[Federal Register Volume 84, Number 172 (Thursday, September 5, 2019)]
[Proposed Rules]
[Pages 46688-46703]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-18951]
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Proposed Rules
Federal Register
________________________________________________________________________
This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.
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Federal Register / Vol. 84, No. 172 / Thursday, September 5, 2019 /
Proposed Rules
[[Page 46688]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 216
[Docket No. FDA-2018-N-4845]
RIN 0910-AH81
Amendments to the List of Bulk Drug Substances That Can Be Used
to Compound Drug Products in Accordance With Section 503A of the
Federal Food, Drug, and Cosmetic Act
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA or Agency) has issued a
regulation creating a list of bulk drug substances (active
pharmaceutical ingredients) that can be used to compound drug products
in accordance with certain compounding provisions of the Federal Food,
Drug, and Cosmetic Act (FD&C Act), although they are neither the
subject of an applicable United States Pharmacopeia (USP) or National
Formulary (NF) monograph nor components of FDA-approved drugs. This
proposed rule would amend that list by placing five additional bulk
drug substances on the list. This proposed rule also identifies 26 bulk
drug substances that FDA has considered and proposes not to include on
the list. Additional substances nominated by the public for inclusion
on this list are currently under consideration and will be the subject
of a future rulemaking.
DATES: Submit either electronic or written comments on the proposed
rule by December 4, 2019. See section VI for the proposed effective
date of a final rule based on this proposed rule.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time on the comment due date provided in the DATES
section. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or
the delivery service acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2018-N-4845 for ``Amendments to the List of Bulk Drug Substances
That Can Be Used to Compound Drug Products in Accordance With Section
503A of the Federal Food, Drug, and Cosmetic Act.'' Received comments,
those filed in a timely manner (see ADDRESSES), will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Rosilend Lawson, Center for Drug
Evaluation and Research, Office of Unapproved Drugs and Labeling
Compliance, Food and Drug Administration, 10903 New Hampshire
[[Page 46689]]
Ave., Bldg. 51, Rm. 5197, Silver Spring, MD 20993, 240-402-6223,
[email protected].
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
IV. Legal Authority
V. Description of the Proposed Rule
A. Criteria for Evaluating Bulk Drug Substances for the 503A
Bulks List
B. Methodology for Developing the 503A Bulks List
C. Substances Proposed for Inclusion on the 503A Bulks List
D. Substances Considered and Not Proposed for Inclusion on the
503A Bulks List
VI. Proposed Effective Date
VII. Preliminary Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose of the Proposed Rule
FDA is proposing to amend its regulations to add substances to the
list of bulk drug substances that can be used in compounding under
section 503A of the FD&C Act (21 U.S.C. 353a) (referred to as ``the
503A Bulks List''). Bulk drug substances that appear on the 503A Bulks
List can be used to compound drug products subject to the conditions of
section 503A, even though those substances are not the subject of an
applicable USP or NF monograph or components of approved drug products.
B. Summary of the Major Provisions of the Proposed Rule
Based on the results of its evaluation of nominated bulk drug
substances to date, as well as consultation with the Pharmacy
Compounding Advisory Committee (PCAC), and the United States
Pharmacopoeia Convention, Incorporated, FDA is proposing to amend the
503A Bulks List to include five additional bulk drug substances:
Glutaraldehyde, glycolic acid, L-citrulline, pyruvic acid, and
trichloroacetic acid (TCA). FDA is also proposing that 26 other
substances not be included on the list: 7-keto dehydroepiandrosterone
(DHEA), acetyl-L-carnitine (ALC), alanyl-L-glutamine, Aloe vera 200:1
freeze dried, artemisinin, astragalus extract 10:1, boswellia serrata
extract (BWSE), cesium chloride, chondroitin sulfate, chrysin,
curcumin, D-ribose, deoxy-D-glucose, diindolylmethane, domperidone,
epigallocatechin gallate (EGCG), germanium sesquioxide, glycyrrhizin,
kojic acid, nettle, nicotinamide adenine dinucleotide (NAD),
nicotinamide adenine dinucleotide disodium reduced (NADH), rubidium
chloride, sodium dichloroacetate, vanadyl sulfate, and vasoactive
intestinal peptide (VIP).
C. Legal Authority
Section 503A of the FD&C Act, in conjunction with our general
rulemaking authority in section 701(a) of the FD&C Act (21 U.S.C.
371(a)), serves as our principal legal authority for this proposed
rule.
D. Costs and Benefits
FDA evaluated 31 bulk drug substances for this proposed rule,
proposing to place 5 bulk drug substances on the 503A Bulks List, and
not to place 26 substances on the 503A Bulks List. The primary estimate
of the present value of the costs over 10 years is $1.03 million. The
primary estimate of the annualized costs is $0.15 million at a 7
percent discount rate and $0.12 million at a 3 percent discount rate.
Because we lack sufficient information to quantify most of the costs
and benefits of this proposed rule, we also include a qualitative
description of potential benefits and potential costs. We expect that
the rule will affect compounding pharmacies and other producers that
market the affected substances or drug products made from the affected
substances, consumers of drug products containing the affected
substances, and payers that cover these drug products or alternative
treatments.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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ALC.................................. Acetyl-L-carnitine.
BWSE................................. Boswellia serrata extract.
CFR.................................. Code of Federal Regulations.
CFS.................................. Chronic fatigue syndrome.
CIRS................................. Chronic inflammatory response
syndrome.
DHEA................................. Dehydroepiandrosterone.
EGCG................................. Epigallocatechin gallate.
FD&C Act............................. Federal Food, Drug, and Cosmetic
Act.
FDA.................................. Food and Drug Administration.
GAIT................................. Glucosamine/Chondroitin Arthritis
Intervention Trial.
GRAS................................. Generally recognized as safe.
HSV.................................. Herpes simplex virus.
IND.................................. Investigational new drug.
IV................................... Intravenous.
MS................................... Multiple sclerosis.
NAICS................................ North American Industry
Classification System.
NAD.................................. Nicotinamide adenine
dinucleotide.
NADH................................. Nicotinamide adenine dinucleotide
disodium reduced.
NF................................... National Formulary.
NPRM................................. Notice of proposed rulemaking.
OA................................... Osteoarthritis.
PCAC................................. Pharmacy Compounding Advisory
Committee.
RA................................... Rheumatoid arthritis.
RFA.................................. Regulatory Flexibility Analysis.
SBA.................................. Small Business Administration.
TCA.................................. Trichloroacetic acid.
UCD.................................. Urea cycle disorder.
USP.................................. United States Pharmacopeia.
[[Page 46690]]
VIP.................................. Vasoactive intestinal peptide.
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III. Background
Section 503A of the FD&C Act describes the conditions under which a
compounded drug product may qualify for an exemption from certain
sections of the FD&C Act. Those conditions include that a licensed
pharmacist in a State-licensed pharmacy or Federal facility or a
licensed physician compounds the drug product using bulk drug
substances that: (1) Comply with the standards of an applicable USP or
NF monograph,\1\ if a monograph exists, and the USP chapter on pharmacy
compounding; (2) if such a monograph does not exist, are drug
substances that are components of drugs approved by the Secretary of
the Department of Health and Human Services (Secretary); or (3) if such
a monograph does not exist and the drug substance is not a component of
a drug approved by the Secretary, appear on the 503A Bulks List. (See
section 503A(b)(1)(A)(i) of the FD&C Act.)
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\1\ FDA has interpreted the statutory language ``applicable
United States Pharmacopoeia or National Formulary monograph'' to
refer only to official USP or NF monographs for drug substances.
Therefore, a substance that is the subject of a dietary supplement
monograph, but not a USP or NF drug substance monograph, does not
satisfy the condition regarding bulk drug substances in section
503A(b)(1)(A)(i)(I) of the FD&C Act. Such a substance may only be
used as a bulk drug substance under section 503A of the FD&C Act if
it is a component of an FDA-approved drug product or is on the 503A
Bulks List.
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On February 19, 2019, FDA published a final rule establishing the
criteria for evaluating substances for inclusion on the 503A Bulks
List, placing six substances on the list, and identifying four other
substances that were evaluated and not included on the 503A Bulks List
(84 FR 4696). That final rule noted that additional substances were
under evaluation, and that new substances may be added to the list
through subsequent rulemaking. This proposed rule would amend that list
by adding five additional substances. It also identifies 26 other
substances that FDA has evaluated and proposes not to include on the
list.
Section 503A of the FD&C Act adopts the definition of ``bulk drug
substance'' in FDA's drug establishment registration and listing
regulations, which was codified at Sec. 207.3(a)(4) (21 CFR
207.3(a)(4)) at the time section 503A was enacted. (See section
503A(b)(1)(A) of the FD&C Act.) Under the definition, bulk drug
substance means any substance that is represented for use in a drug and
that, when used in the manufacturing, processing, or packaging of a
drug, becomes an active ingredient or a finished dosage form of the
drug, but the term does not include intermediates used in the synthesis
of such substances.
On August 31, 2016, FDA published a final rule in the Federal
Register to update its registration and listing regulations in part 207
(21 CFR part 207), which included minor changes to the definition of
bulk drug substance and moved the definition to Sec. 207.3 (see 81 FR
60170 at 60175). This definition became effective on November 29, 2016.
As set forth in Sec. 207.3, ``bulk drug substance,'' as referenced in
section 503A(b)(1)(A) of the FD&C Act, means the same as ``active
pharmaceutical ingredient'' as defined in Sec. 207.1 (21 CFR 207.1).
An ``active pharmaceutical ingredient'' is 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. The term ``active
pharmaceutical ingredient'' does not include intermediates used in the
synthesis of the substance (Sec. 207.1).
Inactive ingredients used in compounded drug products, such as
flavorings, dyes, or diluents, need not appear on the 503A Bulks List
to be eligible for use in compounding drug products and will not be
included on the list.
For regulatory history of the 503A Bulks List, see 81 FR 91071
(December 16, 2016).
