Notice2023-17881
List of Bulk Drug Substances for Which There is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act
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Published
August 21, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is evaluating substances that have been nominated for inclusion on a list of bulk drug substances (active pharmaceutical ingredients) for which there is a clinical need (the 503B Bulks List). Drug products that outsourcing facilities compound using bulk drug substances on the 503B Bulks List can qualify for certain exemptions from the Federal Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are met. This notice identifies two bulk drug substances that FDA has considered and is not including on the list at this time: ephedrine sulfate and hydroxychloroquine sulfate. Additional bulk drug substances nominated by the public for inclusion on this list are currently under consideration and will be the subject of future notices.
Full Text
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<title>Federal Register, Volume 88 Issue 160 (Monday, August 21, 2023)</title>
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[Federal Register Volume 88, Number 160 (Monday, August 21, 2023)]
[Notices]
[Pages 56837-56843]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-17881]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2018-N-3240]
List of Bulk Drug Substances for Which There is a Clinical Need
Under Section 503B of the Federal Food, Drug, and Cosmetic Act
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
evaluating substances that have been nominated for inclusion on a list
of bulk drug substances (active pharmaceutical ingredients) for which
there is a clinical need (the 503B Bulks List). Drug products that
outsourcing facilities compound using bulk drug substances on the 503B
Bulks List can qualify for certain exemptions from the Federal Food,
Drug, and Cosmetic Act (FD&C Act) provided certain conditions are met.
This notice identifies two bulk drug substances that FDA has considered
and is not including on the list at this time: ephedrine sulfate and
hydroxychloroquine sulfate. Additional bulk drug substances nominated
by the public for inclusion on this list are currently under
consideration and will be the subject of future notices.
DATES: The announcement of the notice is published in the Federal
Register on August 21, 2023.
ADDRESSES: For access to the docket to read background documents or the
electronic and written/paper 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 document, into the ``Search'' box and follow the
prompts, and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Tracy Rupp, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, Silver Spring, MD 20993, 301-796-3100.
SUPPLEMENTARY INFORMATION:
I. Background
Section 503B of the FD&C Act (21 U.S.C. 353b) describes the
conditions that must be satisfied for drug products compounded in an
outsourcing facility to be exempt from section 505 (21 U.S.C. 355)
(concerning the approval of drugs under new drug applications (NDAs) or
abbreviated new drug applications (ANDAs)), section 502(f)(1) (21
U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate
directions for use), and section 582 of the FD&C Act (21 U.S.C. 360eee-
1) (concerning drug supply chain security requirements).\1\
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\1\ Section 503B(a) of the FD&C Act.
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Compounded drug products that meet the conditions set forth in
section 503B are not exempt from current good manufacturing practice
(CGMP) requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C.
351(a)(2)(B)).\2\ Outsourcing facilities are also subject to FDA
inspections according to a risk-based schedule, adverse event reporting
requirements, and other conditions that help to mitigate the risks of
the drug products they compound.\3\ Outsourcing facilities may or may
not obtain prescriptions for identified individual patients and can,
therefore, distribute compounded drugs to healthcare
[[Page 56838]]
practitioners for ``office stock,'' to hold in their offices in advance
of patient need.\4\
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\2\ Compare section 503A(a) of the FD&C Act (21 U.S.C. 353a(a)
(exempting drugs compounded in accordance with that section)) with
section 503B(a) of the FD&C Act (not providing an exemption from
CGMP requirements).
\3\ Section 503B(b)(4) and (5) of the FD&C Act.
\4\ Section 503B(d)(4)(C) of the FD&C Act.
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One of the conditions that must be met for a drug product
compounded by an outsourcing facility to qualify for the exemptions
under section 503B of the FD&C Act is that the outsourcing facility may
not compound a drug using a bulk drug substance unless: (1) the bulk
drug substance appears on a list established by the Secretary of Health
and Human Services (the Secretary) identifying bulk drug substances for
which there is a clinical need (the 503B Bulks List) or (2) the drug
compounded from the bulk drug substance appears on the drug shortage
list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at
the time of compounding, distribution, and dispensing.\5\
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\5\ Section 503B(a)(2)(A) of the FD&C Act.
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Section 503B of the FD&C Act directs FDA to establish the 503B
Bulks List by: (1) publishing a notice in the Federal Register
proposing bulk drug substances to be included on the list, including
the rationale for such proposal; (2) providing a period of not less
than 60 calendar days for comment on the notice; and (3) publishing a
notice in the Federal Register designating bulk drug substances for
inclusion on the list.\6\
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\6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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FDA has published a series of Federal Register notices addressing
bulk drug substances nominated for inclusion on the 503B Bulks List.\7\
This notice identifies two bulk drug substances that FDA has considered
and is not including on the 503B Bulks List.
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\7\ See Federal Register of August 28, 2018 (83 FR 43877), March
4, 2019 (84 FR 7383), September 3, 2019 (84 FR 46014), July 31, 2020
(85 FR 46126), March 24, 2021 (86 FR 15673), November 23, 2022 (87
FR 71642), and April 6, 2023 (88 FR 20531). The comment period for
the July 2020 notice was reopened for 30 days on January 8, 2021 (86
FR 1515), to allow interested parties an additional opportunity to
comment. FDA has not yet reached a final determination on whether
each of the substances evaluated in the September 2019, July 2020,
or March 2021 notices will be added to the 503B Bulks List. In
addition, bumetanide, which was considered in the August 2018
notice, remains under consideration by the Agency.
