[Federal Register Volume 84, Number 42 (Monday, March 4, 2019)]
[Notices]
[Pages 7383-7388]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-03810]
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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 or Agency) is evaluating
substances that have been nominated for inclusion on a list of bulk
drug substances (active pharmaceutical ingredients) for which there is
a clinical need (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 two bulk drug substances that FDA has considered and
is not including on the list at this time: Nicardipine hydrochloride
and vasopressin. 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 March 4, 2019.
ADDRESSES: Submit electronic comments on bulk drug substances nominated
for the 503B Bulks List to Docket No. FDA-2015-N-3469. Submit written
comments on bulk drug substances nominated for the 503B Bulks List to
the Dockets Management Staff (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should
be identified with the docket number found in brackets in the heading
of this document.
FOR FURTHER INFORMATION CONTACT: Elizabeth Hankla, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5216,
[[Page 7384]]
Silver Spring, MD 20993, 301-796-3110.
SUPPLEMENTARY INFORMATION:
I. Background
A. Drug Compounding
Compounded drug products can serve an important role for patients
for whom an FDA-approved drug product is not appropriate, such as
patients who have an allergy and need a medication to be made without a
certain dye or hospital inpatients who need infusions of a drug
combined with a particular diluent not specified in the approved
product labeling. However, they also pose a higher risk to patients
than FDA-approved drugs. In 2012, contaminated injectable drug products
that a State-licensed compounding pharmacy shipped to patients and
healthcare practitioners across the country caused a fungal meningitis
outbreak that resulted in more than 60 deaths and 750 cases of
infection.\1\ This was the most serious of a long history of outbreaks
and other serious adverse events associated with contaminated,
superpotent, or otherwise poor quality compounded drugs.
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\1\ See https://www.cdc.gov/HAI/outbreaks/meningitis.html.
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In response to this outbreak, Congress enacted the Drug Quality and
Security Act (Pub. L. 113-54), which, among other things, added new
section 503B to the FD&C Act (21 U.S.C. 353b) and created a new
category of compounders known as outsourcing facilities.\2\ Drug
products compounded by outsourcing facilities in accordance with the
conditions of section 503B are exempt from the following three sections
of the FD&C Act: 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 (21 U.S.C. 360eee-1) (concerning drug supply chain
security requirements).\3\
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\2\ See Public Law 113-54, section 102(a), 127 Stat. 587, 587-
588 (2013). Other compounders, which are not the subject of this
notice, are regulated under section 503A of the FD&C Act (21 U.S.C.
353a). These include licensed pharmacists in State-licensed
pharmacies or Federal facilities, and licensed physicians, who have
not registered an outsourcing facility with FDA. Drug products
compounded by section 503A compounders are exempt from sections 505
(new drug approval requirements), 502(f)(1) (labeling with adequate
directions for use), and 501(a)(2)(B) (CGMP requirements) if the
conditions of section 503A are met, including that compounding is
based on the receipt of valid prescriptions for identified
individual patients (section 503A(a)). In general, section 503A
compounders do not register with and are not routinely inspected by
FDA and are primarily overseen by the States.
\3\ Section 503B(a) of the FD&C Act.
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Drug products compounded under 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)).\4\
Outsourcing facilities are also subject to FDA inspections according to
a risk-based schedule, specific adverse event reporting requirements,
and other conditions that help to mitigate the risks of the drug
products they compound.\5\ Outsourcing facilities may or may not obtain
prescriptions for identified individual patients and may, therefore,
distribute compounded drugs to healthcare practitioners for ``office
stock'' to hold in their offices in advance of patient need.\6\
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\4\ Compare section 503A(a) of the FD&C Act (exempting drugs
compounded in accordance with section 503A from CGMP requirements)
with section 503B(a) of the FD&C Act (not exempting drugs compounded
in accordance with section 503B from CGMP requirements).
\5\ Section 503B(b)(4) and (5) of the FD&C Act.
\6\ Section 503B(d)(4)(C) of the FD&C Act.
