[Federal Register Volume 87, Number 18 (Thursday, January 27, 2022)]
[Notices]
[Pages 4240-4252]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-01558]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3240]


List of Bulk Drug Substances for Which There Is a Clinical Need 
Under Section 503B of the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA, the Agency or we) is 
evaluating substances that have been nominated for inclusion on a list 
of bulk drug substances (i.e., 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 four bulk drug substances that FDA has 
considered and is including on the list at this time: 
Diphenylcyclopropenone (DPCP) for topical use only, glycolic acid for 
topical use only in concentrations up to 70 percent, squaric acid 
dibutyl ester (SADBE) for topical use only, and trichloroacetic acid 
(TCA) for topical use only. This notice also identifies eight bulk drug 
substances that FDA has considered and is not including on the list at 
this time: diazepam, dipyridamole, dobutamine hydrochloride (HCl), 
dopamine HCl, edetate calcium disodium, folic acid, glycopyrrolate, and 
sodium thiosulfate (except for topical administration). Additional bulk 
drug substances nominated by the public for inclusion on this list are 
currently under consideration and will be the subject of future 
notices.

DATES: The announcement of the notice is published in the Federal 
Register on January 27, 2022.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this notice 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: Kemi Asante, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New

[[Page 4241]]

Hampshire Ave., Bldg. 51, Rm. 2247, Silver Spring, MD 20993, 301-796-
3110.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 503B of the FD&C Act (21 U.S.C. 353b) describes the 
conditions that must be satisfied for drug products compounded in an 
outsourcing facility to be exempt from section 505 (21 U.S.C. 355) 
(concerning the approval of drugs under new drug applications (NDAs) or 
abbreviated new drug applications (ANDAs)), section 502(f)(1) (21 
U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate 
directions for use), and section 582 of the FD&C Act (21 U.S.C. 360eee-
1) (concerning drug supply chain security requirements).\1\
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    \1\ Section 503B(a) of the FD&C Act.
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    Compounded drug products that meet the conditions in section 503B 
are not exempt from current good manufacturing practice (CGMP) 
requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 
351(a)(2)(B)).\2\ Outsourcing facilities are also subject to FDA 
inspections according to a risk-based schedule, adverse event reporting 
requirements, and other conditions that help to mitigate the risks of 
the drug products they compound.\3\ Outsourcing facilities may or may 
not obtain prescriptions for identified individual patients and can, 
therefore, distribute compounded drugs to healthcare 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 the exemptions 
under section 503B of the FD&C Act is that the outsourcing facility may 
not compound a drug using a bulk drug substance unless: (1) The bulk 
drug substance appears on a list established by the Secretary of Health 
and Human Services (the Secretary) identifying bulk drug substances for 
which there is a clinical need (the 503B Bulks List) or (2) the drug 
compounded from the bulk drug substance appears on the drug shortage 
list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at 
the time of compounding, distribution, and dispensing.\5\
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    \5\ Section 503B(a)(2)(A) of the FD&C Act.
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    Section 503B of the FD&C Act directs FDA to establish the 503B 
Bulks List by: (1) Publishing a notice in the Federal Register 
proposing bulk drug substances to be included on the list, including 
the rationale for such proposal; (2) providing a period of not less 
than 60 calendar days for comment on the notice; and (3) publishing a 
notice in the Federal Register designating bulk drug substances for 
inclusion on the list.\6\
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    \6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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    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.\7\ 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.<SUP>8 9</SUP>
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    \7\ 21 CFR 207.3.
    \8\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
    \9\ Inactive ingredients are not subject to section 503B(a)(2) 
of the FD&C Act and will not be included in the 503B Bulks List 
because they are not included within the definition of a bulk drug 
substance. Pursuant to section 503B(a)(3), inactive ingredients used 
in compounding must comply with the standards of an applicable 
United States Pharmacopeia (USP) or National Formulary (NF) 
monograph, if a monograph exists.
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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.\10\ This notice identifies four bulk drug substances that FDA has 
considered and is including on the 503B Bulks List and eight bulk drug 
substances that FDA has considered and is not including on the 503B 
Bulks List.
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    \10\ See Federal Register of August 28, 2018 (83 FR 43877), 
March 4, 2019 (84 FR 7383), September 3, 2019 (84 FR 46014), July 
31, 2020 (85 FR 46126), and March 24, 2021 (86 FR 15673). 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. In this notice, FDA is reaching a 
final determination on whether certain substances evaluated in the 
September 2019 and July 2020 notices will be included on the 503B 
Bulks List. The substances considered in the September 2019 and July 
2020 notices that are not addressed in this notice remain under 
consideration by the Agency. In addition, bumetanide, which was 
considered in the August 2018 notice remains under consideration by 
the Agency.
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II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

    FDA requested nominations for specific bulk drug substances for the 
Agency to consider for inclusion on the 503B Bulks List in the Federal 
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination 
process in the Federal Register of July 2, 2014 (79 FR 37747), and 
provided more detailed information on what FDA needs to evaluate 
nominations for the list. In the Federal Register of October 27, 2015 
(80 FR 65770), the Agency opened a new docket, FDA-2015-N-3469, to 
provide an opportunity for interested persons to submit new nominations 
of bulk drug substances, renominate substances with sufficient 
information, or submit comments on nominated substances.
    As FDA evaluates bulk drug substances, it intends to publish 
notices for public comment in the Federal Register that describe its 
proposed position on each substance along with the rationale for that 
position.\11\ After considering any comments on FDA's proposals 
regarding whether to include nominated substances on the 503B Bulks 
List, FDA intends to consider whether input from the Pharmacy 
Compounding Advisory Committee (PCAC) on the nominations would be 
helpful to the Agency in making its determination, and if so, it will 
seek PCAC input.\12\ Depending on its review of the docket comments and 
other relevant information before the Agency, FDA may finalize its 
proposed determination without change, or it may finalize a 
modification to its proposal to reflect new evidence or analysis 
regarding clinical need. FDA will then publish in the Federal Register 
a final determination identifying the bulk drug substances for which it 
has determined there is a clinical need and FDA's rationale in making 
that final determination. FDA will also publish in the Federal Register 
a final determination regarding those substances it considered but 
found that there is no clinical need to use in compounding and FDA's 
rationale in making this decision.
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    \11\ This is consistent with procedures set forth in section 
503B(a)(2)(A)(i) of the FD&C Act. Although the statute only directs 
FDA to issue a Federal Register notice and seek public comment when 
it proposes to include bulk drug substances on the 503B Bulks List, 
we intend to seek comment when the Agency has evaluated a nominated 
substance and proposes either to include or not to include the 
substance on the list.
    \12\ Section 503B of the FD&C Act does not require FDA to 
consult the PCAC before developing the 503B Bulks List.
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    FDA intends to maintain a list of all bulk drug substances it has 
evaluated on its website, and separately identify bulk drug substances 
it has placed on the 503B Bulks List and those it has decided not to 
place on the 503B Bulks List. This list is available at https://www.fda.gov/media/120692/download. FDA will only place a bulk drug 
substance on the 503B Bulks List when it has determined there

[[Page 4242]]

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\ In January 2017, FDA announced the availability of a 
revised final guidance for industry that provides additional 
information regarding FDA's policies for bulk drug substances 
nominated for the 503B Bulks List pending 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'' (the ``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 evaluating 
bulk drug substances that were nominated for inclusion on the 503B 
Bulks List, proceeding case by case, under the standard provided by the 
statute (Ref. 2).\14\ In applying this standard to make determinations 
regarding the substances set forth 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 of the FD&C Act 
separately provides for compounding from bulk drug substances under the 
exemptions from the FD&C Act discussed above if the drug product 
compounded from the bulk drug substance is on the FDA drug shortage 
list at the time of compounding, distribution, and dispensing. 
Additionally, we are not considering cost of the compounded drug 
product as compared with an FDA-approved drug product when assessing 
``clinical need.''
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    \14\ In March 2019, FDA announced the availability of a final 
guidance entitled ``Evaluation of Bulk Drug Substances Nominated for 
Use in Compounding Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act'' (the ``Clinical Need Guidance''), available at 
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. 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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    Eight of the bulk drug substances that we are addressing in this 
notice are components of FDA-approved drug products,\15\ and we 
evaluated them by asking one or both of the following questions:
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    \15\ Specifically, diazepam, dipyridamole, dobutamine HCl, 
dopamine HCl, edetate calcium disodium, folic acid, glycopyrrolate, 
and sodium thiosulfate.
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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 to be 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. When it is feasible to compound a drug product by 
starting with an approved drug product, there are certain benefits of 
doing so over starting with a bulk drug substance, including that 
approved drugs have undergone premarket review for safety, 
effectiveness, and quality, and are manufactured by a facility that is 
subject to premarket assessment, including site inspection, as well as 
routine post-approval risk-based inspections. In contrast, FDA does not 
conduct a premarket review of the quality standards, specifications, 
and controls for bulk drug substances used in compounding and does not 
conduct a premarket assessment of the manufacturer of the bulk drug 
substance.
    If the answer to both of the above questions is ``yes,'' there may 
be a clinical need for outsourcing facilities to compound using the 
bulk drug substance, and we would evaluate the substance further, 
applying the factors described below. If the answer to either of these 
questions is ``no,'' we generally would not include the bulk drug 
substance on the 503B Bulks List, because there would not be a basis to 
conclude that there may be a clinical need to compound drug products 
using the bulk drug substance instead of administering or compounding 
starting with an approved drug product. FDA did not answer ``yes'' to 
both of the threshold questions for the eight 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 have decided not to 
include them on the 503B Bulks List.
    With respect to four bulk drug substances we are addressing in this 
notice that are not components of FDA-approved drug products, DPCP, 
glycolic acid, SADBE, and TCA, we conducted a balancing test with four 
factors, considered each factor in the context of the others, and 
balanced them to determine whether the statutory ``clinical need'' 
standard was met. The balancing test includes the following factors:
    <bullet> The physical and chemical characterization of the 
substance;
    <bullet> any safety issues raised by the use of the substance in 
compounding;
    <bullet> the available evidence of effectiveness or lack of 
effectiveness of a drug product compounded with the substance, if any 
such evidence exists; and
    <bullet> 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

