Federal Register, Volume 86 Issue 55 (Wednesday, March 24, 2021)

[Federal Register Volume 86, Number 55 (Wednesday, March 24, 2021)]
[Notices]
[Pages 15673-15682]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-06060]

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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 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 or Agency) is developing
a list of bulk drug substances (active pharmaceutical ingredients) for
which there is a clinical need (the 503B Bulks List). Drug products
that outsourcing facilities compound using bulk drug substances on the
503B Bulks List can qualify for certain exemptions from the Federal
Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are
met. This notice identifies one bulk drug substance that FDA has
considered and proposes to include on the 503B Bulks List: Quinacrine
hydrochloride (``quinacrine''). This notice identifies four bulk drug
substances that FDA has considered and proposes not to include on the
list: Bromfenac sodium, mitomycin-C, nepafenac, and hydroxychloroquine
sulfate. Additional bulk drug substances nominated by the public for
inclusion on this list are currently under consideration and may be the
subject of future notices.

[[Page 15674]]

DATES: Submit either electronic or written comments on the notice by
May 24, 2021.

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 May 24, 2021. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of May 24, 2021. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
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: Elizabeth Hankla, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5216, Silver Spring, MD 20993, 240-402-
3359.

SUPPLEMENTARY INFORMATION:

I. Background

Section 503B of the FD&C Act (21 U.S.C. 353b) describes the
conditions that must be satisfied for drug products compounded 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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Drug products compounded 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) with
section 503B(a) of the FD&C Act (not providing the 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 exemptions under
section 503B of the FD&C Act is that the outsourcing facility may not
compound a drug using a bulk drug substance unless: (1) The bulk drug
substance appears on a list established by the Secretary of Health and
Human Services identifying bulk drug substances for which there is a
clinical need (the 503B Bulks List) or (2) the drug compounded from
such bulk drug substances 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

[[Page 15675]]

calendar days for comment on the notice; and (3) publishing a notice in
the Federal Register designating bulk drug substances for inclusion on
the list.\6\
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\6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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FDA has published a series of Federal Register notices addressing
bulk drug substances nominated for inclusion on the 503B Bulks List.\7\
This notice identifies one bulk drug substance that FDA has considered
and proposes to include on the 503B Bulks List and four 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), and July 31,
2020 (85 FR 46126). The comment period for the July 2020 notice was
reopened for 30 days on January 8, 2021 (86 FR 1515), to allow
interested parties an additional opportunity to comment. FDA has not
yet reached a final determination on whether the substances
evaluated in the September 2019 or July 2020 notice will be added to
the 503B Bulks List. In addition, bumetanide, which was considered
in the August 2018 notice remains under consideration by the Agency.
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For purposes of section 503B of the FD&C Act, bulk drug substance
means an active pharmaceutical ingredient as defined in 21 CFR
207.1.\8\ Active pharmaceutical ingredient means any substance that is
intended for incorporation into a finished drug product and is intended
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body, but the term does not
include intermediates used in the synthesis of the
substance.^{9 10}
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\8\ 21 CFR 207.3.
\9\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
\10\ Inactive ingredients are not subject to section 503B(a)(2)
of the FD&C Act and will not be included in the 503B Bulks List
because they are not included within the definition of a bulk drug
substance. Pursuant to section 503B(a)(3) of the FD&C Act, inactive
ingredients used in compounding must comply with the standards of an
applicable U.S. Pharmacopeia (USP) or National Formulary monograph,
if a monograph exists.
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For further information about drug compounding and the background
for the 503B Bulks List, see 83 FR 43877 (August 28, 2018).

II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

FDA requested nominations for specific bulk drug substances for the
Agency to consider for inclusion on the 503B Bulks List in the Federal
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination
process in the Federal Register of July 2, 2014 (79 FR 37747), and
provided more detailed information on what FDA needs to evaluate
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency
opened a new docket, FDA-2015-N-3469, to provide an opportunity for
interested persons to submit new nominations of bulk drug substances or
to renominate substances with sufficient information.
As FDA evaluates bulk drug substances, it intends to publish
notices for public comment in the Federal Register that describe the
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 its determination, and if so, it will
seek PCAC input.\12\ Depending on its review of the docket comments and
other relevant information before the Agency, FDA may finalize its
proposed determination without change, or it may finalize a
modification to its proposal to reflect new evidence or analysis
regarding clinical need. FDA will then publish in the Federal Register
a list identifying the bulk drug substances for which it has determined
there is a clinical need and FDA's rationale in making that final
determination. FDA will also publish in the Federal Register a list of
those substances it considered but found that there is no clinical need
to use in compounding and FDA's rationale in making this decision.
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\11\ This is consistent with 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 a 503B Bulks List.
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FDA intends to maintain a list of all bulk drug substances it has
evaluated on its website, and separately identify bulk drug substances
it has placed on the 503B Bulks List and those it has decided not to
place on the 503B Bulks List. This list is available at https://www.fda.gov/media/120692/download. FDA will only place a bulk drug
substance on the 503B Bulks List where it has determined there is a
clinical need for outsourcing facilities to compound drug products
using the bulk drug substance. If a clinical need to compound drug
products using the bulk drug substance has not been demonstrated, based
on the information submitted by the nominator and any other information
considered by the Agency, FDA will not place a bulk drug substance on
the 503B Bulks List.
FDA is evaluating bulk drug substances nominated for the 503B Bulks
List on a rolling basis. FDA intends to evaluate and publish in the
Federal Register its proposed and final determinations in groups of
bulk drug substances until all nominated substances that were
sufficiently supported have been evaluated and either placed on the
503B Bulks List or identified as bulk drug substances that were
considered but determined not to be appropriate for inclusion on the
503B Bulks List (Ref. 1).\13\
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\13\ On January 13, 2017, FDA announced the availability of a
revised final guidance for industry that provides additional
information regarding FDA's policies for bulk drug substances
nominated for the 503B Bulks List pending our review of nominated
substances under the ``clinical need'' standard entitled Interim
Policy on Compounding Using Bulk Drug Substances Under Section 503B
of the Federal Food, Drug, and Cosmetic Act'' (``Interim Policy'');
available at https://www.fda.gov/media/94402/download.
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B. Analysis of Substances Nominated for the List

