not
``meaningful differences'' such that the prescription and
nonprescription products could be marketed simultaneously.
There are also examples in which FDA has determined that, based on
the data submitted, a drug meets the criteria in section 503(b)(1) of
the FD&C Act for certain conditions of use; however, for other
conditions of use, it does not meet the criteria in section 503(b)(1)
of the FD&C Act. For example, Nasonex (mometasone furoate) nasal spray,
50 microgram (mcg)/spray (NDA 020762) was approved with two
indications. FDA determined that data supported that the indication
related to treatment of allergy symptoms did not meet the criteria for
a prescription drug in section 503(b)(1) of the FD&C Act and that
consumers could self-select and use the drug product for that
indication in the nonprescription setting. Therefore, on March 17,
2022, based on data submitted by the applicant, FDA approved
nonprescription Nasonex 24HR Allergy (mometasone furoate) nasal spray,
50 mcg/spray (NDA 215712) for the temporary relief of allergy symptoms.
However, Nasonex's indication of ``treatment of chronic rhinosinusitis
with nasal polyps in adult patients 18 years of age and older''
continues to meet the criteria in section 503(b)(1) of the FD&C Act.
Therefore, FDA made a scientific determination that there is a
meaningful difference between the prescription and nonprescription drug
products because of their different indications, and the prescription
and nonprescription drug products may be marketed simultaneously
consistent with section 503(b).
Another example involves Xyzal (levocetirizine dihydrochloride) 0.5
mg/milliliter (mL) solution. The prescription product (NDA 022157) was
approved in 2008 for the relief of symptoms associated with seasonal
allergic rhinitis (SAR) and perennial allergic rhinitis (PAR), and the
treatment of uncomplicated skin manifestations of chronic idiopathic
urticaria (CIU) for patients 6 years of age and older. In 2009, it was
approved for SAR for patients 2 years of age and older, and PAR and CIU
in adults and children 6 months of age and older. In 2017, Xyzal
Allergy 24HR (NDA 209090) was approved for nonprescription use with the
previously prescription indication of SAR in adults and children 2
years of age and older. The nonprescription drug product was also
approved with the PAR indication, but only for adults and children 2
years of age and older. The younger age range (6 months of age to under
2 years) remained prescription because the diagnosis of PAR in infants
and children under the age of 2 years is more complex and requires the
evaluation of a physician. The indication for CIU for all age ranges
continues to meet the criteria for prescription use. Thus, the
meaningful difference between the prescription and nonprescription
versions of Xyzal (levocetirizine dihydrochloride) for the PAR
indication is a difference in patient population (i.e., certain age
groups).
An ACNU is a condition that must be affirmatively fulfilled by a
consumer before they can self-select, use, or both self-select and use,
a nonprescription drug product. Therefore, a consumer will generally
need to act to fulfill an ACNU, and, as explained further in response
to Comment 42 below, this distinguishes it from labeling. Similar to
the different indications and patient population in the above examples
for Nasonex and Xyzal, an ACNU will be a meaningful difference that
exists between two drugs that makes the prescription drug product safe
only under the supervision of a practitioner licensed by law to
administer the drug and the nonprescription drug product safe for use
without the supervision of such a practitioner. If an NDA is submitted
for a nonprescription drug with an ACNU, FDA would only approve it if
FDA determines that the applicant's studies and other information in
the application demonstrate the ACNU would make the nonprescription
drug product safe for use without the supervision of a practitioner
licensed by law to administer the drug product. However, without the
ACNU, the drug product would be safe and effective only under the
supervision of a practitioner licensed by law to administer the drug
product, and FDA could not approve the drug product as nonprescription.
(Comment 41) Some commenters argue that FDA's position that an ACNU
is a meaningful difference ignores the statutory language in section
503(b) of the FD&C Act, legislative history of the Durham-Humphrey
Amendments to the FD&C Act, legal precedent, specifically the D.C.
Circuit's decision in the MiraLAX case, Breckenridge Pharm., Inc. v.