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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 decision to include four bulk drug substances on the 
503B Bulks List.

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

    In evaluating a substance for 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 entries on the 503B Bulks List to reflect its findings 
related to clinical need for these bulk substances. Specifically, the 
listings for DCPC, glycolic acid, SADBE, and TCA are limited to the use 
of these bulk drug substances to compound drug products for topical use 
only.
    In the Federal Register notice of July 31, 2020, which proposed 
updates to the 503B Bulks List, FDA solicited comment on whether: (1) 
To allow compounding of drug products containing only the listed bulk 
drug substance and no other active ingredients or (2) to allow 
compounding of drug products that contain the listed bulk drug 
substance without limits on compounding a drug product that contains 
other active ingredients (85 FR 46126). FDA received a comment 
supporting the first option and stating that ``FDA should restrict the 
use of any bulk drug substance on the 503B Bulks List in combination 
with one or more other active ingredients, unless there is specific 
clinical need for the combination product, as determined through FDA 
evaluation.'' In addition, the comment stated that this approach is 
important to limit safety risks to patients, particularly given the 
higher complexity of combination formulations.
    FDA has determined that to be eligible for the statutory exemptions 
under section 503B, drug products compounded using a bulk drug 
substance that appears on the 503B Bulks List cannot contain other 
active pharmaceutical ingredients unless those active pharmaceutical 
ingredients have been listed in combination on the 503B Bulks List. 
FDA's assessment of the clinical need for compounding with a particular 
bulk drug substance or combination of bulk drug substances could be 
affected if a bulk drug substance is commonly used in compounded drug 
products that contain multiple bulk drug substances (active 
pharmaceutical ingredients). The use of certain active pharmaceutical 
ingredients in combination with other active pharmaceutical ingredients 
in a compounded drug product could also pose a safety risk or affect 
the compounded drug product's effectiveness. These considerations of 
the composition of a nominated compounded combination, the history of 
its use in compounding, and evidence of safety or effectiveness would 
be included in FDA's clinical need evaluation.

III. FDA's Determinations Regarding Substances Proposed for the 503B 
Bulks List

    In September 2019, the Agency issued a Federal Register notice in 
which it evaluated nine nominated bulk drug substances under the 
section 503B statutory standard--dipyridamole, ephedrine sulfate, 
famotidine, hydralazine HCl, methacholine chloride, sodium bicarbonate, 
sodium tetradecyl sulfate, trypan blue, and vecuronium bromide--and 
proposed not to include them on the 503B Bulks List (the September 2019 
notice).\16\ In this notice, after review of the comments submitted to 
the docket for the September 2019 notice, FDA is making its final 
determination with regard to dipyridamole. At this time, FDA is not 
making a final determination regarding ephedrine sulfate, famotidine, 
hydralazine HCl, methacholine chloride, sodium bicarbonate, sodium 
tetradecyl sulfate, trypan blue, and vecuronium bromide. These 
substances remain under consideration by FDA.
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    \16\ See 84 FR 46014.
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    In July 2020, the Agency issued a Federal Register notice in which 
it evaluated 23 nominated bulk drug substances under the section 503B 
statutory standard (the July 2020 notice).\17\ FDA proposed to include 
DPCP, glycolic acid, SADBE, and TCA on the 503B Bulks List. FDA 
proposed not to include diazepam, dobutamine HCl, dopamine HCl, edetate 
calcium disodium, folic acid, glycopyrrolate, hydroxyzine HCl, 
ketorolac tromethamine, labetalol HCl, mannitol, metoclopramide HCl, 
moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium acetate, 
procainamide HCl, sodium nitroprusside, sodium thiosulfate, and 
verapamil HCl on the 503B Bulks List. In this notice, after review of 
the comments submitted to the docket for the July 2020 notice, FDA is 
making its final determination for DPCP, glycolic acid, SADBE, TCA, 
diazepam, dobutamine HCl, dopamine HCl, edetate calcium disodium, folic 
acid, glycopyrrolate, and sodium thiosulfate. At this time, FDA is not 
making a final determination regarding hydroxyzine HCl, ketorolac 
tromethamine, labetalol HCl, mannitol, metoclopramide HCl, moxifloxacin 
HCl, nalbuphine HCl, polidocanol, potassium acetate, procainamide HCl, 
sodium nitroprusside, and verapamil HCl. These substances remain under 
consideration by FDA. 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.
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    \17\ See 85 FR 46126.
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A. Substances Evaluated and Included on the 503B Bulks List

    Because the substances in this section are not components of FDA-
approved drug products, FDA applied the balancing test described above. 
The four bulk drug substances that FDA evaluated, proposed to include 
on the 503B Bulks List in a July 2020 Federal Register notice, and is 
now placing on the 503B Bulks List are: DPCP, glycolic acid, SADBE, and 
TCA. The reasons for FDA's proposals are included below (Refs. 3-
6).\18\ Having received no adverse comment, and for the same reasons 
set forth in those proposals, FDA is now placing these four bulk drug 
substances on the 503B Bulks List.
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    \18\ As explained in the July notice, the Agency considered data 
and information from its earlier evaluations regarding the use of 
these bulk drug substances for the list of bulk drug substances that 
can be used in compounding under section 503A of the FD&C Act (the 
503A Evaluations) in addition to the nominations for the 50B Bulks 
List. 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.
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1. Diphenylcyclopropenone (DPCP)
    DPCP was nominated as a bulk drug substance for the 503B Bulks List 
to compound drug products for topical use at variable concentrations, 
usually 2 percent, in the treatment of alopecia areata.\19\ The 
nominated bulk drug substance is not a component of an FDA-approved 
drug product. We evaluated DPCP 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 DPCP, safety issues raised by use of this 
substance in compounding, available evidence of effectiveness or lack 
of