IV. Legal Authority
As described in Section III. Background, section 503A of the FD&C
Act describes the conditions that must be satisfied for human drug
products compounded by a licensed pharmacist or licensed physician to
be exempt from three sections of the FD&C Act (sections 501(a)(2)(B),
502(f)(1), and 505 (21 U.S.C. 351(a)(2)(B), 352(f)(1), and 355)). One
of the conditions that must be satisfied for a compounded drug to
qualify for the exemptions under section 503A of the FD&C Act is that a
licensed pharmacist in a State-licensed pharmacy or Federal facility or
a licensed physician compounds the drug product using bulk drug
substances that: (1) Comply with the standards of an applicable USP or
NF monograph, if a monograph exists, and the USP chapter on pharmacy
compounding; (2) if such a monograph does not exist, are drug
substances that are components of drugs approved by the Secretary; or
(3) if such a monograph does not exist and the drug substance is not a
component of a drug approved by the Secretary, appear on the 503A Bulks
List. (See section 503A(b)(1)(A)(i) of the FD&C Act.) Section
503A(c)(1) of the FD&C Act also states that the Secretary shall issue
regulations to implement section 503A, and that before issuing
regulations to implement section 503A(b)(1)(A)(i)(III) pertaining to
the 503A bulks list, among other sections, the Secretary shall convene
and consult an advisory committee on compounding unless the Secretary
determines that the issuance of such regulations before consultation is
necessary to protect the public health. Section 503A(c)(2) of the FD&C
Act requires the Secretary to issue the regulations in consultation
with the USP, and to include in the regulation the criteria for such
substances that shall include historical use, reports in peer-reviewed
journals, or other criteria the Secretary identifies. Thus, section
503A of the FD&C Act, in conjunction with our general rulemaking
authority in section 701(a) of the FD&C Act, serves as our principal
legal authority for this proposed rule.
V. Description of the Proposed Rule
FDA proposes to amend Sec. 216.23 (21 CFR 216.23) to include 5 of
the bulk drug substances that were considered on the 503A Bulks List
and to identify 26 substances that were considered and would not be
included on the list. The criteria and methodology for evaluating bulk
drug substances for inclusion on the list, and FDA's proposals
regarding the substances addressed in this notice of proposed
rulemaking (NPRM) are described in the paragraphs that follow.
A. Criteria for Evaluating Bulk Drug Substances for the 503A Bulks List
Section 503A(c)(2) of the FD&C Act provides that the criteria for
determining which substances should appear on the 503A Bulks List shall
include historical use, reports in peer-reviewed medical literature, or
other
[[Page 46691]]
criteria the Secretary may identify. Under Sec. 216.23, the following
criteria are used to evaluate the nominated substances:
The physical and chemical characterization of the
substance;
Any safety issues raised by the use of the substance in
compounded drug products;
The available evidence of effectiveness or lack of
effectiveness of a drug product compounded with the substance, if any
such evidence exists; and
Historical use of the substance in compounded drug
products, including information about the medical condition(s) the
substance has been used to treat and any references in peer-reviewed
medical literature.
In evaluating candidates for the 503A Bulks List under these
criteria, the Agency uses a balancing test. Specifically, the Agency
considers each criterion in the context of the others and balance them,
on a substance-by-substance basis, to decide whether a particular
substance is appropriate for inclusion on the 503A Bulks List. The
criteria are discussed in further detail in the Agency's previous
rulemaking on the 503A Bulks List (81 FR 91071; 84 FR 4696).
B. Methodology for Developing the 503A Bulks List
FDA reviewed the substances addressed in this proposed rule in the
context of adequately supported uses that were proposed with the
nomination. In certain circumstances, FDA also reviewed substances in
the context of uses that were not proposed with the nomination or
proposed uses that were inadequately supported because, for example,
such uses appear to be widespread, are intended to treat serious
conditions, or pose serious risks to patients. The information that FDA
assessed to evaluate the substances addressed in this proposed rule
under each of the evaluation criteria was obtained from publicly
available sources, including peer-reviewed medical literature. Some of
this information was referenced in the nominations, and the remainder
FDA gathered through independent searches of medical and pharmaceutical
databases. FDA did not review raw data. The nature, quantity, and
quality of the information FDA assessed varied considerably from
substance to substance. In some cases, there were very little data. For
other substances, reports in the literature were more plentiful and
sometimes comprised hundreds or thousands of articles. In those cases,
generally the Agency limited its review to a sample of the best
literature sources available (e.g., review articles in widely known,
peer-reviewed journals; meta-analyses; reports of randomized controlled
trials).
FDA's evaluation of the nominated substances was, necessarily, far
less rigorous and less comprehensive than the Agency's review of drugs
as part of the new drug approval process. The new drug approval process
is conducted based on extensive data compiled and submitted with new
drug and abbreviated new drug applications, which are not available for
the nominated substances. Additionally, the Agency's review during the
drug approval process includes premarket evaluation of a specific drug
formulation, the applicant's chemistry and manufacturing controls, and
inspection of the establishments where approved drugs will be
manufactured. In contrast, these bulk drug substances will be evaluated
only for possible use in compounded drugs.
Therefore, the proposed inclusion of a drug substance on the 503A
Bulks List should not, in any way, be equated with or considered an FDA
approval, endorsement, or recommendation of any drug compounded using
the substance. Nor should it be assumed that a drug compounded using
the substances on the proposed list has been proven to be safe and
effective under the standards required for Agency approval. Any person
who represents that a compounded drug made with a bulk drug substance
that appears on this list is approved by FDA, or otherwise endorsed by
FDA generally, or for a particular indication, will cause the drug to
be misbranded under section 502(a) (labeling) and/or 502(bb)
(advertising or promotion) of the FD&C Act.
On October 27 and 28, 2015, March 8, 2016, June 23, 2016, November
3, 2016, May 8 and 9, 2017, and November 20, 2017, FDA consulted with
the PCAC created under section 503A(c)(1) of the FD&C Act about the 31
substances that are addressed in this proposed rule (Refs. 1 to 11).
The Agency considered the PCAC's recommendations in developing this
proposed rule, and the Agency intends to continue to consult with the
PCAC in evaluating future candidates for the 503A Bulks List. Going
forward, FDA intends to publish NPRMs proposing additional substances
be included on the list or not included on the list on a rolling basis
as evaluations are completed. Depending on the length of time it takes
to complete a rulemaking, multiple rulemakings may be ongoing
simultaneously.
Section 503A of the FD&C Act also requires that FDA create the 503A
Bulks List in consultation with the USP. (See section 503A(c)(2) of the
FD&C Act.) To this end, FDA has consulted with USP about the substances
that are the subject of this proposed rule (Refs. 12 to 16). After
publication of this NPRM, the public will have an opportunity to submit
comments on the proposed rule to the docket. After considering those
comments, FDA will publish a final rule amending the 503A Bulks List
codified at Sec. 216.23. The final version of the rule may include
all, none, or only some of the substances proposed here for inclusion
on the 503A Bulks List, based upon the Agency's consideration of the
comments received, and will also identify those substances the Agency
has determined should not be included on the list. The Agency may amend
the 503A Bulks List to add or delete substances after further notice
and comment rulemaking.
With respect to any substance already addressed in a final rule,
individuals and organizations may petition FDA to amend the 503A Bulks
List (to add or delete those bulk drug substances or to consider
information about those bulk drug substances that is different from
that which FDA presented to the PCAC) (see 21 CFR 10.30). With respect
to substances that have not been addressed in rulemaking, individuals
and organizations may submit nominations of new substances or comments
on nominated substances to Docket No. FDA-2015-N-3534.
C. Substances Proposed for Inclusion on the 503A Bulks List
Under section 503A(c)(2) of the FD&C Act, FDA is proposing that the
following five bulk drug substances, which are neither the subject of
an applicable USP or NF monograph nor components of FDA-approved drugs,
be included on the 503A Bulks List, and the drug products compounded
with those substances may qualify for the exemptions provided for in
section 503A of the FD&C Act (i.e., from sections 501(a)(2)(B),
502(f)(1), and 505 of the FD&C Act). When a salt or ester of an active
moiety is listed, only that particular salt or ester may be used for
compounding under section 503A of the FD&C Act. The base compound and
other salts or esters of the same active moiety must be evaluated
separately for inclusion on the 503A Bulks List. Additionally, when a
bulk drug substance is included on the 503A Bulks List subject to
certain restrictions (for example, for a particular route of
administration (e.g., topical)), only drug
[[Page 46692]]
products that conform to that restriction may qualify for the 503A
exemptions.
The following bulk drug substances are being proposed for placement
on the 503A Bulks List, to appear in Sec. 216.23(a) of title 21 of the
CFR:
(1) Glutaraldehyde. Glutaraldehyde \2\ was evaluated for topical
use in the treatment of warts. Glutaraldehyde is well characterized
physically and chemically. Glutaraldehyde is reasonably safe to use
topically in 0.1 percent to 10 percent solutions for the treatment of
warts. Nonclinical studies do not show safety issues in vivo other than
irritation and skin sensitization. Skin discoloration has been observed
with the use of glutaraldehyde in the treatment of warts, which
eventually subsides after treatment. Other risks, such as allergic
contact dermatitis, skin ulceration, and necrosis, were observed when
high strengths of glutaraldehyde were used. These risks should be
managed by the use of glutaraldehyde in strengths of 10 percent or
lower.
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\2\ Note that there is a USP monograph for glutaral concentrate
(glutaraldehyde in a 50 percent aqueous solution), which is a
different concentration than that proposed in the nominations. USP
Guidelines state that ``[s]ome drug substances are available as
concentrated solutions . . . and are intended to be used as
intermediates for final formulations.'' USP Nomenclature Guideline
Outline, available at https://www.usp.org/sites/default/files/usp/document/about/expert-volunteers/expert-committees/nomenclature-guideline.pdf. The glutaral concentrate that is the subject of the
USP monograph is intended to be used as an intermediate for a final
formulation; the USP monograph for glutaral concentrate states that
it should be labeled with the statement that it is not intended for
direct administration to humans or animals. Under Sec. 207.3(a)(4),
the definition of ``bulk drug substance'' excludes intermediates
used in the synthesis of the bulk drug substance. Therefore, we are
proposing glutaraldehyde for inclusion on the list in forms or
concentrations other than those provided in the USP monograph.