FDA, 754 Fed. Appx. 1 (D.C. Cir. 2018), and decades of Agency
precedent. A commenter explains that the Durham-Humphrey Amendments
amended section 503(b) of the FD&C Act to add the definition for
prescription drug, which effectively established prescription and
nonprescription drugs as two separate categories. The commenter further
explains that legislative history shows that Congress amended the FD&C
Act to address confusion that arose due to the fact that the same drug
could be characterized as a prescription drug by one manufacturer and
as nonprescription by another. The commenter further explains that the
mutually exclusive nature of the classification of a drug product as
either prescription or nonprescription is manifest in the statutory
language. The commenter asserts that if FDA were to collapse the two
categories for simultaneous marketing of a prescription drug product
with a nonprescription drug product with an ACNU, it would not only
contradict the plain-language meaning of the FD&C Act but also cause
confusion that the Durham-Humphrey Amendments were meant to address. In
discussing FDA's decision to withdraw approval of ANDA products that
referenced MiraLAX, PEG-3350, the commenters argue that, in reaching
its decision that the ANDA products did not have a meaningful
difference from the RLD product (NDA 02698, MiraLAX (PEG-3350) powder
for occasional constipation), FDA looked to differences in indication,
strength, route of administration, dosage form, and patient population,
but did not look to whether the product had an ACNU (see also Comment
40).
(Response 41) As discussed in response to Comments 39 through 40
above, and discussed further below in responses to Comments 42 through
43, FDA's position is entirely consistent with, and is in fact the best
reading of, the statutory language in section 503(b) of the FD&C Act.
Under section 503(b), the same active ingredient can be simultaneously
marketed in both a prescription drug product and nonprescription drug
product if a meaningful difference exists between the two that makes
the prescription product safe only under the supervision of a
practitioner licensed by law to administer the drug. FDA disagrees with
commenters who argue that a
[[Page 105310]]
meaningful difference between two drug products must exist in
indication, strength, route of administration, dosage form, or patient
population, and that an ACNU is not a meaningful difference because it
does not implicate any of these factors.
Recognizing that an ACNU can be a meaningful difference that allows
for simultaneous marketing is also consistent with the legislative
history of the Durham-Humphrey Amendments of 1951 (Pub. L. 82-215, 65
Stat. 648). Until 1951, the FD&C Act did not contain criteria for
determining when to limit a drug's approval to prescription use. As a
result, different manufacturers made different decisions about whether
to market a drug as prescription or nonprescription. This resulted in
confusion and uncertainty for pharmacists and consumers about whether
certain drugs were safe for use without the supervision of a physician.
To eliminate this confusion and uncertainty, and to protect the public
health, Congress amended section 503(b) of the FD&C Act with the
Durham-Humphrey Amendments, which had two primary objectives: (1) to
protect the public from abuses in the sale of potent prescription
drugs; and (2) to relieve retail pharmacists and the public from
burdensome and unnecessary restrictions on the dispensing of drugs that
are safe for use without the supervision of a physician (see S. Rep.
No. 946, at 1 (1951), reprinted in 1951 U.S.C.C.A.N. 2454). By
recognizing that there are circumstances under which an ACNU (e.g.,
restricting access to the drug unless a consumer demonstrates an
appropriate medical history through a questionnaire) can help ensure
that a patient can self-select and use a drug safely and effectively
without the supervision of a practitioner licensed by law to administer
such drug, this rulemaking advances the second primary objective of
these amendments. Simultaneous marketing of a prescription drug product
and a nonprescription drug product with an ACNU that do not have other
meaningful differences can reduce burdens on access for patients for
whom a drug is safe and effective for use without supervision of a
practitioner licensed by law to administer such drug, without causing
confusion. The ACNU would be a meaningful difference that consumers and
pharmacists would recognize, along with its associated labeling
including the ACNU Instructions and Statement, as differentiating the
product from a potential prescription version of the product.