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effectiveness, and historical and current use in compounding (Ref. 3).
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    \19\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-1363.
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    DPCP is well characterized, but there are concerns about stability 
and consistency in product quality. Although there are still gaps in 
the evidence for DPCP's safety and effectiveness, including a lack of 
long-term safety data, substantial human safety data have been 
collected and clinicians worldwide have gained experience in the use of 
DPCP to treat alopecia areata. DPCP has been used for several decades 
to compound drug products for dermatologists to treat alopecia areata 
and continues to be used for this purpose. The reported adverse effects 
are related to DPCP's mechanism of therapeutic action as a sensitizer, 
causing allergic contact dermatitis in treated patients. Alopecia 
areata may not respond adequately to available treatments. DPCP can be 
a potentially effective agent for patients who have failed FDA-approved 
and other therapies for this condition.
    On balance, the physical and chemical characterization, safety, 
effectiveness, and historical and current use of DPCP weigh in favor of 
including this substance on the 503B Bulks List. No commenters 
disagreed with FDA's proposal to include DPCP for topical use only on 
the 503B Bulks List. Accordingly, we are adding DPCP to the 503B Bulks 
List for topical use only.
2. Glycolic Acid
    Glycolic acid was nominated as a bulk drug substance for the 503B 
Bulks List to compound drug products for topical use at concentrations 
ranging from 0.08 to 70 percent for the treatment of hyperpigmentation 
and photodamaged skin.\20\ The nominated bulk drug substance is not a 
component of an FDA-approved drug product. We evaluated glycolic acid 
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 
glycolic acid, 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. 4).
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    \20\ See Docket No. FDA-2015-N-3469, document nos. FDA-2015-N-
3469-0035 and FDA-2015-N-3469-0123. One of the nominations also 
states that prescribers may want glycolic acid compounds in other 
formulations to treat other conditions, but does not identify the 
conditions or formulations. It also refers to the use of glycolic 
acid in combination with other ingredients and, in particular, to 
compounding a formulation containing hydroquinone 6 percent and 
tretinoin 0.1 percent. Information submitted with this nomination 
relevant to compounding with glycolic acid for the treatment of 
hyperpigmentation disorders and photodamaged skin was considered. 
FDA's evaluation in this notice does not consider whether there is a 
clinical need for outsourcing facilities to compound drug products 
containing glycolic acid and hydroquinone or tretinoin, or other 
bulk drug substances, which may be the subject of future Federal 
Register notices.
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    Glycolic acid, also known as hydroxyacetic acid, is physically and 
chemically well characterized. When used in high concentrations, 
glycolic acid causes local effects that are typical of a strong acid, 
such as dermal and eye irritation. Reported adverse reactions were 
generally limited in duration and readily manageable. There is no 
information available on long-term outcomes. The available data on 
short-term outcomes do not raise major safety concerns associated with 
the topical use of glycolic acid.
    Data from controlled clinical trials have shown consistently 
positive results in the treatment of epidermal melasma or other forms 
of hyperpigmentation. The available evidence suggests that there is a 
role for glycolic acid in the treatment of melasma, typically as a 
second line treatment. There is also some evidence indicating that 
glycolic acid may be effective for the mitigation of manifestations of 
photodamaged skin. Glycolic acid has been used for several decades to 
compound drug products for dermatologists and continues to be used for 
this purpose. Conclusions regarding each of these factors are for use 
at concentrations up to 70 percent; data and evidence regarding use of 
higher concentrations are very limited.
    On balance, the physical and chemical characterization, safety, 
effectiveness, and historical and current use of glycolic acid weigh in 
favor of including this substance on the 503B Bulks List at 
concentrations up to 70 percent. No commenters disagreed with FDA's 
proposal to include glycolic acid on the 503B Bulks List. Accordingly, 
we are adding glycolic acid to the 503B Bulks List for topical use only 
in concentrations up to 70 percent.
3. Squaric Acid Dibutyl Ester (SADBE)
    SADBE was nominated as a bulk drug substance for the 503B Bulks 
List to compound drug products for topical use at variable 
concentrations, ranging from 2 percent initially to 0.0001 percent to 
0.001 percent for maintenance, for the treatment of alopecia areata and 
warts.\21\ The nominated bulk drug substance is not a component of an 
FDA-approved drug product. We evaluated SADBE 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 SADBE, 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. 5).
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    \21\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-1363.
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    SADBE is well-characterized, but there are concerns about stability 
and consistency in product quality. There is a lack of adequate 
nonclinical data, long-term safety data, and safety information about 
use in specific populations such as pregnant and lactating women. 
Despite these data gaps, considerable human safety data have 
accumulated over the past 40 years from its use in compounding drug 
products for dermatologists to treat alopecia areata and resistant non-
genital warts and from reports of its use internationally. The reported 
adverse effects are related to SADBE's mechanism of therapeutic action 
as a sensitizer causing allergic contact dermatitis in treated 
patients.
    In addition, both alopecia areata and warts may not respond 
adequately to available treatments. SADBE can be a potentially 
effective agent for patients who have failed FDA-approved and other 
therapies for these conditions. We recognize that treatment with SADBE 
requires initial sensitization and typical protocols involve a SADBE 
concentration of 2 percent, but lower concentrations may be used in 
other patients.
    On balance, the physical and chemical characterization, safety, 
effectiveness, and historical and current use of SADBE weigh in favor 
of including this substance on the 503B Bulks List. No commenters 
disagreed with FDA's proposal to include SADBE on the 503B Bulks List. 
Accordingly, we are adding SADBE to the 503B Bulks List for topical use 
only.
4. Trichloroacetic Acid (TCA)
    TCA was nominated as a bulk drug substance for the 503B Bulks List 
to compound drug products for topical use at concentrations ranging 
from 6 percent to 20 percent as a chemical skin peeling agent for the 
treatment of acne and melasma.\22\ The nominated bulk drug substance is 
not a component of an FDA-approved drug product. We evaluated TCA 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 
TCA, safety

[[Page 4245]]

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. 6).
---------------------------------------------------------------------------

    \22\ See Docket No. FDA-2018-D-1067, document no. FDA-2018-D-
1067-0005.
---------------------------------------------------------------------------

    TCA is well characterized in its physical and chemical properties. 
Nonclinical evidence suggests that topical use of TCA does not raise 
serious safety issues for humans. Although there have been no clinical 
trials specifically designed to address the safety of TCA, safety 
assessments were among the study procedures in several clinical trials 
and reports of adverse reactions have included burning, pain, erythema, 
hyperpigmentation, and hypopigmentation. More serious adverse reactions 
reported were ulcerations, scarring, and pustules. Adverse events were 
reported more frequently with higher concentrations. Several studies 
indicate that TCA may be effective as a chemical peel for the treatment 
of acne (Ref. 7) and melasma (Ref. 8), but there is a lack of evidence 
comparing TCA to FDA-approved drug products for those uses. TCA has 
been used, in the United States and worldwide, for dermatologic 
conditions for over 40 years and for at least 20 years in pharmacy 
compounding.
    On balance, the physical and chemical characterization, safety, 
effectiveness, and historical and current use of TCA weigh in favor of 
including this substance on the 503B Bulks List. No commenters 
disagreed with FDA's proposal to include TCA on the 503B Bulks List. 
Accordingly, we are adding TCA to the 503B Bulks List for topical use 
only.

B. Substances Evaluated and Not Included on the 503B Bulks List

    Because the substances in this section are components of FDA-
approved drug products, FDA considered one or both of the following 
questions: (1) Is there a basis to conclude that an attribute of each 
FDA-approved drug product containing the bulk drug substance makes each 
one medically unsuitable to treat certain patients for a condition that 
FDA has identified for evaluation, and the drug product 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 eight bulk drug substances that FDA has evaluated, proposed not 
to include on the 503B Bulks List in a Federal Register notice, and has 
now decided not to place on the 503B Bulks List are: Diazepam, 
dipyridamole, dobutamine HCl, dopamine HCl, edetate calcium disodium, 
folic acid, glycopyrrolate, and sodium thiosulfate (except for topical 
administration).
1. Diazepam
    Diazepam was nominated for inclusion on the 503B Bulks List to 
compound drug products that are used for alcohol withdrawal syndrome, 
anxiety, and as premedication before surgery, endoscopic procedures, 
and cardioversion, among other conditions.\23\ The proposed route of 
administration is intravenous or intramuscular, the proposed dosage 
form is a preserved solution, and the proposed concentration is 5 
milligrams per milliliter (mg/mL). The nominators propose to compound a 
preserved solution. However, they fail to acknowledge that there is an 
FDA-approved formulation of diazepam that is preserved and do not 
explain why that formulation would be medically unsuitable for certain 
patients. The nominations state that diazepam might also be used to 
compound other drug products, but do not identify those products. The 
nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., ANDA 072079). FDA-approved diazepam is available as a 
preserved 10 mg/2 mL (5 mg/mL) and 50 mg/10 mL (5 mg/mL) solution for 
intravenous or intramuscular administration.<SUP>24 25 26 </SUP>
---------------------------------------------------------------------------

    \23\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \24\ See, e.g., ANDA 072079 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/4e800d0d-2181-49b1-a2c8-4c6c49edd83a/4e800d0d-2181-49b1-a2c8-4c6c49edd83a.xml.
    \25\ Per the label for ANDA 072079, each mL contains 5 mg 
diazepam, 40 percent propylene glycol, 10 percent alcohol, 5 percent 
sodium benzoate and benzoic acid added as buffers, and 1.5 percent 
benzyl alcohol added as a preservative.
    \26\ Diazepam is also approved as an oral tablet, oral 
concentrate, oral solution, and rectal gel.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of each of the FDA-
approved preserved 5 mg/mL solution products is medically unsuitable 
for certain patients or identify an attribute of the approved drug 
products that the proposed compounded drug product (also a preserved 5 
mg/mL solution) is intended to address.
    Two commenters agreed with FDA's proposal not to include diazepam 
on the 503B Bulks List. Several commenters objected generally to FDA's 
proposals in the July 2020 notice and these overarching concerns are 
addressed in section IV. No new information supporting the clinical 
need for compounding from the bulk drug substance diazepam was provided 
by the commenters.
    Accordingly, 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 a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not identify specific differences between drug 
products that would be compounded using diazepam and approved drug 
products containing diazepam, and no further information was supplied 
on this point during the comment period. Therefore, FDA finds no basis 
to conclude that the drug product proposed to be compounded must be 
prepared using a bulk drug substance.
2. Dipyridamole
    Dipyridamole was nominated for inclusion on the 503B Bulks List to 
compound drug products that are used for thallium myocardial perfusion 
imaging for the evaluation of coronary artery disease in patients who 
cannot exercise adequately.\27\ The proposed route of administration is 
intravenous, the proposed dosage form is an injection, and the proposed 
strength is 1 milligram per milliliter (mg/mL) in a 50 mL and 60 mL 
syringe. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDAs 074521 and 074939). FDA-approved 
dipyridamole is available as a 5 mg/mL injection for intravenous 
administration.\28\ \29\ Per its labeling, it should be diluted to a 
final concentration of less than or equal to 2.5 mg/mL.\30\
---------------------------------------------------------------------------