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Although there is no standard regimen for its use, there is
available evidence from uncontrolled clinical studies and one
randomized controlled trial demonstrating the effectiveness of
glutaraldehyde in nongenital cutaneous wart treatment. There are no
approved prescription therapies for warts outside of the genital area.
Glutaraldehyde has been used in compounded drug products for over 40
years, primarily in the treatment of nongenital warts.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of glutaraldehyde weigh in favor of
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance be included on the 503A Bulks List for topical use,
at concentrations of 10 percent or lower (Ref. 17). At its meeting on
October 28, 2015, the PCAC voted to include glutaraldehyde on the list
(Ref. 3). We have also consulted with USP regarding placement of this
substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 14). This
proposed rule would place glutaraldehyde on the 503A Bulks List for
topical use at concentrations of 10 percent or lower.
(2) Glycolic Acid. Glycolic acid for topical use was evaluated for
use in the treatment of hyperpigmentation and photodamaged skin.
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. Historically, glycolic acid has been used in
compounded drug products for several decades.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of glycolic acid weigh in favor of
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance be included on the 503A Bulks List, for topical use
in concentrations up to 70 percent (Ref. 18). At its meeting on
November 3, 2016, the PCAC voted to include glycolic acid for topical
use on the list (Ref. 8). We have also consulted with USP regarding
placement of this substance on the 503A Bulks List, and USP did not
identify any additional quality concerns related to this substance
(Ref. 15). This proposed rule would place glycolic acid for topical
use, in concentrations up to 70 percent, on the 503A Bulks List.
(3) L-citrulline. L-citrulline for oral use was evaluated for use
in the treatment of certain urea cycle disorders (UCDs). L-citrulline,
a non-essential amino acid, is well characterized physically and
chemically. The available nonclinical and clinical data are inadequate
to evaluate the safety of L-citrulline for oral use, but no serious
adverse events have been linked to its use.
Regarding effectiveness, we found no clinical trials supporting the
effectiveness of the use of L-citrulline for UCDs. This lack of data is
expected given the small number of patients with UCDs. However, there
is a strong mechanistic rationale supporting the use of L-citrulline
for UCDs, based on the pathophysiology of the disorder and the goals of
treatment. There have also been anecdotal reports of successful
treatment of certain UCDs with L-citrulline. Historically, the duration
of use of L-citrulline in compounded drug products is not clear. L-
citrulline has been used clinically in the treatment of certain UCDs
for approximately 30 to 40 years. Oral L-citrulline is part of the
standard of care for certain UCDs.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of L-citrulline weigh in favor of
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance, for oral use, be included on the 503A Bulks List
(Ref. 19). At its meeting on November 20, 2017, the PCAC voted to
include L-citrulline for oral use on the list (Ref. 10). We have also
consulted with USP regarding placement of this substance on the 503A
Bulks List, and USP did not identify any additional quality concerns
related to this substance (Ref. 15). This proposed rule would place L-
citrulline for oral use on the 503A Bulks List.
(4) Pyruvic Acid. Pyruvic acid for topical use was evaluated for
use in the treatment of acne, melasma, and warts. It is physically and
chemically well characterized, but it is unlikely to be stable in
ambient conditions. Stability concerns can be addressed by carefully
sealing the drug product and isolating it from moisture and light.
Regarding safety, we identified no significant safety concerns related
to the topical use of pyruvic acid in compounded drug products. The
available data indicate that the topical use of pyruvic acid is
associated with local irritancy, but reported adverse reactions were
generally limited in duration and readily manageable. The most serious
risk reported was upper respiratory tract irritation due to inhaled
vapors, which can be avoided when patients and healthcare providers
take appropriate precautionary measures (e.g., ensuring the product is
administered in a room with adequate ventilation) to protect against
inhalation.
Regarding effectiveness, limited data derived from small, open-
label trials indicate that the topical use of pyruvic acid might be
somewhat effective in the treatment of acne, melasma, and warts,
[[Page 46693]]
which are not serious or life-threatening conditions. There are no
approved prescription therapies for warts outside of the genital area.
Pyruvic acid has been used in compounded drug products for
approximately 30 years.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of pyruvic acid weigh in favor of
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance be included on the 503A Bulks List for topical
administration (Ref. 20). At its meeting on June 23, 2016, the PCAC
voted to include pyruvic acid for topical use on the list (Ref. 7). We
have also consulted with USP regarding placement of this substance on
the 503A Bulks List, and USP did not identify any additional quality
concerns related to this substance (Ref. 14). This proposed rule would
place pyruvic acid for topical use on the 503A Bulks List.
(5) TCA. TCA for topical use was evaluated for the treatment of
warts and as a chemical peeling agent. TCA is well characterized
physically and chemically and is likely to be stable when refrigerated.
The safety profile shows that TCA commonly causes erythema, crusting,
hyperpigmentation and hypopigmentation, burning, and pain at the
application site. The reported incidents of adverse effects have
increased in correlation with the concentration of TCA used (e.g.,
adverse reactions were observed more frequently with a 95 percent TCA
solution as compared with 85 percent or 50 percent solutions), and more
adverse effects have been reported when TCA was used in the facial and
genital areas. At higher concentrations, the potential for ulceration
and subsequent absorption through open wounds increases. Ulcerations
have been reported in most studies of TCA in the treatment of genital
warts.
Regarding effectiveness, the available information suggests that
TCA may have some effectiveness for the treatment of warts when used at
higher concentrations (e.g., in one comparative study, more subjects
had a ``good'' response with an 80 percent TCA solution as compared
with a 35 percent solution) or in conjunction with an additional wart
treatment, and thus may have a role in treating refractory warts or
patients intolerant of other therapies. Warts generally are not a
serious or life-threatening condition. There are no approved
prescription therapies for warts outside of the genital area.
Historically, TCA has been used in compounded drug products for at
least 20 years.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of TCA weigh in favor of inclusion of
this substance on the list. FDA recommended to the PCAC that this
substance be included on the 503A Bulks List for topical use (Ref. 18).
At its meeting on November 3, 2016, the PCAC voted to include TCA on
the list for topical use (Ref. 8). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 15). This proposed rule would place TCA on the 503A
Bulks List for topical use.
D. Substances Considered and Not Proposed for Inclusion on the 503A
Bulks List
FDA is proposing that 26 of the bulk drug substances that it has
evaluated not be included on the 503A Bulks List. Bulk drug substances
that are considered for the 503A Bulks list, but not placed on the
list, cannot be used to compound drug products that would qualify for
the exemptions in section 503A.\3\
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\3\ If a prescribing practitioner nevertheless believes that a
patient should be treated with a drug product compounded from such a
bulk drug substance, it may be possible to obtain the drug under an
investigational new drug (IND) application. For information about
the requirements for proceeding under an IND application, visit
FDA's website at https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm.
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The 26 bulk drug substances that have been evaluated and that FDA
is proposing not be placed on the list, and the reasons for that
proposal, are as follows:
(1) 7-keto DHEA. 7-keto DHEA was evaluated for use in the treatment
of Raynaud's phenomena and weight loss. 7-keto DHEA is physically and
chemically well characterized. Although we did not identify a safety
signal from available information, there are minimal data available,
and we could not adequately assess whether it is safe to use 7-keto
DHEA in compounded drug products. Similarly, there are insufficient
data to establish whether 7-keto DHEA would be effective in the
treatment of Raynaud's phenomena or obesity. Historically, it appears
that 7-keto DHEA has been used in compounded drug products for
approximately 7 years.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of 7-keto DHEA weigh against
inclusion of this substance on the 503A Bulks List. FDA proposed to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
19). At its meeting on November 20, 2017, the PCAC voted not to include
7-keto DHEA on the list (Ref. 11). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 15). The proposed rule would not place 7-keto DHEA on
the 503A Bulks List.
(2) ALC. ALC was evaluated for use in the treatment of Alzheimer's
disease, chemotherapy-induced peripheral neuropathy, and hepatic
encephalopathy. ALC is well characterized physically and chemically but
given that hydrolysis may occur on its ester group in aqueous
solutions, it is unlikely to be stable when formulated as an aqueous
solution. But it is likely to be stable in solid dosage forms.
Regarding safety, the available information, which is limited, did not
indicate toxicity, and it appears to be well-tolerated when given
orally up to 3 grams daily. However, the labeling of FDA-approved
products that contain L-carnitine, a closely related drug substance,
indicates that those products may affect blood clotting and pose a risk
for seizures. There may be similar risks with the use of ALC.
There is insufficient evidence to indicate that ALC is effective
for the treatment of the evaluated conditions. FDA-approved drug
products have been demonstrated to be safe and effective under the
conditions of use set forth in their labeling for the treatment of
Alzheimer's disease, chemotherapy-induced peripheral neuropathy, and
hepatic encephalopathy, which are serious conditions. The history of
ALC use in compounded drug products is unknown.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of ALC weigh against inclusion of
this substance on the list. FDA recommended to the PCAC that this
substance not be included on the 503A Bulks List (Ref. 21), and at its
meeting on March 8, 2016, the PCAC voted not to include ALC on the list
(Ref. 6). We have also consulted with USP regarding placement of this
substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 14). This
proposed rule would not place ALC on the 503A Bulks List.
(3) Alanyl-L-Glutamine. Alanyl-L-glutamine was evaluated for use in
nutritional support and reducing rates of infectious complications in
critically ill and surgical patients. Alanyl-L-glutamine is well
characterized
[[Page 46694]]
physically and chemically, but there are toxicity concerns with
potential impurities, specifically, solvents, endotoxins, bioburden,
and heavy metal impurities linked to the source of the starting
material and the reagents used in processing. Exposure to elemental
impurities such as heavy metals has been associated with proven
toxicities, such as irreversible neurological impairment and
hepatotoxicity. We could not adequately assess whether the substance
would be sufficiently free of such impurities to be suitable for
compounding into parenteral solutions for intravenous (IV)
administration, which would result in 100 percent bioavailability of
impurities. Additionally, safety concerns were observed in a large,
randomized controlled trial of critically ill patients who received
glutamine supplementation, the results of which demonstrated the
potential toxicity of alanyl-L-glutamine, including increased frequency
of increased serum urea levels and an increase of in-hospital, 28-day,
and 6-month mortality rates.