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For purposes of section 503B of the FD&C Act, bulk drug substance
means an active pharmaceutical ingredient as defined in 21 CFR
207.1.\8\ Active pharmaceutical ingredient means any substance that is
intended for incorporation into a finished drug product and is intended
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body, but the term does not
include intermediates used in the synthesis of the substance.\9\ \10\
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\8\ See section 503B(a)(2) of the FD&C Act, which defines bulk
drug substances used in compounding under section 503B according to
21 CFR 207.3(a)(4) ``or any successor regulation.'' 21 CFR 207.1 is
the successor regulation.
\9\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
\10\ Inactive ingredients are not subject to section 503B(a)(2)
of the FD&C Act and will not be included in the 503B Bulks List
because they are not included within the definition of a bulk drug
substance. Pursuant to section 503B(a)(3), inactive ingredients used
in compounding must comply with the standards of an applicable U.S.
Pharmacopeia (USP) or National Formulary (NF) monograph, if a
monograph exists.
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II. Methodology for Developing the 503B Bulks List
A. Process for Developing the List
FDA requested nominations for specific bulk drug substances for the
Agency to consider for inclusion on the 503B Bulks List in the Federal
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination
process in the Federal Register of July 2, 2014 (79 FR 37747) and
provided more detailed information on what FDA needs to evaluate
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency
opened a new docket, FDA-2015-N-3469, to provide an opportunity for
interested persons to submit new nominations of bulk drug substances,
renominate substances with sufficient information, or submit comments
on nominated substances.
As FDA evaluates bulk drug substances, it intends to publish
notices for public comment in the Federal Register that describe its
proposed position on each substance along with the rationale for that
position.\11\ After considering any comments on FDA's proposals
regarding whether to include nominated substances on the 503B Bulks
List, FDA intends to consider whether input from the Pharmacy
Compounding Advisory Committee (PCAC) on the nominations would be
helpful to the Agency in making its determination, and if so, it will
seek PCAC input.\12\ Depending on its review of the docket comments and
other relevant information before the Agency, FDA may finalize its
proposed determination without change, or it may finalize a
modification to its proposal to reflect new evidence or analysis
regarding clinical need. FDA will then publish in the Federal Register
a final determination identifying the bulk drug substances for which it
has determined there is a clinical need and FDA's rationale in making
that final determination. FDA will also publish in the Federal Register
a final determination regarding those substances it considered but
found that there is no clinical need to use in compounding and FDA's
rationale in making this decision.
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\11\ This is consistent with procedures set forth in section
503B(a)(2)(A)(i) of the FD&C Act. Although the statute only directs
FDA to issue a Federal Register notice and seek public comment when
it proposes to include bulk drug substances on the 503B Bulks List,
we intend to seek comment when the Agency has evaluated a nominated
substance and proposes either to include or not to include the
substance on the list.
\12\ Section 503B of the FD&C Act does not require FDA to
consult the PCAC before developing the 503B Bulks List.
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FDA intends to maintain a list of all bulk drug substances it has
evaluated on its website and separately identify bulk drug substances
it has placed on the 503B Bulks List and those it has decided not to
place on the 503B Bulks List. This list is available at <a href="https://www.fda.gov/media/120692/download">https://www.fda.gov/media/120692/download</a>. FDA will only place a bulk drug
substance on the 503B Bulks List when it has determined there is a
clinical need for outsourcing facilities to compound drug products
using the bulk drug substance. If a clinical need to compound drug
products using the bulk drug substance has not been demonstrated, based
on the information submitted by the nominator and any other information
considered by the Agency, FDA will not place a bulk drug substance on
the 503B Bulks List.
FDA is evaluating bulk drug substances nominated for the 503B Bulks
List on a rolling basis. FDA intends to evaluate and publish in the
Federal Register the proposed and final determinations in groups of
bulk drug substances until all nominated substances that were
sufficiently supported have been evaluated and either placed on the
503B Bulks List or identified as bulk drug substances that were
considered but determined not to be appropriate for inclusion on the
503B Bulks List.\13\
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\13\ In January 2017, FDA announced the availability of a
revised final guidance for industry that provides additional
information regarding FDA's policies for bulk drug substances
nominated for the 503B Bulks List pending FDA's evaluation under the
``clinical need'' standard, entitled ``Interim Policy on Compounding
Using Bulk Drug Substances Under Section 503B of the Federal Food,
Drug, and Cosmetic Act'' (the ``Interim Policy''), available at
<a href="https://www.fda.gov/media/94402/download">https://www.fda.gov/media/94402/download</a>. We update guidances
periodically. For the most recent version of a guidance, check the
FDA guidance web page at <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>.
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B. Analysis of Substances Nominated for the List
As noted above, the 503B Bulks List will include bulk drug
substances for which there is a clinical need. The
[[Page 56839]]
Agency is evaluating bulk drug substances that were nominated for
inclusion on the 503B Bulks List, proceeding case by case, under the
standard provided by the statute.\14\ In applying this standard to make
its determinations regarding the substances set forth in this notice,
FDA interprets the phrase ``bulk drug substances for which there is a
clinical need'' to mean that the 503B Bulks List may include a bulk
drug substance if: (1) there is a clinical need for an outsourcing
facility to compound the drug product and (2) the drug product must be
compounded using the bulk drug substance. FDA does not interpret supply
issues, such as backorders, to be within the meaning of ``clinical
need'' for compounding with a bulk drug substance. Section 503B of the
FD&C Act separately provides for compounding from a bulk drug substance
under the exemptions from the FD&C Act discussed above if the drug
product compounded from the bulk drug substance is on the FDA drug
shortage list at the time of compounding, distribution, and dispensing.
Additionally, FDA does not consider convenience in administering a
particular compounded drug product (e.g., a ready-to-use form) or the
cost of the compounded drug product as compared with an FDA-approved
drug product when assessing ``clinical need.''
