[Federal Register Volume 84, Number 33 (Tuesday, February 19, 2019)]
[Rules and Regulations]
[Pages 4696-4710]
[FR Doc No: 2019-02367]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 216

[Docket No. FDA-2016-N-3464]
RIN 0910-AH29

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: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a final rule to establish criteria for and identify an initial
list of bulk drug substances 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.
Specifically, the Agency is placing six bulk drug substances on the
list. This final rule also identifies four bulk drug substances that
FDA has considered and is not including on the list. Additional bulk
drug substances nominated by the public for inclusion on this list are
currently under consideration and will be the subject of a future
rulemaking.

DATES: This rule is effective March 21, 2019.

ADDRESSES: For access to the docket to read background documents or

comments received, go to https://www.regulations.gov and insert the
docket number found in brackets in the heading of this final rule 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 Ave.,
Bldg. 51, Rm. 5197, Silver Spring, MD 20993,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Need for and History of This Rulemaking
    B. Summary of Comments to the Proposed Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of General Comments and FDA Response
    C. Specific Comments and FDA Response
VI. Effective Date
VII. 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 Final Rule

    FDA is amending title 21 of the Code of Federal Regulations to add
a 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'' or ``the 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, although 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 Final Rule

    In this final rule, FDA is establishing the criteria for evaluation
of bulk drug substances for inclusion on the 503A Bulks List: (1) The
physical and chemical characterization of the substance; (2) any safety
issues raised by the use of the substance in compounded drug products;
(3) the available evidence of effectiveness or lack of effectiveness of
a drug product compounded with the substance, if any such evidence
exists; and (4) 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.
    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 USP, FDA is including six
bulk drug substances on the list: Brilliant Blue G, also known as
Coomassie Brilliant Blue G-250; cantharidin (for topical use only);
diphenylcyclopropenone (for topical use only); N-acetyl-D-glucosamine
(NAG) (for topical use only); squaric acid dibutyl ester (for topical
use only); and thymol iodide (for topical use only). FDA is also
identifying four other bulk drug substances that will not be included
on the list: Oxitriptan, piracetam, silver protein mild, and tranilast.
Drugs compounded with these substances will not qualify for the 503A
exemptions and cannot be used in compounding under section 503A of the
FD&C Act.

C. Legal Authority

    Section 503A, 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 final rule.

D. Costs and Benefits

    FDA is establishing criteria for evaluating inclusion of bulk drug
substances on the 503A Bulks List, placing six bulk drug substances on
the 503A Bulks List, and not including four bulk drug substances on the
503A Bulks List. The present value of the costs of the final rule
equals $3.33 million at a 7 percent discount rate and $3 million at a 3
percent discount rate. The final rule will result in annualized costs
of $0.42 million at a 7 percent discount rate, or $0.31 million at a 3
percent discount rate. Because we lack sufficient information to
quantify many of the costs and the benefits of this final rule, we also
include a qualitative description of potential benefits and potential
costs. We expect that the rule would affect compounding pharmacies and
certain other entities that market the affected substances or drug
products made from the affected substances, consumers of drug products
containing the affected drug substances, and payers that cover these
drug products or alternative drug products.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

------------------------------------------------------------------------
       Abbreviation/ acronym                    What it means
------------------------------------------------------------------------
APA...............................  Administrative Procedure Act.
5-HTP.............................  5-hydroxytryptophan.
CFR...............................  Code of Federal Regulations.
DQSA..............................  Drug Quality and Security Act.
FD&C Act..........................  Federal Food, Drug, and Cosmetic
                                     Act.
FDA...............................  Food and Drug Administration.
GRAS..............................  Generally recognized as safe.
HPUS..............................  Homeopathic Pharmacopeia of the
                                     United States.
IND...............................  Investigational new drug.
NAG...............................  N-acetyl-D-glucosamine.
NDA...............................  New drug application.
NF................................  National Formulary.
NPRM..............................  Notice of proposed rulemaking.
OTC...............................  Over-the-counter.
PCAC..............................  Pharmacy Compounding Advisory
                                     Committee.
PDUFA.............................  Prescription Drug User Fee Act.
USP...............................  United States Pharmacopeia.
------------------------------------------------------------------------

III. Background

A. Need for and History of This Rulemaking

    Section 503A describes the conditions under which a compounded drug
product qualifies for exemptions 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, 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 Health and Human Services (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, that appear on the 503A Bulks List.
(See section 503A(b)(1)(A)(i) of the FD&C Act.) This final rule
establishes criteria for evaluating bulk drug substances for inclusion
on the 503A Bulks List and identifies six bulk drug substances the
Secretary is placing on the list. The Agency considered four other bulk
drug substances and is not including those substances on the 503A Bulks
List. Additional bulk drug substances are under evaluation, and new
substances may be added to the list through subsequent rulemaking.
    The definitions that are relevant to this final rule are set forth
in the notice of proposed rulemaking (NPRM) published in the Federal
Register of

December 16, 2016 (81 FR 91071). The 2016 proposed rule also includes a
complete history of this rulemaking. In that proposed rule, FDA
discussed the 10 bulk drug substances nominated for inclusion on the
503A Bulks List that are the subject of this final rule, along with the
criteria FDA proposed to use when determining whether to place bulk
drug substances on the 503A Bulks List.
    Under this final rule, drug products compounded with the six
substances that are being placed on the 503A Bulks List qualify for the
503A exemptions if the conditions of section 503A of the FD&C Act are
met. In contrast, drugs compounded with the other four substances
evaluated in this rulemaking--which are not being placed on the 503A
Bulks List-- do not qualify for the 503A exemptions and cannot be used
in compounding under section 503A of the FD&C Act. As discussed in the
2016 proposed rule and in the guidance for industry entitled ``Interim
Policy on Compounding Using Bulk Drug Substances Under Section 503A of
the Federal Food, Drug, and Cosmetic Act'' (Interim Policy Guidance)
(Ref. 1), FDA generally has not intended to take regulatory action for
the use of certain substances, including the 10 substances that are the
subject of this final rule, while those substances were being
considered for inclusion on the 503A Bulks List (interim policy). Since
the rulemaking is now complete for these 10 nominated substances, the
interim policy no longer applies to those substances.

B. Summary of Comments to the Proposed Rule

    We received eight substantively relevant, unique comments to the
2016 proposed rule. The comments addressed FDA's proposals on the
criteria for evaluating bulk drug substances for inclusion on the 503A
Bulks List, including some comments on how FDA has been using the
criteria in practice. The comments also addressed FDA's proposals on
particular bulk drug substances. In addition to these topics, which
addressed the language proposed to be included in the Code of Federal
Regulations (CFR), commenters addressed a variety of topics related to
FDA's evaluation of bulk drug substances, including procedural issues
related to meetings of the PCAC, and compounding policies generally.

IV. Legal Authority

    As described in the Background section, section 503A 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
compounding drug products using bulk drug substances, must use 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 certain parts of 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, and any 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 final
rule.

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received 12 total comments posted to the docket for the proposed
rule by the close of the comment period. Of the 12 comments received, 3
addressed subjects other than the proposed rule, and 9 were related to
the proposed rule. Of the nine comments substantively related to the
proposed rule, one was a duplicate. Of the eight unique, substantively
relevant comments received, each discussed one or more issues. We
received comments from consumers; trade organizations, including those
representing compounders and clinicians with particular specialties; a
company that sells bulk drug substances and other materials for
compounding; and other organizations.
    We describe and respond to the issues raised in the comments in
sections V.B. and V.C. of this document. We have consolidated and
grouped the issues raised in the comments, and assigned each issue a
``comment number'' to help distinguish among different issues raised in
the comments. We have grouped similar issues raised in the comments
together under the same comment number, and, in some cases, we have
separated different issues discussed in the same comment and designated
them with distinct comment numbers for purposes of our responses. The
comment number assigned to each issue or topic is purely for
organizational purposes and does not signify the value or importance of
the issue or the order in which comments were received.
    We received some comments that raised issues that are outside the
scope of this rulemaking (e.g., animal testing, access to compounded
drug products as ``office stock,'' FDA's interpretation of the phrase
``clinical need'' as used in section 503B of the FD&C Act, competition
and drug pricing). To the extent issues raised in comments are
unrelated to this rulemaking, we do not respond to those comments.

B. Description of General Comments and FDA Response

    (Comment 1) Some comments made general remarks supporting the
proposed rule. These comments supported the proposed criteria, the
proposed placement of the six substances listed above on the 503A Bulks
List, the proposal not to include the four substances listed above on
the 503A Bulks List, and FDA's Interim Policy Guidance.
    (Response 1) We appreciate the support expressed in the comments
received.

