[Federal Register Volume 91, Number 84 (Friday, May 1, 2026)]
[Notices]
[Pages 23431-23444]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2026-08552]
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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 for outsourcing facilities to use in
compounding (the 503B Bulks List). This notice identifies three bulk
drug substances that FDA has considered and proposes not to include on
the 503B Bulks List: semaglutide, tirzepatide, and liraglutide.
Additional bulk drug substances nominated for inclusion on this list
are under consideration and may be the subject of future notices.
DATES: Either electronic or written comments on the notice must be
submitted by June 30, 2026.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before June 30, 2026. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of June 30, 2026. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
[[Page 23432]]
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2018-N-3240 for ``List of Bulk Drug Substances for Which There is a
Clinical Need Under Section 503B of the Federal Food, Drug, and
Cosmetic Act.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts, and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Tracy Rupp, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Silver Spring, MD 20993, 240-402-0260, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
(21 U.S.C. 353b) describes the conditions that must be satisfied for
drug products compounded by 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 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, specific 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 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 from
CGMP requirements) 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
does 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 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
[[Page 23433]]
identifies three bulk drug substances that FDA has considered and
proposes not to include 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), January 27, 2022 (87 FR
4240), November 23, 2022 (87 FR 71642), April 6, 2023 (88 FR 20531),
and August 21, 2023 (88 FR 56837).
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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 Sec. 207.1 (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.'' Section 207.1 is
the successor regulation.
\9\ Section 503B(a)(2) of the FD&C Act and Sec. 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) of the FD&C Act, inactive
ingredients used in compounding must comply with the standards of an
applicable U.S. Pharmacopeia or National Formulary monograph, if a
monograph exists.
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II. Methodology for Developing the 503B Bulks List
A. Process for Developing the List
In the Federal Register of December 4, 2013 (78 FR 72838), FDA
requested nominations for specific bulk drug substances for the Agency
to consider for inclusion on the 503B Bulks List. 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. In the Federal Register of 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, we intend to publish notices
for public comment in the Federal Register that describe FDA's 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 our determination, and if so, we will
seek PCAC input.\12\ Depending on our review of the docket comments and
other relevant information before the Agency, FDA may finalize the
proposed determination without change, or we may finalize a
modification to the proposal to reflect new evidence or analysis
regarding clinical need. FDA intends to then publish in the Federal
Register a final determination identifying the bulk drug substances for
which we have determined there is a clinical need and our rationale in
making that final determination. FDA also intends to publish a final
determination in the Federal Register for those substances which we
considered but found that there is no clinical need to use in
compounding and our rationale in making this decision.
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\11\ This is consistent with procedure 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 maintains a list of all bulk drug substances we have evaluated
on our website and separately identify bulk drug substances we have
placed on the 503B Bulks List and those we have decided not to place on
the 503B Bulks List. This list is available at https://www.fda.gov/drugs/human-drug-compounding/503b-bulk-drug-substances-list. FDA will
only place a bulk drug substance on the 503B Bulks List when we have
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
the 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 the
proposed and final determinations in the Federal Register 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\ FDA's guidance for industry titled ``Interim Policy on
Compounding Using Bulk Drug Substances Under Section 503B of the
Federal Food, Drug, and Cosmetic Act'' (January 2025) 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. This guidance is
available on the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
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B. Analysis of Substances Nominated for the List
As noted above, the 503B Bulks List includes bulk drug substances
for which the Agency has determined there is a clinical need. The
Agency is evaluating bulk drug substances that were nominated for
inclusion on the 503B Bulks List, proceeding case by case, under the
clinical need standard provided by the statute.\14\ In applying this
standard to develop the proposals 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 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 titled ``Evaluation of Bulk Drug Substances Nominated for
Use in Compounding Under Section 503B of the Federal Food, Drug, and
Cosmetic Act'' (84 FR 7390). 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 of the FD&C Act. 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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For purposes of this analysis, FDA assumes without deciding that
semaglutide, tirzepatide, and liraglutide are components of FDA-
approved drug
[[Page 23434]]
products.\15\ We begin our evaluation of bulk drug substances which are
components of an FDA-approved drug by asking one or both, as
applicable, of the following questions:
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\15\ The nominators take the position that the nominated
semaglutide, tirzepatide, and liraglutide are the active ingredient
in the approved drug products. For purposes of this analysis, FDA
assumes without deciding that these substances are components of
FDA-approved drug products, as proposed in the nominations. Part 1
of the clinical need analysis primarily concerns attributes of the
relevant FDA-approved drugs. Specifically, under the clinical need
standard, FDA considers in Part 1 of its analysis whether there is a
clinical need for an outsourcing facility to compound a drug with a
bulk drug substance because the FDA-approved drug is medically
unsuitable. Here, irrespective of any differences in the attributes
of the bulk drug substances used in the FDA-approved drug products
compared to compounded drug products, FDA has not identified a basis
to conclude that an attribute of the approved products makes them
medically unsuitable such that a compounded drug is needed to
address any such attribute. The commenters' arguments, and
nominator's responses, about safety and quality concerns with the
nominated bulk drug substances for use in compounding would be
addressed in Part 2 of the clinical need analysis, which we do not
reach here.
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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 makes it 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 these 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. Each of the following factors is
considered in the context of the others, balancing them to determine
whether the statutory ``clinical need'' standard has been met:
the physical and chemical characterization of the
substance;
any safety issues raised by the use of the substance in
compounding;
the available evidence of effectiveness or lack of
effectiveness of a drug product compounded with the substance, if any
such evidence exists; and
current and historical use of the substance in compounded
drug products, including information about the medical condition(s)
that the substance has been used to treat and any references in peer-
reviewed medical literature.\16\
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\16\ See section 503B(a)(2)(A) of the FD&C Act and FDA's
guidance titled ``Evaluation of Bulk Drug Substances Nominated for
Use in Compounding Under Section 503B of the Federal Food, Drug, and
Cosmetic Act.''
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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 or starting with an FDA-approved drug product.
FDA did not answer ``yes'' to both of the threshold questions for
the bulk drug substances we are addressing in this notice. Accordingly,
as explained below, we did not proceed further in our evaluation of
these substances and are proposing not to include these bulk drug
substances on the 503B Bulks List.
In this notice, FDA evaluated certain nominated bulk drug
substances for potential inclusion on the 503B Bulks List either alone
or in combination with other bulk drug substances. FDA does not intend
to consider comments raising different bulk drug substances or
combinations of bulk drug substances other than those evaluated by FDA
in this notice to be within the scope of this notice. New bulk drug
substance nominations may be submitted to Docket No. FDA-2015-N-3469.
The docket is available on https://www.regulations.gov.
To assess whether there is a clinical need for outsourcing
facilities to use a bulk drug substance in compounding, FDA must
consider the drug products that have been proposed to be made from the
nominated bulk drug substances. Therefore, FDA's evaluation of a bulk
drug substance includes detailed consideration of the drug products
that are proposed to be compounded, including the conditions justifying
clinical need under the applicable statutory standard. Comments on
FDA's preliminary evaluation of a bulk drug substance should include
adequate support for the commenter's position. For example, a commenter
writing to support inclusion of a nominated bulk drug substance on the
503B Bulks List should include sufficient information to permit a
meaningful clinical need evaluation by FDA of the proposed product.
Commenters writing in favor of or in opposition to a proposal to
include or not to include an entry on the 503B Bulks List should
address, for each proposed compounded drug product, the factors FDA
evaluated in making our proposal.\17\ After FDA publishes a Federal
Register notice making a final determination regarding whether a bulk
drug substance will be placed on the 503B Bulks List, FDA will no
longer consider comments submitted to the docket regarding that bulk
drug substance, but interested parties may submit a citizen petition to
FDA requesting specific action or relief (see 21 CFR 10.30).
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\17\ See also FDA's guidance for industry, ``Evaluation of Bulk
Drug Substances Nominated for Use in Compounding Under Section 503B
of the Federal Food, Drug, and Cosmetic Act'' (March 2019), and our
Federal Register notice of October 27, 2015 (80 FR 65770).
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III. Substances Evaluated and Not Proposed for Inclusion on the 503B
Bulks List
This notice identifies three bulk drug substances that FDA has
evaluated and is proposing not to include on the 503B Bulks List:
semaglutide, tirzepatide, and
[[Page 23435]]
liraglutide. The reasons for FDA's proposals are set forth below.
A. Semaglutide
Semaglutide has been nominated \18\ for use in compounded drug
products for ``Type 2 diabetes mellitus,'' as ``an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes
mellitus''; \19\ ``[t]o reduce the risk of major adverse cardiovascular
events (cardiovascular death, non-fatal myocardial infarction, or non-
fatal stroke) in adults with established cardiovascular disease and
either obesity or overweight''; ``to reduce the risk of major adverse
cardiovascular events (cardiovascular death, non-fatal myocardial
infarction or non-fatal stroke) in adults with type 2 diabetes mellitus
and established cardiovascular disease''; ``[t]o reduce excess body
weight and maintain weight reduction long term in adults and pediatric
patients aged 12 years and older with obesity [and] adults with
overweight in the presence of at least one weight-related comorbid
condition''; ``to reduce the risk of sustained eGFR [estimated
Glomerular Filtration Rate] decline, end-stage kidney disease, and
cardiovascular death in adults with type 2 diabetes mellitus and
chronic kidney disease''; and for ``related health conditions as
determined appropriate by medical provider.''
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\18\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0388 and FDA-2015-N-3469-0411.