As noted above, the 503B Bulks List will include bulk drug
substances for which there is a clinical need. The Agency is currently
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 (Ref. 2).\14\ In applying this
standard to develop the proposals in this notice, FDA is interpreting
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 is not interpreting supply issues, such as
backorders, to be within the meaning of ``clinical need'' for
compounding with a bulk drug substance. Section 503B separately
provides for compounding from bulk drug substances under the exemptions
from the FD&C Act

[[Page 15676]]

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, we are not considering cost
of the compounded drug product as compared with an FDA-approved drug
product to be within the meaning of ``clinical need.''
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\14\ On March 4, 2019, FDA announced the availability of a final
guidance entitled ``Evaluation of Bulk Drug Substances Nominated for
Use in Compounding Under Section 503B of the Federal Food, Drug, and
Cosmetic Act'' (84 FR 7390); available at https://www.fda.gov/media/121315/download. 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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Some of the bulk drug substances that we are addressing in this
notice are components of FDA-approved drug products,\15\ and we
therefore began our evaluation of these bulk drug substances by asking
one or both of the following questions:
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\15\ Specifically, bromfenac sodium, mitomycin-C, nepafenac, and
hydroxychloroquine sulfate.
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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 is medically unsuitable for certain patients, and a drug
product compounded using a bulk drug substance that is a component of
the 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.
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. 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 compounding starting
with an approved drug product. FDA did not answer ``yes'' to both of
the threshold questions for the four bulk drug substances that are
components of approved drug products that we are addressing in this
notice. Accordingly, as explained further below, we did not proceed
further in our evaluation of these substances and are proposing not to
include them on the 503B Bulks List.
With respect to one bulk drug substance we are addressing in this
notice that is not a component of an FDA-approved drug product,
quinacrine, we are conducting a balancing test with four factors,
considering each factor in the context of the others and balancing them
to determine whether the statutory ``clinical need'' standard has been
met. The balancing test includes the following factors:
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.
The discussion below reflects FDA's consideration of these four
factors where they are applicable and describes how they were applied
to develop FDA's proposal to include one bulk drug substance on the
503B Bulks List.

C. Inclusion of a Bulk Drug Substance on the 503B Bulks List

In preparing its proposal to include a substance on the 503B Bulks
List, FDA considered whether the clinical need for the bulk drug
substance in the compounded drug product is limited, by, for example,
route of administration or dosage form. As appropriate, and as
explained further below, the Agency tailored its proposed entry on the
503B Bulks List to reflect its findings related to clinical need for
the bulk substance proposed for inclusion on the list. Specifically,
the proposed entry would authorize use of this bulk drug substance to
compound drug products for oral use only.\16\
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\16\ FDA requested comments on the proposal to limit listings in
this manner in notice of July 31, 2020 (85 FR 46126). The comment
period for the July 2020 notice was reopened for 30 days on January
8, 2021 (86 FR 1515), to allow interested parties an additional
opportunity to comment. The Agency has not finished evaluating the
comments received on this proposal, and we intend to take all
comments on this issue into consideration in developing our final
approach to listing substances on the 503B Bulks List.
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III. Substance Considered and Proposed for Inclusion on the 503B Bulks
List

Because the substance in this section is not a component of an FDA-
approved drug product, we applied the balancing test described above.
The bulk drug substance that has been evaluated and that FDA is
proposing to place on the 503B Bulks List is quinacrine HCl. The
reasons for FDA's proposal is included below (Ref. 3).\17\
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\17\ In addition to FDA's quinacrine nomination for the 503B
Bulks List, the Agency considered data and information from its
earlier evaluation regarding the use of this bulk drug substance for
the list of bulk drug substances that can be used in compounding
under section 503A of the FD&C Act (the 503A Evaluation). See
Appendices A-D in ``FDA Memo to File, Clinical Need for Quinacrine
Hydrochloride in Compounding Under Section 503B of the FD&C Act''
(Ref. 3). FDA also considered a report provided by the University of
Maryland Center of Excellence in Regulatory Science and Innovation
and conducted a search for relevant scientific literature and safety
information, focusing on materials published or submitted to FDA
since the 503A Evaluations (see Appendix H in Ref. 3).
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Quinacrine

FDA nominated quinacrine as a bulk drug substance for the 503B
Bulks List to compound drug products in oral dosage forms at strengths
of 25-100 milligram (mg) for the treatment of cutaneous lupus
erythematosus (CLE).\18\ The nominated bulk drug substance is not a
component of an FDA-approved drug product. We evaluated quinacrine for
potential inclusion on the 503B Bulks List under the clinical need
standard in section 503B of the FD&C Act, considering data and
information regarding the physical and chemical characterization of
quinacrine, safety issues raised by use of this substance in
compounding, available evidence of effectiveness or lack of
effectiveness, and historical and current use in compounding (Ref. 3).
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\18\ See Appendix G in Ref. 3.
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Quinacrine is well-characterized physically and chemically.
Although there are concerns about its safety profile in certain patient
populations, we believe these risks are well known within the
rheumatology and dermatology specialties that most often treat CLE, and
the known risks could be

[[Page 15677]]

controlled with appropriate dosing and monitoring. Quinacrine has been
used for several decades to treat systemic lupus erythematosus and CLE,
and there is a significant body of experience, documented in the
scientific literature, that quinacrine may be effective in the
treatment of patients with cutaneous lupus, and patients who are not
fully clinically responsive to, or are intolerant of, treatment with
FDA approved products alone. These patients may respond to the addition
of quinacrine to their existing therapy, or to the use of quinacrine
alone. On balance, the physical and chemical characterization, safety,
effectiveness, and historical and current use of quinacrine weigh in
favor of including this substance on the 503B Bulks List. Accordingly,
we propose adding quinacrine to the 503B Bulks List for oral use only.
We have not identified sufficient evidence to support its use in other
routes of administration.
Due to the safety risks referred to above, if quinacrine is placed
on the 503B Bulks List, FDA intends to make safety information about
the use of quinacrine available to prescribers, pharmacists,
outsourcing facilities, and the public through information on FDA's
website, in a safety guide, or through other mechanisms, as
appropriate.