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\14\ In March 2019, FDA announced the availability of a final
guidance entitled ``Evaluation of Bulk Drug Substances Nominated for
Use in Compounding Under Section 503B of the Federal Food, Drug, and
Cosmetic Act'' (the ``Clinical Need Guidance''), available at
<a href="https://www.fda.gov/media/121315/download">https://www.fda.gov/media/121315/download</a>. This guidance describes
FDA policies for developing the 503B Bulks List and the Agency's
interpretation of the phrase ``bulk drug substances for which there
is a clinical need'' as it is used in section 503B. The analysis
under the statutory ``clinical need'' standard described in this
notice is consistent with the approach described in FDA's guidance.
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Both bulk drug substances addressed in this notice, ephedrine
sulfate and hydroxychloroquine sulfate, are components of FDA-approved
drug products. FDA therefore began its evaluation by asking one or
both, as applicable, of the following questions:
1. Is there a basis to conclude, for each FDA-approved product that
includes the nominated bulk drug substance, that (a) an attribute of
the FDA-approved drug product makes it medically unsuitable to treat
certain patients for a condition that FDA has identified for
evaluation, and (b) the drug product proposed to be compounded is
intended to address that attribute?
2. Is there a basis to conclude that the drug product proposed to
be compounded must be produced from a bulk drug substance rather than
from an FDA-approved drug product?
The reason for question 1 is that unless an attribute of the FDA-
approved drug is medically unsuitable for certain patients, and a drug
product to be compounded using a bulk drug substance that is a
component of the FDA-approved drug is intended to address that
attribute, there is no clinical need to compound a drug product using
that bulk drug substance. Rather, such compounding would unnecessarily
expose patients to the risks associated with drug products that do not
meet the standards applicable to FDA-approved drug products for safety,
effectiveness, quality, and labeling and would undermine the drug
approval process. The reason for question 2 is that to place a bulk
drug substance on the 503B Bulks List, FDA must determine that there is
a clinical need for outsourcing facilities to compound a drug product
using the bulk drug substance rather than starting with an FDA-approved
drug product. When it is feasible to compound a drug product by
starting with an FDA-approved drug product, there are certain benefits
of doing so over starting with a bulk drug substance, including that
FDA-approved drugs have undergone premarket review for safety,
effectiveness, and quality, and are manufactured by a facility that is
subject to premarket assessment, including site inspection, as well as
routine post-approval risk-based inspections. In contrast, FDA does not
conduct a premarket review of the quality standards, specifications,
and controls for bulk drug substances used in compounding and does not
conduct a premarket assessment of the manufacturer of the bulk drug
substance.
If the answer to both of the above questions is ``yes,'' there may
be a clinical need for outsourcing facilities to compound using the
bulk drug substance, and we would evaluate the substance further,
applying the factors described below. If the answer to either of these
questions is ``no,'' we generally would not include the bulk drug
substance on the 503B Bulks List, because there would not be a basis to
conclude that there may be a clinical need to compound drug products
using the bulk drug substance instead of administering an FDA-approved
drug or compounding starting with an FDA-approved drug product. FDA did
not answer ``yes'' to both of the threshold questions for the two bulk
drug substances that are components of FDA-approved drug products that
we are addressing in this notice. Accordingly, as explained below, we
did not proceed further in our evaluation of these substances and have
decided not to include them on the 503B Bulks List.
III. FDA's Determinations Regarding Substances Proposed for the 503B
Bulks List
The two bulk drug substances that FDA has evaluated, proposed not
to include on the 503B Bulks List in a Federal Register notice, and has
now decided not to place on the 503B Bulks List are ephedrine sulfate
(Refs. 1 and 2) and hydroxychloroquine sulfate (Ref. 3).
In September 2019, the Agency issued a Federal Register notice in
which it evaluated nine nominated bulk drug substances under the
section 503B statutory standard--dipyridamole, ephedrine sulfate,
famotidine, hydralazine HCl, methacholine chloride, sodium bicarbonate,
sodium tetradecyl sulfate, trypan blue, and vecuronium bromide--and
proposed not to include them on the 503B Bulks List (the September 2019
notice).\15\ In the present notice, after review of the comments
submitted to the docket for the September 2019 notice, FDA is making
its final determination not to include ephedrine sulfate on the 503B
Bulks List. At this time, FDA is not making a final determination
regarding famotidine, hydralazine HCl, sodium tetradecyl sulfate,
trypan blue, and vecuronium bromide.\16\ These substances remain under
consideration by FDA.
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\15\ See 84 FR 46014.
\16\ FDA made a final determination not to include dipyridamole
on the 503B Bulks List (see 87 FR 4240). FDA made a final
determination not to include methacholine chloride and sodium
bicarbonate on the 503B Bulks List (see 88 FR 20531).
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In March 2021, the Agency issued a Federal Register notice in which
it evaluated five nominated bulk drug substances under the section 503B
statutory standard (the March 2021 notice).\17\ FDA proposed to include
quinacrine hydrochloride (for oral use only) on the 503B Bulks List.
FDA proposed not to include bromfenac sodium, mitomycin-C, nepafenac,
and hydroxychloroquine sulfate on the 503B Bulks List. In April 2023,
after review of comments submitted to the March 2021 docket, the Agency
issued a Federal Register notice, making its final determination to
include quinacrine hydrochloride on the 503B Bulks List to compound
drug products for oral use only.\18\ In the present notice, after
review of the comments submitted to the docket for the March 2021
notice, FDA is making its final determination
[[Page 56840]]
not to include hydroxychloroquine sulfate on the 503B Bulks List. At
this time, FDA is not making a final determination regarding bromfenac
sodium, mitomycin-C, and nepafenac. These substances remain under
consideration by FDA.