FDA's decision to withdraw approval of ANDA products that
referenced NDA 020698 MiraLAX (PEG-3350) powder for occasional
constipation, and the D.C. Circuit's decision in Breckenridge Pharm.,
Inc. v. FDA upholding the Agency's position, have no bearing on whether
an ACNU is a meaningful difference between prescription and
nonprescription drug products. As a threshold matter, MiraLAX is not a
nonprescription drug product with an ACNU. Additionally, when FDA made
its decision, and when Breckenridge Pharm., Inc. v. FDA was decided,
this regulation had not yet been promulgated. Instead, the court
focused on whether labeling regarding duration of use could constitute
a meaningful difference; the court upheld FDA's conclusion that it did
not in that case, while expressly leaving open the possibility that it
might in another case (see 754 Fed. Appx. at 4). Accordingly, whether
an ACNU is an example of a meaningful difference with regard to the
PEG-3350 products was not relevant to FDA's withdrawal decision for
MiraLAX and, likewise, was not at issue in Breckenridge Pharm., Inc. v.
FDA. As discussed further in response to Comment 42 below, as defined
in this rule, an ACNU cannot consist merely of labeling, even if one
aspect of it includes labeling, nor is an ACNU ``functionally
equivalent to labeling.''
Furthermore, FDA's determination here that an ACNU would constitute
a meaningful difference is consistent with FDA's approach to the
MiraLAX proceedings. There, FDA stated: ``In determining whether an Rx
drug product and an OTC drug product are the same, FDA considers
whether there are any meaningful differences between the OTC and Rx
products that would justify the different marketing status of the
products'' (see 73 FR 63491 at 63492, October 24, 2008). As explained
in our response to Comment 40, FDA's considered judgment is that an
ACNU, as defined in this rule, would be such a meaningful difference
because it would allow a drug product that would otherwise require a
prescription to be marketed as a nonprescription drug product.
(Comment 42) One comment argues that an ACNU is labeling or
``functionally equivalent to labeling'' because it is intended to
enable an individualized consumer response for the purpose of self-
selection and/or actual use, the same role played by traditional drug
labeling, and therefore it does not constitute a meaningful difference
between a prescription drug product and a nonprescription drug product.
(Response 42) FDA does not agree that an ACNU is labeling or
``functionally equivalent to labeling,'' or that legal precedent is
being ignored. Prescription drug labeling is designed to inform
healthcare practitioners and thus contains more detailed information
than nonprescription drug labeling. Nonprescription drug labeling is
designed for consumers. As illustrated in the MiraLAX proceedings in
Breckenridge Pharm., Inc. v. FDA, we determined that the differences in
the labeling between the nonprescription drug product and the generic
prescription drug products that were ``simply . . . due to the
different audiences (i.e., learned intermediary versus lay consumer)
and the difference in setting (i.e., use with a physician's supervision
versus consumer self-directed use)'' were not meaningful differences
for purposes of section 503(b) of the FD&C Act (see 83 FR 14007).
However, certain meaningful differences between drugs may be reflected
in their labeling (e.g., indication or patient population).
This is consistent with FDA's determination than an ACNU is a
meaningful difference because an ACNU (as defined in this regulation)
cannot consist merely of labeling, even if one aspect of it includes
labeling. A label is the written, printed, or graphic matter on the
immediate container of the drug product (see section 201(k) of the FD&C
Act). Labeling is all labels or other written, printed, or graphic
matter on the drug product or any of its containers or wrappers, or
accompanying the drug product (see section 201(m) of the FD&C Act).
Labeling for nonprescription drugs provides information to consumers to
self-select and use the drug product, and the consumer reads this
information to self-select and use the drug product.
In contrast to labeling, an ACNU is a condition that must be
affirmatively fulfilled by a consumer before they can self-select, use,
or both self-select and use, a nonprescription drug product. Therefore,
a consumer will generally need to act to fulfill an ACNU. For example,
with Drug X (see more information about Drug X, a fictitious
nonprescription drug product with an ACNU, in the proposed rule (87 FR
38313 at 38319)), the ACNU requires all consumers to complete a
questionnaire located on a secure website created by the applicant to
determine whether Drug X is appropriate for the consumer. Using a
consumer's answers to the questions, the underlying program or other
operating information used by the secure website, not the consumer,
[[Page 105311]]
calculates the risk score for a serious side effect and determines if
the consumer has an acceptable disease-specific risk score to use Drug
X and therefore purchase Drug X. As shown in this example, an ACNU may
include labeling, but the ACNU is not in itself labeling. It is a
condition that a consumer must affirmatively satisfy, which ensures
that a drug product can be appropriately selected and used safely and
effectively without the supervision of a practitioner licensed by law
to administer such drug.