\19\ One nomination proposes to compound semaglutide for ``type
2 diabetes mellitus.'' For purposes of this evaluation, we have
interpreted this proposed use to be as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
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Semaglutide is an active ingredient in FDA-approved drug products:
2 mg/3 mL, 4 mg/3 mL, and 8 mg/3 mL solutions for subcutaneous (SC)
injection which contain propylene glycol (Ozempic, NDA 209637); 0.25
mg/0.5 mL, 0.5 mg/0.5 mL, 1 mg/0.5 mL, 1.7 mg/0.75 mL, 2.4 mg/0.75 mL,
and 7.2 mg/0.75 mL solutions for SC injection which do not contain
propylene glycol (Wegovy and Wegovy HD, NDA 215256); 1.5 mg, 4 mg, 9
mg, and 25 mg oral tablets (Wegovy, NDA 218316); and 1.5 mg, 3 mg, 4
mg, 7 mg, 9 mg, and 14 mg oral tablets (Rybelsus and Ozempic, NDA
213051).20 21
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\20\ Ozempic is FDA-approved as a single-patient-use pen in the
listed concentrations, and Wegovy and Wegovy HD are FDA-approved as
a single-dose pen in the listed concentrations.
\21\ According to the ``Dosage and Administration'' section of
the FDA-approved labeling for NDA 213051, there are two formulations
that are not substitutable on a milligram per milligram basis.
Formulation R1 (Rybelsus) includes strengths 3 mg, 7 mg, and 14 mg
and Formulation R2 (Rybelsus and Ozempic) includes strengths 1.5 mg,
4 mg, and 9 mg.
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Semaglutide was nominated and evaluated for the SC injection,
sublingual, buccal, and oral routes of administration in various
strengths. The nominations provide examples of such strengths and state
that different strengths may be compounded ``depending on medical
provider requests.'' \22\ In addition, the nominations propose to
compound semaglutide as an injectable product without propylene glycol
and as ``combination injectables including those doses above combined
with [p]yridoxine or an antiemetic medication'' (Ref. 1).
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\22\ Nominators included the following examples of strengths for
injectable products: 2 mg/3 mL (0.68 mg/mL), 4 mg/3 mL (1.34 mg/mL),
8 mg/3 mL (2.68 mg/mL), 0.00067 g/1 mL, 0.00167 g/1 mL, 0.0025 g/1
mL, 5 mg/1 mL, 8 mg/2 mL, 8 mg/1 mL, and 16 mg/1 mL. For the
sublingual route of administration, the nominators included the
following example strengths: 1.5 mg/mL, 2 mg/mL, 2.5 mg/mL, and 3
mg/mL. For oral tablets or capsules, the nominators provided the
following example strengths: 25 mg and 50 mg.
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1. Suitability of FDA-Approved Drug Product(s)
The nominations propose to compound a ``subcutaneous injection,
oral sublingual, buccal, and oral tablet or capsule'' in various
strengths.\23\ The nominators indicate that semaglutide might also be
used to compound other drug products, but the nominators do not
identify those products. To assess clinical need, we consider whether
the nomination identifies an attribute of the approved drug that makes
it medically unsuitable to treat certain patients for a condition that
FDA has identified for evaluation. With respect to the nominator's
statement that the compounded products will be used for ``related
health conditions as determined appropriate by medical provider,'' we
cannot find that there is a clinical need for an outsourcing facility
to compound semaglutide for unidentified health conditions.
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\23\ Some of the proposed concentrations are the same as the
FDA-approved injectable product (i.e., 2 mg/3 mL (0.68 mg/mL), 4 mg/
3 mL (1.34 mg/mL), 8 mg/3 mL (2.68 mg/mL)) or the FDA-approved oral
tablet (i.e., 25 mg)).
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``Oral Sublingual'' and Buccal Products
For ``oral sublingual'' products, the nominators identify
concentrations of 1.5 mg/mL, 2 mg/mL, 2.5 mg/mL, and 3 mg/mL as
examples; the nominators do not provide a proposed concentration for
buccal administration. One nominator states that ``the challenge of
swallowing this tablet . . . can be daunting and can discourage
[patients] from using the tablet'' and that ``difficulty swallowing is
a well-documented issue . . . with dysphagia affecting up to 33% of
older adults.'' \24\ The nominator further states that the injection
route of administration is ``linked to patient discomfort and is
subject to refrigerated storage.'' The nominator states that the buccal
and sublingual routes ``are recognized as valid alternatives'' and that
these routes ``in varying strengths would satisfy this clinical need.''
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\24\ OFA cites Shanojan Thiyagalingam et al., Dysphagia in older
adults, 96 Mayo Clinic Proceedings 488-497 (2021); Statements of
Margaret A. Hamburg, Commissioner, Food & Drug Administration. The
Fungal Meningitis Outbreak: Could It Have Been Prevented? Hearing
Before The Subcommittee On Oversight And Investigations Of The
Committee on Energy and Commerce House of Representatives One
Hundred Twelfth Congress Second Session November 14, 2012 Serial No.
112-181.
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For the reasons below, FDA has not identified a basis to conclude
that the oral and injectable routes of administration of the FDA-
approved semaglutide products cause those products to be medically
unsuitable for certain patients and that a compounded buccal or
sublingual product would address such an attribute. While we have no
reason to disagree with the proposition that difficulty swallowing is a
``well-documented issue'' and that compounded drugs can serve an
important need for patients who cannot swallow tablets, the nominators
refer to concerns about oral routes of administration generally; they
do not identify any unsuitability with approved semaglutide products.
Nor do they explain why the injectable drug products would be medically
unsuitable for patients who cannot swallow a tablet.
One nominator refers to an article, Pratap-Singh et al. (2023),
that the authors characterize as ``a guideline for future investigators
in creating buccal or sublingual tablets for the delivery of [peptide]
drugs used to treat diabetes.'' The article explains that ``clinical
use [of peptides for diabetes mellitus] is limited by the challenges of
subcutaneous injection,'' referencing ``patient discomfort as well as
being subjected to refrigerated storage and the requirement for
efficient supply chain logistics.'' The article states that ``[t]he
oral route is possibly the most common and the most acceptable for
patients'' but that ``oral delivery faces challenges such as low
permeation, proteolysis enzymes in the upper gastrointestinal tract,
low gastric pH, and bioavailability.'' The article further states that
``the gastrointestinal route is unpredictable and usually involves high
losses of the delivered drug.'' The paper
[[Page 23436]]
refers to buccal or sublingual routes as ``[a] potential alternative,''
citing ``[a]ccessibility and easy administration'' as the ``main
advantages connected to these types of routes.'' However, the authors
also note that these routes of administration present challenges. The
article ``describes the current state of the art with respect to the
creation of nanoparticles containing peptides such as insulin,
glucagon-like peptide 1 (GLP-1), and their agonists, and theorizes the
production of mucoadhesive unidirectional release buccal tablets or
films.'' The paper identifies potential ``challenges'' that could
emerge with the development of new formulations of peptide drugs that
could be administered via non-parenteral routes of administration for
the treatment of diabetes mellitus (e.g., insulin, GLP-1 receptor
agonists).
The authors did not design their study to assess, and, accordingly,
do not identify, any medical unsuitability of FDA-approved GLP-1
receptor agonists for treatment of diabetes mellitus. Further, the
article refers only to general concerns associated with injectable
routes of administration (e.g., patient discomfort), which does not
support the nominator's position that the FDA-approved products are
medically unsuitable for patients. We also note that the paper
discusses GLP-1 drugs generally, and not the approved semaglutide drug
products (Ref. 2).
Injectable Products
The nominators refer to ``[r]anges depending on medical provider
requests'' and list examples of such strengths. For products proposed
for the SC route of administration, the nominators provide example
concentrations of 0.00067 g/mL (0.67 mg/mL), 2 mg/3 mL (0.68 mg/mL), 4
mg/3 mL (1.34 mg/mL), 0.00167 g/mL (1.67 mg/mL), 0.0025 g/mL (2.5 mg/
mL), 8 mg/3 mL (2.68 mg/mL), 8 mg/2 mL (4 mg/mL), 5 mg/mL, 8 mg/mL, and
16 mg/mL injections. As these are identified as examples, the
nominations do not identify each of the concentrations--and therefore
the drug products--proposed to be compounded for the SC route of
administration.
Several of the concentrations identified differ from the approved
products. At the time the nominations were submitted, the proposed
concentrations of 8 mg/2 mL (4 mg/mL), 5 mg/mL, and 8 mg/mL exceeded
the concentrations of the approved semaglutide products. In addition,
the nominators proposed to compound a 16 mg/mL solution for SC
injection. However, semaglutide is also now approved as a 7.2 mg/0.75
mL (9.6 mg/mL) solution for SC injection. Therefore, the proposed
concentrations of 8 mg/2 mL (4 mg/mL), 5 mg/mL, and 8 mg/mL no longer
exceed the concentrations of the approved semaglutide products. The
nominations did not provide supporting data or information for the use
of products with a higher concentration.25 26 FDA is also
not aware of data or information that identifies patients for whom the
concentrations of the FDA-approved SC injections are medically
unsuitable.