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\17\ 86 FR 15673.
\18\ 88 FR 20531.
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Because both ephedrine sulfate and hydroxychloroquine sulfate are
components of FDA-approved drug products, FDA considered one or both of
the following questions: (1) is there a basis to conclude that an
attribute of each FDA-approved drug product containing the bulk drug
substance makes each one medically unsuitable to treat certain patients
for a condition that FDA has identified for evaluation, and the drug
product(s) proposed to be compounded is intended to address that
attribute in each FDA-approved drug product and (2) is there a basis to
conclude that the drug product(s) proposed to be compounded must be
compounded using a bulk drug substance. FDA considered comments to the
docket submitted within the public comment period, but as explained
below, none of the comments received on these bulk drug substances
provided information that led FDA to change its determination.
A. Ephedrine Sulfate
Ephedrine sulfate was nominated for inclusion on the 503B Bulks
List to compound drug products to treat acute bronchospasm, drug
induced hypotension due to anesthesia, and nasal congestion.\19\ The
proposed route of administration is intravenous, the proposed dosage
form is a preservative-free solution, and the proposed strengths are 5
mg/mL and 10 mg/mL.\20\ During the comment period for the September
2019 notice, a commenter proposed that there was a clinical need to
compound higher concentration ephedrine sulfate drug products to treat
priapism. The proposed route of administration for this new proposed
use is intracorporeal, the proposed dosage form is a solution, and the
proposed strength is 100 mg/mL.\21\ Because additional references were
provided supporting this proposed use and route of administration, FDA
considered this use and this route of administration before reaching a
final clinical need determination (Ref. 2).
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\19\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\20\ Nominator(s) proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is a
preservative-free formulation of ephedrine sulfate that is marketed
or explain why that formulation would be medically unsuitable for
certain patients. Additionally, since the September 2019 notice,
ephedrine sulfate has been FDA-approved as a preservative-free, 25
mg/5mL (5 mg/mL) single dose, premixed, labeled syringe (not for
dilution) (See NDA 213407 labeling available as of the date of this
notice at <a href="https://www.accessdata.fda.gov/spl/data/3155f177-4aff-4560-9f7c-f77649d065d9/3155f177-4aff-4560-9f7c-f77649d065d9.xml">https://www.accessdata.fda.gov/spl/data/3155f177-4aff-4560-9f7c-f77649d065d9/3155f177-4aff-4560-9f7c-f77649d065d9.xml</a>) and
a preservative-free, 50 mg/10mL (5 mg/mL) single dose, premixed vial
(See NDA 213407 labeling available as of the date of this notice at
<a href="https://www.accessdata.fda.gov/spl/data/54276f21-7800-44f4-ae51-0060fb1c43ad/54276f21-7800-44f4-ae51-0060fb1c43ad.xml">https://www.accessdata.fda.gov/spl/data/54276f21-7800-44f4-ae51-0060fb1c43ad/54276f21-7800-44f4-ae51-0060fb1c43ad.xml</a>).
\21\ See Docket No. FDA-2018-N-3240, document no. FDA-2018-N-
3240-0047. Other commenters proposed additional uses and routes of
administration: intramuscular administration of a higher
concentration of ephedrine sulfate for postoperative nausea and
vomiting refractory to traditional antiemetics; intravenous or
intrathecal administration of ephedrine sulfate for hypotension in
patients that received a certain type of anesthesia or received an
overdose of a drug that can lower blood pressure; and continuous
(intravenous) infusion to prevent hypotension secondary to spinal
anesthesia during cesarean section. These other uses will not be
considered further because the commenters either proposed uses or
routes of administration already evaluated in the September 2019
notice and the literature provided in the comments did not contain
any new information that would support FDA's reconsideration of its
proposal on the substance, or the commenters proposed new uses or
routes of administration but did not provide sufficient information,
including citations to relevant literature, supporting a clinical
need.
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As noted above, ephedrine sulfate is a component of FDA-approved
drug products (e.g., NDAs 208943 and 208289). FDA-approved ephedrine
sulfate is available as a 1 mL single-dose drug product that contains
50 mg/mL (50 mg/mL) ephedrine sulfate, preservative-free, for
intravenous administration, and as a 10 mL multi-dose vial that
contains 500 mg/10 mL (50 mg/mL) ephedrine sulfate, with preservative,
for intravenous administration.\22\ These ephedrine sulfate drug
products must be diluted before administration to achieve the desired
concentration for their labeled indications. Ephedrine sulfate is also
available as a 5 mL single dose, prefilled syringe that contains 25 mg/
5 mL (5 mg/mL) ephedrine sulfate, preservative-free, for intravenous
administration, and as a 10 mL single dose, prefilled syringe that
contains 50 mg/10 mL (5 mg/mL) ephedrine sulfate, preservative-free,
for intravenous administration.\23\ The products available as prefilled
syringes are premixed formulations and do not require dilution prior to
administration for their labeled indications.
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\22\ See, e.g., NDAs 208943 and 208289.
\23\ See, e.g., NDAs 208289 and NDA 213407.