    \27\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0031.
    \28\ See, e.g., ANDA 074521 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175.xml.
    \29\ Dipyridamole is also approved as an oral tablet and in 
combination with aspirin as an extended release capsule.
    \30\ According to the label for ANDA 074521, dipyridamole 
injection should be diluted in at least a 1:2 ratio with sodium 
chloride injection 0.45%, sodium chloride injection 0.9% or dextrose 
injection 5% for a total volume of approximately 20 to 50 mL.

---------------------------------------------------------------------------

[[Page 4246]]

a. Suitability of FDA-Approved Drug Product
    The nomination does not identify an attribute of the FDA-approved 
drug products that makes them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nomination does not explain why the 5 mg/mL 
injection (for dilution) is medically unsuitable for certain patients.
    Several commenters agreed with FDA's proposal not to include 
dipyridamole on the 503B Bulks List. One commenter objected generally 
to FDA's proposals in the September 2019 notice asserting that FDA was 
inappropriately engaging in the practice of medicine. This overarching 
concern is addressed in section IV. No new information supporting the 
clinical need for compounding from the bulk drug substance dipyridamole 
was provided by commenters. Accordingly, 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 a proposed compounded product is 
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not take the position or provide support for 
the position that drug products containing dipyridamole must be 
compounded from bulk drug substances rather than by diluting the 
approved drug product, and no further information was supplied on this 
point during the comment period. Therefore, FDA finds no basis to 
conclude that the dipyridamole drug products proposed in the 
nominations must be compounded using a bulk drug substance rather than 
an approved drug product.
3. Dobutamine HCl
    Dobutamine HCl was nominated for inclusion on the 503B Bulks List 
to compound drug products for ionotropic support in the short-term 
treatment of adults with cardiac decompensation due to depressed 
contractility resulting either from organic heart disease or from 
cardiac surgical procedures.\31\ The proposed route of administration 
is intravenous, the proposed dosage form is an injection, and the 
proposed concentrations are 1 mg/mL, 2 mg/mL, and 4 mg/mL in various 
volumes of intravenous infusions (large volume parenterals). The 
nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., ANDA 074086 and NDA 020201). FDA has approved 
dobutamine HCl drug products as equivalent (EQ) 50 mg base/100 mL (EQ 
0.5 mg base/mL), EQ 100 mg base/100 mL (EQ 1 mg base/mL), EQ 200 mg 
base/100 mL (EQ 2 mg base/mL), and EQ 400 mg base/100 mL (EQ 4 mg base/
mL) ready-to-administer forms (no further dilution needed) for 
intravenous administration and as an EQ 12.5mg base/mL single-dose vial 
that must be diluted prior to infusion.\32\ \33\
---------------------------------------------------------------------------

    \31\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0032.
    \32\ See, e.g., ANDA 074086 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/7b9ea626-7073-2e77-e053-2a91aa0a9215/7b9ea626-7073-2e77-e053-2a91aa0a9215.xml.
    \33\ See, e.g., NDA 020201 (ready-to-use version) labeling 
available as the date of this notice at https://www.accessdata.fda.gov/spl/data/d1873a74-56e6-4a01-8e4d-875789e5e344/d1873a74-56e6-4a01-8e4d-875789e5e344.xml.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nomination does not explain why an attribute of each of the 
FDA-approved EQ 12.5 mg base/mL solution for dilution for intravenous 
administration products and each of the approved EQ 1 mg base/mL, EQ 2 
mg base/mL, and EQ 4 mg base/mL ready-to-administer forms is medically 
unsuitable for certain patients, or identify an attribute of the 
approved drug products that the proposed compounded drug products are 
intended to address.
    Two commenters agreed with FDA's proposal not to include dobutamine 
HCl on the 503B Bulks List. Several commenters objected generally to 
FDA's proposals in the July 2020 notice and these overarching concerns 
are addressed in section IV. No new information supporting the clinical 
need for compounding from the bulk drug substance dobutamine HCl was 
provided by the commenters.
    Accordingly, 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 a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not identify specific differences between drug 
products that would be compounded using dobutamine HCl and approved 
drug products containing dobutamine HCl, and no further information was 
supplied on this point during the comment period. Therefore, FDA finds 
no basis to conclude that the drug product proposed to be compounded 
must be prepared using a bulk drug substance.
4. Dopamine HCl
    Dopamine HCl has been nominated for inclusion on the 503B Bulks 
List to compound drug products that treat cardiogenic shock, congestive 
heart failure, decreased cardiac output, and renal failure, among other 
conditions.\34\ The proposed route of administration is intravenous, 
the proposed dosage form is a preservative-free solution, and the 
proposed concentration is 80 mg/mL. The nominators proposed to compound 
a preservative-free solution. However, they did not acknowledge that 
there is a preservative-free formulation of dopamine HCl available that 
is FDA-approved or explain why that formulation would be medically 
unsuitable for certain patients. The nominations state that dopamine 
HCl might also be used to compound other drug products, but do not 
identify those products. The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., ANDA 207707). FDA-
approved dopamine HCl is available as a single-dose, preservative-free 
40 mg/mL or 80 mg/mL solution for intravenous 
administration.<SUP>35 36</SUP>
---------------------------------------------------------------------------

    \34\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \35\ See, e.g., ANDA 207707 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/d2927591-5fe5-4704-9091-82ab08bb792b/d2927591-5fe5-4704-9091-82ab08bb792b.xml.
    \36\ According to the label for ANDA 207707, each mL contains 
metabisulfite 9 mg added as an antioxidant, citric acid, anhydrous 
10 mg, sodium citrate, and dihydrate 5 mg added as a buffer. May 
contain additional citric acid and/or sodium citrate for pH 
adjustment.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of each of the FDA-
approved preservative-free 80 mg/mL solution products is medically 
unsuitable for certain patients or identify an attribute of the 
approved drug products that the proposed compounded drug products are 
intended to address.
    Two commenters agreed with FDA's proposal not to include dopamine 
HCl on the 503B Bulks List. Several commenters objected generally to 
FDA's proposals in the July 2020 notice and these overarching concerns 
are

[[Page 4247]]

addressed in section IV. No new information supporting the clinical 
need for compounding from the bulk drug substance dopamine HCl was 
provided by the commenters.
    Accordingly, 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 a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not identify specific differences between drug 
products that would be compounded using dopamine HCl and approved drug 
products containing dopamine HCl, and no further information was 
supplied on this point during the comment period. Therefore, FDA finds 
no basis to conclude that the drug product proposed to be compounded 
must be prepared using a bulk drug substance.
5. Edetate Calcium Disodium
    Edetate calcium disodium dihydrate was nominated for inclusion on 
the 503B Bulks List to compound drug products that treat cardiovascular 
disease, diabetes, hypercholesterolemia, arthritis, cancer, and chronic 
renal failure, among other conditions.\37\ The proposed route of 
administration is slow intravenous, the proposed dosage form is a 
preservative-free injection, and the proposed concentration is 200 mg/
mL. The nominators proposed to compound a preservative-free solution. 
However, they did not acknowledge that there is a preservative-free 
formulation of edetate calcium disodium available that is FDA-approved 
or explain why that formulation would be medically unsuitable for 
certain patients. The nominated bulk drug substance is a component of 
an FDA-approved drug product (NDA 008922).\38\ FDA-approved edetate 
calcium disodium is available as a preservative-free 200 mg/mL 
injection for intravenous and intramuscular 
administration.<SUP>39 40</SUP>
---------------------------------------------------------------------------