Regarding effectiveness, a meta-analysis published in the
literature suggests that parenteral supplementation with alanyl-L-
glutamine may benefit certain populations, including through potential
decrease in rates of infection or infectious complications; however,
the available data are limited, and some other analyses indicated
unfavorable outcomes. Alanyl-L-glutamine has been used in compounded
drug products for approximately 15 years.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of alanyl-L-glutamine weigh against
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance not be included on the 503A Bulks List (Ref. 17),
and at its meeting on October 27, 2015, the PCAC voted not to include
alanyl-L-glutamine on the list (Ref. 2). We have also consulted with
USP regarding placement of this substance on the 503A Bulks List, and
USP did not identify any additional quality concerns related to this
substance (Ref. 14). This proposed rule would not place alanyl-L-
glutamine on the 503A Bulks List.
(4) Aloe Vera 200:1 Freeze Dried. Aloe vera 200:1 freeze dried \4\
was evaluated as treatment for burns, cuts, and wounds. We found no
information to differentiate ``Aloe vera 200:1 freeze dried'' from
other Aloe vera extracts. Aloe vera extract is not well characterized
physically and chemically. Rather, it is a complex mixture that may
contain various classes of chemical compounds, such as polysaccharides,
organic acids, and anthraquinones.
---------------------------------------------------------------------------
\4\ A USP dietary supplement monograph exists for Aloe (USP 38-
NF33, Aloe). However, no USP or NF monograph exist for Aloe vera
200:1 freeze-dried or Aloe vera gel 200:1 freeze-dried. See Ref. 21
for additional information.
---------------------------------------------------------------------------
Regarding safety, nonclinical data show that Aloe vera has
abortifacient activity when taken orally and induced skeletal
malformations in an oral embryofetal toxicity study in rats. Clinical
data indicate that the topical use of Aloe vera gel can be tolerated
for short durations without serious toxicity, although it is unclear
whether those data are based on 200:1 freeze dried Aloe vera. The
anthraquinone derivative in Aloe vera latex can pose safety concerns,
including potential carcinogenicity, particularly when used repeatedly
at high doses. We found no data on the safety of the long-term use of
Aloe vera.
Regarding effectiveness, there is limited and conflicting
information from controlled clinical trials regarding the effectiveness
of Aloe vera topical products in the treatment of cuts, burns, and
wounds. It is not clear whether these trials used 200: 1 freeze dried
Aloe vera. Historically, Aloe vera has been used in herbal remedies in
many parts of the world. However, we do not have sufficient information
to evaluate the historical use of compounded drug products that include
200:1 freeze dried Aloe vera.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of 200:1 freeze dried Aloe vera weigh
against inclusion of this substance on the list. FDA recommended to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
21), and at its meeting on March 8, 2016, the PCAC voted not to include
200:1 freeze dried Aloe vera on the list (Ref. 6). We have also
consulted with USP regarding placement of this substance on the 503A
Bulks List, and USP did not identify any additional quality concerns
related to this substance (Ref. 14). This proposed rule proposes not to
include Aloe vera 200:1 freeze dried on the 503A Bulks List.
(5) Artemisinin. Artemisinin was evaluated for use in the treatment
of malaria, helminthic infections, protozoal (particularly
toxoplasmosis) infections, stomach ulcers, and cancer. Artemisinin is
well characterized physically and chemically. However, it has a short
half-life and poor oral bioavailability due to excess first pass
metabolism and is poorly soluble in water and oil. Regarding safety,
artemisinin has clinically significant effects on different cytochrome
P450 enzymes. It is possible that artemisinin acts as a perpetrator to
change the exposure of other concomitantly administered drug products
that are substrates of these cytochrome P450 isoforms in patients.
These effects may lead to significant drug-drug interactions when
artemisinin is used with other concomitant medications that are
substrates of these cytochrome P450 isoforms on a daily basis. For use
in the treatment of malaria, when dosing is limited to 1 or 2 days, we
did not identify significant safety concerns associated with the use of
artemisinin in compounded drug products. However, with repeat dosing
(as would be used in the treatment of the other conditions evaluated),
there is evidence of serious adverse events, the most concerning being
drug-induced hepatitis. There are numerous reports in the literature of
elevations of transaminases and bilirubin in patients taking repetitive
doses of artemisinin leading to hospitalization.
Regarding effectiveness, there is evidence indicating that
artemisinin is likely an effective therapy for the treatment of
malaria. However, there are numerous FDA-approved drug products that
have been demonstrated to be safe and effective under the conditions of
use set forth in their labeling for the treatment of malaria.
Additionally, because of concerns about resistance, artemisinin is not
appropriate for use for prophylaxis of malaria when traveling to
countries where malaria is endemic. For the other uses evaluated, there
is insufficient information to evaluate the effectiveness of
artemisinin. We found no information regarding the historical use of
artemisinin in compounded drug products. It does not appear to be
currently used in compounding in the United States.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of artemisinin weigh against
inclusion of this substance on the 503A Bulks List. FDA proposed to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
22). At its meeting on May 9, 2017, the PCAC voted not to include
artemisinin on the list (Ref. 9). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 15). The proposed rule would not place artemisinin on
the 503A Bulks List.
(6) Astragalus Extract 10:1. Astragalus Extract 10:1 (astragalus)
was evaluated for use in the treatment of diabetes
[[Page 46695]]
mellitus, allergic rhinitis, wound healing, asthma, and herpes simplex
keratitis. It is not physically or chemically well characterized.
Rather, it contains hundreds of known and unknown chemical entities,
particularly polysaccharides, most of which would be difficult to
characterize and quantify. Nonclinical data regarding the safety of
astragalus are limited, and the significance of the available data is
unknown given the variability between astragalus compounds. Based on
limited clinical data, it appears that astragalus may be well-
tolerated; however, the limited data are insufficient to allow
evaluation of potential adverse outcomes associated with the use of
astragalus.
Regarding effectiveness, there have been numerous investigations of
astragalus extracts in the treatment of diabetes. Some of these studies
indicate that some formulations of astragalus extracts reduced plasma
glucose and insulin sensitivity. However, as noted above, the
significance of the data from these studies is unknown given the
variability between astragalus compounds. Studies in allergic rhinitis,
wound healing, and asthma were inadequate to assess effectiveness, and
no studies in herpes simplex keratitis were found that assessed
clinically meaningful endpoints. Historically, astragalus has been used
as an herbal treatment for a variety of conditions, but there is
insufficient information to determine whether astragalus has been used
in compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of astragalus weigh against inclusion
of this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 19). At its
meeting on November 20, 2017, the PCAC voted not to include astragalus
on the list (Ref. 11). We have also consulted with USP regarding
placement of this substance on the 503A Bulks List, and USP did not
identify any additional quality concerns related to this substance
(Ref. 15). The proposed rule would not place astragalus on the 503A
Bulks List.
(7) BWSE. BWSE was evaluated as treatment for rheumatoid arthritis
(RA) and osteoarthritis (OA). BWSE is not physically or chemically well
characterized. Rather, because it is a naturally derived, botanical
substance, BWSE's physical and chemical characteristics can vary
according to the source and extraction method and cannot adequately be
controlled to ensure a consistent composition absent proper controls of
the botanical raw materials and manufacturing processes. Regarding
safety, there are reports that resin from Boswellia may be an
emmenagogue and induce abortion. BWSE has also been associated with
gastrointestinal adverse events, including diarrhea, abdominal pain,
and nausea. There are reports of an increase in anticoagulant effect
when BWSE interacts with oral anticoagulants.
There is some evidence that BWSE might improve symptoms of OA in
some patients, but BWSE has not been shown to be effective in
inhibiting radiographic progression of RA. There are numerous FDA-
approved drug products that have been demonstrated to be safe and
effective under the conditions of use set forth in their labeling for
both RA and OA. Regarding its historical use, Boswellia has been used
for millennia, particularly in Ayurvedic and traditional Chinese
medicine, for a variety of uses, including wound care, pain, and
arthritis, although we don't know how long it has been used in
compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of BWSE weigh against inclusion of
this substance on the list. FDA recommended to the PCAC that this
substance not be included on the 503A Bulks List (Ref. 21), and at its
meeting on March 8, 2016, the PCAC voted not to include BWSE on the
list (Ref. 6). We have also consulted with USP regarding placement of
this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 14). This
proposed rule would not place BWSE on the 503A Bulks List.
(8) Cesium Chloride. Cesium chloride, an inorganic chloride salt,
was evaluated for use in the treatment of cancer. It is well
characterized physically and chemically. Both nonclinical and clinical
studies give rise to significant safety concerns related to the use of
cesium chloride in compounded drug products. Those concerns include
links between cesium chloride use and hypokalemia, seizures, QT
prolongation, and cardiac arrhythmias. There is no evidence that cesium
chloride would be effective in the prevention or treatment of cancer.
In contrast, there are numerous FDA-approved drug products that have
been demonstrated to be safe and effective under the conditions of use
set forth in their labeling for the treatment of cancer. We found no
evidence regarding the historical use of cesium chloride in compounded
drug products, although it appears to have been used for the treatment
of cancer. Literature discussing studies of the substance date back to
the 1980s
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of cesium chloride weigh against
inclusion of this substance on the 503A Bulks List. FDA proposed to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
20). At its meeting on June 23, 2016, the PCAC voted not to include
cesium chloride on the list (Ref. 7). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 14). The proposed rule would not place cesium chloride
on the 503A Bulks List.
(9) Chondroitin Sulfate. Chondroitin sulfate was evaluated for use
in the treatment of OA. Chondroitin sulfate is an unspecified mixture,
composed mainly of chondroitin 4-sulfate and chondroitin 6-sulfate in
varying percentages. The relative amounts of chondroitin sulfate A and
chondroitin sulfate C in the mixture are not well defined and can vary.