IV. Substances Evaluated and Not Proposed for Inclusion on the 503B
Bulks List

Because the substances in this section are components of FDA-
approved drug products, we considered one or both of the following
questions: (1) Is there is a basis to conclude that an attribute of
each FDA-approved drug product containing the bulk drug substance makes
each one medically unsuitable to treat certain patients for a condition
that FDA has identified for evaluation, and the drug product proposed
to be compounded is intended to address that attribute and (2) is there
a basis to conclude that the drug product proposed to be compounded
must be compounded using a bulk drug substance.
The four bulk drug substances that have been evaluated and that FDA
is proposing not to place on the list are as follows: Bromfenac sodium,
mitomycin-C, nepafenac, and hydroxychloroquine sulfate. The reasons for
FDA's proposals are included below.

A. Bromfenac Sodium

Bromfenac sodium was nominated in combination with moxifloxacin
hydrochloride and prednisolone for inclusion on the 503B Bulks List to
compound drug products for postoperative inflammation and pain
following cataract surgery.\19\ The proposed route of administration is
ophthalmic, the proposed dosage forms are an ophthalmic injection \20\
and a topical ophthalmic solution,\21\ and the proposed compounded
product is prednisolone-moxifloxacin-bromfenac (1-0>.5/0.4 percent).
The nominated bulk drug substance, bromfenac sodium, is a component of
FDA-approved drug products (e.g., ANDA 203395, NDA 206911, and NDA
203168). FDA has approved bromfenac sodium products as 0.07 percent,
0.075 percent, and 0.09 percent EQ \22\ acid ophthalmic solution.\23\
\24\ The nomination proposes to combine bromfenac sodium with two other
bulk drug substances, moxifloxacin hydrochloride and prednisolone, both
of which are components of FDA-approved products. Prednisolone acetate
\25\ is a component of FDA-approved drug products (NDA 017469 and NDA
017011) \26\ \27\ and is available in a 1 milliliter (mL), 5 mL, 10 mL,
and 15 mL suspension containing prednisolone acetate 1.0 percent.
Moxifloxacin hydrochloride is a component of FDA-approved drug products
(e.g., NDA 021598 and NDA 022428) \28\ \29\ and is available as an EQ
0.5 percent base ophthalmic solution.
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\19\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0004. We assume ``bromfenac'' as used in the nomination refers
to bromfenac sodium. The nominator did not nominate moxifloxacin
hydrochloride or prednisolone separately.
\20\ We assume ``injection'' as used in the nomination refers to
ophthalmic injection.
\21\ The nominator did not specify whether they propose to make
an ophthalmic solution or an ophthalmic suspension. We only
considered ophthalmic solutions for this review because ``[a]ll drug
products containing bromfenac sodium (except ophthalmic solutions)''
is on the list of ``Drug products withdrawn or removed from the
market for reasons of safety or effectiveness,'' codified at 21 CFR
216.24 and available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=216.24, and should not be used in
compounding.
\22\ EQ refers to the equivalent strength of the active moiety.
See https://www.fda.gov/drugs/development-approval-process-drugs/orange-book-preface.
\23\ See, e.g., ANDA 203395 labeling available as of the date of
this notice at http://fdalabel.fda.gov/fdalabel-r/services/spl/set-ids/e853723e-8419-4444-89e9-ee3f571b0974/spl-doc.
\24\ See, e.g., NDA 206911 labeling available as the date of
this notice at https://www.accessdata.fda.gov/spl/data/3ae02266-5a0f-4bf2-bc68-ae1c7d2f5239/3ae02266-5a0f-4bf2-bc68-ae1c7d2f5239.xml.
\25\ The nomination did not specify which prednisolone active
pharmaceutical ingredient (API) is proposed to be included in their
combination. There are several approved ophthalmic formulations of
prednisolone acetate or prednisolone sodium phosphate in combination
with anti-infectives. The only single ingredient 1% suspension
approved for ophthalmic use is prednisolone acetate. It is approved
under two separate NDAs, 017469 as OMNIPRED and 017011 as Pred-
Forte[supreg]. OMNIPRED is available as 5 mL and 10 mL and Pred-
Forte[supreg] is available in 1 mL, 5 mL, 10 mL, and 15 mL
suspension containing prednisolone acetate 1.0%.
\26\ See, e.g., NDA 017011 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/3fbf3327-59a2-4e6e-9e43-4f63ea23d54e/3fbf3327-59a2-4e6e-9e43-4f63ea23d54e.xml.
\27\ See, e.g., NDA017469 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/00c60dec-b63c-43ac-9f87-88aeff333136/00c60dec-b63c-43ac-9f87-88aeff333136.xml.
\28\ See, e.g., NDA 021598 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/f9febc6f-db6d-44e8-9730-f7c1a2354d71/f9febc6f-db6d-44e8-9730-f7c1a2354d71.xml.
\29\ See, e.g., NDA 022428 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/41ea7ffb-02e7-44bd-8ec6-6d4c8e116b99/41ea7ffb-02e7-44bd-8ec6-6d4c8e116b99.xml.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nomination does not identify a medical unsuitability in any of
the FDA-approved products that contain bromfenac, prednisolone, or
moxifloxacin hydrochloride when these products are administered
separately. Instead, it states that the single active-ingredient
formulation of these products may make them unsuitable for co-
administration after ocular surgeries. Specifically, the nomination
states that ``Compounded formulations may alleviate the need for
multiple postoperative drops. Topical compounded formulations also may
improve patient compliance and alleviate patient confusion because they
typically require use of fewer drops.''
However, the labeling for the FDA-approved bromfenac sodium
products (e.g., ANDA 203395) specifically warns against the use of
bromfenac sodium with topical corticosteroids, which include
prednisolone. This is because the use of bromfenac sodium with topical
corticosteroids may increase the potential for healing problems.\30\
The nomination does not address this warning or provide support for the
co-administration of these drug products. We decline to find that the
approved drugs are medically unsuitable for some patients because they
may be difficult to administer to patients under circumstances that are
specifically