---------------------------------------------------------------------------
\25\ For example, one nomination states that patients may
benefit from higher doses but does not identify higher doses to be
delivered from the proposed compounded drug product. The nominations
also do not identify patients for whom the concentrations of the
FDA-approved SC injections that were approved at the time are
medically unsuitable such that a higher concentration is needed. The
nominations advance a general hypothesis that higher doses have a
``superior effect'' relative to approved oral products, and
``potentially'' to injectable formulations. With respect to the
assertion that ``[c]ertain patients benefit from higher doses than
are commercially available,'' even if accurate, any improved
outcomes from the higher strength, or the fact that a higher
strength is being studied, would not mean that the approved product
does not achieve the intended clinical benefit or that it is
otherwise medically unsuitable for patients. The nominators did not
provide a basis to conclude that patients need the specific
concentrations proposed. As noted, FDA has now approved a
concentration that is higher than those of the products approved at
the time the nominations were submitted.
\26\ In addition, since submission of the nominations, the
results of the study a nominator cited from clinicaltrials.gov,
NCT05486065, have been published (Aroda et al. 2025). The results do
not support the nominator's argument. In this phase 2 clinical
trial, 8 mg and 16 mg doses of semaglutide were compared to 2 mg
doses of semaglutide and placebo. The study did not demonstrate a
statistically significant improvement in glycemic control (as
measured by hemoglobin A1c) in subjects treated with the 8 mg or 16
mg dose compared to the 2 mg dose using the treatment policy
estimand. There was a statistically significant decrease in body
weight when the semaglutide 16 mg dose was compared to the 2 mg dose
using the treatment policy estimand, but the study did not
demonstrate a statistically significant decrease in body weight when
the 8 mg dose was compared to the 2 mg dose. We note that adverse
events and treatment discontinuations due to adverse events were
more frequent in the 8 mg and 16 mg groups than in the 2 mg dose
group.
---------------------------------------------------------------------------
The nominators state that some patients are ``hyper-responders''
and that they may ``need a lower dose than what is commercially
available.'' One nominator states that ``[i]t has been estimated that
5-15% of the population are hyper-responders to this medication (and
15% have been estimated to be non-responders).'' The nominator provides
no reference that supports its statement about what ``has been
estimated.'' The nominator cites Wilding et al. (2021), which does not
mention ``hyper-responders'' or the 5-15% statistic (Ref. 3). As the
nominator notes, the study showed that more patients in the semaglutide
group than the placebo group discontinued treatment after
gastrointestinal events, and that nausea occurred ``primarily during
the dose-escalation period'' (Wilding et al. 2021). However, the
article also states that ``[m]ost gastrointestinal events were mild-to-
moderate in severity, were transient, and resolved without permanent
discontinuation of the regimen.'' One nominator states that ``[i]t is
believed with alternative maintenance doses and/or a slower titration
schedule, more patients will remain on the treatment and have
clinically meaningful outcomes as a result.'' The nominator again
provides no support for its statement that this is ``believed'' to be
the case, and the results of a study describing mild-to-moderate,
transient gastrointestinal events primarily during a dose escalation
period do not support the proposition that there are ``hyper-
responders'' for whom the strength of the approved product makes it
medically unsuitable.
One nominator states that ``hyper-responders'' are those who are
``sensitive'' to the drug and thus may need either a slower titration
or a lower maintenance dose, noting that only the 1.7 mg and 2.4 mg
weekly doses are approved for maintenance.\27\ Noting that semaglutide
is only FDA-approved in single patient use pens, one of the nominators
states that ``[i]t is impossible to achieve lower or higher doses with
an auto-injector pen.'' However, the nominations do not explain why, if
a patient requires a lower maintenance dose, one of the FDA-approved
products that contain a lower concentration (i.e., 0.25 mg/0.5 mL, 0.5
mg/0.5 mL, 1 mg/0.5 mL) could not be used.\28\ The nominations also do
not explain why a slower titration using the FDA-approved products
could not be used in patients who do not tolerate dose escalation every
4 weeks.\29\
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\27\ While not specified in the nomination, we assume the
nominator is referencing semaglutide approved by FDA under the brand
name Wegovy, NDA 215256. Additionally, we note that with the
approval of Wegovy HD 7.2 mg/0.75 mL, the approved maintenance doses
are now 1.7 mg, 2.4 mg, and 7.2 mg weekly.
\28\ While the ``Dosage and Administration'' section of the FDA-
approved labeling for NDA 215256 states that the maintenance dose is
1.7 mg, 2.4 mg, and 7.2 mg, the section also states to ``[c]onsider
treatment response and tolerability when selecting the maintenance
dosage.'' See https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215256s029lbl.pdf. Accessed 3/31/26.
\29\ According to the ``Dosage and Administration'' section of
the FDA-approved labeling for NDA 215256, ``[i]f patients do not
tolerate a dose during dosage escalation, consider delaying dosage
escalation for 4 weeks.'' See https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215256s029lbl.pdf. Accessed 3/31/26.
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[[Page 23437]]
In its nomination, BPI Labs, LLC refers to ``[i]njectable dosing,
or microdosing,'' for use in controlling side effects. In its
nomination, the Outsourcing Facilities Association (OFA) states that a
different dose may be ``more suitable for their patient in order to
manage side effects and increase adherence''--but does not identify
alternative doses to be delivered from the proposed compounded drug
product. Further, the general statement that a different dose may be
``more suitable'' does not mean that the concentration of the approved
product is not suitable. In addition, OFA included in its comment that
``[m]icrodosing trends have been widely reported and allow patients
otherwise intolerant to standard doses to continue treatment,'' citing
an article published in The New York Times (Ref. 4). However, the New
York Times article does not include any data or information to support
the proposition that the FDA-approved product could not be used to
obtain lower doses or that it is otherwise medically unsuitable. In
assessing clinical need, we consider, in part, whether there is a basis
to conclude that an attribute of the FDA-approved product makes it
medically unsuitable--not whether the approved product in fact meets
medical needs. Nor does the clinical need analysis turn on information
about general ``trends'' without identifying patients for whom the
approved drug would be medically unsuitable.
Oral Products
The nominators also propose to compound semaglutide as oral tablets
and capsules.\30\ The nominations refer to ``[r]anges depending on
medical provider requests'' and list examples of such strengths. For
products proposed for the oral route of administration, the nominators
provide strengths of 25 mg and 50 mg oral tablets and capsules. As
these are listed as examples, the nominations do not identify each of
the strengths--and therefore the drug products--proposed to be
compounded for the oral route of administration. Semaglutide is FDA-
approved as 1.5 mg, 3 mg, 4 mg, 7 mg, 9 mg, 14 mg, and 25 mg oral
tablets; there are no FDA-approved oral capsules. The nominators do not
explain why capsules would be needed.
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\30\ One nomination states that 3 mg, 7 mg, and 14 mg are the
currently available dosages. We note that semaglutide is also
approved as 1.5 mg, 4 mg, 9 mg, and 25 mg oral tablets. The
nomination was received prior to the approval of these strengths,
but there is no information in the nomination, and the nominator did
not supplement its nomination after the approval, to show that these
approved products would be medically unsuitable for any patient who
would need a higher strength.
---------------------------------------------------------------------------
One nominator states that the current FDA-approved oral tablets
``are inadequate to treat all cases of obesity in patients with
inadequately controlled type 2 diabetes.'' The other nominator states
that ``[o]ral dosages, other than commercially avaialble [sic]
strenghts [sic], are required for those requiring side effect based
minimum or maximum dosing regimens'' and that ``according to published
data, up to 10% [of] the current population deals with Trypanophobia
(fear of needles) and up to 33% in children.'' This nominator further
states that ``[t]he current oral offerings of commercial Rybelsus do
not fit all patient populations and often need to be individualized.''
The nominators also assert that ``[t]here is evidence that higher doses
than are currently commercially available show a superior effect as
compared to the commercially available doses for oral formulations.''
The nominations do not identify, and FDA is not otherwise aware of,
data or information that identifies patients for whom the strengths of
the FDA-approved oral tablets are medically unsuitable. In addition,
semaglutide was approved as a 25 mg tablet after the nominators
submitted their nomination. The nominators did not supplement their
nominations after the approval to provide any data or information
bearing on medical suitability. The nominators have not provided a
basis to conclude that the FDA-approved 25 mg oral tablet is medically
unsuitable for any patients who would need the 25 mg strength. Thus, we
address here the proposal for 50 mg oral tablets.
One nominator submitted two articles, Aroda et al. (2023) and Knop
et al. (2023), in which patients received oral semaglutide at doses of
25 mg and 50 mg. Aroda et al. 2023 (PIONEER PLUS) was a multi-center,
randomized, double-blind, phase 3b trial that studied the use of 25 mg
and 50 mg once-daily oral doses of semaglutide in adults with type 2
diabetes compared to the approved once-daily 14 mg dose. The 25 mg and
50 mg tablets ``were a new formulation developed to enhance
bioavailability compared with the 14 mg dose'' (Ref. 5). Knop et al.
(2023) (OASIS 1) was a randomized, double-blind, placebo-controlled,
phase 3 superiority trial that studied the use of semaglutide 50 mg
once daily compared to placebo in adults with overweight or obesity
without type 2 diabetes (Ref. 6). The formulation used for the 25 mg
and 50 mg doses was developed to enhance bioavailability. First, while
Aroda et al. (2023) found that the 25 mg and 50 mg doses ``were
superior to 14 mg in reducing HbA1c and bodyweight,'' the
authors noted that ``dosing might not reflect clinical practice since
participants were escalated to higher doses according to randomisation
and irrespective of clinical need.'' Additionally, the study developed
a new formulation of semaglutide in order to enhance the
bioavailability compared to the approved 14 mg tablet.\31\ The authors
of the article noted the following study limitation: ``it was not
possible to assess whether the efficacy and tolerability of oral
semaglutide were directly affected specifically by the new formulation.