The data available are inadequate to evaluate the safety of the use
of chondroitin sulfate in compounded drug products, although there have
been no significant safety signals associated with the use of topical
chondroitin sulfate. While most adverse events reported in the
literature with the use of chondroitin sulfate orally have not been
serious in nature, there have been adverse event reports of concern,
including reports of increased effectiveness of anticoagulants (leading
to a risk of bleeding) when given in combination with chondroitin
sulfate and reports of abnormal liver function. Regarding
effectiveness, a large, well-controlled trial, the NIH-sponsored
``Glucosamine/chondroitin Arthritis Intervention Trial (GAIT)'' (Ref.
21), showed that, whether alone or in combination with glucosamine, the
oral use of chondroitin sulfate appears to be ineffective for the
treatment of pain associated with OA. Other trials reported positive
results, including with the topical use of chondroitin sulfate, but
those trials were generally smaller and of shorter duration, and
suggest that, at best, any effect may be transient. As noted above,
there are numerous FDA-approved drug products that have been
demonstrated to be safe and effective under the conditions of use set
forth in their labeling for the treatment of OA.
Regarding historical use, the use of chondroitin sulfate has been
reported in medical literature dating back to the 1980s, but that
discussion was not
[[Page 46696]]
specific to its use in compounded drug products. We found no
information regarding how long chondroitin sulfate has been used in
compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of chondroitin sulfate weigh against
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance not be included on the 503A Bulks List (Ref. 21),
and at its meeting on March 8, 2016, the PCAC voted not to include
chondroitin sulfate on the list (Ref. 6). We have also consulted with
USP regarding placement of this substance on the 503A Bulks List, and
USP did not identify any additional quality concerns related to this
substance (Ref. 14). This proposed rule would not place chondroitin
sulfate on the 503A Bulks List.
(10) Chrysin. Chrysin was evaluated for use as an aromatase
inhibitor.\5\ Chrysin is well characterized physically and chemically.
Regarding safety, limited nonclinical studies show chrysin has the
potential for mutagenicity and neurotoxicity. Clinically, systemic
exposure to chrysin is low due to poor oral bioavailability and rapid
metabolism and elimination. We found insufficient information about the
topical or oral use of chrysin to evaluate its safety.
---------------------------------------------------------------------------
\5\ Chrysin was proposed for use ``as an aromatase inhibitor
which prevents the conversion of testosterone to estrogen'' for the
treatment of ``high estrogen and low testosterone.'' (Ref. 20).
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Regarding effectiveness, in vitro data shows that chrysin inhibits
aromatase at high concentrations, but we found no clinical data
indicating that chrysin would be effective in the treatment of cancer,
which is the use for which FDA-approved aromatase inhibitors are
indicated, specifically, for the treatment of breast cancer in women.
There are also FDA-approved products indicated for testosterone
replacement, another common use of compounded chrysin products. We
found insufficient information to evaluate the historical use of
chrysin in compounded drug products. It is currently being compounded
for use in drug products promoted for bodybuilding and ``men's
health.''
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of chrysin weigh against inclusion of
this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 20). At its
meeting on June 23, 2016, the PCAC voted not to include chrysin on the
list (Ref. 7). We have also consulted with USP regarding placement of
this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 14). The
proposed rule would not place chrysin on the 503A Bulks List.
(11) Curcumin. Curcumin, a dye obtained from turmeric, was
evaluated as treatment for familial adenomatous polyposis, gastric
metaplasia, and oral leukoplakia. Although curcumin and its major
components are well characterized physically and chemically, the term
``curcumin'' is used to refer to a wide range of substances comprised
of different amounts of different curcuminoids, which might have
different physical and chemical characteristics.
Curcumin appears to be mostly well tolerated for short durations,
and the most common adverse events were mild. However, the evaluated
conditions can be chronic, requiring treatment for years. There are
limited data about the safety of curcumin in compounded drug products
given its poor bioavailability, lack of exposure-response for safety,
lack of uniformity of the curcumin used, and lack of information from
well-designed clinical trials. Although preliminary signs of activity
related to curcumin (generally related to biomarkers or effects on
disease processes) have been reported in small and uncontrolled
studies, there is insufficient evidence that it would be effective for
the proposed conditions. Further, there is a risk that patients might
use curcumin to treat the conditions reviewed in lieu of FDA-approved
products that have been demonstrated to be safe and effective under the
conditions of use set forth in their labeling, or that they might delay
the use of such products. Familial adenomatous polyposis in particular
is a serious condition; virtually all patients will develop colon
cancer if it is left untreated. Turmeric has historically been used in
traditional Indian medicine, but we found no information on the length
of time curcumin has been used in compounded drug products. It has been
used in an IV dosage form to treat eczema and thrombocytopenia (Ref.
23).
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of curcumin weigh against inclusion
of this substance on the list. FDA recommended to the PCAC that this
substance not be included on the 503A Bulks List (Ref. 17), and at its
meeting on October 27, 2015, the PCAC voted not to include curcumin on
the list (Ref. 2). We have also consulted with USP regarding placement
of this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 14). This
proposed rule would not place curcumin on the 503A Bulks List.
(12) D-Ribose. D-Ribose was evaluated as treatment for heart
disease and chronic fatigue syndrome (CFS).\6\ D-ribose is well
characterized physically and chemically. It is commercially available
for use as a food additive and has been designated as Generally
Recognized as Safe (GRAS). However, a substance that is safe when used
as a food might not be safe as an active ingredient in a drug product,
for example, when used for a route of administration other than oral.
In addition, a GRAS determination does not indicate that a substance
would have any effectiveness for a proposed use when used in a
compounded drug product. When used as a drug product D-ribose may cause
a false hypoglycemia if the dose constitutes a substantial fraction of
total daily caloric intake.\7\ The use of D-ribose in compounded drug
products poses a particular safety concern to patients with diabetes
mellitus, since they often have concomitant coronary artery disease or
ischemic cardiac myopathy/ischemic heart failure. Hypoglycemia,
detected with glucose monitoring, could complicate the titration of
insulin in patients with diabetes, particularly when high pharmacologic
doses of D-ribose and insulin are administered close in time.
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\6\ Currently, FDA does not recognize a particular definition or
name as appropriate for use in clinical trials of drug products for
CFS, which is also referred to as myalgic encephalomyelitis or
systemic exertion intolerance disease. CFS is used in this NPRM
because it was the term used in the nomination for D-ribose.
\7\ Food products that contain D-ribose as a food additive at
>=1 percent per volume or weight also contain other sources of
carbohydrates (and thus glucose), and thus might not pose the same
risk of false hypoglycemia.
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Regarding effectiveness, there is a lack of proven benefit
associated with D-ribose for the treatment of either heart disease or
CFS. The reported studies of the utility of D-ribose for the treatment
of cardiovascular disease provide no convincing evidence of a
meaningful clinical benefit. There are many FDA-approved drug products
that have been demonstrated to be safe and effective under the
conditions of use set forth in their labeling for the treatment of
heart disease, which is a serious condition. While we recognize that
there are no FDA-approved therapies indicated for CFS, the treatment of
CFS with D-ribose has been evaluated in only a single
[[Page 46697]]
small uncontrolled, unblinded study (Ref. 24). We do not believe that
this study demonstrates that there is a benefit to CFS patients that
would outweigh the risks of using D-ribose outlined above.
Regarding the historical use of D-ribose, we do not know how long
it has been used as a compounded drug product. It first appeared in the
medical literature in 1946.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of D-ribose weigh against inclusion
of this substance on the list. FDA recommended to the PCAC that this
substance not be included on the 503A Bulks List (Ref. 21), and at its
meeting on March 8, 2016, the PCAC voted not to include D-ribose on the
list (Ref. 6). We have also consulted with USP regarding placement of
this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 14). This
proposed rule would not place D-ribose on the 503A Bulks List.
(13) Deoxy-D-Glucose. Deoxy-D-glucose, also known as 2-deoxy-D-
glucose, was evaluated for use in the treatment of cancer and herpes
simplex virus (HSV). Deoxy-D-glucose is physically and chemically well
characterized. Regarding safety, in rats, dietary supplementation with
deoxy-D-glucose showed cardiac toxicity, developmental and reproductive
toxicity, carcinogenicity, and decreased median survival. In humans,
the safety profile of deoxy-D-glucose was only manageable at lower
doses used with combination treatments; when used as a single agent,
based on limited clinical evidence, the high dose of deoxy-D-glucose
required was unacceptably toxic.
Regarding effectiveness, we found no evidence indicating that
deoxy-D-glucose would be effective as a treatment for cancer or HSV. In
the reported clinical trials that studied the use of deoxy-D-glucose
for the treatment of cancer, toxicity was reached before there was
evidence of effectiveness. We located only one clinical trial that
studied deoxy-D-glucose in the treatment of HSV, from which no
conclusions regarding efficacy could be drawn due to the quality of the
study. Each of these serious conditions has a number of FDA-approved
drug products that have been demonstrated to be safe and effective
under the conditions of use set forth in their labeling. We found
insufficient evidence to evaluate the historical use of deoxy-D-glucose
in compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of deoxy-D-glucose weigh against
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance not be included on the 503A Bulks List (Ref. 17),
and at its meeting on October 27, 2015, the PCAC voted not to include
deoxy-D-glucose on the list (Ref. 2). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 14). This proposed rule would not place deoxy-D-glucose
on the 503A Bulks List.
(14) Diindolylmethane. Diindolylmethane was evaluated for use in
the treatment of cancer. It is well characterized physically and
chemically. Oral administration of diindolylmethane caused white pulp
atrophy and decreased immune cell counts in the spleen of neonatal mice
and increased serum cytokines in adult mice. Diindolylmethane induced
hepatic CYP1A1, CYP1A2, and CYP3A2 in rats, suggesting that drug-drug
interactions might occur with its use in patients. While the
nonclinical data are limited, the available data suggest that there may
be a safety concern with the use of diindolylmethane in compounded drug
products. Although we identified no serious adverse events reports
related to the use of diindolylmethane in humans, the available
clinical data are too limited to draw conclusions regarding the safety
of diindolylmethane.