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Because compounded drug products are not FDA-approved, they have
not undergone FDA premarket review for safety, effectiveness, and
quality. Although outsourcing facilities must comply with CGMP
requirements and are inspected by FDA according to a risk-based
schedule, their drug products have not been determined to be safe or
effective for the conditions of use reflected in drug product labeling
and have not been subjected to a premarket inspection or associated
with a finding of manufacturing quality, all of which are part of the
drug approval process. Because compounded drug products are subject to
a lower regulatory standard than FDA-approved drug products, they
should only be used by patients who could not use an FDA-approved drug
product.
When a compounded drug is appropriate for a patient, outsourcing
facilities may be able to prepare that drug using an FDA-approved drug
product as the starting material. On other occasions it may be
necessary to compound the drug from a bulk drug substance.\7\ Section
503B 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. Section 503B includes this limitation,
among others, to help prevent outsourcing facilities from growing into
conventional manufacturing operations making unapproved new drug
products. 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, for instance, economic incentives, when a patient's
clinical needs could be met by the approved drug product or a drug
product compounded from the approved drug product would reduce the
incentive for applicants to seek FDA approval of drug products and to
continue to market them. The drug approval process is critical to
ensure pharmaceuticals meet regulatory standards established for
quality, safety, and effectiveness. In addition, 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 benefits relating to the assurances associated
with premarket review by FDA for safety, effectiveness, and quality.
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\7\ For a fuller discussion of these issues, see FDA's guidance
for industry entitled ``Evaluation of Bulk Drug Substances Nominated
for Use in Compounding Under Section 503B of the Federal Food, Drug,
and Cosmetic Act'' (503B Bulks Evaluation Guidance), particularly
sections II.B. and C., available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf.
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In sum, section 503B's limitation on the 503B Bulks List to bulk
drug substances for which there is a clinical need serves important
public health functions. First, it helps to limit patient exposure to
compounded drug products, which have not been demonstrated to be safe
and effective, to those situations in which the compounded drug product
is necessary for patient treatment. Second, it preserves the incentives
for applicants to invest in the research and testing required to obtain
FDA approval and to continue to manufacture FDA-approved drug products,
thereby helping to maintain a supply of high-quality, safe, and
effective drugs.
B. Statutory and Regulatory Background
Section 503B of the FD&C Act describes the conditions that must be
satisfied for drug products compounded by an outsourcing facility to be
exempt from the approval, labeling, and drug supply chain security
requirements cited above.\8\ One of the conditions that must be met for
a drug product compounded by an outsourcing facility to qualify for
exemptions under section 503B is that the outsourcing facility may not
compound a drug using a bulk drug substance unless the bulk drug
substance appears on a list established by the Secretary of Health and
Human
[[Page 7385]]
Services identifying bulk drug substances for which there is a clinical
need (the 503B Bulks List); or the drug compounded from such bulk drug
substances appears on the drug shortage list in effect under section
506E of the FD&C Act (FDA's drug shortage list) (21 U.S.C. 356e) at the
time of compounding, distribution, and dispensing.\9\
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\8\ Section 503B(a) of the FD&C Act.
\9\ Section 503B(a)(2)(A) of the FD&C Act.
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Section 503B 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.\10\
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\10\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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For purposes of section 503B, bulk drug substance means an active
pharmaceutical ingredient as defined in 21 CFR 207.1(b).\11\ 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.12 13
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\11\ 21 CFR 207.3.
\12\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
\13\ 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 or National Formulary monograph, if a
monograph exists.
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II. Methodology for Developing the 503B Bulks List
A. Process for Developing the List
In the Federal Register of December 4, 2013 (78 FR 72838), FDA
requested nominations for specific bulk drug substances for the Agency
to consider for inclusion on the 503B Bulks List. In response to that
request, interested groups and individuals nominated a wide variety of
substances. However, many of those nominations were not for substances
used in compounding as active pharmaceutical ingredients or did not
include sufficient information to allow FDA to evaluate the nominated
substance. To improve the efficiency of the process for the development
of the list of bulk drug substances, FDA reopened the nomination
process in the Federal Register of July 2, 2014 (79 FR 37750) and
provided more detailed information on what it needs to evaluate
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency
opened a new docket, FDA-2015-N-3469, to provide an opportunity for
interested persons to submit new nominations of bulk drug substances or
to renominate substances with sufficient information.