It is therefore possible that the additional benefit of the 25 mg and
50 mg doses was not only dose-related, but also reflected the higher
bioavailability of this formulation.'' The nomination does not provide
any information regarding the formulation of the compounded product,
and the nomination does not explain, or even assert, that the
compounded product would overcome the poor bioavailability of oral
semaglutide. As noted, FDA has
[[Page 23438]]
approved a 25 mg semaglutide oral tablet. With respect to the 50 mg
tablet proposed in the nomination, improved outcomes from the higher
strength, or the fact that a higher strength is being studied, does not
mean that the approved product does not achieve the intended clinical
benefit or is otherwise medically unsuitable for patients.
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\31\ There are three formulations of semaglutide for oral
administration that are approved. One is approved under the brand
name Rybelsus, one under the brand name Ozempic, and one under the
brand name Wegovy. According to the Prescribing Information for
Rybelsus and Ozempic, the population pharmacokinetics estimated
absolute bioavailability of semaglutide is approximately 0.4-1%
following oral administration of 3 mg, 7 mg, and 14 mg of Rybelsus
(formulation R1) and 1-2% following oral administration of 1.5 mg, 4
mg, and 9 mg of Ozempic (formulation R2); both drug products are co-
formulated with salcaprozate sodium (SNAC), which facilitates the
absorption of semaglutide after oral administration. Refer to the
``Clinical Pharmacology--Pharmacokinetics'' section of the FDA-
approved labeling for NDA 213051 available at https://www.accessdata.fda.gov/spl/data/d66c588c-f975-45de-819e-f879c453385d/d66c588c-f975-45de-819e-f879c453385d.xml and https://www.accessdata.fda.gov/spl/data/dfe441cd-c20f-452b-a8a5-3a6017b6b006/dfe441cd-c20f-452b-a8a5-3a6017b6b006.xml. Accessed 3/
25/26. According to the Prescribing Information for Wegovy, the
population pharmacokinetics estimated absolute bioavailability of
semaglutide is approximately 1-2% following oral administration of
Wegovy and is co-formulated with salcaprozate sodium, which
facilitates the absorption of semaglutide after oral administration.
Refer to the ``Clinical Pharmacology--Pharmacokinetics'' section of
the FDA-approved labeling for NDA 218316 available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/218316s005lbl.pdf.
Accessed 3/31/26. As described in the Supplementary Appendix of the
PIONEER PLUS article (Aroda et al. 2023), the oral semaglutide 25 mg
and 50 mg tablets used in the study consisted of a new formulation
developed to enhance bioavailability compared with the 14 mg dose.
The Supplementary Appendix is available online at https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01127-3/
abstract. Two excipients (microcrystalline cellulose [filler] and
povidone K 90 [binder]) were omitted, with magnesium stearate
remaining as the only excipient besides the active drug substance
and the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino)
caprylate (SNAC).
---------------------------------------------------------------------------
The Knop et al. study was a placebo-controlled trial that
determined that oral semaglutide 50 mg is superior to placebo in
decreasing bodyweight. Similar to the Aroda et al. (2023) study, this
study utilized a new formulation of semaglutide to enhance the
bioavailability.\32\ While the study found, and the nominator cited,
that oral semaglutide 50 mg daily ``led to a superior and clinically
meaningful decrease in bodyweight compared with placebo,'' this does
not support a conclusion that an attribute of the approved semaglutide
makes it medically unsuitable. Obtaining a better response with a
higher dose does not mean that the strengths of the currently approved
products are not effective or that they are otherwise medically
unsuitable.
---------------------------------------------------------------------------
\32\ As described in the Methods section of the OASIS-1 article
(Knop et al. 2023), two excipients (microcrystalline cellulose and
povidone K 90) included in the oral formulation currently approved
at the time of publication for the treatment of type 2 diabetes were
omitted in order to enhance bioavailability.
---------------------------------------------------------------------------
The nominators' statements that the strengths of the approved
tablets ``are inadequate'' or ``do not fit all patient populations'' do
not explain why the approved products are inadequate or identify
patients for whom they are inadequate. To the extent the nominators are
referring to the arguments discussed above about obtaining a better
response with a higher dose, as discussed, that does not mean that the
approved product is medically unsuitable for patients.
Proposals for Formulations Without Certain Excipients
One nominator states that ``[a]n individual patient may have
intolerances or sensitivities to inactive ingredients in the
commercially available drug product,'' but does not identify which
inactive ingredients they are referring to. Therefore, the nominator
does not identify an attribute of the approved drugs that makes them
medically unsuitable or a compounded drug intended to address that
attribute.
Some of the proposed concentrations are the same as the FDA-
approved product (i.e., 2 mg/3 mL (0.68 mg/mL), 4 mg/3 mL (1.34 mg/mL),
8 mg/3 mL (2.68 mg/mL)). One nominator states that the ``FDA-approved
semaglutide injections indicated for type 2 diabetes contain propylene
glycol, which has caused an increase in irritation at the injection
site.'' The nominator claims that ``type 2 diabetic patients that
require doses not offered in the non-propylene glycol formulations can
benefit [from] compounded semaglutide'' and included one article,
Snitker et al. (2022), that evaluated the injection-site experience of
two formulations of semaglutide, semaglutide C and semaglutide D,
compared to semaglutide multidose pen injector (MPI) (Ref. 7).\33\ The
article does not appear to support the nominator's position. The
article does not, as the nominator claims, find that ``95% of patients
preferred the formulation without propylene glycol.'' When comparing
semaglutide D, the formulation that did not contain propylene glycol,
with semaglutide MPI, a formulation that contains propylene glycol, the
authors concluded that ``[t]he injection-site experience with
semaglutide D was almost indistinguishable from semaglutide MPI . . .
with either product associated with no or very mild injection-site
pain.'' Additionally, what the nomination describes as ``patient
preference'' for a different formulation than the approved drug does
not mean that the formulation of the approved drug is medically
unsuitable.
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\33\ Semaglutide C is a single-dose pen injector that does not
contain phenol and contained a higher concentration (1.9%) of
propylene glycol than the semaglutide MPI. This formulation is not
similar to any formulation approved in the United States.
Semaglutide D is a single-dose pen injector that does not contain
phenol and contained sodium chloride instead of propylene glycol.
This formulation is similar to the formulation of FDA-approved
Wegovy. Semaglutide MPI contains phenol and propylene glycol. This
formulation is similar to the formulation of FDA-approved Ozempic.
The authors stated that this formulation is ``a benchmark for low
injection-site pain.''
---------------------------------------------------------------------------
Semaglutide for SC injection is approved by FDA under the brand
names Ozempic, Wegovy, and Wegovy HD. Ozempic is approved in three
concentrations as a multidose pen injector, each of which contains
propylene glycol 14 mg/mL; Wegovy is approved in five concentrations as
a single-dose pen injector, none of which contain propylene glycol; and
Wegovy HD is approved in one concentration as a single-dose pen
injector, which does not contain propylene glycol. One nominator
observes that ``type 2 diabetic patients that require doses not offered
in the non-propylene glycol formulations can benefit [from] compounded
semaglutide.''
A search of the FDA Adverse Event Reporting System (FAERS) database
identified numerous reports associated with semaglutide and injection
site reactions and, despite the presence or absence of propylene glycol
in the FDA-approved formulation, injection site reactions occurred in
both Ozempic and Wegovy users. Of the reports identified, one case
referenced propylene glycol. The report described a patient with a
history of severe allergy to propylene glycol who, after treatment with
Ozempic for 2 months for type 2 diabetes mellitus, developed a ``red,
swollen bubble at the injection site the size of a quarter'' that
resolved after discontinuing Ozempic. It is unclear whether the
reaction experienced can be attributed to propylene glycol.\34\
---------------------------------------------------------------------------
\34\ It is important to note that FAERS data have limitations.
First, there is no certainty that the reported adverse event was due
to the suspect product. FDA does not require that a causal
relationship between a product and event be proven, and the report
may not always contain enough detail to properly evaluate an event.
---------------------------------------------------------------------------
FDA has not identified any data or information to suggest that
propylene glycol would cause a drug product containing semaglutide to
be medically unsuitable. Injection site reaction is an adverse event
reported in trials with various injectable therapeutic products,
including other anti-hyperglycemic products not formulated with
propylene glycol (e.g., insulin products, other GLP-1 receptor
agonists, tirzepatide). Additionally, all FDA-approved semaglutide
injections, including the propylene glycol-free formulations of Wegovy
and Wegovy HD, are labeled for injection site reactions.\35\ The data
and information do not suggest that a formulation without propylene
glycol would mitigate the skin irritation that can be associated with
subcutaneously injected therapies such as semaglutide.\36\ Even if the
formulations containing propylene glycol were medically unsuitable for
certain patients, the nominator has provided no basis to conclude that
those patients could not use the FDA-approved products that are not
formulated with propylene glycol.\37\ Additionally, the
[[Page 23439]]
notion that a patient ``can benefit'' from a compounded formulation
does not mean that the approved formulation is medically unsuitable.
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\35\ Refer to the ``Adverse Reactions'' section of the FDA-
approved labeling for NDA 209637 and NDA 215256 available at https://www.accessdata.fda.gov/spl/data/341dc8b9-9576-48a7-b8d8-c583c67b7007/341dc8b9-9576-48a7-b8d8-c583c67b7007.xml and https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215256s029lbl.pdf.