[[Page 15678]]

warned against in the approved labeling.
---------------------------------------------------------------------------

\30\ According to the ``Warnings and Precautions'' section of
the FDA-approved labeling for ANDA 203395, ``All topical
nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay
healing. Topical corticosteroids are also known to slow or delay
healing. Concomitant use of topical NSAIDs and topical steroids may
increase the potential for healing problems.'' See http://fdalabel.fda.gov/fdalabel-r/services/spl/set-ids/e853723e-8419-4444-89e9-ee3f571b0974/spl-doc.
---------------------------------------------------------------------------

Because co-administration of these products is the subject of a
labeled warning, and therefore an inappropriate basis for a finding of
clinical need, we do not evaluate the nomination's claims further.
However, to help explain our thinking about this nomination and inform
public comment, we address the nomination's statement that there is a
clinical need to compound a drug containing multiple active ingredients
because it may improve patient compliance relative to prescribing FDA-
approved drugs that contain a single active ingredient. The nomination
does not state that the approved drugs would be medically unsuitable
for some patients for the conditions identified in the nomination, and
it does not provide data or evidence to support that proposition.
Reducing the number of drugs administered for the purpose of
convenience is not ``clinical need''; medical unsuitability of the
approved drugs is required. While clinical need does not have to be
fully established in FDA's analysis of questions 1 and 2, there must be
a basis to conclude that such a need may exist before FDA will proceed
to the more searching analysis conducted under the balancing test. No
such basis is present here.\31\
---------------------------------------------------------------------------

\31\ 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.
---------------------------------------------------------------------------

Accordingly, with respect to the bromfenac sodium drug products
proposed to be compounded by the nominator, FDA finds no basis to
conclude that there is an attribute of each of the FDA approved drug
products that makes each one medically unsuitable to treat certain
patients who undergo cataract surgery. There is therefore no attribute
of the approved drug products that the proposed compounded drug
products are intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because we have not identified a population for whom the approved
products are medically unsuitable for the proposed uses under question
1, we are not considering whether there is a basis to conclude that the
drug products proposed to be compounded must be produced from a bulk
drug substance rather than from an FDA-approved drug product under
question 2.
3. Additional Comments
For the reasons stated above, we are not evaluating this nomination
under the balancing test. However, if this nomination for bromfenac
sodium was to proceed to the balancing test, there would be some
significant safety and effectiveness concerns to evaluate, which are
not addressed in the nomination.
Each of the three ingredients proposed to be used in combination by
the nomination is indicated for different medical conditions and has a
different FDA-approved dosing regimen: Once daily for bromfenac sodium
0.09 percent,\32\ four times daily for prednisolone acetate \33\ and
three times daily for moxifloxacin hydrochloride.\34\ The duration of
treatment for each individual drug also differs.
---------------------------------------------------------------------------

\32\ Bromfenac sodium EQ 0.09% acid solution (e.g., ANDA 203395)
should be applied to the affected eye once daily beginning 1 day
prior to cataract surgery, continued on the day of surgery, and
through the first 14 days of the postoperative period.
\33\ Two drops topically in the eye(s) four times daily (e.g.,
NDA 017469).
\34\ Instill one drop in the affected eye 3 times a day for 7
days (e.g., NDA 021598).
---------------------------------------------------------------------------

The nomination also describes compounding drug products that
include bromfenac sodium in a concentration (EQ 0.4 percent acid) \35\
that is more than four times higher than the FDA-approved product (the
approved product is available at concentrations of EQ 0.07 percent
acid, EQ 0.075 percent acid, and EQ 0.09 percent acid). The nomination
does not provide any data or information supporting the need for a
higher concentration than the approved drug.
---------------------------------------------------------------------------

\35\ The nomination states ``0.4%.'' We assume the nominator
intended a concentration of EQ 0.4% acid.
---------------------------------------------------------------------------

Most of the bulk drug substance nominations FDA has evaluated to
date have only proposed to compound drug products containing a single
active ingredient. This nomination proposed to compound drug products
containing more than one active ingredient. If FDA finalizes its
proposal not to include bromfenac sodium on the 503B Bulks List, we
intend to remove the substance from Category 1 for purposes of the
Interim Policy, which would mean that ophthalmic solutions compounded
using the bulk drug substance bromfenac sodium, including the proposed
compounded products addressed in this notice, would fall outside the
enforcement discretion described in the Interim Policy. We note that
FDA's evaluation of bromfenac sodium for inclusion on the 503B Bulks
List will not impact FDA's evaluation of any other bulk drug substances
for inclusion on the 503B Bulks List, including prednisolone and
moxifloxacin hydrochloride, because each bulk drug substance nominated
for inclusion on the 503B Bulks List undergoes its own evaluation. We
previously proposed not to include moxifloxacin hydrochloride on the
503B Bulks List (85 FR 46126), and we are currently reviewing comments
on that nomination. Nominations for prednisolone, if they are not
withdrawn, remain the subject of future evaluations. Finally, if FDA
determines there is a clinical need for outsourcing facilities to use
bulk drug substances to compound the proposed drug products, we would
include each substance or combination of substances, as appropriate, on
the 503B Bulks List at the time that final determination is made.