FDA disagrees that an ACNU is ``functionally equivalent to
labeling.'' With previous prescription-to-nonprescription switches that
have been approved by FDA, including the one at issue in the MiraLAX
proceedings in Breckenridge Pharm., Inc. v. FDA, the drug product was
safe for use without the supervision of a practitioner licensed by law
to administer such drug under section 503(b) of the FD&C Act; it simply
needed to be labeled to satisfy the requirement for adequate directions
for use and other labeling requirements for nonprescription marketing
under the FD&C Act and FDA regulations. On the other hand, for a
nonprescription drug product approved with an ACNU, FDA has determined
that labeling alone is insufficient to ensure appropriate self-
selection or appropriate actual use, or both (see generally 21 CFR
314.56 of this final rule). Therefore, a drug product approved with an
ACNU could not satisfy the requirement for adequate directions for use
for a layperson under the FD&C Act and FDA regulations, and would not
be safe for use without the supervision of a practitioner licensed by
law to administer such drug. We have provided in this rule an exemption
from the requirement for adequate directions for use on the condition
that, among other conditions, the approved ACNU is implemented as
approved under the application, so that the drug would then become safe
for use in the nonprescription setting (see 21 CFR 201.130 in this
final rule).
With regard to the comment's argument that an ACNU is functionally
equivalent to labeling because they both ``ensure appropriate self-
selection and use of the OTC product,'' the comment does not explain
why this is different from other characteristics of a drug that it
concedes are meaningful differences. In particular, the comment
``request[s] that the final rule acknowledge and maintain FDA's prior
position that it will look to indication, strength, route of
administration, dosage form, and patient population to determine
whether there are meaningful differences between two products with the
same active ingredient . . . .'' The comment therefore concedes that
the indication and patient population can be meaningful differences for
purposes of simultaneous marketing under section 503(b) of the FD&C
Act, but does not acknowledge that these conditions, which are only
reflected in the labeling, also serve to ``ensure appropriate self-
selection and use of the OTC product.'' Such conditions are, in fact,
critical to appropriate self-selection and use. Because the ACNU would
similarly provide a difference for the drug that is meaningful, the
nonprescription drug with an ACNU would be a different drug product
from a prescription version, even if it does not have other meaningful
differences for purposes of simultaneous marketing under section 503(b)
of the FD&C Act.
(Comment 43) We received a comment that argues that this rule, by
allowing the simultaneous marketing of the prescription version of the
drug product and a nonprescription with an ACNU version of the drug
product, ``indisputably triggers the major questions doctrine because
it would radically overhaul the OTC drug market and limit consumer
access to OTC drugs . . . which is undeniably an issue of `vast
economic and political significance.' '' (quoting West Virginia v. EPA,
142 S. Ct. 2587, 2605).
(Response 43) We do not agree that this rule implicates the ``major
questions doctrine'' because of the provision providing for
simultaneous marketing. In West Virginia v. EPA, the Supreme Court
found that, ``to substantially restructure the American energy
market,'' the `` `claim[ed] to discover in a long-extant statute an
unheralded power' representing a `transformative expansion in [its]
regulatory authority,' '' and that the Agency ``located this newfound
power in the vague language of an `ancillary provision[ ]' of the
Act.'' 597 U.S. 697, 724 (2022) (citations omitted). The Court further
found that this ancillary provision ``had rarely been used in the
preceding decades,'' but was then used ``to adopt a regulatory program
that Congress had conspicuously and repeatedly declined to enact
itself.'' Id. Consequently, the Court stated that ``there is every
reason to `hesitate before concluding that Congress' meant to confer .