    \37\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2302, FDA-2013-N-1524-2301, FDA-2013-N-1525-0225, FDA-2013-N-
1524-2305, and FDA-2013-N-1524-2297.
    \38\ In the nominations, the name of the nominated substance is 
listed as ``edetate calcium disodium dihydrate.'' Since the 
nominated dosage form is an injection, ``edetate calcium disodium'' 
and ``edetate calcium disodium dihydrate'' result in the same entity 
when in solution.
    \39\ See NDA 008922 labeling available as of the date of this 
notice at https://www.accessdata.fda.gov/spl/data/143830d7-46a5-49a3-b8b2-457a59533008/143830d7-46a5-49a3-b8b2-457a59533008.xml.
    \40\ Per the label for NDA 008922, edetate calcium disodium 
dihydrate is available in a preservative-free ampule. Each 5 ml 
ampule contains 1,000 mg of edetate calcium disodium (equivalent to 
200 mg/ml) in water for injection.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of the FDA-approved 
preservative-free 200 mg/mL injection is medically unsuitable for 
certain patients or identify an attribute of the approved drug product 
that the proposed compounded drug product is intended to address.
    Several commenters on FDA's proposal not to include edetate calcium 
disodium on the 503B Bulks List assert that there is a clinical need 
for a compounded drug product containing edetate calcium disodium for 
intravenous administration for heavy metal chelation and conditions 
including coronary artery disease, neuropathy, and memory loss. 
However, the commenters do not explain why an attribute of the FDA-
approved product is medically unsuitable for certain patients or 
identify an attribute of the approved drug product that the proposed 
compounded drug product is intended to address.
    Several commenters also claimed that FDA erroneously stated that 
edetate calcium disodium was available as an FDA-approved product in 
the July 2020 notice when the product was discontinued and is not 
available in manufactured form. FDA disagrees with these comments. FDA 
correctly identified the nominated bulk drug substance as a component 
of an FDA-approved drug product (NDA 008922), which is a preservative-
free 200 mg/mL injection for intravenous and intramuscular 
administration.\41\ Although a 500 mg tablet containing edetate calcium 
was approved under the same NDA number and was discontinued, this has 
no bearing on the availability of the currently marketed approved 
formulation for injection.\42\ The fact that the 500 mg tablet is no 
longer marketed does not affect our evaluation of the nomination for 
edetate calcium disodium because there is a currently-marketed FDA-
approved drug product for injection that contains edetate calcium 
disodium, and the nominators proposed to compound a drug product for 
injection. Other commenters agreed with FDA's proposal not to include 
edetate calcium disodium on the 503B Bulks List.
---------------------------------------------------------------------------

    \41\ See fn. 40.
    \42\ See drug products on NDA 008922 available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=008922.
---------------------------------------------------------------------------

    As described above, no new information supporting the clinical need 
for compounding from the bulk drug substance edetate calcium disodium 
was provided by the commenters. Taking into consideration the comments 
submitted and FDA's clinical need analysis, FDA finds no basis to 
conclude that an attribute of the approved drug product makes it 
medically unsuitable to treat certain patients for a condition that FDA 
has identified for evaluation and that a proposed compounded product is 
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not identify specific differences between drug 
products that would be compounded using edetate calcium disodium and 
the approved drug product containing edetate calcium disodium, and no 
further information was supplied on this point during the comment 
period. Therefore, FDA finds no basis to conclude that the drug product 
proposed to be compounded must be prepared using a bulk drug substance.
6. Folic Acid
    Folic acid was nominated for inclusion on the 503B Bulks List to 
compound drug products that treat megaloblastic and macrocytic 
anemias.\43\ The proposed routes of administration are intravenous, 
intramuscular, and subcutaneous, the proposed dosage forms are 
injection solutions, and the proposed concentration is 5 mg/mL. The 
nomination states that folic acid might also be used to compound other 
drug products but does not identify those products. The nominated bulk 
drug substance is a component of FDA-approved drug products (e.g., ANDA 
089202). FDA-approved folic acid is available as a 50 mg/10 mL (5 mg/
mL) solution for intravenous, intramuscular, and subcutaneous 
administration.<SUP>44 45</SUP>
---------------------------------------------------------------------------

    \43\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
    \44\ See, e.g., ANDA 089202 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26.xml.
    \45\ Folic acid is also approved as a single-active-ingredient, 
oral tablet.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nomination does not explain why an attribute of each of the 
FDA-approved 5 mg/mL solution products for

[[Page 4248]]

intravenous, intramuscular, and subcutaneous administration is 
medically unsuitable for certain patients or identify an attribute of 
the approved drug products that the proposed compounded drug product is 
intended to address.
    Two commenters agreed with FDA's proposal not to include folic acid 
on the 503B Bulks List. Several commenters objected generally to FDA's 
proposals in the July 2020 notice and these overarching concerns are 
addressed in section IV. No new information supporting the clinical 
need for compounding from the bulk drug substance folic acid was 
provided by the commenters.
    Accordingly, 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 a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not identify specific differences between drug 
products that would be compounded using folic acid and approved drug 
products containing folic acid, and no further information was supplied 
on this point during the comment period. Therefore, FDA finds no basis 
to conclude that the drug product proposed to be compounded must be 
prepared using a bulk drug substance.
7. Glycopyrrolate
    Glycopyrrolate bromide was nominated for inclusion on the 503B 
Bulks List to compound drug products that treat cardiac dysrhythmia, 
surgically induced or drug-induced vagal reflex, and peptic ulcer 
disease, among other conditions. The proposed route of administration 
is intravenous, the proposed dosage forms are both a preservative-free 
and a preserved solution, and the proposed concentration is 0.2 mg/mL. 
The nominators proposed to compound a preservative-free solution. 
However, they did not acknowledge that there is a preservative-free 
formulation of glycopyrrolate available that is FDA-approved or explain 
why that formulation would be medically unsuitable for certain 
patients. The nominations state that glycopyrrolate might also be used 
to compound other drug products, but do not identify those products. 
The nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., NDA 210997). FDA-approved glycopyrrolate is available 
as a 0.2 mg/mL in 1 mL or 2 mL preserved and preservative-free, single-
dose vials for intramuscular or intravenous 
administration.<SUP>46 47 48</SUP>
---------------------------------------------------------------------------

    \46\ See, e.g., NDA 210997 and ANDA 208973 labeling available as 
of the date of this notice at https://www.accessdata.fda.gov/spl/data/6a379327-0f29-44a4-ba4f-54cb9379f854/6a379327-0f29-44a4-ba4f-54cb9379f854.xml and https://www.accessdata.fda.gov/spl/data/fdebc248-87d3-4afd-a5ed-592fcaddab1c/fdebc248-87d3-4afd-a5ed-592fcaddab1c.xml.
    \47\ Per the label for NDA 210997, glycopyrrolate is available 
in a preservative-free, single-dose vial. Per the label for ANDA 
208973, glycopyrrolate is available in preserved, single-dose and 
multiple-dose vials.
    \48\ Glycopyrrolate is also approved as an oral tablet, oral 
solution, and for inhalation as a single-active-ingredient product.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not explain why an attribute of the FDA-approved 
0.2 mg/mL preservative-free and the FDA-approved preserved solutions 
for intramuscular or intravenous administration are medically 
unsuitable for certain patients or identify an attribute of the 
approved drug products that the proposed compounded drug products are 
intended to address. Two commenters agreed with FDA's proposal not to 
include glycopyrrolate on the 503B Bulks List. No new information 
supporting the clinical need for compounding from the bulk drug 
substance glycopyrrolate was provided by the commenters.
    Accordingly, 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 a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not identify specific differences between drug 
products that would be compounded using glycopyrrolate and approved 
drug products containing glycopyrrolate.
    One commenter submitted arguments regarding the need for 
compounding from the bulk drug substance. The commenter stated that 
outsourcing facilities supply a substantial portion of the market for 
glycopyrrolate injectable products and not including glycopyrrolate on 
the 503B Bulks List will remove substantial volume from the market and 
may create a shortage for that product. In addition, the commenter 
stated that glycopyrrolate products compounded from bulk drug 
substances are ready-to-use, an attribute that is essential for a 
medication used in emergency situations, and are a safer alternative to 
commercially available drug products. The commenter also stated that 
the additional manipulations required to compound a drug product using 
the FDA-approved finished product as a starting material would be 
costly in both labor and time.
    FDA disagrees with this comment. Regarding the comment's concern 
about a shortage, as noted above, section 503B(a)(2)(A) of the FD&C Act 
allows compounding from bulk drug substances if the drug product 
compounded from such bulk drug substance is on the drug shortage list 
in effect under section 506E of the FD&C Act at the time of 
compounding, distribution, and dispensing. The Agency does not 
interpret supply issues, such as shortages and backorders, to be within 
the meaning of ``clinical need'' for compounding with a bulk drug 
substance.\49\
---------------------------------------------------------------------------

    \49\ See the 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) (Ref. 2) and 
the March 2019 Federal Register notice entitled ``List of Bulk Drug 
Substances for Which There Is a Clinical Need Under Section 503B of 
the Federal Food, Drug, and Cosmetic Act'' (84 FR 7383).
---------------------------------------------------------------------------