B. Mitomycin-C

Mitomycin-C was nominated for inclusion on the 503B Bulks List to
compound drug products that treat stomach, pancreas, anal
(nonmetastatic), bladder, cervical (recurrent or metastatic),
esophageal, gastric, and non-small cell lung cancer.\36\ The proposed
route of administration is injection and the proposed concentration is
20-40 mg. We evaluated the proposed products for both the intravenous
and intravesical routes of administration because the nomination
proposed that there is a need for a compounded mitomycin-C drug product
for injection and we understand that mitomycin-C is used for both
intravesical and intravenous administration in certain oncological
conditions. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDA 064144, NDA 022572, and NDA
211728).\37\ FDA-approved mitomycin-C

[[Page 15679]]

(e.g., ANDA 064114) is available as a 5, 20, and 40 mg/mL vial for
intravenous administration.\38\ Mitomycin is also approved as a 0.2 mg
vial, which when reconstituted with Sterile Water for Injection,
provides a solution for application in glaucoma filtration surgery for
use as an adjunct to ab externo glaucoma surgery (e.g., NDA 022572).
---------------------------------------------------------------------------

\36\ See Docket No.FDA-2013-N-1524, document no. FDA-2013-N-
1524-2219.
\37\ Jelmyto, NDA 211728 was approved on April 15, 2020, as a 40
mg/vial powder for pyelocaliceal administration for the treatment of
adult patients with low-grade Upper Tract Urothelial Cancer (LG-
UTUC). Jelmyto has not been considered in this memorandum because of
the complex nature of the approved product and the fact that there
is a more appropriate comparator approved drug product (mitomycin as
a 5, 20, and 40 mg vial for solution for intravenous
administration). While the nominated dosage form is unclear
(``injection''), we assume that the nominator intended to nominate a
solution or a powder for solution for intravesical administration
(not, as Jelmyto is, a gel for pyelocaliceal administration).
\38\ See, e.g., ANDA 064144 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/55ab68d0-c46a-2f41-e054-00144ff88e88/55ab68d0-c46a-2f41-e054-00144ff88e88.xml. When reconstituted with Sterile Water for
Injection, ANDA 064144, and other ANDAs like it, provide a solution
for intravenous administration for therapy of disseminated
adenocarcinoma of the stomach or pancreas in proven combinations
with other approved chemotherapeutic agents and as palliative
treatment when other modalities have failed.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
Regarding the proposed use to treat bladder cancer, the nomination
does not explain why an attribute of each of the FDA-approved 5, 20,
and 40 mg vials of lyophilized powder for reconstituting into solution
is medically unsuitable for the proposed use. For example, if there are
patients for whom products for intravenous administration would be
medically unsuitable, the nomination does not provide support or
explain why the FDA-approved products, or products prepared using the
FDA-approved products could not be used for intravesical
administration.\39\ The nomination states that it may be necessary to
compound a mitomycin-C drug product to attain a ``higher, more
efficacious dose,'' but the nomination does not identify any specific
higher concentrations that the nominator proposes to compound. The
approved product is available as a lyophilized powder, which according
to the approved labeling, is reconstituted to a final concentration of
0.5 mg/mL or below.\40\ While the nomination includes two articles
which indicate that there could be a need for a product with a
concentration above 0.5 mg/mL,\41\ the nomination does not identify an
attribute of the FDA-approved products that makes them medically
unsuitable to treat certain patients and that the proposed compounded
drug products are intended to address. Further, the nomination proposes
to ``include excipients to prevent urine acidification,'' but the
nomination does not identify which excipients are proposed for the
compounded product, nor does the nomination provide any data or
information supporting how the proposed compounded drug products will
address that concern.\42\
---------------------------------------------------------------------------

\39\ In noting this issue, FDA is not suggesting or implying
that the approved drug products, or products prepared from them, are
approved for the use proposed by the nomination. Mitomycin-C 5, 20,
or 40 mg vials of lyophilized powders for solution (for
reconstitution) have not been shown to be safe and effective for
intravesical administration to treat any condition or disease.
\40\ The approved product (e.g., ANDA 064144) is available as a
5, 20, and 40 mg vial of lyophilized powder, which according to the
approved labeling, is reconstituted in 10 mL, 40 mL or 80 mL Sterile
Water for Injection respectively for intravenous administration.
\41\ For example, the nomination cites two articles which used
mitomycin administered intravesically for bladder cancer (Refs. 4
and 5). Colombo et al, 2012 administered mitomycin 40 mg in 40 mL
saline (1 mg/mL) intravesically to patients and Au et al, 2001
administered mitomycin 40 mg in 20 mL of sterile water (2 mg/mL) or
20 mg in 20 mL of sterile water (1 mg/mL) intravesically to patients
(Ref. 4).
\42\ The nomination included one article that states, ``[i]n the
case of mitomycin C, instability of the drug in acidic urine is an
additional problem.'' However, the article does not identify
excipients that could be added to intravesically administered
mitomycin drug products to address this particular attribute of the
approved product. Nor does the article provide data or information
to support the need for a compounded drug product containing such
excipients. Rather, it discusses administering oral doses of sodium
bicarbonate before treatment with an intravesical mitomycin drug
product to reduce the acidity of the patient's urine (Ref. 5).
---------------------------------------------------------------------------

Regarding the proposed use to treat stomach, pancreas, anal
(nonmetastic), cervical (recurrent or metastic), esophageal, gastric,
and non-small cell lung cancer, the nomination does not identify an
attribute for each FDA-approved product that makes it medically
unsuitable to treat certain patients for these conditions and that the
proposed compounded products are intended to address.
Accordingly, with respect to the mitomycin products proposed to be
compounded, FDA finds no basis to conclude that an attribute of the
FDA-approved products makes them medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that the proposed compounded drug products are intended to address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nomination does not identify a population for whom the
FDA-approved products are medically unsuitable for the proposed uses,
FDA did not consider whether there is a basis to conclude that the drug
products proposed to be compounded must be produced from a bulk drug
substance rather than from an FDA-approved drug product under question
2.