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1. Suitability of FDA-Approved Drug Product
In its proposal to not include ephedrine sulfate on the 503B Bulks
List, FDA explained that the nominations did not identify an attribute
of the FDA-approved drug products that make them medically unsuitable
to treat certain patients and that the proposed compounded drug
products are intended to address. Several comments received agreed with
FDA's proposal not to include ephedrine sulfate on the 503B Bulks
List.\24\ Several comments were not supportive. However, none of the
comments received on FDA's proposal provided information that led FDA
to change its position on this question. A commenter stated that there
is a clinical need for an intracorporeal, single-ingredient, higher
concentration ephedrine sulfate compounded drug product for use to
treat priapism.\25\ However, the commenter failed to identify an
attribute of the FDA-approved drug products, including the intravenous
formulations of ephedrine sulfate 50 mg/mL solution for dilution (e.g.,
NDA 208943), that is medically unsuitable for patients with priapism or
identify an attribute of the FDA-approved products that the proposed
compounded drug product is intended to address. The FDA-approved
products are available in the concentration of 50 mg/mL (undiluted) and
can be administered in a sufficient volume or in multiple doses to
achieve the proposed dose of 100 mg for the treatment of
priapism.<SUP>26 27</SUP> A commenter also stated that the FDA-approved
ephedrine sulfate products are not compatible with new technology such
as syringe-robotics and vial docking technology to easily make stock
[[Page 56841]]
solutions to produce onsite.\28\ However, FDA is not aware of issues
with using the FDA-approved product when the compounding process and
equipment are appropriately selected. Additionally, these arguments do
not take into account the approval by FDA of two ephedrine sulfate drug
products that are pre-diluted and thus would not need additional
manipulation at the bedside by a medical provider before use for their
labeled indications.\29\ Commenters also made various arguments
addressing supply issues, convenience, and cost.\30\ However, as
explained above, FDA does not consider supply issues, convenience, and
costs to be within the meaning of ``clinical need'' for compounding
with a bulk drug substance under section 503B of the FD&C Act.
Accordingly, with respect to the ephedrine sulfate drug products
proposed to be compounded, FDA finds no basis to conclude that an
attribute of the FDA-approved product makes it medically unsuitable to
treat certain patients for a condition that FDA has identified for
evaluation.
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\24\ See Docket No. FDA-2018-N-3240, document nos. FDA-2018-N-
3240-0043, FDA-2018-N-3240-0045, FDA-2018-N-3240-0050, FDA-2018-N-
3240-0052.
\25\ See Docket No. FDA-2018-N-3240, document no. FDA-2018-N-
3240-0047.
\26\ In noting this issue, we do not mean to suggest or imply
that the approved drug products, or products prepared from them, are
approved for the use proposed by the commenter. For the Part 1.a.
analysis we asked a limited, threshold question to determine whether
there might be clinical need for a compounded drug product, by
asking what attributes of the FDA-approved drug the proposed
compounded drug would change, and why. Because this proposed product
did not pass through Part 1.a. (for the reasons described in the
memo) we did not reach Part 2 and therefore did not consider the
Part 2 factors, including the available evidence of effectiveness or
lack of effectiveness of a drug product compounded with ephedrine
sulfate. FDA-approved ephedrine sulfate 50 mg/mL solution for
dilution has not been shown to be safe and effective for
intracorporal administration to treat priapism.
\27\ The commenter proposes that in order to achieve a 100 mg/mL
dose, more than one vial of FDA-approved ephedrine sulfate is
needed. While there is a 50 mg/mL formulation that is available in 1
mL vials, there is also an FDA-approved formulation of intravenous
ephedrine sulfate solution that is available as a 500 mg/10 mL vial
(dilution required). In order to achieve the 100 mg/mL dose, 2 mL of
ephedrine sulfate could be used.
\28\ See Docket No. FDA-2018-N-3240, document no. FDA-2018-N-
3240-0047.
\29\ See footnote 20 above.
\30\ See Docket No. FDA-2018-N-3240, document nos. FDA-2018-N-
3240-0053, FDA-2018-N-3240-0049, and FDA-2018-N-3240-0047.
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2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not provide support for the position that drug
products containing ephedrine sulfate must be compounded from bulk drug
substances rather than the approved drug product. No further
information was supplied during the comment period that supports the
need for compounding ephedrine sulfate drug products from bulk drug
substances. Because there is no basis to conclude that an attribute of
the FDA-approved ephedrine sulfate products makes them medically
unsuitable for some patients; however, FDA has not considered whether
there is a basis to conclude that the proposed compounded products must
be made from a bulk drug substance rather than from an FDA-approved
product.
B. Hydroxychloroquine Sulfate
Hydroxychloroquine sulfate was nominated for inclusion on the 503B
Bulks List to compound drug products to treat rheumatoid arthritis and
juvenile arthritis (also known as juvenile idiopathic arthritis).\31\
The proposed route of administration is oral, the proposed dosage forms
are a capsule or suspension, and the proposed doses or concentrations
are 200 to 500 mg capsules and 100 to 200 mg/mL suspension. The
nominated bulk drug substance is a component of FDA-approved drug
products (e.g., NDA 009768, ANDA 040104, and ANDA
213342).<SUP>32 33 34</SUP>
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\31\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0165.
\32\ See, e.g., NDA 009768 labeling available as of the date of
this notice at <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf</a>.
\33\ See, e.g., ANDA 040104 labeling available as of the date of
this notice at <a href="https://www.accessdata.fda.gov/spl/data/e5375cf7-9423-40a4-bd33-ce5812da4a73/e5375cf7-9423-40a4-bd33-ce5812da4a73.xml">https://www.accessdata.fda.gov/spl/data/e5375cf7-9423-40a4-bd33-ce5812da4a73/e5375cf7-9423-40a4-bd33-ce5812da4a73.xml</a>.
\34\ See, e.g., ANDA 213342 labeling available as of the date of
this notice at <a href="https://www.accessdata.fda.gov/spl/data/a594d892-e496-38f5-e053-2a95a90a9da8/a594d892-e496-38f5-e053-2a95a90a9da8.xml">https://www.accessdata.fda.gov/spl/data/a594d892-e496-38f5-e053-2a95a90a9da8/a594d892-e496-38f5-e053-2a95a90a9da8.xml</a>.