    Regarding the concern about ready-to-use drug products, the comment 
does not establish that drug products, including ready-to-use products, 
cannot be prepared from the approved glycopyrrolate drug products. 
Rather, the commenter proposes to compound ready-to-use products from 
bulk drug substances to seek improved efficiency for prescribers or 
healthcare providers and to address the possibility that the approved 
drug might be mishandled by a medical professional; neither of which 
falls within the meaning of clinical need to compound a drug product 
using a bulk drug substance.
    Regarding the concern about starting from an FDA-approved drug 
product, FDA does not interpret considerations of cost to be within the 
meaning of ``clinical need.'' Allowing outsourcing facilities to 
compound a drug product from a bulk drug substance that is a component 
of an FDA-approved drug product because of economic incentives, when 
the approved drug product, or a drug product compounded from the 
approved drug product, would be medically appropriate for the patient, 
would undermine the incentive for applicants to seek FDA approval of 
drug products.
    Having considered these arguments, and because and no further 
information

[[Page 4249]]

was supplied regarding the clinical need for compounding from the bulk 
drug substance, FDA finds no basis to conclude that the drug product 
proposed to be compounded must be prepared using a bulk drug substance.
8. Sodium Thiosulfate
    Sodium thiosulfate was nominated for inclusion on the 503B Bulks 
List for the treatment of calciphylaxis, cyanide toxicity, 
extravasation, Malassezia furfur, and nephrotoxicity prophylaxis.\50\ 
Sodium thiosulfate was nominated as a 250 mg/mL injectable, for 
intravenous, intradermal, intramuscular, and subcutaneous 
administration, and in a topical dosage form at an unknown 
concentration. FDA intends to address the topical route of 
administration in a future Federal Register notice because a comment 
provided additional support for FDA to evaluate it. FDA is not making a 
decision on sodium thiosulfate for topical administration at this time 
and compounded drug products that contain sodium thiosulfate for 
topical administration may be eligible for the enforcement discretion 
policy described in FDA's Interim Policy provided the circumstances 
described in the guidance are present. FDA's evaluation here addresses 
the clinical need for a compounded sodium thiosulfate drug product 
except for topical administration. The nominated bulk drug substance is 
a component of an FDA-approved drug product (NDA 203923). FDA-approved 
sodium thiosulfate is available as a 12.5 g/50 mL (250 mg/mL) solution 
for intravenous administration.<SUP>51 52</SUP>
---------------------------------------------------------------------------

    \50\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0173.
    \51\ See, e.g., NDA 203923 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/29449d76-f4c7-4571-b7bb-5c2a55f637b5/29449d76-f4c7-4571-b7bb-5c2a55f637b5.xml.
    \52\ Sodium thiosulfate is also approved for sequential use with 
sodium nitrite for intravenous administration.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    As relevant to the present analysis, sodium thiosulfate was 
nominated for injectable (intravenous, intradermal, intramuscular, 
subcutaneous) administration for the treatment of calciphylaxis, 
cyanide toxicity, extravasation, and nephrotoxicity prophylaxis.
i. Calciphylaxis
    The nominator proposes to produce an injectable compounded sodium 
thiosulfate drug product without potassium chloride to be used in the 
treatment of calciphylaxis. The nominator asserts that the safety of 
the approved product is of concern because the potassium level of the 
product is too high for patients with renal disease or impairment. This 
assertion is inaccurate because the amount of potassium from the 
approved sodium thiosulfate product (440 mg of a 25 g dose) is small 
relative to the amount removed in a typical dialysis session (Refs. 14 
and 15).\53\
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    \53\ Even in circumstances where it is not administered during 
dialysis, the amount of potassium in the approved product is small 
and potassium levels could be monitored for safety. See, e.g., Ref. 
9 (providing, ``The median dose of STS treatment was 25 g 
administered intravenously in 100 ml of normal saline given over the 
last half-hour of each HD session'') and Ref. 10 (studying dialysis 
patients on ``25 grams intravenously diluted in 100 mL of sodium 
chloride 0.9 percent administered over 30 to 60 minutes 3 times per 
week during the last hour or after the hemodialysis session.'')
---------------------------------------------------------------------------

    The nomination proposes to make a 250 mg/mL injectable, as well as 
unspecified higher concentrations. The nomination states that it may be 
necessary to compound a product with a greater concentration than is 
commercially available, but the nomination does not identify specific 
higher concentrations that the nominator proposes to compound or 
provide any data or information supporting the need for a higher 
concentration. In addition, FDA is not aware of patients who would need 
concentrations above 250 mg/mL. The approved product is available as a 
concentrated solution (12.5 g/50 mL). Although the product is generally 
diluted in normal saline before administration to minimize potential 
complications associated with the intravenous infusion of a hypertonic 
solution, it logically follows that a concentrated, compounded sodium 
thiosulfate product would also need to be diluted before administration 
for the same reason. In addition, when used for the treatment of 
calciphylaxis in hemodialysis patients, the product is administered 
during dialysis, which allows for removal of excess fluid (Refs. 9 to 
11) (discussing how sodium thiosulfate is generally used to treat 
calciphylaxis).
    Commenters on FDA's proposal not to include sodium thiosulfate on 
the 503B Bulks List continue to assert that there is a clinical need 
for potassium-free compounded sodium thiosulfate to treat calciphylaxis 
in hemodialysis patients. However, none of the literature pertaining to 
potassium referenced in the comments demonstrates that there is an 
attribute of the FDA-approved sodium thiosulfate drug product that 
makes it medically unsuitable to treat certain patients for 
calciphylaxis due to the presence of potassium in the approved product. 
None of the referenced literature pertaining to potassium provided 
additional justification or data to support the commenters' assertion 
that the amount of potassium in the approved sodium thiosulfate 
injectable product is clinically significant and problematic for some 
calciphylaxis patients receiving dialysis. We disagree that the 
potassium content in the approved sodium thiosulfate product poses an 
increased risk of hyperkalemia when used off-label for the management 
of calciphylaxis during hemodialysis. Patients on hemodialysis are 
generally permitted to take in potassium (i.e., <3 g or ~70 
milliequivalents (mEq/day). The amount of potassium being administered 
with the approved sodium thiosulfate product, i.e., 440 mg of potassium 
chloride or ~ 6 mEq of potassium, is a fraction of the amount that the 
average dialysis patient is permitted per day.
    Accordingly, FDA finds no basis to conclude that an attribute of 
the FDA-approved product makes it medically unsuitable to treat 
patients with calciphylaxis and that the sodium thiosulfate drug 
products proposed to be compounded are intended to address.\54\
---------------------------------------------------------------------------

    \54\ In making this observation, we do not suggest that the 
approved drug product, or products prepared from it, are approved 
for the use proposed by the nomination. Here we are asking a 
limited, threshold question to determine whether there might be 
clinical need for a compounded drug product, by asking what 
attributes of the approved drug the proposed compounded drug would 
change, and why. Asking this question helps ensure that if a bulk 
drug substance is included on the 503B Bulks List, it is to compound 
drugs that include a needed change to an approved drug product 
rather than to produce drugs without such a change. Because our 
answer to question 1. is ``no'', we do not evaluate the available 
evidence of effectiveness or lack of effectiveness of a drug product 
compounded with sodium thiosulfate for the treatment of 
calciphylaxis. We note that the references cited by the nominator 
appear to be general reviews of potassium homeostasis and studies in 
other populations showing associations between potassium excretion 
or potassium levels and clinical outcomes. None of these references 
address whether there is a risk posed by the amount of potassium in 
the approved product to patients receiving sodium thiosulfate for 
the treatment of calciphylaxis.
---------------------------------------------------------------------------

ii. Cyanide Toxicity
    The nomination also proposes to combine sodium thiosulfate with 
sodium nitroprusside to reduce the risk of cyanide toxicity during 
sodium nitroprusside administration. Sodium thiosulfate is FDA-approved 
for sequential use with sodium nitrite for treatment of acute cyanide 
poisoning that is judged to be serious or life-

[[Page 4250]]

threatening. The nomination states that sodium thiosulfate is commonly 
administered with sodium nitroprusside, but the nomination does not 
identify the final product formulation proposed to be compounded (e.g., 
dosage form and strength of each ingredient).\55\ Sodium nitroprusside 
was also nominated separately (see FDA's analysis in the July 2020 
notice), but that nomination does not mention the use of sodium 
nitroprusside in combination with sodium thiosulfate.
---------------------------------------------------------------------------

    \55\ While the nomination does not provide final product 
formulation information, it does include an article (Ref. 12), which 
reports on the stability of a 1:10 sodium nitroprusside: sodium 
thiosulfate admixture stored up to 48 hours when compounded from the 
approved products.
---------------------------------------------------------------------------