Accessed 3/31/26.
\36\ The presence of propylene glycol in Ozempic and the absence
of this excipient in Wegovy suggests that determinants of injection
site reactions are likely more complex than the inclusion or
exclusion of propylene glycol in the formulation.
\37\ We note that the semaglutide drug products approved for use
as an SC injection (i.e., Ozempic, Wegovy, Wegovy HD) have differing
concentrations and labeled indications. Wegovy and Wegovy HD, the
approved formulations that do not contain propylene glycol, have not
been shown to be safe and effective for the treatment of type 2
diabetes. For the Part 1(a) analysis, we ask a limited, threshold
question to determine whether there might be 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 Part 1(a), 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 semaglutide.
---------------------------------------------------------------------------
Multi-ingredient Products
The nominators also propose to compound semaglutide as
``combination injectables including those doses above combined with
[p]yridoxine or an antiemetic medication.'' However, the nominations
provide no other information about the proposed compounded products, or
why they think patients would use these combinations. For example, the
nominations do not identify the drug products containing semaglutide
and pyridoxine, or semaglutide and ``an antiemetic,'' proposed to be
compounded.\38\ Without identifying an attribute of the approved drugs
that make them medically unsuitable (e.g., why a patient could not
receive an FDA-approved semaglutide product and separately an FDA-
approved pyridoxine product or antiemetic) or the product proposed to
be compounded to address that attribute, we do not have a basis to
conclude that there is a clinical need for an outsourcing facility to
compound semaglutide to make this multi-ingredient product.
---------------------------------------------------------------------------
\38\ Even if the nominations had provided sufficient information
to ascertain the drug product proposed to be compounded, we note
that, in general, we do not expect to find clinical need for a bulk
drug substance to compound drug products containing two or more bulk
drug substances unless: (1) combining the substances is intended to
address the medical unsuitability of the FDA-approved drug products
for certain patients and (2) the combination is likely to address a
clinical need that could not be addressed by delivering each
component of the drug product alone. Not including drug products
with two or more active ingredients on the 503B Bulks List unless
these conditions are met helps to ensure that patients are not
exposed to a drug product containing an unnecessary active
ingredient, helps avoid risks of unwanted interactions or
complications in formulation, and protects the integrity of the drug
approval process.
---------------------------------------------------------------------------
Whether for convenience or for some other purpose, as noted, the
nominators provide no information (e.g., proposed use, active
ingredients, strength) about the drug product that would be compounded
as a multi-active pharmaceutical ingredient (API) product. The
nominators do not identify an attribute of the approved product that
makes the product medically unsuitable or explain why the addition of a
second active ingredient would address any such attribute.
Other Issues
One nomination also states that ``a medical professional may
determine that a different dose than is commercially available is more
suitable for their patient in order to manage side effects and increase
adherence,'' and that ``[a]n administration device, such as an auto-
injector, that only provides a fixed dose does not allow for these more
tailored doses''; it is, according to the nomination, ``impossible to
achieve lower or higher doses with an auto-injector pen.'' The
nomination further states that ``an administration device, such as an
auto-injector, may not be suitable for a specific patient'' and that
``an alternative container/closure [system] or administration device
may improve patient compliance and safety.'' We have addressed above
the arguments about a need for different strengths than the approved
products; we explained that FDA has not identified a basis to conclude
that the strengths of such products cause them to be medically
unsuitable for certain patients. To the extent the nominator is arguing
that a different container-closure device would necessitate compounding
from a bulk drug substance rather than an approved drug, that question
is inapplicable to this Part 1(a) analysis. Thus, we need not reach the
argument about use of a different container-closure to achieve
different strengths.
The nominators also state that semaglutide should be added to the
503B Bulks List because FDA-approved products containing semaglutide
are in or could be subject to shortage, drugs produced by outsourcing
facilities are produced in accordance with CGMP, and there are also
potential concerns related to growth demand and access to these
products. However, FDA does not interpret such issues, such as
shortages and backorders, to be within the meaning of ``clinical need''
for compounding with a bulk drug substance. As noted above, section
503B contains a separate provision for compounding from bulk drug
substances if the drug product compounded from such bulk drug substance
is on the FDA drug shortage list at the time of compounding,
distribution, and dispensing.
For these reasons, FDA tentatively finds no basis to conclude that
there is an attribute of the FDA-approved drug products containing
semaglutide that makes them medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that the proposed compounded products are intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because there is no basis to conclude that there is an attribute of
the FDA-approved drug products containing semaglutide which makes them
medically unsuitable to treat certain patients, FDA does not need to
evaluate whether the proposed drug products containing semaglutide must
be compounded from a bulk drug substance rather than using an FDA-
approved drug product.
3. Docket Comments
To the extent relevant to the clinical need analysis, FDA has
considered the following submissions to the docket regarding the
nomination of semaglutide for the 503B Bulks List (FDA-2015-N-3469):
Covington & Burling LLP on behalf of Novo Nordisk, Inc. (NNI)
submitted a comment dated October 21, 2024 (FDA-2015-N-3469-0402),\39\
opposing the nomination of semaglutide to the 503B Bulks
List.40 41 OFA submitted comments dated October 24, 2024
(FDA-2024-P-4937-0003),\42\ and dated February 13, 2025 (FDA-2024-P-
4937-0004),\43\ regarding the arguments made in the citizen petition.
NNI submitted a supplement to its earlier comment dated April 15, 2025
(FDA-2015-N-3469-
[[Page 23440]]
0413 and FDA-2024-P-4937-0005),\44\ responding to OFA's comments.
---------------------------------------------------------------------------
\39\ Available at https://www.regulations.gov/comment/FDA-2015-N-3469-0402.
\40\ The comment enclosed a citizen petition submitted by
Covington & Burling LLP on behalf of NNI (FDA-2024-P-4937-0001).
\41\ For purposes of this clinical need evaluation, we address
the arguments from the petition that are directly relevant to the
clinical need analysis, including those that engage with arguments
in the nominations. We also note that this preliminary Federal
Register notice does not reflect a final Agency decision on any of
the arguments raised in the petition. FDA is issuing the preliminary
Federal Register notice to seek public comment on the issues raised
in the nominations and comments to the docket, including relevant
portions of the petition that was enclosed in NNI's comment. FDA's
final decision on those issues will be reflected in the final
Federal Register notice and response to the petition. FDA intends to
issue the response to the petition concurrently with the Federal
Register notice setting forth FDA's final decision about whether
semaglutide will be added to the 503B Bulks List.
\42\ Available at https://www.regulations.gov/comment/FDA-2024-P-4937-0003.
\43\ Available at https://www.regulations.gov/comment/FDA-2024-P-4937-0004.
\44\ Available at https://www.regulations.gov/comment/FDA-2015-N-3469-0413 and https://www.regulations.gov/document/FDA-2024-P-4937-0005.
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B. Tirzepatide
Tirzepatide has been nominated \45\ for use in compounded drug
products for ``Type 2 diabetes mellitus,'' \46\ ``as an adjunct to diet
and exercise to improve glycemic control in adults with type 2 diabetes
mellitus''; ``[t]o reduce the risk of major adverse cardiovascular
events (cardiovascular death, non-fatal myocardial infarction, or non-
fatal stroke) in adults with established cardiovascular disease and
either obesity or overweight''; ``[t]o reduce excess body weight and
maintain weight reduction long term in adults and pediatric patients
aged 12 years and older with obesity [and] adults with overweight in
the presence of at least one weight-related comorbid condition''; ``to
treat moderate to severe obstructive sleep apnea (OSA) in adults with
obesity''; and ``related health conditions as determined appropriate by
medical provider.''
---------------------------------------------------------------------------
\45\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0389 and FDA-2015-N-3469-0411.
\46\ One nomination proposes to compound tirzepatide for ``type
2 diabetes mellitus.'' We understand the nomination to have intended
this proposed use to be as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus. We
note that tirzepatide was approved on December 19, 2025, for
pediatric patients 10 years of age and older (NDA 215866). The
nomination was received prior to the approval of tirzepatide for
this patient population, and the nominator did not supplement its
nomination after the approval to show that these approved products
would be medically unsuitable for such patients.
---------------------------------------------------------------------------
Tirzepatide is an active ingredient,\47\ as both a single-dose pen
and a single-dose vial, in FDA-approved drug products: 2.5 mg/0.5 mL, 5
mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, and 15 mg/0.5
mL solutions for SC injection (Mounjaro, NDA 215866; Zepbound, NDA
217806). Tirzepatide is also an active ingredient, as both a multi-dose
vial and a single-patient-use KwikPen, in FDA-approved drug products:
10 mg/2.4 mL (4.17 mg/mL) for four 2.5 mg/0.6 mL doses, 20 mg/2.4 mL
(8.33 mg/mL) for four 5 mg/0.6 mL doses, 30 mg/2.4 mL (12.5 mg/mL) for
four 7.5 mg/0.6 mL doses, 40 mg/2.4 mL (16.7 mg/mL) for four 10 mg/0.6
mL doses, 50 mg/2.4 mL (20.8 mg/mL) for four 12.5 mg/0.6 mL doses; and
60 mg/2.4 mL (25 mg/mL) for four 15 mg/0.6 mL doses solutions for SC
injection (Mounjaro, NDA 215866; Zepbound, NDA 217806).