C. Specific Comments and FDA Response

1. Proposed Criteria
    (Comment 2) Some comments objected to the proposed criteria as too
broad and vague to provide standards by which ingredients will be
judged. For example, one comment stated that FDA fails to define what
constitutes ``significant'' toxicity or ``other safety concerns,''
which are vague and give FDA too much discretion. The comments stated
that the proposed

criteria will lead to highly subjective decisions.
    (Response 2) We disagree and find no basis to change the criteria
proposed in the 2016 proposed rule based on this comment. We
acknowledge that the criteria have been and will be applied on a
substance-by-substance basis, given the risks and benefits that may be
presented by a particular substance. The Agency believes some measure
of flexibility is necessary for FDA to evaluate the nominated bulk drug
substances. We have applied and will continue to apply the criteria
consistently, weighing them as appropriate based on the nature of the
substance and proposed use, among other things. FDA also notes that its
application of the criteria to particular bulk drug substances is
subject to discussion with the PCAC and USP, and also is the subject of
notice and comment rulemaking. If, through the rulemaking process, FDA
receives feedback that any party believes it is not applying the
criteria correctly in any particular case, FDA will consider that
feedback before finalizing its proposal to include, or not include, a
substance on the 503A Bulks List.
    (Comment 3) One commenter objected to the fourth criterion FDA
proposed in the 2016 proposed rule: ``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.'' The commenter explained that
current use is more relevant than historical use.
    (Response 3) We disagree that FDA should not consider historical
use. Further, we note that consideration of current use is encompassed
in the historical use criterion. Regarding the criteria used to
determine whether a bulk drug substance should be placed on the 503A
Bulks List, section 503A(c)(2) of the FD&C Act specifies that the
criteria shall include historical use, reports in peer reviewed medical
literature, or other criteria the Secretary may identify. We are,
therefore, required by statute to consider the historical use of a bulk
drug substance. As we explained in the 2016 proposed rule, the Agency
is considering how widespread the use of a bulk drug substance has
been, as well as references in peer-reviewed medical literature, as
part of the evaluation of the historical use.
    (Comment 4) One commenter objected to FDA's consideration of the
historical use criterion, noting that FDA has not been giving this
factor adequate weight. This commenter suggested that, instead of
applying the criterion as proposed, FDA should recommend a bulk drug
substance for the 503A Bulks List if it has historically been in
significant use by a particular specialty or community of physicians
unless there is reliable evidence that the ingredient presents
unacceptable sterility concerns or potential for adverse reactions.
    (Response 4) As noted above, FDA is statutorily required to
consider historical use when evaluating the nominated bulk drug
substances, and the Agency has been doing so. To the extent information
pertaining to historical use has been available, it has been discussed
at length in each of the reviews underlying FDA's recommendations to
the PCAC and its proposals in the 2016 proposed rule. As noted above,
each criterion may weigh differently in the context of the risks and
benefits presented by a particular bulk drug substance, and historical
use may weigh more heavily in some cases than others. As also stated
above, FDA's application of the criteria to particular bulk drug
substances is subject to discussion with the PCAC and USP, and is the
subject of notice and comment rulemaking. If, through the rulemaking
process, FDA receives feedback that any party believes it is not giving
the historical use criterion adequate weight in any particular case,
FDA will consider that feedback before finalizing its proposal to
include, or not include, a substance from the 503A Bulks List. We
decline to adopt the commenter's suggestion to consider historical use
as dispositive in certain cases, as we believe doing so would give
disproportionate weight to the historical use criterion and would not
give adequate consideration to a substance's physical and chemical
characterization, safety, or effectiveness.
    (Comment 5) Some commenters objected to FDA's consideration of the
availability of approved drug products or drug products that conform to
an over-the-counter (OTC) monograph to treat the same condition as the
proposed bulk drug substance, and proposed that these alternatives not
weigh against inclusion of the substance on the 503A Bulks List. The
commenters noted that drug products are compounded because the drugs
already available are not appropriate or effective for individual
patients. Further, the commenters opposed the consideration of
alternative therapies because they assert FDA has failed to consider
the side effects of FDA-approved products, and any concern that use of
compounded drugs could delay use of approved products is baseless. One
of the commenters suggested that the approved alternatives should only
be considered where the approved medication leads to a complete cure or
remission of illness or otherwise fully addresses the purpose intended
for the compounded drug product, and there is no other reason a
compounded drug product containing the nominated bulk drug substance
should be available.
    (Response 5) We disagree with this comment and believe that the
existence of FDA-approved drug products or drug products that conform
to an OTC monograph may be relevant in the evaluation of particular
bulk drug substances. However, the existence of alternative therapies
is not one of the four criteria FDA is using to evaluate nominated bulk
drug substances, nor is the availability of approved alternatives
dispositive when considering whether to add a substance to the list.
Rather, as explained in the 2016 proposed rule, we consider the
existence of FDA-approved or OTC-monograph drug products relevant to
FDA's consideration of the safety criterion, to the extent there may be
therapies that have been demonstrated to be safe under the conditions
of use set forth in the approved labeling, and the effectiveness
criterion, to the extent there may be alternative therapies that have
been demonstrated to be effective for certain conditions. Therefore, we
find no reason to exclude consideration of the existence of FDA-
approved or OTC monograph drug products where relevant.
    Regarding the comment that FDA has not adequately considered the
side effects of alternative therapies, we disagree and have considered
the side effects of alternative therapies as part of the safety
criterion where information is available and relevant. We note,
however, that data comparing the safety profiles of compounded drug
products with approved drug products are generally not available. In
fact, in many cases, there are minimal data available concerning the
safety, including side effects, of compounded drugs. The absence of
information does not mean that safety risks do not exist. In contrast,
approved drug products have been demonstrated to be safe under the
conditions of use set forth in the approved labeling, and the benefits
of the drug product for the approved conditions of use have been found
to outweigh the risks. Similarly, regarding effectiveness, often there
are minimal data supporting the effectiveness of a compounded drug
product, and it may be preferable for a patient to use a drug product
with side effects when that drug product has been proven to be
effective. Even if a compounded drug product has fewer side effects
than an FDA-

approved or OTC monograph drug product, if it does not treat the
condition at issue, it may be of no or limited benefit to the patient.
    Regarding the comment that approved alternatives should only be
considered when there is evidence that the FDA-approved drug product or
OTC monograph product fully addresses patients' needs, we disagree.
While not one of the four criteria, as described in the 2016 proposed
rule and reflected in reviews completed and presented to the PCAC,
under certain circumstances, the existence of an approved drug product
or OTC monograph product to treat the condition, even where the product
may not fully address patients' needs, is relevant to FDA's evaluation
of one or more of the four criteria. For example, in considering the
effectiveness criterion, the existence of an approved drug product or
OTC monograph product may weigh against placing a substance on the 503A
Bulks List when the condition to be treated is very serious or life
threatening because of the serious consequences that could result from
use of an ineffective or less effective treatment alternative (2016
proposed rule, 81 FR 91071 at 91075.) Likewise, in considering the
safety criterion, the existence of an approved drug product or OTC
monograph product likely would weigh against placing a substance on the
503A Bulks List when the toxicity of the substance appears to be
significant, or other safety concerns are associated with the use of
the substance (id.).
    Further, we note that, as stated above, FDA's application of the
criteria to particular bulk drug substances is subject to discussion
with the PCAC and USP, and is also the subject of notice and comment
rulemaking. If, through the rulemaking process, FDA receives feedback
that any party believes it is not adequately considering the side
effects of FDA-approved products in any particular case, the Agency
will consider that feedback before finalizing its proposal to include,
or not include, a substance on the 503A Bulks List.
    (Comment 6) One commenter proposes that a substance should be added
to the 503A Bulks List if the Center for Food Safety and Applied
Nutrition (CFSAN) has determined the substance is generally recognized
as safe (GRAS).\1\
---------------------------------------------------------------------------

    \1\ Under sections 201(s) and 409 of the FD&C Act (21 U.S.C.
321(s) and 348), any substance that is intentionally added to food
is a food additive that is subject to premarket review and approval
by FDA, unless the substance is generally recognized, among
qualified experts, as having been adequately shown to be safe under
the conditions of its intended use, or unless the use of the
substance is otherwise excepted from the definition of a food
additive. For more information, see https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/.
---------------------------------------------------------------------------