As FDA evaluates bulk drug substances, it intends to publish
notices for public comment in the Federal Register that describe its
proposed position on each substance along with the rationale for that
position.\14\ 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.\15\ 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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\14\ This is consistent with procedures set forth in section
503B(a)(2)(A)(i). 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.
\15\ Section 503B does not require FDA to consult the PCAC
before developing a 503B Bulks List.
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FDA intends to maintain a current list of all bulk drug substances
it has evaluated on its website, with separate lists for bulk drug
substances it has placed on the 503B Bulks List and those it has
decided not to place on the 503B Bulks List. FDA will only place a bulk
drug substance on the 503B Bulks List where it has determined there is
a clinical need for outsourcing facilities to compound drug products
using the bulk drug substance. If a clinical need to compound drug
products using the bulk drug substance has not been demonstrated, based
on the information submitted by the nominator and any other information
considered by the Agency, FDA will not place a bulk drug substance on
the 503B Bulks List.
FDA intends to evaluate the bulk drug substances nominated for the
503B Bulks List on a rolling basis. FDA will 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.\16\
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\16\ On June 10, 2016 (81 FR 37502), FDA announced the
availability of a guidance for industry (revised January 2017)
entitled ``Interim Policy on Compounding Using Bulk Drug Substances
Under Section 503B of the Federal Food, Drug, and Cosmetic Act'';
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469122.pdf.
This guidance 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.
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B. Analysis of Substances Nominated for the List
As noted above, section 503B(a)(2)(A)(i) provides that the 503B
Bulks List is to 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.\17\ In applying this
standard to make determinations regarding the substances set forth in
this notice, FDA interprets the phrase ``bulk drug substances for which
there is a clinical need'' to mean that the 503B Bulks List may include
a bulk drug substance if: (1) There is a clinical need for an
outsourcing facility to compound a drug product, and (2) the drug
product must be compounded using the bulk drug substance. FDA is not
interpreting supply issues, such as backorders, to be within the
meaning of ``clinical need'' for compounding with a bulk drug
substance. Section 503B separately provides for compounding from bulk
drug substances under the exemptions from the FD&C Act discussed above
if the drug product compounded from the bulk drug
[[Page 7386]]
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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\17\ See 503B Bulks Evaluation Guidance, supra n.7 (describing
FDA's policies for developing the 503B Bulks List, including the
interpretation of the phrase ``bulk drug substances for which there
is a clinical need,'' as it is used in section 503B).
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The bulk drug substances that we are addressing in this notice are
components of FDA-approved drug products, and we evaluated them by
asking the following questions:
(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 the
drug product to be compounded is intended to address that attribute, we
do not expect that there will be a clinical need for a patient to use a
compounded drug product. Rather, such compounding would unnecessarily
expose patients to the risks associated with drug products that have
not been shown to meet the standards applicable to FDA-approved drug
products for safety, effectiveness, quality, and labeling and would
undermine the drug approval process. The reason for question (2) is
that to place a bulk drug substance on the 503B Bulks List, FDA must
determine that there is a clinical need for outsourcing facilities to
compound a drug product using the bulk drug substance rather than
starting with an FDA-approved drug product.
If the answer to both of these questions is ``yes,'' there may be
clinical need for outsourcing facilities to compound using the bulk
drug substance, and we would analyze the question further.\18\ If the
answer to either of these questions is ``no,'' there generally would
not be a basis to conclude that there is a clinical need to compound
drug products using the bulk drug substance instead of administering or
starting with an approved drug product, and we would generally not
include the bulk drug substance on the 503B Bulks List.
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\18\ Under the analysis described in FDA's 503B Bulks Evaluation
Guidance, the additional analysis would consist of the consideration
of four additional factors. We did not answer ``yes'' to both of the
threshold questions for nicardipine hydrochloride or vasopressin, so
we did not consider these additional factors in our determination
not to include nicardipine hydrochloride or vasopressin on the 503B
Bulks List.
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III. Substances Proposed for the 503B Bulks List
In August 2018, the Agency issued a Federal Register notice in
which it evaluated three nominated bulk drug substances under the
statutory standard--bumetanide, nicardipine hydrochloride, and
vasopressin--and proposed not to include them on the 503B Bulks List
(the August notice). In this notice, after review of the comments
submitted to the docket for the August notice, FDA is making its final
determination with regard to nicardipine hydrochloride and vasopressin.