---------------------------------------------------------------------------
\47\ Contains sodium chloride 4.1 mg, sodium phosphate dibasic
heptahydrate 0.7 mg, and water for injection.
---------------------------------------------------------------------------
Tirzepatide was nominated and evaluated for the SC injection,
sublingual, buccal, and oral routes of administration in various
strengths. The nominations provide examples of such strengths and state
that different strengths may be compounded ``depending on medical
provider requests.'' \48\ In addition, the nominations propose to
compound tirzepatide as ``combination injectables including those doses
above combined with [p]yridoxine or an antiemetic medication'' (Ref.
8).
---------------------------------------------------------------------------
\48\ Nominators included the following examples of strengths for
injectable products: 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10
mg/0.5 mL, 12.5 mg/0.5 mL, 15 mg/0.5 mL, 20mg/0.5 mL, and 30mg/0.5
mL. For the sublingual route of administration, nominators proposed
5 mg/mL and 7.5 mg/mL.
---------------------------------------------------------------------------
1. Suitability of FDA-Approved Drug Product(s)
The nominators propose to compound a ``subcutaneous injection, oral
sublingual, buccal, and oral tablet or capsule'' in various strengths.
The nominators propose to compound drug products in various routes of
administration and provide examples of strengths associated with some
of those routes. The nominators suggest that tirzepatide might also be
used to compound other drug products, but the nominators do not
identify those products. To assess clinical need, we consider whether
the nomination identifies an attribute of the approved drug that makes
it medically unsuitable to treat certain patients for a condition that
FDA has identified for evaluation. With respect to the nominator's
statement that the compounded products will be used for ``related
health conditions as determined appropriate by medical provider,'' we
cannot find that there is a clinical need for an outsourcing facility
to compound tirzepatide for unidentified health conditions. With
respect to the proposed use of ``to reduce the risk of major adverse
cardiovascular events in adults with established cardiovascular disease
and either obesity or overweight,'' the nominator did not provide any
supporting data or information for this use. Additionally, the
nominator does not identify an attribute of the FDA-approved drug
containing tirzepatide that would make it medically unsuitable to treat
this condition.
Oral, ``Oral Sublingual'' and Buccal Products
We address here the proposals for oral, ``oral sublingual,'' and
buccal products because no tirzepatide drug product is approved in
these routes of administration.
The nominators refer to ``[r]anges depending on medical provider
requests'' and list examples of such strengths. For products proposed
for the sublingual route of administration, the nominators provide
example concentrations of 5 mg/mL and 7.5 mg/mL; the nominators do not
provide any concentrations of products proposed to be compounded for
oral and buccal administration. As the proposed concentrations for the
sublingual route of administration are listed as examples, the
nominations do not identify each of the strengths--and therefore the
drug products--proposed to be compounded for the oral, sublingual, and
buccal routes of administration.
One nominator states that the injection route of administration is
``linked to patient discomfort and is subject to refrigerated
storage.'' The nominator further states that ``[a]n injectable only
formulation causes unnecessary fears in these patients and may lead to
adherence failure,'' and that ``an oral tablet, capsule, sublingual or
buccal tablet in varying strengths would satisfy this clinical need.''
Regarding sublingual and buccal forms, the nominators state that
``there are certain patients who cannot swallow and an injectable may
not be preferable . . . therefore there is a clinical need for
sublingual dosage forms.'' One nominator claims that the buccal and
sublingual routes ``are recognized as valid alternatives'' and that
these routes ``in varying strengths would satisfy this clinical need.''
One nominator refers to an article, Pratap-Singh et al. (2023), that
the authors characterize as ``a guideline for future investigators in
creating buccal or sublingual tablets for the delivery of [peptide]
drugs used to treat diabetes.'' For the reasons noted in our discussion
of this article in the semaglutide section, addressing similar
arguments from the nominators, we tentatively find that it provides no
basis to conclude that the routes of administration of FDA-approved
tirzepatide products make them medically unsuitable for certain
patients.
FDA has not identified a basis to conclude that the injectable
routes of administration of the FDA-approved tirzepatide products cause
those products to be medically unsuitable for certain patients and that
a compounded oral, buccal, or sublingual product would address such
attribute. For example, with respect to the argument that ``an
injectable may not be preferable'' for some patients, the
[[Page 23441]]
statutory standard for inclusion of a substance on the 503B Bulks List
is clinical need--not ``preference.'' Similarly, the potential for a
patient to experience ``discomfort'' after receiving an injection does
not mean that injectable product is medically unsuitable for the
patient.
Injectable Products
The nominators refer to ``[r]anges depending on medical provider
requests'' and list examples of such strengths. For products proposed
for the SC route of administration, the nominators provide example
concentrations of 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5
mL, 12.5 mg/0.5 mL, 15 mg/0.5 mL, 20 mg/0.5 mL, and 30 mg/0.5 mL
injection. As these concentrations are listed as examples, the
nominations do not identify each of the concentrations--and therefore
the drug products--proposed to be compounded for the SC route of
administration.
One nominator states that a different dose may be ``more suitable
for their patient in order to manage side effects and increase
adherence.'' However, the nominator does not identify alternative doses
to be delivered from the proposed compounded drug. Further, the general
statement that a different dose may be ``more suitable'' does not mean
that the available strengths of the approved product are not suitable.
Regarding the proposals to compound tirzepatide for use as an SC
injection in concentrations that exceed the concentrations of the
approved tirzepatide products (proposed concentrations of 20 mg/0.5 mL
and 30 mg/0.5 mL), the nominations do not provide supporting data or
information for the use of compounded products with a higher
concentration than the approved product. The nominations state that
patients may benefit from higher doses but do not identify higher doses
to be delivered from the proposed compounded drug product; nor do the
nominations identify patients for whom the concentrations of the FDA-
approved SC injections are medically unsuitable because a higher
concentration is needed. With respect to the assertion that ``[c]ertain
patients benefit from higher doses than are commercially available,''
even if accurate, obtaining a better response with a higher dose does
not mean that the approved product does not achieve the intended
clinical benefit or that it is otherwise medically unsuitable for
patients. The nominators have not provided a basis to conclude that
patients need the specific concentrations proposed. FDA is also not
aware of data or information that identifies patients for whom the
concentrations of the FDA-approved SC injections are medically
unsuitable.\49\
---------------------------------------------------------------------------
\49\ We note that tirzepatide was approved as both a multi-dose
vial and a single-patient-use KwikPen after the nominators submitted
their nomination. There is no information in the nominations, and
the nominators did not supplement their nominations after the
approval, to show that this approved product would be medically
unsuitable for any patient who would need a higher dose.
---------------------------------------------------------------------------
The nominators state that some patients are ``hyper-responders''
and that they may ``need a lower dose than what is commercially
available.'' One nominator states that ``hyper-responders'' are those
who are ``very sensitive'' to the drug and thus may need either a
slower titration or a lower maintenance dose, noting that only the 5
mg, 10 mg, and 15 mg weekly doses are approved for maintenance. One
nominator states that ``an auto-injector that only provides a fixed
dose does not allow for these more tailored doses.'' \50\ However, the
nominations do not explain why, if a patient requires a lower
maintenance dose, the FDA-approved products that contain a lower
concentration (i.e., 2.5 mg/0.5 mL) or smaller volumes from the vials
could not be used. The nominations also do not explain why a slower
titration using the FDA-approved products could not be used in patients
who do not tolerate dose escalation every 4 weeks.\51\ In addition, the
nominations do not provide specific lower maintenance dosages that are
different from the FDA-approved products,\52\ and they do not provide
sufficient information about the products proposed to be compounded for
FDA to assess whether the products would address the attribute, if
there were one, that makes the approved drugs medically unsuitable.
---------------------------------------------------------------------------
\50\ We note that tirzepatide is approved by FDA as single-
patient-use pens and vials.
\51\ While the ``Dosage and Administration'' section of the FDA-
approved labeling for NDA 217806 states that the recommended
maintenance dose is 5 mg, 10 mg, or 15 mg, the section also directs
prescribers to ``[c]onsider treatment response and tolerability when
selecting the maintenance dosage.'' See https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215866s009lbl.pdf.
Accessed 4/15/26.
\52\ According to the ``Dosage and Administration'' section of
the FDA-approved labeling for NDA 217806, ``[i]f patients do not
tolerate a maintenance dosage, consider a lower maintenance
dosage.'' See https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215866s009lbl.pdf. Accessed 4/15/26.
---------------------------------------------------------------------------
Multi-ingredient Products
The nominators also propose to compound tirzepatide as
``combination injectables including those doses above combined with
[p]yridoxine or an antiemetic medication.'' However, the nominations
provide no other information about the proposed compounded products, or
why they think patients would need these combinations. For example, the
nominations do not identify the drug products containing tirzepatide
and pyridoxine, or tirzepatide and ``an antiemetic,'' proposed to be
compounded.\53\ They do not even identify which antiemetic would be
included in the compounded product. Without identifying an attribute of
the approved drugs that makes them medically unsuitable (e.g., why a
patient could not receive an FDA-approved tirzepatide product and
separately an FDA-approved pyridoxine product or antiemetic), or the
product proposed to be compounded to address that attribute, we cannot
find that there is a clinical need for an outsourcing facility to
compound tirzepatide to make this multi-ingredient product.