    (Response 6) We disagree. GRAS determinations for food are made
under food safety standards and thus are not dispositive when
considering the use of a substance as an active ingredient in a
compounded drug product. 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.
Moreover, such a GRAS determination does not indicate that a substance
would have any effectiveness for a particular proposed use when used in
a compounded drug product. We note, however, that FDA has considered
CFSAN's GRAS notices and their implications in reviews completed to
date where relevant, for example, in our review of safety or physical
and chemical properties.
    As stated above, FDA's application of the criteria to particular
substances is subject to discussion with the PCAC and USP, and is also
the subject of notice and comment rulemaking. If, through the
rulemaking process, FDA receives feedback that any party believes it is
not adequately considering the GRAS determination of a substance in any
particular case, FDA will consider that feedback before finalizing its
proposal to include, or not include, a substance on the 503A Bulks
List.
    (Comment 7) One comment objected to FDA's consideration of the
seriousness of the condition the drug product compounded with the
nominated bulk drug substance is proposed to treat. In the 2016
proposed rule, FDA proposed to weigh the effectiveness criterion more
heavily when the bulk drug substance was proposed to treat a serious or
life-threatening disease, and to give the safety criterion more weight
when the substance was proposed for treatment of a less serious
disease. The commenter asserted that there is no rational basis for
such a standard.
    (Response 7) We disagree with the comment. As we explain in the
2016 proposed rule, when a bulk drug substance is proposed to treat a
more serious or life-threatening disease, there may be more serious
consequences associated with ineffective therapy. When evaluating a
bulk drug substance that is proposed for the treatment of a less
serious illness, FDA will generally be more concerned about the safety
of the substance than about its effectiveness. For these reasons, we
find no reason to discontinue consideration of the seriousness of the
condition the bulk drug substance is nominated to treat.
    (Comment 8) One comment objected to the process FDA used to
implement the criteria, noting that FDA was required to consult with
the PCAC and obtain stakeholder input through notice and comment
rulemaking before going forward with substance evaluations using the
proposed criteria. The commenter asserts that there was no formal
debate or discussion of the criteria with the PCAC.
    (Response 8) We acknowledge that FDA began considering the proposed
criteria and presenting recommendations to the PCAC before the criteria
were finalized in this rulemaking. We believe that the criteria could
not have been fully vetted and considered, by both the PCAC and USP, as
well as commenters to the 2016 proposed rule, without illustration of
how those criteria would apply in practice to evaluation of nominated
bulk drug substances. As discussed in this rulemaking, FDA has
considered the comments received on the proposed criteria and has found
no basis to change those criteria based on the comments received.
    We disagree, however, with the comment asserting that there was no
formal debate or discussion of the criteria with the PCAC. As discussed
in the 2016 proposed rule, FDA presented the criteria to the PCAC and
discussed the criteria with the PCAC at its February 23, 2015, meeting
(Ref. 2). The public had the opportunity to attend and speak at the
PCAC meeting at which these criteria were discussed. The public also
had the opportunity to review the transcript of the discussion that
took place at the PCAC meeting, both prior to the publication of the
proposed rule via publication of the transcript on the FDA website and
through the docket for the proposed rule, where the transcript was
included as a reference. FDA also consulted with USP regarding the
criteria, and USP agreed with the proposed criteria (Refs. 3 and 4).
2. Application of the Proposed Criteria to Date
    (Comment 9) Some commenters objected to the proposed criteria as
being underinclusive of the factors FDA has been applying in practice
in its evaluations of the nominated bulk drug substances. Specifically,
several comments stated that FDA's application of the proposed criteria
has been skewed by inappropriate consideration of the availability of
an investigational new drug (IND) application pathway,

which should not be relevant to FDA's recommendation of whether to
include a particular bulk drug substance on the 503A Bulks List.
    (Response 9) We disagree with the comment that the proposed
criteria are underinclusive of the factors FDA has been applying in
practice. While the PCAC presentations and discussions have encompassed
some information of interest that is not directly related to the four
criteria, such as the differences in regulatory standards between
dietary supplements and drug products, or general information about
compounding facilities, that information was not the basis of FDA's
recommendations or decisions with respect to the bulk drug substances.
Rather, in each of FDA's reviews (included in the record for the 2016
proposed rule), our recommendations have been derived directly from
consideration and balancing of the four criteria: (1) Physical and
chemical characterization of the substance; (2) any safety issues
raised by the use of the substance in compounded drug products; (3)
available evidence of effectiveness or lack of effectiveness of a drug
product compounded with the substance, if any such evidence exists; and
(4) 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.
    The option of making a substance available through an IND
application has been discussed by the PCAC and addressed in some
reviews to help inform the public of ways in which the drug can be
further studied and used to treat patients. In no review to date,
however, has the option of pursuing an IND been a basis in FDA's
proposals to include, or not to include, a nominated bulk drug
substance on the 503A Bulks List. For each substance evaluated to date,
FDA has made its proposals based on the four criteria described above,
without regard to the existence of, or option to pursue, an IND. We
note that FDA can make recommendations to the PCAC, but the Agency
cannot control the content of the PCAC's discussions or its advice. FDA
takes the PCAC's discussions and advice, including the basis for any
advice, into account when considering whether to propose a substance be
placed on the 503A Bulks List.
    As stated above, FDA's application of the criteria to particular
bulk drug substances is subject to discussion with the PCAC and USP,
and is also the subject of notice and comment rulemaking. If, through
the rulemaking process, FDA receives feedback that any party believes
it has inappropriately considered the availability of an IND in any
particular case, FDA will consider that feedback before finalizing its
proposal to include, or not include, a substance on the 503A Bulks
List.
    (Comment 10) One comment asserted that FDA's application of
criteria to evaluate bulk drug substances to date has been
inconsistent. For example, according to the commenter, in some cases
FDA and the PCAC recommended to include a bulk drug substance on the
503A Bulks List so there is an alternative to approved products, but in
other cases, FDA and the PCAC recommended to not include a substance on
the list because there is already an approved product available.
    (Response 10) We disagree with this comment. As we noted above, the
criteria are applied on a substance-by-substance basis, and a criterion
that may be weighed heavily for one bulk drug substance might be
weighed differently for another, given the risks and benefits that may
be presented by a particular substance. We have applied, and will
continue to apply, the criteria consistently, weighing them as
appropriate based on the nature of the substance and proposed use,
among other things. Also as stated above, FDA's application of the
criteria to particular bulk drug substances is subject to discussion
with the PCAC and USP and is the subject of notice and comment
rulemaking. If, through the rulemaking process, FDA receives feedback
that any party believes it has not applied the criteria correctly in
any particular case, FDA will consider that feedback before finalizing
its proposal to include, or not include, a substance on the 503A Bulks
List.
    (Comment 11) One comment objected to the level of evidence of
clinical effectiveness and toxicology FDA has been considering in its
application of the proposed criteria. According to the comment, these
high standards of evidence are unreasonable and change fundamental
standards of practice. The comment asserts that FDA appears to be
requiring studies that can survive any criticism and is ignoring the
role of physician decisions based on clinical experience.
    (Response 11) We disagree with the comment. As stated in the 2016
proposed rule, FDA recognizes that it is unlikely that candidates for
the 503A Bulks List will have been thoroughly investigated in in vitro
or in animal toxicology studies, or that there will be well-controlled
clinical trials to substantiate their safe use in humans. We note that
the evidence that has supported FDA's recommendations to place
particular substances on the 503A Bulks List to date has not been of
the type or quality that is ordinarily required and evaluated as part
of the drug approval process. We further note that we considered the
input of physicians and their clinical experience to the extent that
information is provided to the Agency, including that provided during
PCAC meetings. We find no reason to reduce the amount of evidence FDA
has considered necessary to support a recommendation to include a bulk
drug substance on the 503A Bulks List and believe that doing so would
not be in the interest of public health.
    (Comment 12) One comment asserted that application of the criteria
to date has been too narrow in its application to a particular proposed
use.
    (Response 12) We disagree and believe that it is necessary to
evaluate a nominated bulk drug substance in the context of the uses
proposed for compounded drug products that include the substance. We
acknowledge that inclusion of a substance on the 503A Bulks List is not
limited to a specific use. However, for evaluation purposes, FDA finds
it necessary to consider the criteria, particularly the effectiveness
criterion, in the context of a specific proposed use or uses. Given the
number of substances nominated for inclusion on the list, it would not
be possible for FDA to consider all possible uses for a compounded drug
product that includes the nominated substance. Therefore, we find it
reasonable to rely on information from the interested parties who
nominated the bulk drug substances to identify the proposed uses, and
for FDA to evaluate the substance in the context of those uses.
    Nevertheless, as indicated in the 2016 proposed rule, when FDA is
aware of another use that may be relevant to its evaluation of a
substance for the 503A Bulks List, such as when a use other than that
for which it was nominated is widespread, FDA may consider that use in
its discretion.
    As discussed in the 2016 proposed rule, FDA has opened a docket
through which interested individuals may nominate additional bulk drug
substances or provide additional information about substances already
nominated with sufficient information for the 503A Bulks List (see
Docket No. FDA-2015-N-3534). If an interested party believes that the
nominations for a particular substance did not include a proposed use
that it would like to be reviewed, and that substance has not yet been
addressed in an NPRM, additional