C. Nepafenac

Nepafenac was nominated in combination with other bulk drug
substances, including prednisolone and gatifloxacin,\43\ for inclusion
on the 503B Bulks List to compound drug products for ``post cataract
surgery ocular complications related to pain, inflammation or bacterial
conjunctivitis.'' \44\ The proposed route of administration is topical
ophthalmic, the proposed dosage forms are a preserved (multidose) and a
preservative-free (unit dose) topical ophthalmic suspension, and the
proposed compounded products are: (1) ``Nepafenac 0.1%-Prednisolone
1%;'' and (2) ``Nepafenac 0.1%-Prednisolone 1%-Gatifloxacin 0.5%.'' The
nominated bulk drug substance, nepafenac, is a component of FDA-
approved drug products (e.g., NDA 021862 and NDA 203491).\45\ \46\ FDA
has approved nepafenac as 1.7 mL dropper bottle, and a 4 mL dropper
bottle filled with 3 mL sterile ophthalmic suspension containing 0.1
percent (1 mg/mL) nepafenac and as a 4 mL bottle filled with 1.7 mL and
3 mL sterile ophthalmic suspension containing 0.3 percent (3 mg/mL)
nepafenac for topical administration.\47\ The nomination proposes to
combine nepafenac with two other bulk drug substances, prednisolone and
gatifloxacin, both of which are components of FDA-approved products.
Prednisolone acetate \48\ is a component of FDA-approved drug products
(NDA 017469 and NDA 017011) and is available in a 1 mL, 5 mL, 10 mL,
and 15 mL suspension containing prednisolone acetate 1.0 percent.\49\
\50\ Gatifloxacin is a

[[Page 15680]]

component of FDA-approved drug products (e.g., NDA 022548),\51\ and is
available in a 1 mL or 2.5 mL solution containing gatifloxacin .5
percent.\52\
---------------------------------------------------------------------------

\43\ The nominator did not nominate prednisolone or gatifloxacin
separately.
\44\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0022.
\45\ See, e.g., NDA 021862 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021862s017lbl.pdf.
\46\ See, e.g., NDA 203491 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203491s001lbl.pdf.
\47\ See fns. 45 and 46, above.
\48\ The nominator did not specify which prednisolone API is
proposed to be included in their combinations. There are several
approved ophthalmic formulations of prednisolone acetate or
prednisolone sodium phosphate in combination with anti-infectives.
The only single ingredient 1% suspension approved for ophthalmic use
is prednisolone acetate.
\49\ See, e.g., NDA 017469 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017469s040lbl.pdf.
\50\ See, e.g., NDA 017011 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017011s050lbl.pdf.
\51\ See, e.g., NDA 022548 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022548s002lbl.pdf.
\52\ See fn. 51, above.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
The nomination does not identify a medical unsuitability in any of
the FDA-approved products that contain nepafenac, prednisolone, or
gatifloxacin when these products are administered separately. Instead,
it states that the single active-ingredient formulation of these
products may make them unsuitable for co-administration after ocular
surgeries. Specifically, the nomination states that ``[a]s a solution,
fixed-dosage ophthalmic drug combinations of different pharmacological
classes can be efficacious, reduce the side effects of each component
and improve patient compliance.'' However, the labeling for the FDA-
approved nepafenac products (e.g., NDA 021862 and NDA 203491)
specifically warns against the use of nepafenac with topical
corticosteroids, which include prednisolone. This is because the use of
nepafenac with topical corticosteroids may increase the potential for
healing problems. The nomination does not address this warning or
provide support for the co-administration of these drug products. We
decline to find that the approved drugs are medically unsuitable for
some patients because they may be difficult to administer to patients
under circumstances that are specifically warned against in the
approved labeling.
Because co-administration of these products is the subject of a
labeled warning, and therefore an inappropriate basis for a finding of
clinical need, we do not evaluate the nomination's claims further.
However, to help explain our thinking about this nomination and inform
public comment, we address the nomination's statement that there is a
clinical need to compound a drug containing multiple active ingredients
because it may improve patient compliance relative to prescribing FDA-
approved drugs that contain a single active ingredient. The nomination
does not state that the approved drugs would be medically unsuitable
for some patients for the conditions identified in the nomination, and
it does not provide data or evidence to support that proposition.
Reducing the number of drugs administered for the purpose of
convenience is not ``clinical need''; medical unsuitability of the
approved drugs is required. While clinical need does not have to be
fully established in FDA's analysis of questions 1 and 2, there must be
a basis to conclude that such a need may exist before FDA will proceed
to the more searching analysis conducted under the balancing test. No
such basis is present here.\53\
---------------------------------------------------------------------------

\53\ See supra note 31.
---------------------------------------------------------------------------