---------------------------------------------------------------------------
\53\ Even if the nominations had provided sufficient information
to ascertain the drug product proposed to be compounded, we note
that, in general, we do not expect to find clinical need for a bulk
drug substance to compound drug products containing two or more bulk
drug substances unless: (1) combining the substances is intended to
address the medical unsuitability of the FDA-approved drug products
for certain patients and (2) the combination is likely to address a
clinical need that could not be addressed by delivering each
component of the drug product alone. Not including drug products
with two or more active ingredients on the 503B Bulks List unless
these conditions are met helps to ensure that patients are not
exposed to a drug product containing an unnecessary active
ingredient, helps avoid risks of unwanted interactions or
complications in formulation, and protects the integrity of the drug
approval process.
---------------------------------------------------------------------------
Other Issues
Regarding excipients, one nominator states that patients may have
intolerances or sensitivities to inactive ingredients in the
commercially available drug product. However, the nomination does not
identify which inactive ingredients they are referring to. Therefore,
the nominator does not identify an attribute of the approved drugs that
makes them medically unsuitable, or a compounded drug intended to
address that attribute.
One nomination also states that ``a medical professional may
determine that a different dose than is commercially available is more
suitable for their patient in order to manage side effects and increase
adherence,'' and that ``[a]n administration device, such as an auto-
injector, that only provides a fixed dose does not allow for these more
tailored doses.'' The nomination further states that ``an
administration device, such as an auto-injector, may not be suitable
for a specific patient'' and that ``an alternative container/closure
system or administration device may improve patient compliance and
safety.'' We
[[Page 23442]]
have addressed above the arguments about different strengths than the
approved products; we explained that FDA has not identified a basis to
conclude that the strengths of such products cause them to be medically
unsuitable for certain patients. To the extent the nominator is arguing
that a different container-closure device would necessitate compounding
from a bulk drug substance rather than an approved drug, that question
is inapplicable to this Part 1(a) analysis. Thus, we need not reach the
argument about use of a different container-closure to achieve
different strengths.\54\
---------------------------------------------------------------------------
\54\ We note that the nominators do not acknowledge that
tirzepatide is approved not only in auto-injectors, but also in
vials.
---------------------------------------------------------------------------
The nominators also state that tirzepatide should be added to the
503B Bulks List because FDA-approved products containing tirzepatide
are in shortage and drugs produced by outsourcing facilities are
produced in accordance with CGMP. FDA does not interpret such issues,
such as shortages and backorders, to be within the meaning of
``clinical need'' for compounding with a bulk drug substance. As noted
above, section 503B contains a separate provision for compounding from
bulk drug substances if the drug product compounded from such bulk drug
substance is on the FDA drug shortage list. We also note that as of the
date of this notice, FDA-approved tirzepatide drug products are not on
the FDA drug shortage list.\55\
---------------------------------------------------------------------------
\55\ FDA Drug Shortages Database available at https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm.
---------------------------------------------------------------------------
For these reasons, FDA tentatively finds no basis to conclude that
there is an attribute of the FDA-approved drug products containing
tirzepatide that makes them medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that the proposed compounded products are intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because there is no basis to conclude that there is an attribute of
the FDA-approved drug products containing tirzepatide which makes them
medically unsuitable to treat certain patients, FDA need not evaluate
whether the proposed drug products containing tirzepatide must be
compounded from a bulk drug substance rather than using an FDA-approved
drug product.
3. Docket Comments
To the extent relevant to the clinical need analysis, FDA has
considered the following submission to the docket regarding the
nomination of tirzepatide for the 503B Bulks List (FDA-2015-N-3469):
Eli Lilly and Company submitted a comment to the docket dated
November 4, 2024 (FDA-2015-N-3469-0404),\56\ opposing the nomination of
tirzepatide to the 503B Bulks List.
---------------------------------------------------------------------------
\56\ Available at https://www.regulations.gov/comment/FDA-2015-N-3469-0404.
---------------------------------------------------------------------------
C. Liraglutide
Liraglutide has been nominated \57\ for use in compounded drug
products as ``[a]n adjunct to diet and exercise to improve glycemic
control in adults and pediatric patients aged 10 years and older with
type 2 diabetes mellitus''; ``[t]o reduce the risk of major adverse
cardiovascular events in adults with type 2 diabetes mellitus and
established cardiovascular disease''; ``[a]s an adjunct to a reduced-
calorie diet and increased physical activity for chronic weight
management in [a]dult patients with an initial body mass index (BMI) of
30 kg/m\2\ or greater (obese), or 27 kg/m\2\ or greater (overweight) in
the presence of at least one weight-related comorbid condition (e.g.,
hypertension, type 2 diabetes mellitus, or dyslipidemia)'' and
``[p]ediatric patients aged 12 years and older with body weight above
60 kg and initial BMI corresponding to 30 kg/m\2\ for adults (obesity)
by international cut-offs.''
---------------------------------------------------------------------------
\57\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0391.
---------------------------------------------------------------------------
Liraglutide is an active ingredient in FDA-approved drug products:
18 mg/3 mL (6 mg/mL) solution for SC injection (Saxenda, NDA 206321);
18 mg/3 mL (6 mg/mL) solution for SC injection (Victoza, NDA 022341);
and 18 mg/3 mL (6 mg/mL) solution for SC injection (liraglutide 18 mg/3
mL, e.g., ANDA 215503). Each FDA-approved liraglutide product contains
propylene glycol.
Liraglutide was nominated and evaluated for the SC injection route
of administration in strengths in ``[r]anges depending on medical
provider requests'' (Ref. 9).\58\ The nomination provides an example of
one such strength.
---------------------------------------------------------------------------
\58\ The nomination provided the following examples of strengths
for injectable compounded products: 18 mg/3 mL or 6 mg/mL that
delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3 mg.
---------------------------------------------------------------------------
1. Suitability of FDA-Approved Drug Product(s)
The nominator proposes to compound an SC injection containing
liraglutide. The nominator suggests that liraglutide might also be used
to compound other drug products, but the nominator does not identify
those products. With respect to strengths to be compounded using the
bulk drug substance, the nomination refers to ``[r]anges depending on
medical provider requests.'' The nomination provides just one example
concentration of ``18 mg/3mL or 6 mg/mL that delivers doses of 0.6 mg,
1.2 mg, or 1.8 mg, 2.4 mg or 3 mg.'' This proposed concentration is the
same as that of the FDA-approved products (i.e., Saxenda, Victoza,
liraglutide 18 mg/3 mL), and the proposed doses to be delivered from
the compounded product are the same as those listed in the product
labeling for Saxenda (NDA 206321). With respect to compounded drugs
generally, the nominator states that ``a medical professional may
determine that a different dose than is commercially available is more
suitable for their patient in order to manage side effects and increase
adherence.'' However, the nominator does not state that this is the
case for liraglutide specifically. Even if the statement had been
specific to liraglutide, ``manag[ing] side effects'' and ``increas[ing]
adherence'' do not reflect an unsuitability with the approved products.
Nor did the nomination identify a product proposed to be compounded;
the nomination does not identify the ``different dose[s]'' referenced
in this statement.
After reviewing the nominations and comments to the docket, we
tentatively find no basis to conclude that the strength of FDA-approved
liraglutide products makes them medically unsuitable for certain
patients. The nomination has not provided a basis to conclude that
strength of the approved products is an attribute that makes them
medically unsuitable to treat certain patients; the only proposed
strength the nominator provides is the same as the FDA-approved drugs.
Nor has the nominator identified the drug products proposed to be
compounded; the nominator has provided only one example of a strength.
Vague statements that a healthcare provider may determine that a
different dose is needed for side effects and improved patient
adherence, without identifying the dose, patients, or any attribute
that makes the approved drugs unsuitable for such patients, do not
establish clinical need.\59\
---------------------------------------------------------------------------
\59\ We acknowledge a nominator's comment (FDA-2024-P-5966-0003)
stating that ``microdosing trends have been widely documented and
allow for hypersensitive patients otherwise intolerant to standard
doses to continue treatment,'' citing an article published in the
New York Times. However, the New York Times article does not include
any data or information to support the position that the FDA-
approved product could not be used to obtain lower doses or that it
is otherwise medically unsuitable. In assessing clinical need, we
consider, in part, whether there is a basis to conclude that an
attribute of the FDA-approved product makes it medically
unsuitable--not whether the approved product in fact meets medical
needs. Nor does the clinical need analysis turn on information about
general ``trends'' without identifying patients for whom the
approved drug would be medically unsuitable.
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[[Page 23443]]
The nominator also proposes to compound liraglutide products
without certain excipients. The nominator states that ``[a]n individual
patient may have intolerances or sensitivities to inactive ingredients
in the commercially available drug product,'' but does not identify
which inactive ingredients they are referring to. Therefore, the
nominator does not identify an attribute of the approved drugs that
makes them medically unsuitable, or a compounded drug intended to
address that attribute.
The nominator notes that ``FDA-approved liraglutide injections
indicated for type 2 diabetes contain propylene glycol, which has
caused an increase in irritation at the injection site.'' The
nomination further states that ``[s]ince there are no commercially
available forms of liraglutide that do not contain propylene glycol,
patients with sensitivities to propylene glycol will benefit from
compounds formulated without it.'' Even if this were accurate, the
notion that a patient ``will benefit'' from a compounded formulation
does not mean that the approved formulation is medically unsuitable.