information or nominations may be provided through that docket.
    (Comment 13) One comment asserted that application of the criteria
to date has given undue weight to possible side effects or safety
concerns related to use of compounded drug products, which are often
speculative.
    (Response 13) We disagree with the comment. FDA's reviews of
nominated substances to date have appropriately balanced the safety
criterion with the other three criteria, and FDA has applied its
scientific judgment to identify side effects or safety concerns based
on available data and information. As stated above, FDA's application
of the criteria to particular bulk drug substances is subject to
discussion with the PCAC and USP, and is also the subject of notice and
comment rulemaking. If, through the rulemaking process, FDA receives
feedback that any party believes it has inappropriately considered
safety information related to compounded drug products in any
particular case, FDA will consider that feedback before finalizing its
proposal to include, or not include, a substance on the 503A Bulks
List.
    (Comment 14) One comment objected to statements made during PCAC
meetings indicating concern that, if a bulk drug substance is placed on
the list, drug products compounded with that substance could be
marketed with any claims. The comment notes that marketing a drug
product for unsubstantiated claims is illegal, and if FDA and PCAC are
concerned that this is happening, appropriate action and education
should be undertaken. The commenter asserts that the possibility of
misleading marketing should not be considered when determining whether
to include a bulk drug substance on the 503A Bulks List.
    (Response 14) We did not consider the possibility of misleading
marketing when determining whether to include a bulk drug substance on
the 503A Bulks List. Under section 502(bb) of the FD&C Act, a
compounded drug will be deemed misbranded if the advertising or
promotion of such compounded drug is ``false or misleading in any
particular.'' In addition, under section 502(a) of the FD&C Act, a drug
will be deemed misbranded if its labeling is ``false or misleading in
any particular.'' However, the existence of false or misleading
advertising is not one of the four criteria considered when evaluating
a nominated substance for inclusion on the 503A Bulks List.
3. FDA's Proposals on Specific Substances
    (Comment 15) One comment requests that the listing of NAG codified
at Sec.  216.23(a) (21 CFR 216.23(a)) not be limited to topical use
only, and instead, to allow use of that substance by any route of
administration. The comment notes that one of the nominations for that
bulk drug substance was not limited to topical use.
    (Response 15) We disagree that the listing for NAG in the codified
should be expanded beyond topical use. As we explained in the Federal
Register of July 2, 2014 (79 FR 37747 at 37748 (July 2014 Request for
Nominations)), which detailed the type of information to be provided
with nominations, FDA only intended to review nominations that were
supported with adequate data and information. Doing so has allowed FDA
to focus its limited resources on the nominated uses and routes of
administration for which nominators have provided the most support.
Also, as indicated in the July 2014 Request for Nominations, the Agency
reviewed information for multiple nominations of the same substance
collectively (79 FR 37747 at 37749).
    None of the nominations for NAG proposed or provided information
that would support administration of NAG by any route of administration
other than topical. The nomination from the International Academy of
Compounding Pharmacists mentioned in the comment did not specify a
proposed use or route of administration. Rather, the nomination stated
only that ``[t]he very nature of a compounded preparation for an
individual patient prescription as provided for within FDCA 503A means
that the purpose for which it is prescribed is determined by the health
professional authorized to issue that prescription.'' (Ref. 5.) Taken
alone, this nomination did not provide adequate support to allow FDA to
evaluate the nominated substance (for topical or other routes of
administration), and it was only considered collectively with the other
nominations for NAG for topical use. As noted in the 2016 proposed
rule, individuals and organizations may petition FDA under 21 CFR 10.30
to amend the list, including to request that the Agency evaluate NAG
for routes of administration other than topical. See Response 31 for
further discussion of the petition process.
    (Comment 16) Some comments object to the exclusion of oxitriptan
from the 503A Bulks List and request that oxitriptan be included on the
list codified at Sec.  216.23(a). The comments state that oxitriptan is
widely sold as a dietary supplement and that it has an extensive safety
record through its long history of use as a dietary supplement, which
they believe should be given more weight. The comments assert that
patients benefit from a relationship with their prescriber and
pharmacist that is not available in the dietary supplement context
because dietary supplements are purchased over the counter. According
to one of the commenters, there is no evidence of any risk that
oxitriptan would have the same side effects as other medications used
to treat depression, and the mechanism of action of oxitriptan is
demonstrably different from that of approved therapies. The comment
asserts that oxitriptan's safety profile is significantly better than
that of approved products. One comment also asserts that oxitriptan has
been shown to be effective in the treatment of a variety of conditions,
including depression and insomnia.
    (Response 16) We have considered the comments and the references
cited therein (Refs. 6 to 9), and find no reasoning or data that cause
FDA to change its evaluation not to include this substance on the 503A
Bulks List. As noted above, the availability of a substance as a
dietary supplement is not a criterion considered when evaluating a
substance for inclusion on the 503A Bulks List. Dietary supplements are
intended for oral ingestion only, are not intended to be used to treat
diseases, and therefore, are subject to a different legal and
regulatory scheme than drug products. Section 503A addresses compounded
drug products only. We acknowledge that FDA's reviews and PCAC meetings
included discussions about the availability of dietary supplements with
dietary ingredients that were the same or similar to the nominated bulk
drug substances. As noted in prior PCAC discussions, FDA's proposals in
this context do not impact a substance's availability as a dietary
supplement.
    Regarding the argument that there is no evidence of any risk that
oxitriptan (also known as 5-hydroxytryptophan or 5-HTP) would have the
same side effects as other medications used to treat depression, as
previously stated in FDA's review (Ref. 5), there is a dearth of
reliable scientific data regarding the safety of oxitriptan. We found
no data indicating that the use of oxitriptan for depression would be
free of the same side effects as other medications used to treat
depression, and no reliable scientific data were provided in the
comments received on the proposed rule to support this assertion.

    Regarding the argument that the mechanism of action of oxitriptan
is demonstrably different from that of approved therapies, as
previously stated in FDA's review, the psychoactive action of
oxitriptan is related to increased production of serotonin in central
nervous system tissue (id). Based on this mechanism of action,
oxitriptan, particularly with concomitant use of antidepressant drug
products, could result in serotonin syndrome, a life-threatening drug
interaction, and cases that are likely to be serotonin syndrome have
been reported with the use of oxitriptan as a dietary supplement (Ref.
10). In fact, one source cited by a commenter warns against taking
oxitriptan with certain approved antidepressants because both increase
the brain chemical serotonin and taking both ``might increase serotonin
too much and cause serious side effects including heart problems,
shivering, and anxiety'' (Ref. 7).
    Regarding the argument that oxitriptan's safety profile is
significantly better than that of approved products, we disagree. As
explained in Response 5, data comparing the safety profiles of
compounded drug products with approved drug products are generally not
available, and we do not have any such comparative data here. As stated
above, the absence of information does not mean that safety risks do
not exist. In contrast, approved drug products have been demonstrated
to be safe under the conditions of use set forth in the approved
labeling, and the benefits of the drug product for the approved
conditions of use have been found to outweigh the risks.
    Regarding the argument that oxitriptan has been shown to be
effective for the treatment of a number of conditions, including
depression and insomnia, similarly, the comments provided no reliable
scientific data that would cause FDA to change its evaluation of
oxitriptan, which balanced the available data on effectiveness with the
other three criteria. As stated in the 2016 proposed rule, data
supporting the drug's effectiveness for depression and insomnia are
limited, and there are no data to support the effectiveness of the
long-term use of oxitriptan to treat depression. FDA's conclusion in
the 2016 proposed rule regarding the effectiveness of oxitriptan for
insomnia and depression was based on FDA's consideration of more recent
and comprehensive data than that provided by the commenters, and the
information provided by the commenters does not alter that conclusion.
We also note that one source cited by a commenter stated that there is
insufficient evidence to rate the effectiveness of oxitriptan for
insomnia (Ref. 7).
    In sum, we have reviewed the scientific references and considered
the reasoning set forth in the comments, and they do not change FDA's
analysis of oxitriptan as stated in our review (Ref. 5) or our
conclusion that it should not appear on the 503A Bulks List.
    (Comment 17) Some comments object to the exclusion of piracetam
from the 503A Bulks List and request that piracetam be included on the
list codified at Sec.  216.23(a). The comments note that FDA has
recognized that there is not a significant safety risk related to the
use of piracetam. They assert that the recommendation to exclude
piracetam from the 503A Bulks List was based on a presumption that
piracetam could be obtained through an IND, which was not a proper
consideration. One comment provided data about the effectiveness of
piracetam for short-term cognitive performance (Ref. 11) and the safety
of its administration in high doses to patients with acute stroke (Ref.
12).
    (Response 17) We have considered the comments and references cited
therein and find no reasoning or data that cause FDA to change its
evaluation not to include this substance on the 503A Bulks List.
Regarding the safety of piracetam, we note that while our review of
piracetam indicated that doses of less than 8 grams per day \2\ appear
to be unlikely to cause serious adverse reactions or drug interactions,
the review also described safety concerns associated with certain
patient populations and certain concomitant medications (Ref. 13).
Piracetam is not recommended for patients with severe renal impairment
because clearance of the compound is dependent on the renal creatinine
clearance and would be expected to diminish with renal insufficiency.
Piracetam is also not recommended for those taking concomitant
anticoagulants because piracetam reduces platelet function, interferes
with clotting factors, and prolongs bleeding time at certain doses. We
also note that, in evaluating piracetam, we considered the three other
criteria in addition to the safety of piracetam.
---------------------------------------------------------------------------