    The nomination states that providing sodium thiosulfate and sodium 
nitroprusside in a combined compounded preparation would allow for 
faster administration in the clinical setting and fewer human 
manipulations, thus reducing the rate of error. We do not consider the 
risk that a clinician may mishandle the approved product to be an 
indicator of clinical need. Further, the approved labeling for sodium 
nitroprusside states that no other drugs should be administered in the 
same solution with sodium nitroprusside. The nomination has not 
identified any patients for whom co-administration of both approved 
drug products would not be medically appropriate, and for whom 
compounding a drug product with both active ingredients in one solution 
would address an unmet medical need. No new information supporting the 
clinical need for compounding from the bulk drug substance sodium 
thiosulfate to make drug products for the treatment of cyanide toxicity 
was provided by the commenters.
    Accordingly, with respect to the combination sodium thiosulfate and 
sodium nitroprusside drug 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 and that the 
proposed compounded drug products are intended to address.
iii. Extravasation and Nephrotoxicity Prophylaxis
    The nomination does not identify an attribute of the approved 
products that makes them medically unsuitable for the conditions listed 
above and that the proposed compounded injectable drug products are 
intended to address. No new information supporting the clinical need 
for compounding from the bulk drug substance sodium thiosulfate to make 
drug products for these uses was provided by the commenters. 
Accordingly, FDA finds no basis to conclude that an attribute of the 
FDA-approved products makes them medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because 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 a proposed compounded product is intended to address, for the 
reasons described above, we do not consider whether there is a basis to 
conclude that the drug products proposed to be compounded must be 
prepared using a bulk drug substance rather than an FDA-approved drug 
product.
c. Listing Determination for Sodium Thiosulfate (Except for Topical 
Administration)
    In addition to the comments discussed above, two other commenters 
agreed with FDA's proposal not to include sodium thiosulfate on the 
503B Bulks List. As discussed in more detail above, the information 
supporting the clinical need for compounding from the bulk drug 
substance sodium thiosulfate to produce drug products (except for 
topical administration) provided by the commenters does not alter FDA's 
view that there is no clinical need for compounding from the bulk drug 
substance for these uses. FDA therefore finds that there is no clinical 
need for compounding from the bulk drug substance sodium thiosulfate to 
produce drug products (except for topical administration) under section 
503B of the FD&C Act, and we have determined that it will not be placed 
on the 503B Bulks List. Sodium thiosulfate for topical administration 
only remains under consideration by the Agency at this time, and as 
noted above may be eligible for the enforcement discretion policy 
described in FDA's Interim Policy provided the circumstances described 
in the guidance are present.

IV. Other Issues Raised in Nominations and Comments

    Two commenters expressed concern that nominations submitted before 
FDA issued the Clinical Need Guidance in March 2019 are disadvantaged 
in demonstrating clinical need because the nominators might not have 
fully understood FDA's thinking on clinical need when they submitted 
their nominations.\56\ In addition, one commenter expressed concern 
that FDA is evaluating bulk drug substances for clinical need pursuant 
to a non-binding guidance document. FDA disagrees with these comments. 
First, as explained in section II.B, FDA is evaluating bulk drug 
substances nominated for inclusion on the 503B Bulks List under the 
``clinical need'' standard provided by the FD&C Act as amended by the 
Drug Quality and Security Act in 2013.\57\ The analysis under the 
statutory ``clinical need'' standard described in this notice is 
consistent with the approach described in FDA's Clinical Need Guidance. 
Second, the commenters fail to note the many opportunities that 
nominators and interested members of the public had to provide 
information supporting a clinical need to compound drug products 
containing the bulk drug substances that are the subject of this 
notice. As explained in section II.A, a public docket, FDA-2015-N-3469, 
is available for interested persons to submit nominations, including 
updated or revised nominations, or comments on nominated substances. 
Furthermore, during the comment periods for the September 2019 and July 
2020 Federal Register notices, commenters had an additional opportunity 
to submit comments to the docket associated with those notices to 
provide additional supporting information for the bulk drug substances 
that are the subject of this notice, and many did so. Moreover, in 
response to a request from a commenter, FDA reopened the comment period 
on the July 2020 Federal Register notice for an additional 30 days to 
allow interested persons yet another opportunity to submit additional 
comments.
---------------------------------------------------------------------------

    \56\ See 84 FR 7383, which is available at https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the.
    \57\ See Public Law 113-54, Sec.  102(a), (2013), which is 
available at https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf.
---------------------------------------------------------------------------

    Three commenters on the bulk drug substances addressed in this 
notice assert that FDA is regulating and interfering with the practice 
of medicine by not placing bulk drug substances on the 503B Bulks List 
despite some physicians wanting to prescribe drug products compounded 
from those bulk drug substances. FDA disagrees with these comments. The 
Agency's evaluation under the clinical need standard only regulates the 
ability of certain compounded drug products to reach the market and is 
well within the

[[Page 4251]]

Agency's authorities.\58\ The Agency is fulfilling its statutory 
mandate of regulating outsourcing facilities' production and 
distribution of compounded drug products, not interfering with 
physicians' clinical decisions regarding which drug products to 
prescribe. Indeed, a Federal court considered the very claim raised in 
these comments and determined that FDA's evaluation under the clinical 
need standard ``regulates the type of drug that reaches the 
marketplace,'' a decision that ``rests well within FDA's regulatory 
authority under the FDCA . . . and . . . does not intrude on the 
practice of medicine.'' \59\
---------------------------------------------------------------------------

    \58\ See United States v. Evers, 643 F.2d 1043, 1048 (5th Cir. 
1981) (``[W]hile the [FDCA] was not intended to regulate the 
practice of medicine, it was obviously intended to control the 
availability of drugs for prescribing by physicians.''); United 
States v. Regenerative Scis., LLC, 741 F.3d 1314, 1319-20 (DC Cir. 
2014); (citing Evers and noting that the FDCA ``regulate[s] the 
distribution of drugs by licensed physicians''); Gonzales v. Raich, 
545 U.S. 1, 28 (2005) (``the dispensing of new drugs, even when 
doctors approve their use must await federal approval.'').
    \59\ Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 (D.D.C. 2019).
---------------------------------------------------------------------------

    One commenter expressed concern that FDA is promoting the off-label 
use of FDA-approved drug products. FDA disagrees with this comment. In 
performing the clinical need evaluation, FDA asks a limited, threshold 
question to determine whether there might be a clinical need for a 
compounded drug product, by asking what attributes of the approved drug 
product the proposed compounded drug product would change, and why. 
Asking this question helps ensure that if a bulk drug substance is 
included on the 503B Bulks List, it is to compound drug products that 
include a needed change to an approved drug product rather than to 
compound drug products without such a change. We do not suggest that 
the approved drug product, or products prepared from it, are approved 
for the use proposed by the nomination being evaluated.
    One commenter expressed concern with FDA's decision to evaluate 
clinical need in the context of the specific drug products proposed to 
be compounded in the nomination. These comments stated that requiring 
nominators to provide information on specific drug products is 
unnecessary to determine whether there is a clinical need for the bulk 
drug substance. This commenter also asserts that FDA should not 
evaluate bulk drug substances in the context of finished dosage forms 
for drug products. FDA disagrees with these comments. As explained in 
section I of this notice, section 503B of the FD&C Act limits the bulk 
drug substances that outsourcing facilities can use in compounding to 
those that are used to compound drugs in shortage or that appear on a 
list developed by FDA of bulk drug substances for which there is a 
clinical need.\60\ Section 503B of the FD&C Act includes this 
limitation, among others, to help ensure that outsourcing facilities do 
not grow into conventional manufacturing operations making unapproved 
new drug products without complying with critical requirements, such as 
new drug approval. Outsourcing facilities, as opposed to other 
compounders, may compound and distribute drug products for ``office 
stock'' without first receiving a prescription for an individually 
identified patient \61\ and without conditions on interstate 
distribution that are applicable to other compounded drugs.\62\ Because 
of these differences and others, section 503B of the FD&C Act places 
different conditions on drugs compounded by outsourcing facilities, 
including limitation on the outsourcing facilities' use of bulk drug 
substances, which are more stringent than those placed on other 
compounders' use of bulk drug substances.\63\ The clinical need 
standard in section 503B of the FD&C Act requires FDA to perform a 
sorting function--to distinguish bulk drug substances for which there 
is a clinical need from those for which there is not--and this requires 
the FDA to apply its expertise to consider whether there is a need for 
the finished drug product that would be compounded from the bulk drug 
substance. Indeed, a Federal court considered the very claim raised in 
these comments and determined that ``[o]nly when `clinical need' is 
assessed against the availability and suitability of an approved drug 
does the term perform the classifying function that Congress 
intended.'' In reaching this view, the court found that only when the 
clinical need evaluation ``considers the actual way in which the active 
pharmaceutical ingredient supplies a therapeutic benefit--by its 
administration as a finished drug product--does the inquiry produce the 
categorization that Congress surely envisioned'' in enacting section 
503B of the FD&C Act.\64\ FDA's clinical need assessments help limit 
patient exposure to compounded drug products that have not been 
demonstrated to be safe and effective to those situations in which the 
compounded drug product is necessary for patient treatment. In 
addition, FDA's assessments preserve the incentives for applicants to 
invest in the research and testing required to obtain FDA approval and 
continue to manufacture FDA-approved drug products, thereby helping to 
maintain a supply of high-quality, safe, and effective drugs.
---------------------------------------------------------------------------