Accordingly, with respect to the nepafenac drug products proposed
to be compounded by the nominator, FDA finds no basis to conclude that
there is an attribute of each of the approved drug products that makes
each one medically unsuitable to treat certain patients who undergo
cataract surgery. There is therefore no attribute of the approved drug
products that the proposed compounded drug products are intended to
address.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominator has not identified a population for whom the
approved products are medically unsuitable for the proposed uses under
question 1, we are not considering whether there is 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 under
question 2.
3. Additional Comments
Finally, if this nomination for nepafenac were to proceed to the
balancing test, there would be some significant safety and
effectiveness concerns to evaluate, which are not addressed in the
nomination. Each of the three proposed ingredients intended to be
compounded into a single drug product is indicated for different
medical conditions and has different FDA-approved dosing regimens: One-
time daily for nepafenac,\54\ four times daily for prednisolone,\55\
and two to eight times daily for gatifloxacin.\56\ The duration of
treatment for each individual drug also differs, as do the approved
indications.
---------------------------------------------------------------------------

\54\ One drop of NDA 021862 0.1% should be applied to the
affected eye three times daily beginning 1 day prior to cataract
surgery, continued on the day of surgery and through the first 2
weeks of the postoperative period. One drop of NDA 203491 0.3%
should be applied to the affected eye one time daily beginning 1 day
prior to cataract surgery, continued on the day of surgery and
through the first 2 weeks of the postoperative period. An additional
drop should be administered 30 to 120 minutes prior to surgery.
\55\ Two drops topically in the eye(s) four times daily.
\56\ Day 1: Instill one drop every two hours in the affected
eye(s) while awake, up to 8 times on Day 1. Days 2 through 7:
instill one drop two to four times daily in the affected eye(s)
while awake on Days 2 through 7.
---------------------------------------------------------------------------

Most of the bulk drug substance nominations FDA has evaluated to
date have only proposed to compound drug products containing a single
active ingredient. This nomination proposed to compound drug products
containing more than one active ingredient. If FDA finalizes its
proposal not to include nepafenac on the 503B Bulks List, we intend to
remove the substance from Category 1 for purposes of the Interim
Policy, which would mean that ophthalmic solutions compounded using the
bulk drug substance nepafenac, including the proposed compounded
products addressed in this notice, would fall outside the enforcement
discretion described in the Interim Policy. We note that FDA's
evaluation of nepafenac for inclusion on the 503B Bulks List will not
impact FDA's evaluation of any other bulk drug substances for inclusion
on the 503B Bulks List, including prednisolone and gatifloxacin,
because each bulk drug substance nominated for inclusion on the 503B
Bulks List undergoes its own evaluation. Nominations for prednisolone,
if they are not withdrawn, remain the subject of future evaluations.
Gatifloxacin has not been nominated for inclusion on the 503B Bulks
List, and therefore has not been categorized under the Interim Policy;
its status under the Interim Policy will not be affected if this
proposal is finalized. Finally, if FDA determines there is a clinical
need for outsourcing facilities to use bulk drug substances to compound
the proposed drug products, we would include each substance or
combination of substances, as appropriate, on the 503B Bulks List at
the time that final determination is made.

D. Hydroxychloroquine Sulfate

Hydroxychloroquine sulfate was nominated for inclusion on the 503B
Bulks List to compound drug products that treat rheumatoid arthritis
and juvenile arthritis (also known as juvenile idiopathic
arthritis).\57\ The proposed route of administration is oral, the
proposed dosage forms are a capsule or suspension, and the proposed
concentrations are 200-500 mg capsules and 100-200 mg/mL suspension.
The nominated bulk drug substance is a component of FDA-approved drug
products (e.g., NDA 009768, ANDA

[[Page 15681]]

040104, and ANDA 213342).\58\ \59\ \60\ FDA-approved hydroxychloroquine
sulfate is available as 200 mg (equivalent to 155 mg of
hydroxychloroquine base), film-coated tablets for oral
administration.\61\
---------------------------------------------------------------------------

\57\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0165.
\58\ See, e.g., NDA 009768 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf.
\59\ See, e.g., ANDA 040104 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/a594d892-e496-38f5-e053-2a95a90a9da8/a594d892-e496-38f5-e053-2a95a90a9da8.xml.
\60\ See, e.g., ANDA 213342 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/f6b15217-3b65-4d0e-8546-5056d71d525e/f6b15217-3b65-4d0e-8546-5056d71d525e.xml.
\61\ See, e.g., NDA 009768 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf.
---------------------------------------------------------------------------

1. Suitability of FDA-Approved Drug Product(s)
There is a basis to conclude that an attribute of the approved
hydroxychloroquine sulfate tablets for oral administration makes them
medically unsuitable for the treatment of some patients with rheumatoid
arthritis and juvenile arthritis.\62\ The nomination suggests that the
approved oral tablets, a solid oral dosage form, are medically
unsuitable in pediatric patients who are unable to swallow tablets. We
agree that there may be certain patients for whom the approved oral
tablets are medically unsuitable and this would depend on a patient's
clinical presentation and age, among other considerations. As a general
matter, the drug product proposed to be compounded appears to be
intended to address the potential unsuitability of a solid oral dosage
form because the nominator proposes to compound a suspension of
hydroxychloroquine sulfate for oral administration.
---------------------------------------------------------------------------

\62\ In noting this issue, we do not mean to suggest or imply
that the approved drug products, or products prepared from them, are
approved for all of the uses proposed by the nomination. For the
question 1 analysis we asked a limited, threshold question to
determine whether there might be a clinical need for a compounded
drug product, by asking what attributes of the approved drug the
proposed compounded drug would change, and why. Because this
nomination did not pass through question 2, we did not reach the
balancing test and therefore did not consider the four factors,
including the available evidence of effectiveness or lack of
effectiveness of a drug product compounded with hydroxychloroquine
sulfate. The safety and efficacy of chronic use of
hydroxychloroquine sulfate have not been established for juvenile
idiopathic arthritis.
---------------------------------------------------------------------------

The nominator further states that ``pediatric dosing is not
standardized but weight-based, making getting the correct dose
difficult with tablets.'' We agree that an oral suspension could allow
for more flexible dosing when compared to the approved tablets when
following weight-based dosing recommendations, and that this also
supports the proposition that the approved product may be unsuitable
for certain patients.\63\
---------------------------------------------------------------------------