    \2\ Note that FDA's review stated that doses of less than ``8
kg/day'' appear unlikely to cause serious adverse reactions or drug
interactions, but ``kg'' was a typographical error. That statement
of the review should have been ``8 g/day.''
---------------------------------------------------------------------------

    Although it is well characterized chemically and physically and has
been used in compounded drug products for approximately 40 years, as
stated in its review, FDA is concerned about the effectiveness of
piracetam (id.). The available data do not show a clear benefit
associated with the use of piracetam (id.). Numerous studies of
piracetam have been conducted, and all but a few were designed poorly
or used inappropriate statistical methods to support conclusions that
piracetam is effective as a treatment for the studied condition (id.).
The publications that suggest piracetam is effective for treating
cognitive impairment, acute vertigo, or stroke are inconsistent, and
there are also publications that conclude that piracetam is ineffective
for treating these same conditions (id.). We were able to identify a
single, well-designed and executed study of piracetam, which showed
that it is ineffective for the treatment of cognitive impairment (Ref.
14).
    The two scientific articles referenced in the comments, one of
which is discussed in FDA's evaluation of piracetam (Ref. 11), and the
other of which addressed the safety of high doses of piracetam when
used as a treatment for acute stroke (Ref. 12), do not address FDA's
concerns regarding the lack of data supporting its effectiveness in
treating serious and life-threatening conditions such as stroke. For
the reasons set forth above, neither the scientific references nor the
reasoning set forth in the comments provide a basis for FDA to change
its analysis of piracetam according to the four criteria (Ref. 13), or
FDA's ultimate conclusion that piracetam should not appear on the 503A
Bulks List.
    Finally, we acknowledge that the possibility of pursuing an IND
application for piracetam was discussed at the PCAC meeting (Ref. 15)
to inform the public of a pathway to study and access piracetam. FDA
did not consider the availability of an IND in its review of piracetam
under the four criteria, however (Ref. 13). As FDA explained in its
review, based on the absence of a clear benefit associated with
piracetam, the seriousness of the conditions for which piracetam was
proposed for use, and the availability of safe and effective
medications for many of these uses that have undergone greater
scientific scrutiny (id.), FDA proposed piracetam not be placed on the
503A Bulks List.
    (Comment 18) One comment objects to the exclusion of silver protein
mild from the 503A Bulks List and requests that silver protein mild be
included on the list codified at Sec.  216.23(a). The comment states
that silver protein mild is well characterized physically and
chemically, has a long history of use, is relatively nontoxic, and side
effects are only rarely reported.
    (Response 18) We have considered the comment and find no reasoning
or data therein that cause FDA to change its

evaluation not to include this substance on the 503A Bulks List. As
stated in the 2016 proposed rule, silver protein mild is not well-
characterized, and the term ``silver protein mild'' can refer to a
variety of different drug products. FDA is also concerned about the
safety of silver protein mild, which can cause argyria (a permanent
ashen-gray discoloration of the skin, conjunctiva, and internal organs)
(Ref. 13). Despite the commenter's characterization of the substance as
relatively nontoxic, FDA remains concerned that chronic use of silver
protein mild may result in permanent discoloration of the conjunctiva,
cornea, and/or lens (id.). As for the commenter's characterization that
the side effects are rarely reported, we note that the use of silver
protein mild declined precipitously after the introduction of FDA-
approved ocular anti-infectives. As described in FDA's review, numerous
articles and books published when silver protein mild was more commonly
used described deposits of silver in the conjunctiva, lacrimal sac,
cornea, and lens following administration (id.).
    We also note that there is no reliable evidence that silver protein
mild would be effective for the proposed use. It has been studied in
two controlled studies. In one study, silver protein mild was found to
be numerically, although not statistically, inferior to having no
treatment at all. In the second study, silver protein mild was found to
be inferior to povidone iodine, which is an FDA-approved drug product
(id.). While silver protein mild does have a long history of use,
dating back to the early 1900s, as noted above, the use of silver
protein mild declined dramatically after the introduction of FDA-
approved ocular anti-infectives (id.).
    The reasoning set forth in the comment does not address FDA's
concerns about the characterization, safety, or effectiveness of silver
protein mild, and does not change FDA's conclusion that silver protein
mild should not appear on the 503A Bulks List.
    (Comment 19) Some comments object to the exclusion of tranilast
from the 503A Bulks List and request that tranilast be included on the
codified list at Sec.  216.23(a). The commenters note that FDA's
proposal not to include tranilast is contrary to the advice of the
PCAC. They assert that FDA's view is based on a faulty understanding of
the increased bilirubin observed in clinical trials and note that the
proposed topical dosage is well below that used in those trials. One
comment described anecdotal reports that the topical use of tranilast
has been effective in the treatment of keloids and hypertrophic scars.
Another comment asserted that tranilast has been available in Japan for
over 30 years, apparently without detrimental effects.
    (Response 19) We have considered the comments and decline to
include tranilast on the 503A Bulks List. As stated in the 2016
proposed rule, FDA has serious concerns about the safety of tranilast
when administered orally, and there is insufficient information about
the systemic absorption of topical tranilast formulations to determine
whether topical administration of the drug product presents the same
safety concerns (81 FR 91071 at 91079). No new data about the use of
tranilast were provided in the comments; rather, the comments provided
only anecdotal reports about the use of tranilast and further
discussion of the same data presented to the PCAC, which FDA considered
prior to publishing the 2016 proposed rule. The reasoning in the
comments did not sufficiently address FDA's safety concerns regarding
the use of this substance.
    We acknowledge that the PCAC recommended including tranilast on the
503A Bulks List with a restriction to topical use. However, advisory
committee recommendations are not binding on FDA. Rather, FDA considers
the PCAC's advice but makes an independent judgment regarding whether
particular substances should appear on the 503A Bulks List. As we
explained in our supplemental review of tranilast (Ref. 16) and the
2016 proposed rule, the government-approved Japanese tranilast product
label provided evidence of teratogenicity in animals and
contraindicated the use of tranilast in pregnant women or women who may
become pregnant. We did not find that the risk of prescribing a
potential teratogen to women who may be or may become pregnant was
outweighed by the potential benefit of treating scar tissue. Therefore,
FDA continues to believe that the criteria weigh against placing
tranilast on the 503A Bulks List.
    Regarding the commenter's statements about the effectiveness of
tranilast for keloids and hypertrophic scarring, scientific data
supporting effectiveness for those uses are lacking. While there is
some evidence that tranilast may be effective for allergic disorders,
evidence of effectiveness for those other uses is either not available
or inconclusive (Refs. 5 and 16).
    (Comment 20) One comment objected to the rejection of substances
that are dietary supplements from the 503A Bulks List. The commenter
states that by rejecting these substances from the list, FDA is forcing
consumers to use products that are subject to less quality oversight
and lack physician supervision. The commenter proposes that dietary
supplements only be rejected for proven safety concerns.
    (Response 20) As stated in Response 16, a substance's availability
as a dietary ingredient or supplement is not a criterion when
evaluating a substance for inclusion on the 503A Bulks List. Dietary
supplements are intended for oral ingestion only, and are not intended
to be used to treat diseases, and therefore, are subject to a different
legal and regulatory scheme than drug products. Section 503A of the
FD&C Act addresses compounded drug products only. To the extent FDA's
reviews and PCAC meetings included discussions about the availability
of dietary supplements with dietary ingredients that were the same or
similar to the nominated bulk drug substances, we note that FDA's
proposals in this context do not impact a substance's availability as a
dietary supplement.
    Regarding the comment about the lack of quality oversight for
dietary supplements, we note that dietary supplement manufacturers are
required to comply with FDA's Current Good Manufacturing Practice
regulations for dietary substances and are subject to inspection by FDA
(21 CFR part 111). Regarding physician supervision, we note that
physicians may recommend dietary supplements to their patients
regardless of whether the substance appears on the 503A Bulks List.
4. Dietary Supplement Monographs and Other Monographs
    (Comment 21) Some commenters objected to FDA's interpretation, as
stated in the 2016 proposed rule, that dietary supplement monographs
are not ``applicable monographs'' for purposes of determining which
substances may be included in compounded drug products under section
503A(b)(1)(A)(i)(I) of the FD&C Act. They note that physicians may
prescribe dietary supplements. They also state that in a ``2014
guidance,'' \3\ FDA said that dietary supplement monographs were
``applicable monographs'' under section 503A, and that change in policy
has not been explained.
---------------------------------------------------------------------------