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FDA-approved hydroxychloroquine sulfate is available as 200 mg
(equivalent to 155 mg of hydroxychloroquine base), film-coated tablets
for oral administration.\35\
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\35\ See, e.g., NDA 009768 labeling available as of the date of
this notice at <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf</a>.
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1. Suitability of FDA-Approved Drug Product(s)
As described in FDA's preliminary Federal Register notice
addressing this substance, there is a basis to conclude that an
attribute of the approved hydroxychloroquine sulfate tablets for oral
administration makes them medically unsuitable for the treatment of
some patients with rheumatoid arthritis and juvenile arthritis.\36\ The
nomination suggested that the FDA-approved oral tablets, a solid oral
dosage form, are medically unsuitable in pediatric patients who are
unable to swallow tablets. We agree that there may be certain patients
for whom the approved oral tablets are medically unsuitable, and this
would depend on a patient's clinical presentation and age, among other
considerations. As a general matter, the drug product proposed to be
compounded appears to address the potential unsuitability of a solid
oral dosage form because the nominator proposes to compound a
suspension of hydroxychloroquine sulfate for oral administration.
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\36\ In noting this issue, we do not mean to suggest or imply
that the approved drug products, or products prepared from them, are
approved for all of the uses proposed by the nomination. For the
question 1 analysis we asked a limited, threshold question to
determine whether there might be a clinical need for a compounded
drug product, by asking what attributes of the approved drug the
proposed compounded drug would change, and why. Because this
nomination did not pass through question 2, we did not reach the
balancing test and therefore did not consider the four factors,
including the available evidence of effectiveness or lack of
effectiveness of a drug product compounded with hydroxychloroquine
sulfate. The safety and efficacy of chronic use of
hydroxychloroquine sulfate have not been established for juvenile
idiopathic arthritis.
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The nomination further states that ``pediatric dosing is not
standardized but weight-based, making getting the correct dose
difficult with tablets.'' We agree that an oral suspension could allow
for more flexible dosing when compared to the approved tablets when
following weight-based dosing recommendations, and that this also
supports the proposition that the approved product may be unsuitable
for certain patients.\37\
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\37\ We note that the nominator's proposed concentration of 100
to 200 mg/mL would offer little benefit in the younger aged
pediatric population because a suspension at this strength would
likely require administration of small volumes (e.g., <=1 mL). We
are aware of several published pharmacy compounding formulations for
hydroxychloroquine sulfate 25 mg/mL suspensions (Refs. 4 to 6),
which may be more suitable for the younger pediatric population.
---------------------------------------------------------------------------
In addition to the proposed suspension, the nomination also
proposes that there is a clinical need to compound hydroxychloroquine
sulfate 200 to 500 mg capsules for oral administration. The nomination
does not explain how the proposed compounded capsule products are
intended to address the medical unsuitability of the approved product.
Similar to tablets, capsules are less flexible in dosing and would be
difficult for patients to take if they are unable to swallow tablets.
In addition, the nomination does not identify any data or information
as to the need for compounded products with a higher concentration than
the approved product. No further information was supplied on this point
during the comment period.
The nomination also claims that some patients are ``unable to
tolerate excipients'' in the approved product, but the nomination does
not identify which excipients they are referring to, nor do they
provide any data or information supporting how the proposed drug
products will address that particular attribute. No further information
was supplied on this point during the comment period.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because there is a basis to conclude that an attribute of the
approved hydroxychloroquine sulfate tablets makes them medically
unsuitable for some patients, and the proposed compounded oral
suspension is intended to address that attribute, FDA
[[Page 56842]]
next considers whether there is a basis to conclude that the proposed
oral suspension must be made from a bulk drug substance rather than
from an FDA-approved product. The approved hydroxychloroquine sulfate
drug products are 200 mg immediate release tablets with film
coating.\38\
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\38\ The tablet is not scored. The approved product labeling
states that the ``film-coated tablets cannot be divided, therefore
they should not be used to treat patients who weigh less than 31
kg.''
---------------------------------------------------------------------------
As described in FDA's preliminary Federal Register notice
addressing this substance, although the approved products are film-
coated, the coating is not intended to change/control the release
profile. FDA is not aware of issues with using the FDA-approved product
when the compounding process and equipment are appropriately selected.
No further information was supplied on this point during the comment
period. We also note that there is a draft USP monograph for the
compounded suspension that uses an FDA-approved film-coated tablet as
the starting material (Ref. 6).\39\ As with all suspensions, the
particle size of the powder should be carefully controlled and the
density of suspension vehicle should be selected appropriately in order
to make the oral suspension uniform and stable, which can affect the
dose administrated to the patients.
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\39\ We note that the product labeling for hydroxychloroquine
sulfate film-coated tablets (e.g., NDA 009768, ANDA 213342) states,
``Do not crush or divide hydroxychloroquine sulfate film-coated
tablets.'' However, this does not change our view that the product
can be compounded starting with the approved drug product.
---------------------------------------------------------------------------
One commenter supported FDA's proposal not to include
hydroxychloroquine sulfate on the 503B Bulks List. Commenters provided
no new information supporting the clinical need for compounding from
the bulk drug substance hydroxychloroquine sulfate. Because we do not
find a basis to conclude that a bulk drug substance is needed to
compound the proposed compounded hydroxychloroquine sulfate oral
suspension, rather than starting with the FDA-approved product, we do
not find a clinical need to include hydroxychloroquine sulfate on the
503B Bulks List under question 2.