. . the authority'' in question to the EPA and that the case was a
``major questions case.'' Id. at 724-725. To overcome its hesitation
and ``skepticism toward EPA's claim,'' the Court stated that ``the
Government must--under the major questions doctrine--point to `clear
congressional authorization' to regulate in that manner.'' Id. at 732.
None of the findings described above in West Virginia v. EPA
applies to the provision in this rule providing for simultaneous
marketing of prescription drugs and nonprescription drugs with ACNUs.
As discussed in the response to Comment 2, Congress has given FDA the
authority to make scientific determinations about which drugs may be
marketed as prescription or nonprescription drugs. In addition, section
503(b)(3) gives FDA the authority to issue regulations to remove the
prescription-only dispensing requirements from drugs when such
requirements are not necessary for the protection of the public health.
FDA's finding that an ACNU would constitute a meaningful difference is
simply the latest determination in a series of determinations under
section 503(b) of the FD&C Act regarding whether some difference
constitutes a meaningful difference for purposes of prescription and
nonprescription marketing. For example, in 1984, the Agency approved a
nonprescription ibuprofen product because it had meaningful differences
from the prescription versions of ibuprofen (see 67 FR 54139 for
general background related to this regulatory history).
Likewise, for decades other drug products have been approved as
nonprescription drug products even though prescription drug products
contained the same active ingredient (see 70 FR 52051 for some
examples, including loperamide in a prescription drug product for
chronic diarrhea and in an OTC drug product for acute diarrhea). In
2005, FDA noted that such meaningful differences had, up to that time,
included a difference in indication, strength, route of administration,
and dosage form. FDA also indicated that it was considering whether a
difference in patient population could also constitute a meaningful
difference for purposes of simultaneous marketing (see 70 FR 52050,
September 1, 2005). Later, in the Federal Register of October 24, 2008
(73 FR 63491; see also 83 FR 13994), related to the MiraLAX proceeding,
and in 2013 related to an approval decision for NDA 202211 Oxytrol for
Women (oxybutynin) extended-release film, 3.9 mg, for the treatment of
overactive bladder in women, FDA made clear that patient population
could also be a meaningful difference between a prescription drug
product and a nonprescription drug product.
In addition, in 2018, the D.C. Circuit Court of Appeals in
Breckenridge Pharm, Inc. v. FDA upheld FDA's determination that the
labeled duration of use for the nonprescription MiraLAX
[[Page 105312]]
product did not constitute a meaningful difference from the generic
prescription drugs, and recognized that ``the agency left open the
possibility that differences in duration of use--in other
circumstances--could add up to a `meaningful difference.' '' 754 Fed.
Appx. 1, 4 (citing FDA's publications in the Federal Register related
to the MiraLAX proceeding, at 83 FR 13994 at 13999 and 73 FR 63491 at
634913). Thus, whether a difference between a prescription drug product
and a nonprescription drug product constitutes a meaningful difference
that permits simultaneous marketing in accordance with section 503(b)
of the FD&C Act is something FDA has considered and acted upon in
numerous instances for decades. FDA's determination in this rule that
an ACNU would constitute the same kind of meaningful difference is
hardly a ``sweeping assertion of `unprecedented power over American
industry,' '' as the commenter claims.
The simultaneous marketing provision in this rule is also unlike
the Agency actions in ``major questions'' cases because, among other
things, it does not represent an attempt to ``substantially
restructure'' a market. All that this provision of the rule will do is
provide an additional consideration for applicants seeking
authorization for a product to enter the market. With regard to
simultaneous marketing of prescription drug products and
nonprescription drug products, as noted above, there are currently, and
there have long been, marketed prescription drug products and
nonprescription drug products that contain the same active ingredient
because there is some meaningful difference that supports the
simultaneous marketing of the drug products, and FDA has made
determinations regarding what constitutes a meaningful difference under
section 503(b) of the FD&C Act for decades. For this same reason, the
simultaneous marketing provision in this rule, which simply clarifies
another difference that the Agency has determined would constitute a
meaningful difference between prescription and nonprescription drug
products under section 503(b), does not represent a ``transformative
expansion in . . . regulatory authority'' that is derived from ``vague
language of an `ancillary provision[ ]' of the Act.'' In addition,
inclusion of the simultaneous marketing provision does not create a
``regulatory program that Congress [has] conspicuously and repeatedly
declined to enact itself.'' FDA is not aware of any Congressional
consideration of legislation regarding the marketing of nonprescription
drugs with ACNUs alongside prescription versions of such drugs.