    \3\ One comment appears to refer to the July 2014 Request for
Nominations as ``guidance'' on this topic.
---------------------------------------------------------------------------

    (Response 21) We disagree that dietary supplement monographs should
be considered ``applicable monographs'' for purposes of section 503A of
the FD&C Act. As stated in the 2016 proposed rule, section 503A sets
forth conditions that must be met for a

compounded drug product to qualify for certain exemptions from the FD&C
Act. Among other conditions, section 503A(b)(1)(A)(i) of the FD&C Act
requires that a bulk drug substance used in a compounded drug product
meet one of the following criteria: (1) Comply with the standards of an
applicable USP or NF monograph, if one exists; (2) be a component of an
FDA-approved human drug product, if a monograph does not exist; or (3)
be on a list of bulk drug substances that may be used for compounding,
to be developed by FDA through regulation. FDA has interpreted the term
``an applicable United States Pharmacopoeia (USP) or National Formulary
(NF) monograph'' to refer to official drug substance monographs.
Therefore, a substance that is the subject of a dietary supplement
monograph, but not a drug substance monograph, may only be compounded
if the substance is a component of an FDA-approved drug product or is
on the FDA's list of bulk drug substances that may be used for
compounding.
    This interpretation is both legally supportable and in the best
interest of the public health. Under the FD&C Act, drugs and dietary
supplements are different product categories that are subject to
different regulatory schemes. Section 503A, the key statutory provision
for this rulemaking, concerns pharmacy compounding of drug products,
not dietary supplements. It states that a drug product may be
compounded under section 503A(a) of the FD&C Act if the licensed
pharmacist or licensed physician compounds the drug product using bulk
drug substances that comply with the standards of an applicable United
States Pharmacopoeia or National Formulary monograph, if a monograph
exists, and the United States Pharmacopoeia chapter on pharmacy
compounding (emphasis added). (See section 503A(b)(1) of the FD&C Act.)
    Accordingly, it is reasonable to interpret the phrase ``applicable
United States Pharmacopoeia monograph'' in this statutory provision as
a reference to USP drug monographs, not USP dietary supplement
monographs. Moreover, adopting the alternative interpretation urged by
the comment--i.e., that ``applicable'' USP monographs include dietary
supplement USP monographs--would not be in the best interest of the
public health. USP monographs for dietary supplements can differ in
significant ways from USP monographs for drugs because of the
differences between dietary supplements and drug products. For example,
dietary supplements are intended for ingestion only, and the standards
contained in the USP dietary supplement monographs are likewise
intended for dietary supplements that will be ingested; the standards
are not appropriate for use in compounding drug products that may have
different routes of administration (e.g., intravenous, intramuscular,
topical). In addition, the USP limits for elemental impurities are
different for drugs and dietary supplements: There are limits specified
in USP General Chapters for many more elemental contaminants for drugs
than there are for dietary supplements. Furthermore, the bioburden
allowable for dietary supplements is considerably higher than that
allowed for drug substances. Relying on the standards of a dietary
supplement monograph for a substance that will be used in compounding
drug products could therefore put patients at risk.
    We disagree with the commenter's statement that a 2014 guidance
stated that dietary supplement monographs were ``applicable
monographs'' under section 503A of the FD&C Act. FDA is unaware of any
Agency statements that support that view, including the July 2014
Request for Nominations.
    (Comment 22) One comment asserted that the Homeopathic Pharmacopeia
of the United States (HPUS) homeopathic monographs and other types of
monographs should be considered ``applicable monographs'' under section
503A(b)(1)(A)(i)(I) of the FD&C Act, making substances that are the
subject of such monographs eligible for use in compounding. The comment
asserted that the Drug Quality and Security Act (DQSA) (Pub. L. 113-54)
gives FDA authority to designate sources other than USP or NF
monographs as ``applicable monographs.'' The comment also noted that
the FD&C Act recognizes the HPUS as ``official'' in 21 U.S.C. 358(b),
and in the definitions at 21 U.S.C. 321, the FD&C Act defines ``drug''
to include articles recognized in the HPUS.
    (Response 22) We disagree that HPUS homeopathic monographs and
other types of monographs should be considered ``applicable
monographs'' under section 503A. The provisions of DQSA cited in the
comment do not apply to section 503A of the FD&C Act. Rather, the
language of section 503A explicitly applies only to applicable USP or
NF monographs. Therefore, we decline to consider HPUS or other types of
monographs to be ``applicable monographs'' under section
503A(b)(1)(A)(i)(I) of the FD&C Act.
    (Comment 23) One commenter asserted that incorporating the
statements about FDA's interpretation of ``applicable monographs'' from
the Interim Policy Guidance effectively and improperly converts that
guidance document to rulemaking. The commenter pointed out that
regulations cannot be issued through guidance documents and stated that
the guidance should be rescinded.
    (Response 23) We disagree with this comment. Describing an
interpretation of the applicable statute in both a guidance document
and in a preamble to a proposed rule does not ``convert'' the guidance
document to a rulemaking and has no impact on the status of the
guidance. The guidance document was issued in accordance with our
``Good guidance practices'' regulation (21 CFR 10.115).
5. Conflict of Interest
    (Comment 24) One comment stated that FDA should consider its
``conflict of interest'' arising from the Agency's receipt of funds
under the Prescription Drug User Fee Act (PDUFA) related to new drug
applications (NDAs). According to the commenter, these funds cause FDA
to be biased in favor of approved products.
    (Response 24) We disagree with this comment. It is unclear what
action the commenter was suggesting that FDA take to address this
perceived ``conflict of interest.'' We note that the receipt of PDUFA
fees related to NDAs has not affected FDA's ability to be impartial
when evaluating bulk drug substances for inclusion on the 503A Bulks
List. The Agency believes that compounded drugs can play a critical
role for patients whose medical needs cannot be met by an approved
drug.
    Moreover, FDA's recommendations on particular bulk drug substances
are subject to discussion with the PCAC and USP, and are the subject of
notice and comment rulemaking. If, through the rulemaking process, FDA
receives feedback that any party believes its recommendations are
biased in any particular cases, FDA will consider that feedback before
finalizing its proposal to include, or not include, a substance on the
503A Bulks List.
6. Qualifiers for Use of Substances on the 503A Bulks List
    (Comment 25) One comment requested that FDA allow inclusion of bulk
drug substances on the list with certain qualifiers or limited uses,
such as dose or dosage form. The comment stated that such qualifiers
will give FDA greater leeway to add bulk drug substances to the list,
which will benefit patients.
    (Response 25) We agree that in some limited cases, it may be
appropriate to place bulk drug substances on the 503A

Bulks List subject to a restriction on use, such as the route of
administration. For example, several of the substances that are being
added to the list in this rulemaking are restricted to topical use
only. For the substances we are not including on the list in this
rulemaking, we found no relevant qualifiers on the compounded drug
product, such as route of administration, that would have justified
inclusion of the substances on the list.
7. Process Issues Related to FDA's Evaluation of Nominated Bulk Drug
Substances and PCAC Consultations
    (Comment 26) One comment raised concerns about the composition of
the PCAC. The commenter asserted that the professions most familiar
with compounded drug products are not represented on the PCAC, and
neither FDA nor the PCAC has the necessary expertise to make judgments
on the nominated bulk drug substances. In particular, according to the
commenter, naturopaths need to be consulted, and a counterbalance to
the representation by Public Citizen and the Pew Charitable Trusts is
needed on the committee. The comment stated that PCAC members may have
conflicts of interest.
    (Response 26) We disagree with the comment. Of the current PCAC
members, seven are pharmacists, and five are physicians. Twelve
committee members have experience related to drug compounding,
including experience in the preparation, prescribing, and use of
compounded medications, as well as compounding-related research
activities. In accordance with section 503A of the FD&C Act, one member
is a representative from USP, and one member is a representative from
the National Association of Boards of Pharmacy.
    Industry participated in the selection of two additional committee
members--one from the pharmaceutical manufacturing industry and one
from the compounding industry. Additionally, a consortium of consumer
advocacy representatives participated in the selection of a consumer
representative.
    More than 100 names were submitted to the Agency in response to the
January 13, 2014, Federal Register notices requesting nominations.\4\
(79 FR 2177; 79 FR 2178; 79 FR 2179.) In addition, FDA identified
qualified candidates from its own pool of special government employees.
The selection process of candidates that were not designated
representatives of particular groups included evaluation for conflicts
of interest as required by 21 CFR 14.80, and for the relevancy of their
qualifications for the purpose of the committee. Candidates with actual
or potential conflicts of interest in matters that would come before
the committee were eliminated from consideration. For example, for
those candidates not representing a particular group, FDA reviewed
whether the candidate owned a compounding pharmacy, consulted for the
compounding industry, or supplied bulk drug substances for compounding,
because those activities would likely raise a financial interest that
could be affected by the matters expected to come before the committee.
---------------------------------------------------------------------------