At this time, FDA is not making a final determination regarding
bumetanide. This substance remains under consideration by FDA.
1. Nicardipine Hydrochloride
Nicardipine hydrochloride has been nominated for inclusion on the
503B Bulks List.\19\ The proposed route of administration is
intravenous, the proposed dosage form is injection, and the proposed
strength is 0.1 to 2.5 milligrams per milliliter (mg/mL). This
nominated bulk drug substance is a component of FDA-approved drug
products (e.g., NDAs 022276 and 019734). FDA has approved nicardipine
hydrochloride drug products as 0.1 mg/mL and 0.2 mg/mL solutions ready
for intravenous administration (or ``ready to use'') and as a 2.5 mg/mL
single-dose vial that must be diluted prior to
infusion.20 21 The single dose vial (NDA 022276) contains an
excipient, benzoic acid; the ready-to-use solutions (NDA 019734) do not
contain benzoic acid.
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\19\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0002.
\20\ See, e.g., labeling available as of the date of this notice
at https://www.accessdata.fda.gov/spl/data/32756b4e-a977-47ac-9620-0c1ed74d7606/32756b4e-a977-47ac-9620-0c1ed74d7606.xml (ready-to-use)
and https://www.accessdata.fda.gov/spl/data/5444784f-fefe-4352-afd1-b4c487165f3a/5444784f-fefe-4352-afd1-b4c487165f3a.xml (for
dilution).
\21\ Nicardipine hydrochloride is also approved as an oral
capsule. See, e.g., ANDA 074642.
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Because nicardipine hydrochloride is a component of FDA-approved
drug products, we considered whether (1) there is a basis to conclude
that an attribute of each FDA-approved drug product makes each one
medically unsuitable to treat certain patients for a condition that FDA
has identified for evaluation, and the nicardipine hydrochloride drug
product proposed to be compounded is intended to address that attribute
in each FDA-approved drug product; and (2) whether the drug product
proposed to be compounded must be compounded using a bulk drug
substance.
a. Suitability of FDA-Approved Drug Products.
The nomination proposed to include on the list nicardipine
hydrochloride injection compounded to concentrations of 0.1 mg/mL
through 2.5 mg/mL. The nomination does not identify attributes of the
approved nicardipine hydrochloride products that make them medically
unsuitable to treat certain patients and that the proposed compounded
drug products are intended to address. Specifically, the nomination did
not explain why ready-to-use nicardipine hydrochloride injection at 0.1
mg/mL and 0.2 mg/mL, and the 2.5 mg/mL single dose vial (for dilution)
are medically unsuitable for certain patients.
A commenter on FDA's proposal not to include nicardipine
hydrochloride on the 503B Bulks List indicated that an attribute of
approved nicardipine hydrochloride injections, the presence of the
excipient benzoic acid, makes those approved drug products medically
unsuitable for patients who have an allergy to benzoic acid and that
drug products would be compounded from the bulk drug substance
nicardipine hydrochloride without benzoic acid. However, the commenter
did not acknowledge the availability of FDA-approved benzoic acid-free
nicardipine hydrochloride ready-to-use solutions for intravenous
administration or explain why these approved drug products would be
medically unsuitable for patients who have an allergy to benzoic
acid.\22\
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\22\ See NDAs 022276 and 019734.