    \60\ Section 503B(a)(2(A)(i) and (ii) of the FD&C Act.
    \61\ By contrast, to qualify for the exemptions in section 503A 
of the FD&C Act, drug products compounded by licensed pharmacists in 
State-licensed pharmacies or Federal facilities, or by licensed 
physicians, must be compounded be based on the receipt of a valid 
prescription for an individually identified patient. This means that 
for drug products compounded under section 503A to meet the 
conditions of that section and qualify for the exemptions in the 
statute, the pharmacist or physician compounding under section 503A 
of the FD&C Act must compound either: (1) After receiving a valid 
prescription for an identified, individual patient or (2) before 
receiving a patient-specific prescription, in limited quantities, 
based on a history of receiving valid orders generated solely within 
the context of an established relationship with the patient or 
prescriber. See FDA's final guidance for industry ``Prescription 
Requirement Under Section 503A of the Federal Food, Drug, and 
Cosmetic Act'' (December 2016) (Ref. 13).
    \62\ For drug products compounded under section 503A of the FD&C 
Act to meet the conditions of that section and qualify for the 
exemptions in the statute, drug products must be compounded in a 
State; (i) that has entered into a memorandum of understanding with 
the Secretary which addresses the distribution of inordinate amounts 
of compounded drug products interstate and provides for appropriate 
investigation by a State agency of complaints relating to compounded 
drug products distributed outside such State or (ii) that has not 
entered into the memorandum of understanding described in clause (i) 
and the licensed pharmacist, licensed pharmacy, or licensed 
physician distributes (or causes to be distributed) compounded drug 
products out of the State in which they are compounded in quantities 
that do not exceed 5 percent of the total prescription orders 
dispensed or distributed by such pharmacy or physician (see section 
503A(b)(3)(a)(B)(i) and (ii) of the FD&C Act).
    \63\ Licensed pharmacies and physicians who compound drugs under 
the conditions of section 503A of the FD&C Act, including the 
requirement to compound drugs only pursuant to a prescription for an 
identified individual patient, may use many bulk drug substances by 
operation of the statute, without action by FDA. See section 
503A(b)(1)(A)(i)(I) and (II) of the FD&C Act (providing that a drug 
product may be compounded consistent with the exemptions in section 
503A of the FD&C Act if the licensed pharmacist or licensed 
physician compounds the drug product using bulk drug substances that 
comply with the standards of an applicable USP or NF monograph, if a 
monograph exists, and the USP chapters on pharmacy compounding; or 
if such a monograph does not exist, are drug substances that are 
components of drugs approved by the Secretary).
    \64\ Athenex Inc. at 65.
---------------------------------------------------------------------------

    Some of the bulk drug substance nominations and comments assert 
that there could be a benefit gained from using a bulk drug substance 
to compound drug products that do not require the manipulations that 
the approved drug products that contain these bulk drug substances 
require before they can be administered (e.g., dilution or drawing the 
drug into a syringe before administration). As explained above, when a 
bulk drug substance is a component of an approved drug, we asked 
whether there

[[Page 4252]]

is a basis to conclude that an attribute of each approved drug product 
makes each one medically unsuitable to treat certain patients for their 
condition, an interpretation that protects patients and the integrity 
of the drug approval process. The nominations proposing to compound 
drug products in ready-to-use form containing bulk drug substances in 
one or more FDA-approved drug products do not show that the approved 
drug product, when not manufactured in the ready-to-use form, is 
medically unsuitable for certain patients. Nor do the nominations and 
comments establish that drug products in the relevant concentrations, 
including ready-to-use products, cannot be prepared from the approved 
drug products. Rather, they propose to compound a ready-to-use product 
from bulk drug substances to seek improved efficiency for prescribers 
or healthcare providers, or to address the possibility that the 
approved drug might be mishandled by a medical professional, neither of 
which falls within the meaning of clinical need to compound a drug 
product using a bulk drug substance.
    Two comments requested changes to the Interim Policy. These 
comments are outside the scope of FDA's bulk drug substance evaluations 
and decisions that are the subject of this notice. FDA welcomes public 
comments on its guidance documents that address human drug compounding. 
We encourage comments on the Interim Policy to be submitted the docket 
for the guidance, docket number FDA-2015-D-3539. Comments may be 
submitted to this docket at any time on https://www.regulations.gov.

V. Conclusion

    For the reasons stated above, we find that there is a clinical need 
for outsourcing facilities to compound using the bulk drug substances 
DPCP for topical use only, glycolic acid for topical use only in 
concentrations up to 70 percent, SADBE for topical use only, and TCA 
for topical use only and, therefore, we are now including them on the 
503B Bulks List. In addition, we find that there is no clinical need 
for outsourcing facilities to compound using the bulk drug substances 
diazepam, dipyridamole, dobutamine HCl, dopamine HCl, edetate calcium 
disodium, folic acid, glycopyrrolate, and sodium thiosulfate (except 
for topical administration), and therefore we are not including these 
bulk drug substances on the 503B Bulks List.

VII. 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 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 Diphenylcyclopropenone 
(DPCP) in Compounding Under Section 503B of the FD&C Act, July 2020.
*4. FDA Memorandum to File, Clinical Need for Glycolic Acid in 
Compounding Under Section 503B of the FD&C Act, July 2020.
*5. FDA Memorandum to File, Clinical Need for Squaric Acid Dibutyl 
Ester (SADBE) in Compounding Under Section 503B of the FD&C Act, 
July 2020.
*6. FDA Memorandum to File, ``Clinical Need for Trichloroacetic Acid 
(TCA) in Compounding Under Section 503B of the FD&C Act,'' July 
2020.
7. Leheta, T. M., A. El Tawdy, R. M. Abdel Hay, and S. Farid, 2011, 
``Percutaneous Collagen Induction Versus Full-Concentration 
Trichloroacetic Acid in the Treatment of Atrophic Acne Scars,'' 
Dermatologic Surgery, 37(2):207-216.
8. Kumari, R. and D. M. Thappa, 2010, ``Comparative Study of 
Trichloroacetic Acid Versus Glycolic Acid Chemical Peels in the 
Treatment of Melasma,'' Indian Journal of Dermatology, Venereology 
and Leprology, 76:447, available at https://ijdvl.com/comparative-study-of-trichloroacetic-acid-versus-glycolic-acid-chemical-peels-in-the-treatment-of-melasma/.
9. Nigwekar, S. U., S. M. Brunelli, D. Meade, et al., 2013, ``Sodium 
Thiosulfate Therapy for Calcific Uremic Arteriolopathy,'' Clinical 
Journal of the American Society of Nephrology, 8(7):1162-1170.
10. Generali, J. A. and D. J. Cada, 2015, ``Sodium Thiosulfate: 
Calciphylaxis,'' Hospital Pharmacy, 50(11):975-977.
11. Udomkarnjananun, S., K. Kongnatthasate, K. Praditpornsilpa, et 
al., 2019, ``Treatment of Calciphylaxis in CKD: A Systematic Review 
and Meta-Analysis,'' Kidney International Reports, 4(2):231-244.
12. Schulz, L. T., E. J. Elder, Jr, K. J. Jones, et al., 2010, 
``Stability of Sodium Nitroprusside and Sodium Thiosulfate 1:10 
Intravenous Admixture,'' Hospital Pharmacy, 45(10):779-784.
*13. FDA Guidance for Industry, Prescription Requirement Under 
Section 503A of the Federal Food, Drug, and Cosmetic Act, December 
2016 (available at https://www.fda.gov/media/97347/download).
14. Pun, Patrick H. and John P. Middleton, 2017, ``Dialysate 
Potassium, Dialysate Magnesium, and Hemodialysis Risk,'' Journal of 
the American Society of Nephrology, 28: 3441-3451.
15. De Nicola, L., V. Bellizzi, R. Minutolo, et al., 2000, ``Effect 
of Dialysate Sodium Concentration on Interdialytic Increase of 
Potassium,'' Journal of the American Society of Nephrology, 11:2337-
2343.

    Dated: January 21, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-01558 Filed 1-26-22; 8:45 am]
BILLING CODE 4164-01-P