\63\ We note that the nominator's proposed concentration of 100-
200 mg/mL would offer little benefit in the younger aged pediatric
population because a suspension at this strength would likely
require administration of small volumes (e.g., <=1 mL). We are aware
of several published pharmacy compounding formulations for
hydroxychloroquine sulfate 25 mg/mL suspensions (Refs. 6-8), which
may be more suitable for the younger pediatric population.
---------------------------------------------------------------------------

In addition to the proposed suspension, the nominator also proposes
to compound hydroxychloroquine sulfate 200-500 mg capsules for oral
administration. The nomination does not explain how the proposed
compounded capsule products are intended to address the medical
unsuitability of the approved product. Similar to tablets, capsules are
less flexible in dosing and would be difficult for patients to take if
they are unable to swallow tablets. In addition, the nomination does
not identify any data or information as to the need for compounded
products with a higher concentration than the approved product.
The nomination also claims that some patients are ``unable to
tolerate excipients'' in the approved product, but the nomination does
not identify which excipients they are referring to, nor do they
provide any data or information supporting how the proposed drug
products will address that particular attribute.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because there is a basis to conclude that an attribute of the
approved hydroxychloroquine sulfate tablets makes them medically
unsuitable for some patients, and the proposed compounded oral
suspension is intended to address that attribute, FDA next considers
whether there is a basis to conclude that the proposed oral suspension
must be made from a bulk drug substance rather than from an FDA-
approved product. The approved hydroxychloroquine sulfate drug products
are 200 mg immediate release tablets with film coating.\64\ Although
the approved products are film-coated, the coating is not intended to
change/control the release profile. FDA is not aware of issues with
using the FDA-approved product as the starting material when the
compounding process and equipment are appropriately selected. We also
note that there is a draft USP monograph for the compounded suspension
that uses an FDA-approved film-coated tablet as the starting material
(Ref. 8).\65\ As with all suspensions, the particle size of the powder
should be carefully controlled and the density of suspension vehicle
should be selected appropriately in order to make the oral suspension
uniform and stable, which can affect the dose administrated to the
patients.
---------------------------------------------------------------------------

\64\ The tablet is not scored. The approved product labeling
states that the ``film-coated tablets cannot be divided, therefore
they should not be used to treat patients who weigh less than 31
kg.''
\65\ We note that the product labeling for hydroxychloroquine
sulfate film-coated tablets (e.g., NDA 009768, ANDA 213342) states,
``Do not crush or divide hydroxychloroquine sulfate film-coated
tablets.'' However, this does not change our view that the product
can be compounded starting with the approved drug product.
---------------------------------------------------------------------------

Because we do not find a basis to conclude that a bulk drug
substance is needed to compound the proposed compounded
hydroxychloroquine sulfate oral suspension, rather than starting with
the FDA approved product, we do not find a need to include
hydroxychloroquine sulfate on the 503B Bulks List under question 2.

V. Conclusion

For the reasons stated above, we tentatively conclude that there is
a clinical need for outsourcing facilities to compound drug products
using the bulk drug substance quinacrine for oral use, and we therefore
propose to include it on the 503B Bulks List as described in this
notice.
At this time, we find no basis to conclude that there is a clinical
need for outsourcing facilities to compound drug products using the
bulk drug substances bromfenac sodium, mitomycin-C, nepafenac, and
hydroxychloroquine sulfate. We therefore propose not to include these
bulk drug substances on the 503B Bulks List.

VI. References

The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they are also available electronically at 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. FDA

[[Page 15682]]

has verified the website addresses, as of the date this document
publishes in the Federal Register, but websites are subject to change
over time.

*1. FDA, Guidance for Industry, ``Interim Policy on Compounding
Using Bulk Drug Substances Under Section 503B of the Federal Food,
Drug, and Cosmetic Act,'' January 2017 (available at https://www.fda.gov/media/94402/download).
*2. FDA, 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 (available at https://www.fda.gov/media/121315/download).
*3. FDA Memorandum to File, ``Clinical Need for Quinacrine
Hydrochloride in Compounding Under Section 503B of the FD&C Act,''
January 2021.
4. Colombo, R., L. Rocchini, N. Suardi, F. Benigni, et al., 2012,
``Neoadjuvant Short-Term Intensive Intravesical Mitomycin C Regimen
Compared with Weekly Schedule For Low-Grade Recurrent Non-Muscle-
Invasive Bladder Cancer: Preliminary Results of a Randomised Phase 2
Study,'' European Urology, 62: 797-802.
5. Au, J. L., R. A. Badalament, M. G. Wientjes, D. C. Young, et al.,
and International Mitomycin-C Consortium, 2001. ``Methods to Improve
Efficacy of Intravesical Mitomycin C: Results of a Randomized Phase
III Trial,'' Journal of the National Cancer Institute, 93: 597-604.
6. McHenry, A. R., M. F. Wempe, and P. J. Rice, 2017, ``Stability of
Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL
Suspensions in Plastic Bottles and Syringes,'' International Journal
of Pharmaceutical Compounding, 21(3), 251-254 (APA). Retrieved from
https://ijpc.com/Abstracts/Abstract.cfm?ABS=4322.
7. American Society of Hospital Pharmacists (ASHP 2020), ''
Hydroxychloroquine Sulfate Suspension 25 mg/mL.'' Retrieved from
www.ashp.org.
8. USP 2020, ``USP Draft Compounded Preparation Monograph for
Hydroxychloroquine Sulfate Compounded Oral Suspension.'' Published
for public comment in Pharmacopeial Forum 46(2). Retrieved from
https://go.usp.org/l/323321/2020-04-08/33wcg6.

Dated: March 19, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-06060 Filed 3-23-21; 8:45 am]
BILLING CODE 4164-01-P