Clinical studies published to date show changes in biomarkers, but
no clinical publication to date describes an effect of diindolylmethane
on any endpoint generally accepted in clinical oncology as being of
clinical benefit. There is no evidence that diindolylmethane would be
effective in the treatment of cancer. In contrast, there are numerous
FDA-approved drug products that have been demonstrated to be safe and
effective under the conditions of use set forth in their labeling for
the treatment of cancer. We found no evidence regarding the historical
use of diindolylmethane in compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of diindolylmethane weigh against
inclusion of this substance on the 503A Bulks List. FDA proposed to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
18). At its meeting on November 3, 2016, the PCAC voted not to include
diindolylmethane on the list (Ref. 8). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 15). The proposed rule would not place diindolylmethane
on the 503A Bulks List.
(15) Domperidone. Domperidone was evaluated as treatment for
gastroparesis, nausea and vomiting, and to enhance lactation.
Domperidone is well characterized physically and chemically. Serious
concerns about the safety of domperidone are raised by both clinical
and nonclinical studies. At therapeutic doses approved outside the
United States, domperidone carries a serious risk of life-threatening
cardiac arrhythmias and sudden cardiac death in all populations,
including healthy lactating women, and potentially, their infants.
Domperidone has known risks of QT interval prolongation, and the dose
and exposure at which domperidone can cause serious cardiac arrhythmias
are not well characterized in patients.
The effectiveness of domperidone as a galactagogue is unknown given
the limited evidence available, and evidence suggesting that
domperidone may be beneficial for nausea and vomiting and gastroparesis
is limited due to the small size of the clinical trials that have been
conducted for these uses or design flaws with those trials. Domperidone
has been compounded in the United States for at least a decade and has
been used in other jurisdictions since at least the 1970s.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of domperidone weigh against
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance not be included on the 503A Bulks List (Ref. 17),
and at its meeting on October 28, 2015, the PCAC voted not to include
domperidone on the list (Ref. 4). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 16). This proposed rule would not place domperidone on
the 503A Bulks List.
(16) EGCG. EGCG, or (-)-epigallocatechin-3-gallate, was evaluated
for use in the treatment of obesity, type 1 and type 2 diabetes,
cardiac hypertrophy, corneal neovascularization, non-alcoholic fatty
liver disease, Parkinson's disease, and wound healing. EGCG is the most
abundant type of catechin in green tea. It is well characterized
physically and chemically, but degrades significantly within 1 month.
It was nominated for
[[Page 46698]]
use in capsules, topical gels, and ophthalmic solutions, but it is not
expected to be stable in formulations other than solid oral dosage
forms. Regarding safety, in several nonclinical models, liver and
gastrointestinal toxicities were noted. In humans, there are numerous
case reports of hepatotoxicity, including fulminant hepatic failure,
the need for liver transplantation, or death associated with products
that contain EGCG, which is typically administered as one component of
a multicomponent dietary supplement/botanical product. Establishing
whether EGCG has a causal link with these existing cases is not
feasible, and additional data are needed to evaluate the safety of the
use of EGCG in compounded drug products. A review by Health Canada
published in December 2017 concluded that there may be a link between
the use of green tea extract and a risk of rare and unpredictable liver
injury (Ref. 25).
Regarding effectiveness, there are hypotheses regarding the
potential therapeutic utility of EGCG, as well as nonclinical and
clinical pharmacologic data identifying potential mechanisms of action
in various disease states. However, clinical data for EGCG have not
been identified to support the effectiveness of EGCG for any of the
uses evaluated. We found insufficient information to determine how long
EGCG has been used in compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of EGCG weigh against inclusion of
this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 19). At its
meeting on November 20, 2017, the PCAC voted not to include EGCG on the
list (Ref. 11). We have also consulted with USP regarding placement of
this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 15). The
proposed rule would not place EGCG on the 503A Bulks List.
(17) Germanium Sesquioxide. Germanium sesquioxide was evaluated as
treatment for cancer. It is physically and chemically well
characterized. It can, however, include impurities with significant
toxicities, specifically, potentially dangerous levels of inorganic
germanium salts (e.g., GeO2, germanium lactate citrate, Ge-lac-cit),
which can accumulate in the body. The limited information available
about the safety of germanium sesquioxide gives rise to significant
concerns about its use in compounded drug products, particularly given
the risk of contamination with highly toxic inorganic forms of
germanium salts. The nephrotoxicity of inorganic forms of germanium,
such as germanium dioxide or germanium citrate lactate, is well
established, and prolonged use of germanium products has been
associated with cases of renal failure and death. There is currently a
restriction on the importation of all germanium compounds, except those
used for semiconductors (Ref. 26).
There are very little clinical data regarding the effectiveness of
germanium sesquioxide in the treatment of cancer. We located only a
single case report, from which no conclusions regarding the
effectiveness of germanium sesquioxide could be drawn. In contrast,
there are numerous FDA-approved drug products that have been
demonstrated to be safe and effective under the conditions of use set
forth in their labeling for the treatment of various types of cancer.
We found little information regarding the history of the use of
germanium sesquioxide in compounded drug products and could not
determine whether or how long it has been used in compounded drug
products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of germanium sesquioxide weigh
against inclusion of this substance on the list. FDA recommended to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
17), and at its meeting on October 27, 2015, the PCAC voted not to
include germanium sesquioxide on the list (Ref. 2). We have also
consulted with USP regarding placement of this substance on the 503A
Bulks List, and USP did not identify any additional quality concerns
related to this substance (Ref. 14). This proposed rule would not place
germanium sesquioxide on the 503A Bulks List.
(18) Glycyrrhizin. Glycyrrhizin, also known as glycyrrhizic acid or
glycyrihizinic acid, is a triterpene saponin extracted from licorice.
It was evaluated for use in the treatment of hepatitis C by intravenous
administration. Although glycyrrhizin's molecular structure can be
characterized, the term ``glycyrrhizin'' is used to refer to a variety
of licorice extracts, which are often complex mixtures that are not
well characterized physically or chemically. Glycyrrhizin also poses
safety concerns. The association between glycyrrhizin use and serious
pseudo-hyperaldosterone effects is well established and has been noted
in over 100 case reports. Regarding effectiveness, clinical studies of
IV administration of glycyrrhizin in patients with chronic hepatitis C
have shown no demonstrable antiviral effect.
Regarding its historical use, Glycyrrhiza (licorice) has been used
for curative and flavoring purposes for 4,000 years, and glycyrrhizin
has been used to treat chronic hepatitis in Japan for over 30 years.
However, we found no evidence of the use of glycyrrhizin in IV
compounded drugs products in the United States.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of glycyrrhizin weigh against
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance not be included on the 503A Bulks List (Ref. 17),
and at its meeting on October 28, 2015, the PCAC voted not to include
glycyrrhizin on the list (Ref. 3). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 14). This proposed rule would not place glycyrrhizin on
the 503A Bulks List.
(19) Kojic Acid. Kojic acid was evaluated for use in the treatment
of melasma and as an iron chelator in wound healing and photodamage
prevention. Kojic acid is well characterized physically and chemically,
but it is a very reactive and unstable compound. Nonclinical data
suggest that kojic acid is potentially genotoxic, and data about its
carcinogenicity are equivocal. Data suggest that the use of kojic acid
may be associated with local irritancy, but reported adverse reactions
appear to have been transient and manageable. There have been no
reports of systemic adverse reactions. We identified no major safety
concerns related to the use of kojic acid to treat melasma, but we
found no data evaluating the safety of the use of kojic acid in open
wounds or the prevention of photodamage.
Regarding effectiveness, there is insufficient evidence to show
that kojic acid would be an effective treatment for any of the
evaluated uses. Most trials evaluating the use of kojic acid for
melasma or hyperpigmentation disorders used kojic acid in combination
with other topical therapies, and often flaws in trial design prevented
the data from being sufficiently reliable. Historically, kojic acid has
been used in compounded drug products for decades, often in combination
with other substances.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of kojic acid weigh against inclusion
of this substance on the 503A
[[Page 46699]]
Bulks List. FDA proposed to the PCAC that this substance not be
included on the 503A Bulks List (Ref. 18). At its meeting on November
3, 2016, the PCAC voted not to include kojic acid on the list (Ref. 8).
We have also consulted with USP regarding placement of this substance
on the 503A Bulks List, and USP did not identify any additional quality
concerns related to this substance (Ref. 15). The proposed rule would
not place kojic acid on the 503A Bulks List.
(20) Nettle. Nettle (Urtica dioica L.), a botanical substance, was
evaluated for use in glycemic control. Nettle is not physically or
chemically well characterized. The major and/or active components of
nettle are unknown. There is a dearth of reliable information regarding
the safety of the use of nettle in compounded drug products. The most
frequent adverse effects appear to be mild gastrointestinal irritation
and allergic reactions; however, the available information is based on
formulations with poorly characterized compositions. It is unclear how
the formulations employed in the existing literature might compare
qualitatively or quantitatively to a bulk drug substance used in
compounded drug products.
The effectiveness of nettle has not been adequately assessed with
well-characterized formulations. A small number of clinical
effectiveness investigations of nettle and some nonclinical data in
animal models for diabetes suggest that nettle may have some effect in
reducing fasting blood sugar and other parameters related to diabetes.
However, they do not provide sufficient evidence that nettle would be
effective in providing glycemic control. Historically, nettle has been
used for centuries as an herbal treatment for a variety of conditions.
It has been used in compounded drug products for at least 7 years.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of nettle weigh against inclusion of
this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 22). At its
meeting on May 8, 2017, the PCAC voted not to include nettle on the
list (Ref. 9). We have also consulted with USP regarding placement of
this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 15). The
proposed rule would not place nettle on the 503A Bulks List.
(21) NAD. NAD was evaluated for use in the treatment of fatigue in
patients with multiple sclerosis (MS). It is well characterized
physically and chemically, but it degrades substantially when exposed
to light, moisture, alkaline pH, or standard room temperatures and
would not be stable under ordinary storage conditions absent multiple
compensatory measures. Nonclinical data found in the literature are
inadequate to characterize the potential toxicity profile for NAD,
particularly for use in a chronic disease such as MS. Similarly, we did
not find sufficient clinical data about NAD to evaluate whether it is
safe for use in compounded drug products.