    \4\ FDA issued another request for nominations for the PCAC in
the Federal Register of March 27, 2018 (83 FR 13133).
---------------------------------------------------------------------------

    In general, members are invited to serve for overlapping terms of
up to 4 years. As it has to date, the Agency will consider future
nominations for membership and strive to select members with robust and
relevant experience and expertise related to drug compounding.
    Nominations may be submitted to the Advisory Committee Membership
Portal at any time and submitted nominations will be considered as
vacancies occur. See https://www.accessdata.fda.gov/scripts/FACTRSPortal/FACTRS/index.cfm. See https://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/CommitteeMembership/ApplyingforMembership/default.htm for more information on the
nomination procedure.
    (Comment 27) One comment asserted that FDA has ``unfairly
screen[ed]'' the evidence provided by nominators to the PCAC, has
``misrepresented'' the availability of other routes of approval of drug
products compounded with the nominated bulk drug substance, and has
``manipulated'' the PCAC into rejecting certain nominated substances.
The commenter stated that FDA appeared to be ``cherry-picking'' studies
only to show negative data, and was not scrutinizing studies that
showed safety concerns with the use of the bulk drug substance in the
same way that it has scrutinized studies the nominators put forward to
show effectiveness.
    (Response 27) We disagree with this comment. As stated above, FDA
is determining whether to place a substance on the list after weighing
available data and information in light of the four criteria set forth
in this rulemaking and considering feedback from PCAC, USP, and the
public. FDA considers publicly available studies that are relevant to
the evaluation criteria, regardless of the source of those studies.
    As stated above, if members of the public believe FDA is not giving
adequate weight to certain studies, or is otherwise misrepresenting
information presented to the PCAC in any particular case, they are
encouraged to submit a comment to the docket for the NPRM in which the
substance at issue is addressed. Nominators and the public are also
invited to present at PCAC meetings where they have an opportunity to
discuss their interpretation of the relevant studies and address the
PCAC regarding each substance considered. FDA will consider all
feedback received before finalizing its proposal to include, or not
include, a substance on the 503A Bulks List.
    (Comment 28) Some comments stated that nominators were not being
given equal time with FDA to make presentations to the PCAC, and
instead were limited to 10-minute presentations. Commenters asserted
that this imbalance is unfair and has resulted in skewed decision
making by the PCAC. Commenters also asserted that nominators were given
insufficient notice of PCAC meetings and did not have adequate time to
prepare.
    (Response 28) We acknowledge that FDA presentations have been
allotted more time than those by nominators, which we believe is
appropriate given that FDA is tasked with developing the 503A Bulks
List and is necessary for FDA to present fully on the reviews of the
bulk drug substances.
    Regarding notice of PCAC meetings, FDA has notified the public at
least 20 days prior to PCAC meetings, and the Agency strives to give
notice further in advance where possible. However, further advance
notice is not always possible due to the need to coordinate various
logistical issues.
    (Comment 29) Some commenters noted that it was not possible for
nominators to provide the information FDA requested in its July 2014
Request for Nominations for the list of bulk drug substances that can
be compounded under section 503A of the FD&C Act for two reasons.
First, commenters stated there is a gap between the stated criteria and
how FDA is applying the criteria, and therefore, nominators did not
have sufficient notice of what information would be needed for FDA's
decision making. Second, commenters asserted that it is not possible to
provide the information FDA required for a nomination because decisions
about how a compounded drug is used are at the discretion of the
physician.
    (Response 29) We disagree with this comment. As noted previously,
FDA is applying the four criteria set forth in

this rulemaking when evaluating bulk drug substances for inclusion on
the list. FDA considers the information requested in the July 2014
Request for Nominations and bases its decision on the physical and
chemical characterization, safety, effectiveness, and historical use of
the bulk drug substance in compounded drug products. If nominators
believe that there is additional information relevant to those four
criteria that would be helpful to consideration of nominations that are
still pending with FDA for evaluation, that information can be
submitted for FDA's consideration via Docket No. FDA-2015-N-3534.
    With respect to the concern about challenges in submitting
nominations because physicians may prescribe compounded drug products
tailored to the needs of individual patients, we note that physicians
and prescribers, who may have unique insights on how compounded drug
products are used in particular cases, may submit information for FDA's
consideration via Docket No. FDA-2015-N-3534.
    (Comment 30) Some comments objected to FDA's process regarding bulk
drug substances that were nominated without adequate information for
FDA to evaluate the substance. One commenter requested that FDA issue
letters to the parties whose nominations were rejected informing them
of the specific deficiencies with the nomination. The comment described
this process as resource-intensive, but necessary because access to the
bulk drug substance is being ``cut off.''
    (Response 30) We disagree with this comment. The July 2014 Request
for Nominations identifies the information that the Agency is
requesting in the nominations, and nominations containing the
information requested in the July 2014 Request for Nominations will be
deemed adequate.
    As described in the Interim Policy Guidance, Docket No. FDA-2015-N-
3534 is open to receive new nominations, including renominations of
substances previously nominated with inadequate supporting information,
or additional information about bulk drug substances previously
nominated with adequate information to allow evaluation. FDA is
evaluating new information provided to the docket on a rolling basis
and is periodically adding newly nominated or renominated substances to
``Category 1'' (the category for adequately supported nominations that
will be evaluated for inclusion on the 503A Bulks List) when
appropriate.
    (Comment 31) One comment stated that clarity is needed regarding
the process by which substances that have been ``considered and
rejected'' by the PCAC may be renominated. The comment noted that new
or additional information about the substance may become available that
warrants further evaluation by FDA and the PCAC.
    (Response 31) We have considered this comment and are clarifying
the process for providing additional information about substances that
have been considered by the PCAC. Bulk drug substances, including those
that have been evaluated by FDA and presented to the PCAC and USP,
remain under consideration until they are addressed in a final rule.
Individuals and organizations may submit additional information
relevant to the evaluation criteria about a use proposed in the
original nomination(s) for a bulk drug substance to Docket No. FDA-
2015-N-3534 until that substance is addressed in an NPRM. When a
substance is addressed in an NPRM, individuals and organizations may
submit additional information relevant to the evaluation criteria about
the use(s) evaluated for that bulk drug substance as a comment to that
proposed rule. As noted above, after the substance is addressed in a
final rule, individuals and organizations may submit a citizen petition
to FDA under 21 CFR 10.30 asking FDA to amend the list (i.e., to add or
delete bulk drug substances).
    If an individual or organization seeks to use a bulk drug substance
that has been evaluated by FDA and not recommended in FDA's review for
placement on the 503A Bulks List, for a use, dosage form, or route of
administration that was not previously evaluated by FDA, or where there
is otherwise a substantive change between the use of the bulk drug
substance sought by the individual or organization and how it was
evaluated by FDA, the individual or organization may file a citizen
petition under 21 CFR 10.30 requesting that FDA reconsider its
evaluation of the bulk drug substance, regardless of whether that
substance has been addressed in an NPRM or final rule. In responding to
such citizen petitions, FDA generally intends to consider whether, for
example, the petitioner provides information not previously considered
or shows a significant change in circumstances supported by scientific
references that alters the Agency's analysis of the four criteria.
    (Comment 32) One comment stated that FDA is only sending certain
nominations to the committee and appeared to be ``approving'' some
nominations without consulting the PCAC.
    (Response 32) We disagree with this comment, the basis of which is
unclear. FDA acknowledges that it is evaluating and consulting with USP
and the PCAC only on substances that were nominated with adequate
support to allow the Agency's review, as described in the Interim
Policy Guidance. FDA is not, however, ``approving'' the use of any bulk
drug substances or proposing to include bulk drug substances on the
503A Bulks List, without consulting USP and the PCAC.
    (Comment 33) One comment stated that FDA should have consulted with
the PCAC before seeking nominations for the 503A Bulks List or before
the Agency evaluated the first set of bulk drug substances for
inclusion on the list.
    (Response 33) The statute does not require that FDA seek
nominations for the 503A Bulks List, or that it consult the PCAC, at
any specific stage prior to undertaking rulemaking. Section 503A
requires only that FDA consult with the PCAC before issuing regulations
to implement subsection (b)(1)(A)(i)(III). FDA sought nominations for
the 503A Bulks List and began evaluating substances for inclusion on
the list before consulting with the PCAC because this enabled the
Agency to prepare robust background materials for PCAC meetings and
thereby obtain more meaningful PCAC and public input prior to proposing
a rule describing the criteria.
8. Availability of Ingredients for Physician Use
    (Comment 34) One comment objected to the rulemaking generally as
infringing on the practice of medicine and overregulating physicians'
choices of ingredients that can be used in compounded drug products.
    (Response 34) The FD&C Act establishes the framework for regulating
the drugs that physicians may prescribe. Within this framework, once a
drug becomes legally available, with certain limited exceptions, FDA
does not interfere with physicians' decisions to use it when they
determine that in their judgment it is medically appropriate for their
patients. The Agency believes that this rulemaking is consistent with
this framework and does not overregulate.
    (Comment 35) The comment asserted that this action amounts to poor
public health policy and will stifle innovation, because drugs will not
be researched or considered for new drug applications unless they show
some initial promise.
    (Response 35) We disagree. FDA is carrying out its statutory
mandate in a manner that seeks to protect the public