IV. Other Issues Raised in Nominations and Comments
Commenters expressed concern that nominations submitted before FDA
issued the Clinical Need Guidance in March 2019 are disadvantaged in
demonstrating clinical need because the nominators might not have fully
understood FDA's thinking on clinical need when they submitted their
nominations.\40\ In addition, there was also concern expressed about
whether FDA is evaluating bulk drug substances for clinical need
pursuant to a non-binding guidance document.
---------------------------------------------------------------------------
\40\ See 84 FR 7390, which is available at <a href="https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the">https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the</a>.
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FDA disagrees with these comments. First, as explained in section
II.B of this notice, FDA is evaluating bulk drug substances nominated
for inclusion on the 503B Bulks List under the ``clinical need''
standard provided by the FD&C Act, as amended by the Drug Quality and
Security Act in 2013.\41\ The analysis under the statutory ``clinical
need'' standard described in this notice is consistent with the
approach described in FDA's Clinical Need Guidance. Second, there have
been many opportunities for nominators and interested members of the
public to provide information supporting a clinical need to compound
drug products containing the bulk drug substances that are the subject
of this notice. As explained in section II.A, a public docket, FDA-
2015-N-3469, is available for interested persons to submit nominations,
including updated or revised nominations, or comments on nominated
substances. Furthermore, during the comment periods for the September
2019 and March 2021 Federal Register notices, commenters had an
additional opportunity to submit comments to the docket associated with
those notices to provide additional supporting information for the bulk
drug substances that are the subject of this notice, and many did so.
---------------------------------------------------------------------------
\41\ See Public Law 113-54, section 102(a) (2013), which is
available at <a href="https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf">https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf</a>.
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Another issue raised was whether FDA is regulating and interfering
with the practice of medicine by not placing bulk drug substances on
the 503B Bulks List despite some physicians wanting to prescribe drug
products compounded from those bulk drug substances. FDA disagrees with
these comments. The Agency's evaluation under the clinical need
standard only regulates the ability of certain compounded drug products
to reach the market and is well within the Agency's authorities.\42\
The Agency is fulfilling its statutory mandate of regulating
outsourcing facilities' production and distribution of compounded drug
products, not interfering with physicians' clinical decisions regarding
which drug products to prescribe. Indeed, a Federal court considered
the very claim raised in these comments and determined that FDA's
evaluation under the clinical need standard ``regulates the type of
drug that reaches the marketplace,'' a decision that ``rests well
within FDA's regulatory authority under the [FD&C Act] . . . and . . .
does not intrude on the practice of medicine.'' \43\
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\42\ See United States v. Evers, 643 F.2d 1043, 1048 (5th Cir.
1981) (``[W]hile the [FD&C Act] was not intended to regulate the
practice of medicine, it was obviously intended to control the
availability of drugs for prescribing by physicians.''); United
States v. Regenerative Scis., LLC, 741 F.3d 1314, 1319-20 (D.C. Cir.
2014); (citing Evers and noting that the FD&C Act ``regulate[s] the
distribution of drugs by licensed physicians''); Gonzales v. Raich,
545 U.S. 1, 28 (2005) (``[T]he dispensing of new drugs, even when
doctors approve their use must await federal approval.'').
\43\ Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 (D.D.C. 2019).
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Another concern was the possibility that FDA is promoting the off-
label use of FDA-approved drug products. FDA disagrees that it is
promoting the off-label use of FDA-approved drug products. In
performing the clinical need evaluation, FDA asks a limited, threshold
question to determine whether there might be a clinical need for a
compounded drug product, by asking what attributes of the approved drug
product the proposed compounded drug product would change and why.
Asking this question helps ensure that if a bulk drug substance is
included on the 503B Bulks List, it is to compound drug products that
include a needed change to an approved drug product, rather than to
compound drug products without such a change. We do not suggest that
the approved drug product or products prepared from it are approved for
the use proposed by the nomination being evaluated.
Regarding FDA's decision to evaluate clinical need in the context
of the specific drug products proposed to be compounded in the
nomination, a concern was raised that requiring nominators to provide
information on specific drug products is unnecessary to determine
whether there is a clinical need for the bulk drug substance and that
FDA should not evaluate bulk drug substances in the context of finished
dosage forms for drug products. FDA disagrees with these comments. As
explained in section I of this notice, section 503B of the FD&C Act
limits the bulk drug substances that outsourcing facilities can use in
compounding to those that are used to compound drugs in shortage or
that appear on a list developed by FDA of bulk drug substances for
which there is a clinical need.\44\ Section 503B of the FD&C Act
includes this limitation, among others,
[[Page 56843]]
to help ensure that outsourcing facilities do not grow into
conventional manufacturing operations making unapproved new drug
products without complying with critical requirements, such as new drug
approval. Outsourcing facilities, as opposed to other compounders, may
compound and distribute drug products for ``office stock'' without
first receiving a prescription for an individually identified patient
\45\ and without conditions on interstate distribution that are
applicable to other compounded drugs.\46\ Because of these differences
and others, section 503B of the FD&C Act places different conditions on
drugs compounded by outsourcing facilities, including limitation on the
outsourcing facilities' use of bulk drug substances, which are more
stringent than those placed on other compounders' use of bulk drug
substances.\47\ The clinical need standard in section 503B of the FD&C
Act requires FDA to perform a sorting function--to distinguish bulk
drug substances for which there is a clinical need from those for which
there is not--and this requires FDA to apply its expertise to consider
whether there is a need for the finished drug product that would be
compounded from the bulk drug substance. Indeed, a Federal court
considered the very claim raised in these comments and determined that
``[o]nly when `clinical need' is assessed against the availability and
suitability of an approved drug does the term perform the classifying
function that Congress intended.'' \48\ In reaching this view, the
court found that only when the clinical need evaluation ``considers the
actual way in which the active pharmaceutical ingredient supplies a
therapeutic benefit--by its administration as a finished drug product--
does the inquiry produce the categorization that Congress surely
envisioned'' in enacting section 503B of the FD&C Act.\49\ FDA's
clinical need assessments help limit patient exposure to compounded
drug products that have not been demonstrated to be safe and effective
to those situations in which the compounded drug product is necessary
for patient treatment. In addition, FDA's assessments preserve the
incentives for applicants to invest in the research and testing
required to obtain FDA approval and continue to manufacture FDA-
approved drug products, thereby helping to maintain a supply of high-
quality, safe, and effective drugs.