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Accordingly, with respect to the nicardipine hydrochloride drug
products proposed to be compounded, FDA finds no basis to conclude that
an attribute of each of the approved drug products makes each one
medically unsuitable to treat certain patients for a condition that FDA
has identified for evaluation.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nomination provided no basis to conclude that drug products
containing nicardipine hydrochloride must be compounded using a bulk
drug substance rather than using an FDA-approved drug product. The
nomination
[[Page 7387]]
and a related comment assert that it would be preferable to compound a
drug product using a bulk drug substance than using an approved drug
product that requires dilution. However, the nomination and comment do
not take the position or provide support for the position that a bulk
drug substance must be used to prepare the proposed concentrations of
nicardipine hydrochloride. For example, the nomination does not
indicate that the desired concentrations of nicardipine hydrochloride
could not be prepared by diluting the approved drug product in a form
that is suitable for patient administration. Nor is FDA aware of data
or information suggesting this cannot be done. We note that the
approved labeling of a nicardipine hydrochloride drug product directs
the drug product to be diluted to a concentration within that range. We
do not consider whether a benzoic acid-free nicardipine hydrochloride
drug product must be compounded using the bulk drug substance because
benzoic acid-free nicardipine hydrochloride product is FDA-approved at
concentrations of 0.1 mg/mL and 0.2 mg/mL and because patients for whom
these FDA-approved drug products may be medically unsuitable were not
identified in section III.1.a. In sum, FDA finds no basis to conclude
that drug products must be compounded using a bulk drug substance
rather than the approved drug product.
2. Vasopressin
Vasopressin was nominated for inclusion on the 503B Bulks List to
compound drug products that treat septic shock, post-cardiotomy shock,
diabetes insipidus, and hypotension.\23\ The proposed route of
administration is intravenous; the proposed dosage form is injection.
The nominators proposed a range of specific concentrations (0.1, 0.2,
0.4, and 1 units/mL (U/mL)) and concentrations above that range without
identifying any specific concentration. This nominated bulk drug
substance is the active ingredient of the FDA-approved drug VASOSTRICT
(NDA 204485). VASOSTRICT is approved as a 20 U/mL intravenous infusion
that, per its labeling, should be diluted with normal saline or 5
percent dextrose in water to either 0.1 U/mL or 1 U/mL for intravenous
administration.\24\
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\23\ See Docket No. FDA-2015-N-3469, documents No. FDA-2015-N-
3469-0012 and -0023.
\24\ The labeling as of the date of this notice is available at
https://www.accessdata.fda.gov/spl/data/4166e423-659e-4fe4-8a3c-2394434d00dd/4166e423-659e-4fe4-8a3c-2394434d00dd.xml.
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VASOSTRICT is available in a multidose vial that contains the
preservative agent chlorobutanol and in a single dose vial that does
not contain chlorobutanol. The VASOSTRICT labeling includes a
contraindication regarding chlorobutanol that applies to the
chlorobutanol-containing product.\25\ Because vasopressin is a
component of an FDA-approved drug product, we considered whether (1)
there is a basis to conclude that an attribute of each FDA-approved
drug product containing vasopressin makes each one medically unsuitable
to treat certain patients for a condition that FDA has identified for
evaluation, and the vasopressin drug product proposed to be compounded
is intended to address that attribute; and (2) whether the drug product
proposed to be compounded must be compounded using a bulk drug
substance.
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\25\ The labeling states that VASOSTRICT is ``contraindicated in
patients with known allergy or hypersensitivity to 8-L-arginine
vasopressin or chlorobutanol.'' However, this contraindication is
not applicable to the formulation of VASOSTRICT marketed without
chlorobutanol. As described in the package insert, the VASOSTRICT 10
mL solution contains chlorobutanol, while the 1 mL solution does
not.
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a. Suitability of FDA-Approved Drug Product
The nominations propose vasopressin for the 503B Bulks List so that
it can be used to compound drug product at various concentrations, some
lower than undiluted VASOSTRICT and others higher. However, the
nominations and the comments do not identify an attribute of VASOSTRICT
that makes it medically unsuitable for patients and that the compounded
products are intended to address.
The nomination that refers to products with a higher concentration
than VASOSTRICT does not identify any data or information as to the
need for a higher concentration than the approved product, nor does the
nomination identify specific higher concentrations it proposes to
compound. In addition, the nomination does not identify patients for
whom a concentration at or below 20 U/mL is medically unsuitable and
who would therefore require a higher concentration, and FDA is not
aware of patients who would need concentrations above 20 U/mL.
Both nominations also propose to compound vasopressin at specific
concentrations lower than undiluted VASOSTRICT. However, the proposed
concentrations are within the range described in the labeling for the
FDA-approved drug product, and the proposed route of administration
(intravenous) is the same as that of VASOSTRICT. The nominations do not
identify an attribute of the approved drug product that would make it
medically unsuitable for patients or show that the compounded drug
product would address that attribute.
