Document ID: FDA-2018-N-3240-0282
Agency: fda
Document Type: Notice
Title: List of Bulk Drug Substances for Which There Is a Clinical Need Under  the Federal Food, Drug, and Cosmetic 
Act
Posted Date: 2021-03-24T04:00Z

[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.
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    \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