We identified no published studies that support the use of NAD for
the treatment of fatigue in patients with multiple sclerosis.
Therefore, we have insufficient information on which to evaluate the
effectiveness for NAD for its proposed use. There are FDA-approved drug
products that have been demonstrated to be safe and effective under the
conditions of use set forth in their labeling for the treatment of MS.
We do not have enough information to determine how long NAD has been
used in compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of NAD weigh against inclusion of
this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 22). At its
meeting on May 8, 2017, the PCAC voted not to include NAD on the list
(Ref. 9). We have also consulted with USP regarding placement of this
substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 15). The
proposed rule would not place NAD on the 503A Bulks List.
(22) NADH. NADH was evaluated for use in the treatment of CFS.\8\
It is well characterized physically and chemically, but degrades
substantially when exposed to light, moisture, alkaline pH, or standard
room temperatures and would not be stable under ordinary storage
conditions absent multiple compensatory measures. We found no reports
of serious adverse events; however, the clinical safety data available
for review were minimal. Nonclinical data reported in the literature
suggest that NADH is not stable in an acid medium and is likely to be
degraded before absorption after oral dosing. Nonclinical safety data
are insufficient to characterize the potential toxicity profile for
NADH, particularly for use in a chronic disease such as CFS.
---------------------------------------------------------------------------
\8\ See footnote 5, above, regarding use of the term ``CFS.''
---------------------------------------------------------------------------
Regarding effectiveness, there is insufficient information to
indicate that NADH would be effective for the evaluated use. The
available clinical effectiveness data regarding administration of NADH
to patients with CFS failed to provide an assessment of fatigue
specifically, and it also failed to show statistically significant
improvement on assessment scales of multiple other symptoms. We do not
have enough information to determine how long NAD has been used in
compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of NADH weigh against inclusion of
this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 22). At its
meeting on May 8, 2017, the PCAC voted not to include NADH on the list
(Ref. 9). We have also consulted with USP regarding placement of this
substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 15). The
proposed rule would not place NADH on the 503A Bulks List.
(23) Rubidium Chloride. Rubidium chloride, also known as rubidium
monochloride or rubinorm, was evaluated for use in the treatment of
cancer. Rubidium chloride is physically and chemically well
characterized. We found insufficient information to determine whether
the use of rubidium chloride in compounded drug products would be safe
or effective. Non-clinical studies showed that the administration of
rubidium in rats affected their growth, survival times, and behavior.
Rubidium chloride in the treatment of cancer appears to have only been
studied in clinical trials by one individual in the 1960s and 1970s,
but the role of rubidium in the results of those studies is uncertain
since data were reported in the aggregate. Since that time, there have
been no documented studies of the safety or effectiveness of rubidium
chloride in the treatment of cancer. In contrast, there are numerous
FDA-approved drug products that have been demonstrated to be safe and
effective under the conditions of use set forth in their labeling in
the treatment of various types of cancer. Although rubidium chloride
was first discussed in medical literature in the 1960s, we did not find
information regarding the history of use of rubidium chloride in
compounded drug products.
[[Page 46700]]
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of rubidium chloride weigh against
inclusion of this substance on the list. FDA recommended to the PCAC
that this substance not be included on the 503A Bulks List (Ref. 17),
and at its meeting on October 27, 2015, the PCAC voted not to include
rubidium chloride on the list (Ref. 2). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 14). This proposed rule would not place rubidium
chloride on the 503A Bulks List.
(24) Sodium Dichloroacetate. Sodium dichloroacetate, also known as
dichloroacetate sodium, was evaluated for use in the treatment of
cancer. It is well characterized physically and chemically, but
unlikely to be stable when formulated as a solution for injection.
There are significant safety concerns related to the use of sodium
dichloroacetate in compounded drug products, primarily related to its
toxicity profile, as observed in both nonclinical and clinical studies.
One study of sodium dichloroacetate identified in the literature was
closed due to patient deaths and safety concerns (Ref. 27). There is no
evidence that sodium dichloroacetate would be effective in the
prevention or treatment of cancer. In contrast, there are numerous FDA-
approved drug products that have been demonstrated to be safe and
effective under the conditions of use set forth in their labeling for
the treatment of cancer. We found no evidence regarding the historical
use of sodium dichloroacetate in compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of sodium dichloroacetate weigh
against inclusion of this substance on the 503A Bulks List. FDA
proposed to the PCAC that this substance not be included on the 503A
Bulks List (Ref. 20). At its meeting on June 23, 2016, the PCAC voted
not to include sodium dichloroacetate on the list (Ref. 7). We have
also consulted with USP regarding placement of this substance on the
503A Bulks List, and USP did not identify any additional quality
concerns related to this substance (Ref. 14). The proposed rule would
not place sodium dichloroacetate on the 503A Bulks List.
(25) Vanadyl Sulfate. Vanadyl sulfate was evaluated for use in the
treatment of diabetes, hyperlipidemia, and heart disease, and for the
prevention of cancer. Vanadyl sulfate, an inorganic vanadium salt, is
well characterized physically and chemically. Regarding the safety of
vanadyl sulfate in compounded drug products, nonclinical safety data,
including toxicokinetic data, chronic toxicity data, reproductive data,
and carcinogenicity data, found in the literature suggest the potential
for a high toxicity profile. Administration by injection, the proposed
dosage form, appears to be associated with greater toxicity than the
oral route of administration. Human safety data are limited and do not
reveal the same types or degrees of toxicity that are shown in
nonclinical testing. The differences between nonclinical and clinical
safety findings may be explained by shortcomings in the available
clinical data and limited duration of treatment.
Regarding effectiveness, limited clinical effectiveness data
provide preliminary evidence that vanadyl sulfate or other vanadium
containing compounds could have an effect in treating diabetes or
hyperlipidemia. We identified no clinical effectiveness data for the
treatment of cancer or heart disease with vanadyl sulfate. There is
insufficient evidence to indicate that vanadyl sulfate has any
effectiveness in treating any of the evaluated conditions. Cancer and
heart disease are serious conditions for which there are FDA approved
drugs that have been found to be safe and effective under the
conditions of use set forth in their labeling. We do not have enough
information to determine how long vanadyl sulfate has been used in
compounded drug products.
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of vanadyl sulfate weigh against
inclusion of this substance on the 503A Bulks List. FDA proposed to the
PCAC that this substance not be included on the 503A Bulks List (Ref.
22). At its meeting on May 8, 2017, the PCAC voted not to include
vanadyl sulfate on the list (Ref. 9). We have also consulted with USP
regarding placement of this substance on the 503A Bulks List, and USP
did not identify any additional quality concerns related to this
substance (Ref. 15). The proposed rule would not place vanadyl sulfate
on the 503A Bulks List.
(26) VIP. VIP, a 28-amino acid peptide, was evaluated for use in
the treatment of a condition described as ``chronic inflammatory
response syndrome'' (CIRS).\9\ VIP is well characterized physically and
chemically, but absent sufficient controls on its production, synthesis
is likely to result in peptides of different lengths or different amino
acid sequencing. Although most adverse reactions observed related to
the use of VIP appear to be relatively mild, it has been associated
with severe immunologic reactions. Regarding effectiveness, we located
only one published study of VIP in a condition that appears to be
related to CIRS (Ref. 28), which failed to clearly establish benefits
of the administration of VIP. We did not find sufficient information to
determine the historical use of VIP in compounded drug products.
However, it appears that VIP is currently used in compounded nasal
sprays.
---------------------------------------------------------------------------
\9\ CIRS is a term we located in three publications. It appears
to be the subject of research. It is not listed in the International
Statistical Classification of Diseases and Related Health Problems
(ICD-10), a medical classification list by the World Health
Organization (Ref. 18). Further, CIRS is not listed in the Medical
Dictionary for Regulatory Activities (MedDRA) (id.).
---------------------------------------------------------------------------
On balance, the physiochemical characteristics, safety,
effectiveness, and historical use of VIP weigh against inclusion of
this substance on the 503A Bulks List. FDA proposed to the PCAC that
this substance not be included on the 503A Bulks List (Ref. 18). At its
meeting on November 3, 2016, the PCAC voted not to include VIP on the
list (Ref. 8). We have also consulted with USP regarding placement of
this substance on the 503A Bulks List, and USP did not identify any
additional quality concerns related to this substance (Ref. 15). The
proposed rule would not place VIP on the 503A Bulks List.
VI. Proposed Effective Date
The Agency proposes that any final rule based on this proposed rule
will become effective 30 days after the date of publication of the
final rule in the Federal Register.
VII. Preliminary Economic Analysis of Impacts
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct us to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with significant new regulations
``shall, to the extent permitted by law, be offset
[[Page 46701]]
by the elimination of existing costs associated with at least two prior
regulations.'' We have developed a comprehensive Preliminary Economic
Analysis of Impacts that assesses the impacts of the proposed rule. We
believe that this proposed rule is not a significant regulatory action
as defined by Executive Order 12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because we do not have enough information about the effect of
the proposed rule on small entities, we find that the proposed rule
will have a significant economic impact on a substantial number of
small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $150 million, using the most current (2017) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.
We evaluated 31 bulk drug substances for this proposed rule. We
propose to place 5 bulk drug substances on the 503A Bulks List, and we
propose not to place 26 substances on the 503A Bulks List. We expect
that the rule will affect compounding pharmacies and other producers
that market the affected substances or drug products made from the
affected substances, consumers of drug products containing the affected
substances, and payers that cover these drug products or alternative
treatments. Because we lack sufficient information to quantify most of
the costs and benefits of this proposed rule, we also include a
qualitative description of potential benefits and potential costs.
In table 1, we summarize the impacts of the proposed rule. The
estimated costs are derived from administrative costs related to
reading the rule. The primary estimate of the present value of the
costs over 10 years is $1.03 million. The primary estimate of the
annualized costs is $0.15 million at a 7 percent discount rate and
$0.12 million at a 3 percent discount rate.
Table 1--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
Primary Low High ---------------------------------------------------
Category estimate estimate estimate Year Discount Notes
dollars rate Period covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized ($m/year).
------------------------------------------------------------------------------------------
Annualized Quantified.