The comment also appears to be arguing that the simultaneous
marketing provision implicates the major questions doctrine because it
would ``limit consumer access to OTC drugs.'' But any prediction that
the simultaneous marketing provision would limit consumer access is
highly speculative. To support this assertion, the comment claims that
``prescription drug companies may decide not to pursue OTC switch
opportunities that use an ACNU'' if prescription versions of the drug
continue to be marketed. Similarly, by way of analogy, one might argue
that the benefit of statutory exclusivity, such as that provided at
section 505(j)(5)(F)(iii) of the FD&C Act, would be undermined by FDA's
rule. However, FDA would disagree with this because as noted below in
response to Comment 72, an application--including an application for a
nonprescription drug product with an ACNU--is eligible for exclusivity
if applicable statutory requirements are met. Further, as noted above,
the assertion that the ACNU pathway or the benefit of exclusivity would
be undermined by the rule is speculative, particularly considering the
evidence showing that roughly 60 percent of purchases for a
nonprescription drug product are from new consumers who had not
previously taken the drug before it switched from prescription status,
suggesting that the potential to attract new-to-therapy consumers for
nonprescription drug products is substantial (Ref. 13). Moreover, this
critique is not specific to nonprescription drug products with ACNUs;
it would also apply to other drug products for which there is a
meaningful difference that allows simultaneous marketing. Furthermore,
although we do not anticipate this scenario, even if no applicant
pursues the development and eventual marketing of a nonprescription
drug product with an ACNU, ACNU products do not currently exist in the
marketplace. So, it is not clear how this rule would ``limit consumer
access to OTC drugs,'' or how that would implicate the major questions
doctrine. Rather, the final rule is intended to increase options for
applicants to develop and market safe and effective nonprescription
drug products and increase consumer access to appropriate, safe, and
effective drug products, which could improve public health.
Ultimately, the simultaneous marketing provision in this rule does
not present one of the ``extraordinary cases that call for a different
approach'' in statutory interpretation, because it is not one of the
``cases in which the `history and the breadth of the authority that
[the agency] has asserted,' and the `economic and political
significance' of that assertion, provide a `reason to hesitate before
concluding that Congress' meant to confer such authority.'' 597 U.S. at
721.
We also note that in the context of arguing that the major
questions doctrine applies, this comment further argued that Chevron
deference would consequently not apply. Since this comment was
submitted, the Supreme Court decided Loper Bright Enterprises v.
Raimondo, which overruled Chevron (see 144 S. Ct. 2244 (2024)).
Therefore, we acknowledge Chevron deference would not apply when
analyzing the statutory authority for this rule, including the
simultaneous marketing provision. However, Loper Bright itself
recognized that ``Congress has often enacted . . . statutes'' that by
their terms delegate authority to ``exercise a degree of discretion''
in ``giv[ing] meaning to a particular statutory term'' or ``fill[ing]
up the details of a statutory scheme.'' Loper Bright, 144 S. Ct. at
2263 (cleaned up). Section 503(b)(3) of the FD&C Act, which empowers
the Secretary to adopt regulations ``remov[ing] drugs subject to
section 505 from the requirements of paragraph (1) of this subsection
when such requirements are not necessary for the public health,''
delegates just such an authority. As explained in the response to
comment 2, throughout section 503(b), Congress also more broadly
delegated FDA the explicit authority to use its scientific judgment to
determine which drugs should be prescription or nonprescription, within
the statutory criteria. And as part of its broad authority to approve
and regulate drug products, including to establish specific regulations
for drug products, FDA is authorized to determine the conditions under
which a drug is safe and effective for use without a prescription. See,
e.g., sections 505, 505G, and 701 of the FD&C Act.
