Notice2022-01558
List of Bulk Drug Substances for Which There Is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act
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Published
January 27, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency or we) is evaluating substances that have been nominated for inclusion on a list of bulk drug substances (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.
Full Text
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<title>Federal Register, Volume 87 Issue 18 (Thursday, January 27, 2022)</title>
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[Federal Register Volume 87, Number 18 (Thursday, January 27, 2022)]
[Notices]
[Pages 4240-4252]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 <a href="https://www.fda.gov/media/120692/download">https://www.fda.gov/media/120692/download</a>. FDA will only place a bulk drug
substance on the 503B Bulks List when it has determined there
[[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 <a href="https://www.fda.gov/media/94402/download">https://www.fda.gov/media/94402/download</a>.
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B. Analysis of Substances Nominated for the List
As noted above, the 503B Bulks List will include bulk drug
substances for which there is a clinical need. The 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
<a href="https://www.fda.gov/media/121315/download">https://www.fda.gov/media/121315/download</a>. This guidance describes
FDA policies for developing the 503B Bulks List and the Agency's
interpretation of the phrase ``bulk drug substances for which there
is a clinical need'' as it is used in section 503B. The analysis
under the statutory ``clinical need'' standard described in this
notice is consistent with the approach described in FDA's guidance.
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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
[[Page 4243]]
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
[[Page 4244]]
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).
---------------------------------------------------------------------------
\21\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-1363.
---------------------------------------------------------------------------
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 <a href="https://www.accessdata.fda.gov/spl/data/4e800d0d-2181-49b1-a2c8-4c6c49edd83a/4e800d0d-2181-49b1-a2c8-4c6c49edd83a.xml">https://www.accessdata.fda.gov/spl/data/4e800d0d-2181-49b1-a2c8-4c6c49edd83a/4e800d0d-2181-49b1-a2c8-4c6c49edd83a.xml</a>.
\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 <a href="https://www.accessdata.fda.gov/spl/data/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175.xml">https://www.accessdata.fda.gov/spl/data/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175/baa2cb6d-2b97-4ad3-a5fc-bad3b8bc6175.xml</a>.
\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 <a href="https://www.accessdata.fda.gov/spl/data/7b9ea626-7073-2e77-e053-2a91aa0a9215/7b9ea626-7073-2e77-e053-2a91aa0a9215.xml">https://www.accessdata.fda.gov/spl/data/7b9ea626-7073-2e77-e053-2a91aa0a9215/7b9ea626-7073-2e77-e053-2a91aa0a9215.xml</a>.
\33\ See, e.g., NDA 020201 (ready-to-use version) labeling
available as the date of this notice at <a href="https://www.accessdata.fda.gov/spl/data/d1873a74-56e6-4a01-8e4d-875789e5e344/d1873a74-56e6-4a01-8e4d-875789e5e344.xml">https://www.accessdata.fda.gov/spl/data/d1873a74-56e6-4a01-8e4d-875789e5e344/d1873a74-56e6-4a01-8e4d-875789e5e344.xml</a>.
---------------------------------------------------------------------------
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 <a href="https://www.accessdata.fda.gov/spl/data/d2927591-5fe5-4704-9091-82ab08bb792b/d2927591-5fe5-4704-9091-82ab08bb792b.xml">https://www.accessdata.fda.gov/spl/data/d2927591-5fe5-4704-9091-82ab08bb792b/d2927591-5fe5-4704-9091-82ab08bb792b.xml</a>.
\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 <a href="https://www.accessdata.fda.gov/spl/data/143830d7-46a5-49a3-b8b2-457a59533008/143830d7-46a5-49a3-b8b2-457a59533008.xml">https://www.accessdata.fda.gov/spl/data/143830d7-46a5-49a3-b8b2-457a59533008/143830d7-46a5-49a3-b8b2-457a59533008.xml</a>.
\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 <a href="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=008922">https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=008922</a>.
---------------------------------------------------------------------------
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 <a href="https://www.accessdata.fda.gov/spl/data/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26.xml">https://www.accessdata.fda.gov/spl/data/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26/d1a4f664-040d-4c6d-b137-e0a0a9e7bf26.xml</a>.
\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 <a href="https://www.accessdata.fda.gov/spl/data/6a379327-0f29-44a4-ba4f-54cb9379f854/6a379327-0f29-44a4-ba4f-54cb9379f854.xml">https://www.accessdata.fda.gov/spl/data/6a379327-0f29-44a4-ba4f-54cb9379f854/6a379327-0f29-44a4-ba4f-54cb9379f854.xml</a> and <a href="https://www.accessdata.fda.gov/spl/data/fdebc248-87d3-4afd-a5ed-592fcaddab1c/fdebc248-87d3-4afd-a5ed-592fcaddab1c.xml">https://www.accessdata.fda.gov/spl/data/fdebc248-87d3-4afd-a5ed-592fcaddab1c/fdebc248-87d3-4afd-a5ed-592fcaddab1c.xml</a>.
\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\
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\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).
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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 <a href="https://www.accessdata.fda.gov/spl/data/29449d76-f4c7-4571-b7bb-5c2a55f637b5/29449d76-f4c7-4571-b7bb-5c2a55f637b5.xml">https://www.accessdata.fda.gov/spl/data/29449d76-f4c7-4571-b7bb-5c2a55f637b5/29449d76-f4c7-4571-b7bb-5c2a55f637b5.xml</a>.
\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\
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\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.
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\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 <a href="https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the">https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the</a>.
\57\ See Public Law 113-54, Sec. 102(a), (2013), which is
available at <a href="https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf">https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf</a>.
---------------------------------------------------------------------------
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\
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\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.
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\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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
*1. FDA, 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 <a href="https://www.fda.gov/media/94402/download">https://www.fda.gov/media/94402/download</a>).
*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 <a href="https://www.fda.gov/media/121315/download">https://www.fda.gov/media/121315/download</a>).
*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,''
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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
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</html>Indexed from Federal Register on January 27, 2022.
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