------------------------------------------------------------------------------------------
Qualitative....................... Potential gains or losses in consumer surplus, depending on consumer preferences for
compounded drugs. Potential public health benefits from increased use of other drug
products that may be more effective.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized ($m/year).... $0.15 $0.10 $0.20 2017 7% 10 years.
$0.12 $0.08 $0.16 2017 3% 10 years.
------------------------------------------------------------------------------------------
Annualized Quantified.
------------------------------------------------------------------------------------------
Qualitative....................... Costs to submit investigational new drug applications (INDs) for some compounded drug
products.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized ($m/
year).
------------------------------------------------------------------------------------------
From:
To:
------------------------------------------------------------------------------------------
Other Annualized Monetized ($m/
year).
------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:.............................. State, Local, or Tribal Government: None.
Small Business: None.
Wages: None.
Growth: None.
--------------------------------------------------------------------------------------------------------------------------------------------------------
We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 29) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.
X. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, we
[[Page 46702]]
conclude that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
XI. Consultation and Coordination With Indian Tribal Governments
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.
XII. 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 also are available electronically at https://www.regulations.gov. References without asterisks are not on display at
https://www.regulations.gov because they have copyright restriction.
Some may be available at the website address, if listed. References
without asterisks are available for viewing only at the Dockets
Management Staff. FDA has verified the website addresses, as of the
date this document publishes in the Federal Register, but websites are
subject to change over time.
1. *FDA, Transcript of the October 27, 2015, Meeting of the Pharmacy
Compounding Advisory Committee (Morning Session), 2015. Available at
https://wayback.archive-it.org/7993/20170404155219/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM484905.pdf.
2. *FDA, Transcript of the October 27, 2015, Meeting of the Pharmacy
Compounding Advisory Committee (Afternoon Session), 2015. Available
at https://wayback.archive-it.org/7993/20170404155220/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM484906.pdf.
3. *FDA, Transcript of the October 28, 2015, Meeting of the Pharmacy
Compounding Advisory Committee (Morning Session), 2015. Available at
https://wayback.archive-it.org/7993/20170404155221/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM484907.pdf.
4. *FDA, Transcript of the October 28, 2015, Meeting of the Pharmacy
Compounding Advisory Committee (Afternoon Session), 2015. Available
at https://wayback.archive-it.org/7993/20170404155222/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM484908.pdf.
5. *FDA, Transcript of the March 8, 2016, Meeting of the Pharmacy
Compounding Advisory Committee (Morning Session), 2016. Available at
https://wayback.archive-it.org/7993/20170403224125/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM507771.pdf.
6. *FDA, Transcript of the March 8, 2016, Meeting of the Pharmacy
Compounding Advisory Committee (Afternoon Session), 2016. Available
at https://wayback.archive-it.org/7993/20170404155209/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM507772.pdf.
7. *FDA, Transcript of the June 23, 2016, Meeting of the Pharmacy
Compounding Advisory Committee (Morning Session), 2016. Available at
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM563843.pdf.
8. *FDA, Transcript of the November 3, 2016, Meeting of the Pharmacy
Compounding Advisory Committee (Morning Session), 2016. Available at
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM563842.pdf.
9. *FDA, Transcript of the May 8-9, 2017, Meeting of the Pharmacy
Compounding Advisory Committee, 2017. Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM565933.pdf.
10. *FDA, Transcript of the November 20, 2017, Meeting of the
Pharmacy Compounding Advisory Committee (Morning Session), 2017.
Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM604328.pdf.
11. *FDA, Transcript of the November 20, 2017, Meeting of the
Pharmacy Compounding Advisory Committee (Afternoon Session), 2017.
Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM604329.pdf.
12. *Memorandum to File on FDA Consultations with United States
Pharmacopeia, September 26, 2016.
13. *Letter from the United States Pharmacopeia to FDA, October 7,
2016.
14. *Letter I from the United States Pharmacopeia to FDA, August 17,
2018.
15. *Letter II from the United States Pharmacopeia to FDA, August
17, 2018.
16. *Letter III from the United States Pharmacopeia to FDA, August
17, 2018.
17. *FDA Briefing Document for the October 27-28, 2015, Meeting of
the Pharmacy Compounding Advisory Committee, 2015. Available at
https://wayback.archive-it.org/7993/20170405230355/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM466380.pdf.
18. *FDA Briefing Document for the November 3, 2016, Meeting of the
Pharmacy Compounding Advisory Committee, 2016. Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM524613.pdf.
19. *FDA Briefing Document for the November 20, 2017, Meeting of the
Pharmacy Compounding Advisory Committee, 2017. Available at https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm582868.htm.
20. *FDA Briefing Document for the June 23, 2016, Meeting of the
Pharmacy Compounding Advisory Committee, 2016. Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM505041.pdf.
21. *FDA Briefing Document for the March 8-9, 2016, Meeting of the
Pharmacy Compounding Advisory Committee, 2016. Available at https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/ucm486144.htm.
22. *FDA Briefing Document for the May 8-9, 2017, Meeting of the
Pharmacy Compounding Advisory Committee, 2017. Available at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM553368.pdf.
23. *FDA, August 4, 2017, Statement, ``FDA investigates two serious
adverse events associated with ImprimisRx's compounded curcumin
emulsion product for injection.'' Available at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm570192.htm.
24. Teitelbaum, J.E., et al. ``The Use of D-Ribose in Chronic
Fatigue Syndrome and Fibromyalgia: A Pilot Study,'' Journal of
Alternative and Complementary Medicine, 12:857-862, 2006.
25. *Government of Canada, ``Summary Safety Review-Green Tea
Extract-
[[Page 46703]]
Containing Natural Health Products-Assessing the Potential Risk of
Liver Injury (Hepatotoxicity),'' December 12, 2017. Available at
https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/green-tea-extract-containing-natural-health-products-assessing-potential-risk-liver-injury.html.
26. *FDA Import Alert 54-07. Available at https://www.accessdata.fda.gov/cms_ia/importalert_139.html.
27. Garon, E.B., et al. ``Dichloroacetate Should be Considered with
Platinum-based Chemotherapy in Hypoxic Tumors Rather Than as a
Single Agent in Advanced Non-small Cell Lung Cancer,'' Journal of
Cancer Research and Clinical Oncology, 140:443, 2014.
28. Shoemaker, R.C., et al. ``Vasoactive Intestinal Polypeptide
(VIP) Corrects Chronic Inflammatory Response Syndrome (CIRS)
Acquired Following Exposure to Water-Damaged Buildings,'' Health,
5:396-401, 2013. Available at https://www.scirp.org/journal/health/.
(Open Access)
29. *Amendments to the List of Bulk Drug Substances that Can be Used
to Compound Drug Products in Accordance with Section 503A of the
Federal Food, Drug, and Cosmetic Act, Preliminary Regulatory Impact
Analysis, Initial Regulatory Flexibility Analysis, Unfunded Mandates
Reform Act Analysis, 2018. Available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
List of Subjects in 21 CFR Part 216
Drugs, Prescription drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, we
propose that 21 CFR part 216 be amended as follows:
PART 216--HUMAN DRUG COMPOUNDING
0
1. The authority citation for part 216 continues to read as follows:
Authority: 21 U.S.C. 351, 352, 353a, 353b, 355, and 371.
0
2. In Sec. 216.23, revise paragraphs (a) and (b) to read as follows:
Sec. 216.23 Bulk drug substances that can be used to compound drug
products in accordance with section 503A of the Federal Food, Drug, and
Cosmetic Act.
(a) The following bulk drug substances, which are neither the
subject of a current applicable United States Pharmacopeia or National
Formulary monograph nor components of FDA-approved drugs, can be used
in compounding under section 503A(b)(1)(A)(i)(III) of the Federal Food,
Drug, and Cosmetic Act.
(1) Brilliant Blue G, also known as Coomassie Brilliant Blue G-250.
(2) Cantharidin (for topical use only).
(3) Diphenylcyclopropenone (for topical use only).
(4) Glutaraldehyde (for topical use only, in concentrations of 10
percent or lower).
(5) Glycolic acid (for topical use only, in concentrations of 70
percent or lower).
(6) L-citrulline (for oral administration only).
(7) N-acetyl-D-glucosamine (for topical use only).
(8) Pyruvic acid (for topical use only).
(9) Squaric acid dibutyl ester (for topical use only).
(10) Thymol iodide (for topical use only).
(11) Trichloroacetic acid (for topical use only).
(b) The following bulk drug substances have been nominated and
evaluated for inclusion on the list of substance that can be used in
compounding set forth in paragraph (a) of this section, and FDA has
determined that they do not meet the criteria for inclusion set forth
in paragraph (c) of this section:
(1) 7-keto dehydroepiandrosterone (DHEA).
(2) Acetyl L Carnitine.
(3) Alanyl L Glutamine.
(4) Aloe Vera 200:1 Freeze Dried.
(5) Artemisinin.
(6) Astragalus extract 10:1.
(7) Boswellia.
(8) Cesium Chloride.
(9) Chondroitin Sulfate.
(10) Chrysin.
(11) Curcumin.
(12) D-Ribose.
(13) Deoxy-D-Glucose.
(14) Diindolylmethane.
(15) Domperidone.
(16) Epigallocatechin gallate (EGCG).
(17) Germanium Sesquioxide.
(18) Glycyrrhizin.
(19) Kojic acid.
(20) Nettle.
(21) Nicotinamide adenine dinucleotide (NAD).
(22) Nicotinamide adenine dinucleotide disodium reduced (NADH).
(23) Oxitriptan.
(24) Piracetam.
(25) Rubidium Chloride.
(26) Silver Protein Mild.
(27) Sodium dichloroacetate.
(28) Tranilast.
(29) Vanadyl sulfate.
(30) Vasoactive intestinal peptide.
* * * * *
Dated: July 16, 2019.
Norman E. Sharpless,
Acting Commissioner of Food and Drugs.
Dated: August 13, 2019.
Eric D. Hargan,
Deputy Secretary, Department of Health and Human Services.
[FR Doc. 2019-18951 Filed 9-4-19; 8:45 am]
BILLING CODE 4164-01-P