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\44\ Section 503B(a)(2(A)(i) and (ii) of the FD&C Act.
\45\ By contrast, to qualify for the exemptions in section 503A
of the FD&C Act, drug products compounded by licensed pharmacists in
State-licensed pharmacies or Federal facilities, or by licensed
physicians, must be compounded based on the receipt of a valid
prescription for an individually identified patient. This means that
for drug products compounded under section 503A, to meet the
conditions of that section and qualify for the exemptions in the
statute, the pharmacist or physician compounding under section 503A
of the FD&C Act must compound either: (1) after receiving a valid
prescription for an identified, individual patient or (2) before
receiving a patient-specific prescription, in limited quantities,
based on a history of receiving valid orders generated solely within
the context of an established relationship with the patient or
prescriber. See FDA's final guidance for industry ``Prescription
Requirement Under Section 503A of the Federal Food, Drug, and
Cosmetic Act'' (December 2016).
\46\ For drug products compounded under section 503A of the FD&C
Act to meet the conditions of that section and qualify for the
exemptions in the statute, drug products must be compounded in a
State: (i) that has entered into a memorandum of understanding with
the Secretary which addresses the distribution of inordinate amounts
of compounded drug products interstate and provides for appropriate
investigation by a State agency of complaints relating to compounded
drug products distributed outside such State; or (ii) that has not
entered into the memorandum of understanding described in clause (i)
and the licensed pharmacist, licensed pharmacy, or licensed
physician distributes (or causes to be distributed) compounded drug
products out of the State in which they are compounded in quantities
that do not exceed 5 percent of the total prescription orders
dispensed or distributed by such pharmacy or physician (see section
503A(b)(3)(a)(B)(i) and (ii) of the FD&C Act). See also FDA Guidance
for Industry, ``Prescription Requirement Under Section 503A of the
Federal Food, Drug, and Cosmetic Act,'' December 2016 (available at
<a href="https://www.fda.gov/media/97347/download">https://www.fda.gov/media/97347/download</a>).
\47\ Licensed pharmacies and physicians who compound drugs under
the conditions of section 503A of the FD&C Act, including the
requirement to compound drugs only pursuant to a prescription for an
identified individual patient, may use many bulk drug substances by
operation of the statute, without action by FDA. See section
503A(b)(1)(A)(i)(I) and (II) of the FD&C Act (providing that a drug
product may be compounded consistent with the exemptions in section
503A of the FD&C Act if the licensed pharmacist or licensed
physician compounds the drug product using bulk drug substances that
comply with the standards of an applicable USP or NF monograph, if a
monograph exists, and the USP chapter on pharmacy compounding; or if
such a monograph does not exist, are drug substances that are
components of drugs approved by the Secretary).
\48\ Athenex Inc., 397 F. Supp. 3d at 65.
\49\ Id.
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Finally, changes to the Interim Policy were requested. These
comments are outside the scope of FDA's bulk drug substance evaluations
and decisions that are the subject of this notice. FDA welcomes public
comments on its guidance documents that address human drug compounding.
Comments on the Interim Policy may be submitted to the docket for the
guidance, Docket No. FDA-2015-D-3539, at any time at <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
V. Conclusion
For the reasons stated above, we find that there is no clinical
need for outsourcing facilities to compound using the bulk drug
substances ephedrine sulfate and hydroxychloroquine sulfate, and
therefore we are not including these bulk drug substances on the 503B
Bulks List.
VI. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they are also available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
*1. FDA Memorandum to File, ``Clinical Need for Ephedrine
Sulfate in Compounding Under Section 503B of the FD&C Act,'' March
2021.
*2. FDA Memorandum to File, ``Clinical Need Supplemental
Memorandum for Ephedrine Sulfate in Compounding Under Section 503B
of the FD&C Act,'' August 2023.
*3. FDA Memorandum to File, ``Clinical Need for
Hydroxychloroquine Sulfate in Compounding Under Section 503B of the
FD&C Act,'' March 2021.
4. McHenry, A.R., M.F. Wempe, and P.J. Rice, (2017) ``Stability
of Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL
Suspensions in Plastic Bottles and Syringes,'' International Journal
of Pharmaceutical Compounding, 21(3), 251-254 (APA). Retrieved from
<a href="https://ijpc.com/Abstracts/Abstract.cfm?ABS=4322">https://ijpc.com/Abstracts/Abstract.cfm?ABS=4322</a>.
5. American Society of Hospital Pharmacists (ASHP 2020),
``Hydroxychloroquine Sulfate Suspension 25 mg/mL.'' Retrieved from
<a href="http://www.ashp.org">www.ashp.org</a>.
6. USP 2020, ``USP Draft Compounded Preparation Monograph for
Hydroxychloroquine Sulfate Compounded Oral Suspension.'' Published
for public comment in Pharmacopeial Forum 46(2). Retrieved from
<a href="https://go.usp.org/l/323321/2020-04-08/33wcg6">https://go.usp.org/l/323321/2020-04-08/33wcg6</a>.
Dated: August 15, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-17881 Filed 8-18-23; 8:45 am]
BILLING CODE 4164-01-P
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This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.