In any case, we believe this rule represents the best reading of
the FD&C Act. As explained in the response to comment 39 and in the
proposed rule, section 503(b) of the FD&C Act allows the same active
ingredient to be simultaneously marketed in both a prescription drug
product and nonprescription drug product if a meaningful difference
exists between the two that makes the prescription product safe only
under the supervision of a practitioner licensed by law to
[[Page 105313]]
administer the drug (see 87 FR 68702, 87 FR 38313 at 38321, 83 FR
13994, and 70 FR 52050). Section 503(b)(1)(A) requires a drug to be
limited to prescription-only status if, because of its toxicity or
other potentiality for harmful effect, or the method of its use, or the
collateral measures necessary to its use, it is not safe for use except
under the supervision of a practitioner licensed by law to administer
such drug. Conversely, a drug that can be used safely by consumers
without the supervision of a practitioner licensed by law to administer
such drug does not require a prescription. Under section 503(b)(1), a
drug cannot be both prescription and nonprescription at the same time,
because it cannot be both safe and unsafe for use without the
supervision of a practitioner licensed by law to administer such drug.
For the same reason, two drug products with the same active ingredient
that don't have meaningful differences also can't be simultaneously
marketed as prescription and nonprescription. However, consistent with
section 503(b)(1), if there is a meaningful difference between two drug
products with the same active ingredient that makes one drug product
safe for use only under the supervision of a practitioner licensed by
law to administer such drug, while the other drug product is safe for
use without such supervision, then the two products may be
simultaneously marketed as prescription and nonprescription drug
products, respectively.
In addition, under section 503(b)(4)(B) of the FD&C Act, a drug,
for which the prescription dispensing provisions of section 503(b)(1)
do not apply, shall be deemed to be misbranded if at any time prior to
dispensing, the label of the drug bears the ``Rx only'' symbol.
Likewise, under section 503(b)(4)(A), drugs that are subject to the
prescription dispensing provisions of section 503(b)(1) must bear the
``Rx only'' symbol, or else they are misbranded. The juxtaposition of
these two provisions dictates that, absent a meaningful difference
between the products, simultaneous marketing of two drug products with
the same active ingredient as both a prescription and a nonprescription
drug product would result in one of the two products being misbranded.
However, if there is a meaningful difference between two drug products
with the same active ingredient that makes one drug product safe for
use only under the supervision of a practitioner licensed by law to
administer such drug, then simultaneous marketing of the two products
is permitted.
We believe that FDA's longstanding interpretation of section
503(b), in which a meaningful difference allows prescription and
nonprescription drug products with the same active ingredient to be
simultaneously marketed, represents the best reading of that provision.
A contrary reading would require all ibuprofen products, for example,
to be restricted to prescription status because some products
containing ibuprofen meet the prescription drug definition in section
503(b)(1) of the FD&C Act. Under the Agency's longstanding
interpretation of section 503(b), however, because the nonprescription
versions of ibuprofen have meaningful differences from the prescription
versions, such as different indications and strengths, they are
different drugs that no longer meet the prescription drug definition
for purposes of section 503(b). Likewise, a drug that no longer meets
the prescription drug definition in section 503(b)(1) of the FD&C Act
because it is approved with an ACNU is a different drug for purposes of
simultaneous marketing of prescription drugs containing the same active
ingredient consistent with section 503(b).
We have already explained in this response how the simultaneous
marketing provision of this rule simply reflects another determination
by the Agency regarding whether a particular difference constitutes a
meaningful difference for purposes of simultaneous marketing of
prescription and nonprescription drugs with the same active ingredient
under section 503(b) of the FD&C Act. In our responses to Comments 2
and 39 through 42, we also explained how this is consistent with FDA's
statutory authority to make scientific determinations about which drugs
should be prescription or nonprescription drugs, the legislative
history of the Durham-Humphrey Amendments, which added section 503(b)
to the FD&C Act, as well as legal precedent and Agency practice.