Commenters on FDA's proposal not to include vasopressin on the 503B
Bulks List assert that an attribute of VASOSTRICT that makes it
medically unsuitable to treat patients is that it contains a
preservative, chlorobutanol. Chlorobutanol-containing VASOSTRICT is
contraindicated in patients who have an allergy or hypersensitivity to
this excipient. However, the commenters fail to acknowledge that the
preservative-free formulation of VASOSTRICT is also marketed and fail
to explain why that formulation would be medically unsuitable for
patients who have an allergy to chlorobutanol.
Accordingly, with respect to the vasopressin drug products proposed
to be compounded, FDA finds no basis to conclude that an attribute of
VASOSTRICT makes it medically unsuitable to treat certain patients.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
As noted previously, the nominations propose to compound drug
products containing vasopressin at concentrations that are lower than
undiluted VASOSTRICT, but that are within the range of VASOSTRICT's
final, post-dilution concentrations. The nominations do not take the
position or provide support for the position that a bulk drug substance
rather than the FDA-approved drug product must be used to prepare these
lower concentrations. For example, the nominations do not explain, or
even suggest, that the desired concentration of vasopressin cannot be
prepared by diluting the approved drug product.\26\ We do not consider
whether a chlorobutanol-free vasopressin drug product must be
compounded using the bulk drug substance because a chlorobutanol-free
vasopressin product is FDA-approved and because patients for whom this
FDA-approved drug product may be medically unsuitable were not
identified in section III.2.a. In addition, in light of the analysis in
section III.2.a. above, we do not
[[Page 7388]]
consider whether a bulk drug substance must be used to compound a
vasopressin drug product at concentrations higher than 20 U/mL. In sum,
FDA finds no basis to conclude that drug products must be compounded
using a bulk drug substance rather than the approved drug product.
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\26\ For example, the nomination does not take the position or
provide support for a position that a drug product prepared by
starting with the approved drug product would be unsuitable for
patient administration. We also note that outsourcing facilities
often prepare ready-to-use forms of drug products for healthcare
practitioners by compounding (e.g., diluting) approved drug
products, including VASOSTRICT.
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IV. Other Issues Raised in Nominations and Comments
The nominations for nicardipine hydrochloride and vasopressin and
some comments state that there could be a benefit in the availability
of drug products containing each of these bulk drug substances that do
not require dilution prior to administration. We note first, with
respect to nicardipine hydrochloride, that two ready-to-use nicardipine
drug products are FDA-approved, and the comments do not identify
patients for whom these products are medically unsuitable. More
broadly, as explained above, when a bulk drug substance is a component
of an approved drug, FDA asks whether there 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 and comments 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 nicardipine and vasopressin drug products.\27\
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. That is not clinical need to
compound a drug product using a bulk drug substance.
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\27\ With respect to vasopressin specifically, a comment states
that vasopressin cannot be produced in ready-to-use form because the
approved drug product is labeled with an in-use time of 18 hours
room temperature or 24 hours refrigerated once diluted. In contrast,
the commenter says that it could compound a ``pre-diluted'' drug
product from bulk vasopressin with a beyond-use-date (BUD) of 60
days. We note that, in accordance with CGMP provisions, outsourcing
facilities can conduct stability studies on vasopressin compounded
using the approved drug product to assign a BUD based on data.
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The nominations for nicardipine hydrochloride and vasopressin and
some comments also include statements that these substances should be
added to the 503B Bulks List because compounding from the bulk drug
substance could help outsourcing facilities to address drug shortages
and disruptions in supply of approved drugs intended for injection. As
noted above, section 503B contains a separate provision for compounding
from bulk drug substances to address a drug shortage, and we do not
interpret the other price- and supply-related issues advanced by the
nomination to be within the meaning of ``clinical need'' for
compounding with a bulk drug substance.
V. Conclusion
For the reasons stated above, we find no clinical need for an
outsourcing facility to compound using the bulk drug substances
nicardipine hydrochloride and vasopressin and, therefore, we are not
including nicardipine hydrochloride and vasopressin on the 503B Bulks
List.
Dated: February 26, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-03810 Filed 3-1-19; 8:45 am]
BILLING CODE 4164-01-P