The nominator submitted one article, Snitker et al. (2022), that
evaluated the injection-site experience of two formulations of
semaglutide, semaglutide C and semaglutide D, compared to semaglutide
MPI \60\ This article, which did not evaluate liraglutide, does not
appear to support the nominator's position. The article does not, as
the nominator claims, find that ``95% of patients preferred the
formulation without propylene glycol.'' When comparing semaglutide D,
the formulation that did not contain propylene glycol, with semaglutide
MPI, a formulation that contains propylene glycol, the authors
concluded that ``[t]he injection-site experience with semaglutide D was
almost indistinguishable from semaglutide MPI . . . with either product
associated with no or very mild injection-site pain.'' Additionally, as
discussed above, ``patient preference'' for a different formulation
than the approved drug does not mean that the formulation of the
approved drug is medically unsuitable.
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\60\ Semaglutide C is a single-dose pen injector that does not
contain phenol and contained a higher concentration (1.9%) of
propylene glycol than the semaglutide MPI. This formulation is not
similar to any formulation approved in the United States.
Semaglutide D is a single-dose pen injector that does not contain
phenol and contained sodium chloride instead of propylene glycol.
This formulation is similar to the formulation of FDA-approved
Wegovy. Semaglutide MPI contains phenol and propylene glycol. This
formulation is similar to the formulation of FDA-approved Ozempic.
The authors stated that this formulation is ``a benchmark for low
injection-site pain.''
---------------------------------------------------------------------------
A search of the FAERS database identified numerous reports
associated with liraglutide and injection site reactions occurring in
both Victoza and Saxenda users. The search did not retrieve any reports
of liraglutide and injection site reactions with a case narrative
containing ``propylene.'' \61\ FDA has not identified any data or
information to suggest that propylene glycol would cause a drug product
containing liraglutide to be medically unsuitable. Injection site
reaction is an adverse event reported in trials with various injectable
therapeutic products, including other anti-hyperglycemic products not
formulated with propylene glycol (e.g., insulin products, other GLP-1
receptor agonists, tirzepatide). Additionally, all FDA-approved
liraglutide injections are labeled for injection site reactions.\62\
The data and information do not suggest that a formulation without
propylene glycol would mitigate the skin irritation that can be
associated with subcutaneously injected therapies such as liraglutide.
Additionally, the notion that a patient ``will benefit'' from a
compounded formulation does not mean that the approved formulation is
medically unsuitable. FDA has not identified any data or information
discussing patients for whom propylene glycol would cause a drug
product containing liraglutide to be medically unsuitable.\63\
---------------------------------------------------------------------------
\61\ It is important to note that FAERS data have limitations.
First, there is no certainty that the reported adverse event was due
to the suspect product. FDA does not require that a causal
relationship between a product and event be proven, and the report
may not always contain enough detail to properly evaluate an event.
\62\ Refer to the ``Adverse Reactions'' section of the FDA-
approved labeling for, e.g., NDA 022341 and NDA 206321, available at
https://fdalabel.fda.gov/fdalabel-r/services/spl/set-ids/5a9ef4ea-c76a-4d34-a604-27c5b505f5a4/spl-doc and https://fdalabel.fda.gov/fdalabel-r/services/spl/set-ids/3946d389-0926-4f77-a708-0acb8153b143/spl-doc. Accessed 3/23/26.
\63\ We note that injection site reaction is an adverse event
reported in trials with various injectable therapeutic products,
including other anti-hyperglycemic products not formulated with
propylene glycol (e.g., insulin products, other GLP-1 receptor
agonists, tirzepatide). These data and information do not suggest
that a formulation without propylene glycol would mitigate the skin
irritation that can be associated with subcutaneously injected
therapies such as liraglutide.
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The nomination also states that liraglutide might be used to
compound drug products in different container-closure devices. The
nomination states that use of an alternative container-closure system
or administration device ``may improve patient compliance and safety.''
To the extent the nominator is arguing that a different container-
closure device would necessitate compounding from a bulk drug substance
rather than an approved drug, that question is inapplicable to this
Part 1(a) analysis. With respect to the nominator's statement about
``improve[d] patient compliance and safety,'' the nominator does not
identify an attribute of the approved products that makes them
medically unsuitable.
For these reasons, FDA tentatively finds no basis to conclude that
there is an attribute of the FDA-approved drug products containing
liraglutide that makes them medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that the proposed compounded products are intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because there is no basis to conclude that there is an attribute of
the FDA-approved drug products containing liraglutide which makes them
medically unsuitable to treat certain patients, FDA need not decide
whether the proposed drug products containing liraglutide must be
compounded from a bulk drug substance rather than using an FDA-approved
drug product.
3. Docket Comments
To the extent relevant to the clinical need analysis, FDA has
considered the following submissions to the docket regarding the
nomination of liraglutide for the 503B Bulks List (FDA-2015-N-3469):
Covington & Burling LLP on behalf of NNI submitted a comment dated
December 20, 2024 (FDA-2015-N-3469-0407),\64\ opposing the nomination
of liraglutide to the 503B Bulks List. The comment enclosed a citizen
petition from Covington & Burling LLP on behalf of NNI (FDA-2024-P-
5966-0001).65 66
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\64\ Available at https://www.regulations.gov/comment/FDA-2015-N-3469-0407.
\65\ Available at https://www.regulations.gov/document/FDA-2024-P-5966-0001.
\66\ For purposes of this clinical need evaluation, we address
the arguments from the petition that are directly relevant to the
clinical need analysis, including those that engage with arguments
in the nomination. We also note that this preliminary Federal
Register notice does not reflect a final Agency decision on any of
the arguments raised in the petition. FDA is issuing the preliminary
Federal Register notice to seek public comment on the issues raised
in the nominations and comments to the docket, including relevant
portions of the petition that was enclosed in NNI's comment. FDA's
final decision on those issues will be reflected in the final
Federal Register notice and response to the petition. FDA intends to
issue the response to the petition concurrently with the Federal
Register notice setting forth FDA's final decision about whether
liraglutide will be added to the 503B Bulks List.
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[[Page 23444]]
OFA submitted a comment on March 17, 2025 (FDA-2024-P-5966-
0003),\67\ responding to arguments made in the citizen petition.
Covington & Burling LLP on behalf of NNI submitted a supplement to its
earlier comment on June 17, 2025 (FDA-2024-P-5966-0005),\68\ responding
to OFA's comments.
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\67\ Available at https://www.regulations.gov/document/FDA-2024-P-5966-0003.
\68\ Available at https://www.regulations.gov/document/FDA-2024-P-5966-0005.
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IV. Conclusion
For the reasons stated above, FDA tentatively finds no basis to
conclude that there is a clinical need for an outsourcing facility to
compound using the following bulk drug substances: semaglutide,
tirzepatide, and liraglutide. Therefore, we propose not to include
these bulk drug substances on the 503B Bulks List.
V. 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 https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov 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. Although FDA verified the website addresses
in this document, please note that websites are subject to change over
time.
* 1. FDA Memorandum to File, ``Clinical Need Evaluation for
Semaglutide in Compounding Under Section 503B of the Federal Food,
Drug, and Cosmetic Act,'' April 2026.
2. Pratap-Singh, A, Y Guo, A Baldelli and A Singh, 2023, Concept for
a Unidirectional Release Mucoadhesive Buccal Tablet for Oral
Delivery of Antidiabetic Peptide Drugs Such as Insulin, Glucagon-
Like Peptide 1 (GLP-1), and their Analogs, Pharmaceutics,
15(9):2265.
3. Wilding, JPH, RL Batterham, S Calanna, M Davies, LF Van Gaal, I
Lingvay, BM McGowan, J Rosenstock, MTD Tran, TA Wadden, S Wharton, K
Yokote, N Zeuthen and RF Kushner for the STEP 1 Study Group, 2021,
Once-Weekly Semaglutide in Adults with Overweight or Obesity, N Engl
J Med, 384(11):989-1022.
4. Blum, D, 2024, The Allure of `Microdosing' Ozempic, The New York
Times, available at https://www.nytimes.com/2024/12/05/well/ozempic-microdose-weight-loss.html.
5. Aroda, VR, J Aberle, L Bardtrum, E Christiansen, FK Knop, S
Gabery, SD Pedersen and JB Buse, 2023, Efficacy and Safety of Once-
Daily Oral Semaglutide 25 mg and 50 mg Compared with 14 mg in Adults
with Type 2 Diabetes (PIONEER PLUS): A Multicentre, Randomised,
Phase 3b Trial, Lancet, 402(10403):693-704.
6. Knop, FK, VR Aroda, RD do Vale, T Holst-Hansen, PN Laursen, J
Rosenstock, DM Rubino and WT Garvey for the OASIS 1 Investigators,
2023, Oral Semaglutide 50 mg Taken Once per Day in Adults with
Overweight or Obesity (OASIS 1): A Randomised, Double-Blind,
Placebo-Controlled, Phase 3 Trial, Lancet, 402(10403):705-719.
7. Snitker, S, A Andersen, PS Lindskov, S van Marle, BF Sode and T
Sparre, 2022, Comparison of the Injection-Site Experience of
Semaglutide in a Single-Dose and a Multidose Pen-Injector, Diabetes
Obes Metab, 24(8):1643-1646.
* 8. FDA Memorandum to File, ``Clinical Need Evaluation for
Tirzepatide in Compounding Under Section 503B of the Federal Food,
Drug, and Cosmetic Act,'' April 2026.
* 9. FDA Memorandum to File, ``Clinical Need Evaluation for
Liraglutide in Compounding Under Section 503B of the Federal Food,
Drug, and Cosmetic Act,'' April 2026.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-08552 Filed 4-30-26; 8:45 am]
BILLING CODE 4164-01-P