(Comment 44) We received a few comments asserting that simultaneous
marketing of a prescription drug product and the nonprescription drug
product with an ACNU could lead to inaccurate case reporting of adverse
events for the nonprescription drug product with an ACNU. The comments
describe concerns that reports of adverse events for the prescription
drug product and the nonprescription drug product with an ACNU could be
conflated and identification of a true safety signal for a drug product
may not be detected accurately or could be delayed due to background
noise.
(Response 44) We disagree that simultaneous marketing of a
prescription drug product and a nonprescription drug product with an
ACNU, where the only meaningful difference between the two drug
products is the ACNU, could lead to inaccurate case reporting of
adverse events or delayed identification of a safety signal arising for
either drug product. An applicant must report adverse drug experience
information to FDA in compliance with applicable postmarketing
reporting requirements (Sec. 314.80). Among other information, an
individual case safety report contains certain identifiable information
that would be unique to either the prescription drug product or the
nonprescription drug product with an ACNU, such as application number
and type, drug product name, national drug code, and lot number (Sec.
314.80(f)). Therefore, FDA would have information to investigate
whether the safety signal was associated with a prescription drug
product, nonprescription drug product with an ACNU, or both.
Additionally, FDA has robust reporting systems for consumers to
report adverse drug experiences, complaints, or other issues with FDA-
regulated products, including nonprescription drug products. MedWatch
is FDA's program for reporting serious adverse drug experiences,
product quality problems, therapeutic inequivalence/failure, and
product use errors with human medical products (Ref. 5). Additionally,
consumers can contact the FDA Consumer Complaint Coordinator for the
State in which they reside to report adverse drug experiences or other
problems with FDA-regulated products. FDA's Consumer Complaint
Coordinators, located in FDA offices, will listen, document a complaint
about an FDA-regulated product, and follow up as necessary (Ref. 6). As
with other FDA-regulated products, FDA has experience investigating if
there is a safety signal with a particular product.
(Comment 45) We received a few comments opposing simultaneous
marketing stating that marketing of a prescription drug product and a
nonprescription drug product with an ACNU may lead to consumer
confusion because the labeling information for the prescription drug
product and nonprescription drug product with an ACNU would not be
identical in content or format.
(Response 45) We disagree that simultaneous marketing of a
prescription drug product and a
[[Page 105314]]
nonprescription drug product with an ACNU, where the only meaningful
difference between the two drug products is the ACNU, would cause
consumer confusion because of labeling differences between the
prescription drug product and the nonprescription drug product with an
ACNU. The commenter did not support its assertion with any evidence.
There are numerous drug products with the same active ingredient that
are currently simultaneously marketed as a prescription drug product
and a nonprescription drug product where there is a meaningful
difference between the two products. FDA does not have any data to show
that there is consumer confusion and industry has not previously
conveyed concerns with these products that are currently simultaneously
marketed. Generally, labeling for nonprescription drug products and
prescription drug products are not identical in content and format
because they are directed to different audiences (primarily consumers
for nonprescription drug products and healthcare practitioners for
prescription drug products) to provide the information necessary for
the safe and effective use of the drug product. Therefore, different
content and format regulations apply to prescription and
nonprescription labeling (see generally Sec. Sec. 201.57 and 201.66
(21 CFR 201.57 and 201.66), respectively). Labeling for nonprescription
drug products is directed to consumers (see Sec. 201.66). Although
patient labeling is required for certain prescription drug products
(see, e.g., 21 CFR part 208), generally, labeling for prescription drug
products, including the prescribing information (see Sec. 201.57), is
directed to the healthcare practitioner--not the patient--and a patient
uses the prescription drug product under the supervision of a
practitioner licensed by law to administer such drug.
H. Comments on Refusal To Approve an Application With an ACNU and FDA
Response
FDA specified in the proposed rule that we would refuse to approve
an application for a nonprescription drug product with an ACNU if FDA
has determined the application failed to meet the requirements
specified in proposed 21 CFR 314.56 applicable to NDAs (proposed 21 CFR
314.125(b)(20)) or ANDAs (proposed 21 CFR 314.127(a)(15)). In the
f
[…truncated; see source link]Indexed from Federal Register on December 26, 2024.
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