from exposure to bulk drug substances that are not suitable for use in
compounded drug products. We believe it protects the public health to
prevent the use of drug products for which there is insufficient
evidence that benefits to the patients might outweigh possible risks.
To protect human subjects and the integrity of any research, it is
important that drugs generally not be studied in humans outside of an
investigational new drug application.
9. ``Grandfathering In'' Use of Bulk Drug Substances
    (Comment 36) One comment objected to this rulemaking generally,
based on FDA's lack of regulation in this arena previously. The
commenter asserted that the compounding industry has developed under
State law, and use of bulk drug substances in compounding should be
considered ``grandfathered in.'' The comment noted that many of the
bulk drug substances at issue were in use prior to 1962.
    (Response 36) We disagree with this comment. Section 503A of the
FD&C Act does not provide for ``grandfathering in'' the use of bulk
drug substances, including those in use prior to 1962. Moreover, FDA is
considering the length and extent of the historical use of the bulk
drug substance in compounded drug products when determining whether to
recommend the substance for inclusion on the 503A Bulks List.
10. ``Regulatory Freeze Pending Review'' Memorandum and Executive Order
13771
    (Comment 37) One comment objected to this rulemaking based on the
January 20, 2017, memorandum signed by Reince Priebus on behalf of
President Trump entitled ``Regulatory Freeze Pending Review'' and
January 30, 2017, Executive Order 13771 entitled ``Presidential
Executive Order on Reducing Regulation and Controlling Regulatory
Costs'' because FDA has not identified two regulations to be
eliminated.
    (Response 37) The requirements outlined in Executive Orders 13771
and 13777 have been considered in issuing this final rule, and this
rule will be accounted for as appropriate under both executive orders.
11. Rulemaking
    (Comment 38) Some commenters alleged that FDA's actions related to
this rulemaking, many of which are described in the comments summarized
above, have been arbitrary and capricious in violation of the
Administrative Procedure Act (APA) (5 U.S.C. 551 et seq.). In addition,
one commenter stated that FDA's actions through this rulemaking are
arbitrary and capricious because the rulemaking goes beyond concerns
about the safety of compounded drug products, which applies only to
sterile drug products. That commenter noted that Congress enacted the
DQSA to address concerns surrounding sterility and contamination.
    (Response 38) We disagree with this comment. FDA has followed
proper rulemaking procedures and has not acted in an arbitrary and
capricious manner in violation of the APA.
    Section 503A requires FDA to issue the 503A Bulks List through a
rulemaking process, and it gives the Agency discretion to consider
relevant criteria (see section 503A(c)(2) of the FD&C Act). FDA is
establishing the four criteria described above, and applying these
criteria to bulk drug substances that are not the subject of an
applicable USP-NF monograph or a component of an FDA-approved drug
product. Such substances may be used to compound sterile or non-sterile
drug products. Accordingly, FDA applies the established criteria to
bulk drug substances that may be used to compound sterile or non-
sterile drug products. FDA notes that the safety criterion is not
limited to consideration of sterility and contamination, and FDA may
have safety concerns about bulk drug substances used to compound
sterile and non-sterile drug products.

VI. Effective Date

    This final rule will become effective 30 calendar days after the
date of its publication in the Federal Register.

VII. Economic Analysis of Impacts

    We have examined the impacts of the final 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 by the elimination
of existing costs associated with at least two prior regulations.'' We
believe that this final 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 final rule on small entities, we find that the final 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 issuing ``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 final rule would not result in an
expenditure in any year that meets or exceeds this amount.
    We evaluated 10 bulk drug substances for this final rule. We will
place six bulk drug substances on the 503A Bulks List, and we will not
place four 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 final rule, we also include a qualitative
description of potential benefits and potential costs.
    In table 1, we summarize the impacts of the final rule. The present
value of the costs of the final rule equals $3.33 million at a 7
percent discount rate and $3 million at a 3 percent discount rate. The
final rule will result in annualized costs of $0.42 million at a 7
percent discount rate, or $0.31 million at a 3 percent discount rate.

                Table 1--Summary of Benefits, Costs, and Distributional Effects of the Final Rule
----------------------------------------------------------------------------------------------------------------
                                                                                Units
                                                                     ---------------------------------
              Category                Primary      Low        High                            Period     Notes
                                      estimate   estimate   estimate     Year     Discount   covered
                                                                       dollars   rate  (%)   (years)
----------------------------------------------------------------------------------------------------------------
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).      $0.42      $0.27      $0.56       2016          7         10
    Annualized Quantified..........       0.31       0.21       0.42       2016          3         10
                                    ------------------------------------------------------------------
    Qualitative....................       Costs to submit 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 Economic Analysis of Impacts that
assesses the impacts of the proposed rule. The full analysis of
economic impacts is available in the docket for this final rule (Ref.
17) 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

    This final rule contains no collection of information. Therefore,
FDA is not required to seek clearance by the Office of Management and
Budget under the Paperwork Reduction Act of 1995.

X. Federalism

    We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. We have determined that the rule
does not contain policies that 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 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 rule in accordance with the principles set
forth in Executive Order 13175. We have determined that the rule does
not contain policies that have substantial direct effects 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. Accordingly, we
conclude that the rule does not contain policies that have tribal
implications as defined in the Executive Order and, consequently, a
tribal summary impact statement is not required.

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 have copyright
restriction and can be viewed at Dockets Management Staff. They are not
available publicly on the internet due to copyright restriction. 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. Food and Drug Administration, FDA Guidance for Industry on
Interim Policy on Compounding Using Bulk Drug Substances Under
Section 503A of the Federal Food, Drug, and Cosmetic Act, 2017;
available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469120.pdf.
* 2. Food and Drug Administration, Transcript of the February 23,
2015, Meeting of the Pharmacy Compounding Advisory Committee
(Afternoon Session), 2015; available at https://wayback.archive-it.org/7993/20170404155240/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM444500.pdf.
* 3. Memorandum to File on Food and Drug Administration
Consultations with United States Pharmacopeia, September 26, 2016.
* 4. Letter from the United States Pharmacopeia to FDA, October 7,
2016.
* 5. Food and Drug Administration Briefing Document for the June 17-
18, 2015,

Meeting of the Pharmacy Compounding Advisory Committee, 2015;
available at https://wayback.archive-it.org/7993/20170405230419/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM449535.pdf.
6. Birdsall, T.C., 1998, ``5-Hydroxytryptophan: A Clinically-
Effective Serotonin Precursor,'' Alternative Medicine Review,
3(4):271-80; available at https://www.ncbi.nlm.nih.gov/pubmed/9727088.
7. MedlinePlus, 5-HTP; available at https://medlineplus.gov/druginfo/natural/794.html (last reviewed November 30, 2017).
* 8. Drugs.com, Prozac Side Effects, 2018; available at https://www.drugs.com/sfx/prozac-side-effects.html.
9. Jakoben, J.C., K.K. Katakam, A. Schou, et al., 2017, ``Selective
Serotonin Reuptake Inhibitors Versus Placebo in Patients with Major
Depressive Disorder. A Systematic Review with Meta-Analysis and
Trial Sequential Analysis.'' BMC Psychiatry, 17(1):58.
* 10. Food and Drug Administration Supplemental Review of
Oxitriptan, November 2018.
11. Fang, Y., Z. Qiu, W. Hu, et al., 2014. ``Effect of Piracetam on
the Cognitive Performance of Patients Undergoing Coronary Bypass
Surgery: A Meta-Analysis.'' Experimental and Therapeutic Medicine,
7:429-434; available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881046/.
12. De Reuck, J. and B. Van Vleymen, 1999, ``The Clinical Safety of
High-Dose Piracetam--Its Use in the Treatment of Acute Stroke.''
Pharmacopsychiatry, 32 Suppl 1:33-37; available at https://www.ncbi.nlm.nih.gov/pubmed/10338106.
* 13. Food and Drug Administration Briefing Document for the
February 23-24, 2015, Meeting of the Pharmacy Compounding Advisory
Committee, 2015; available at https://wayback.archive-it.org/7993/20170405230436/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM433804.pdf.
14. UCB Pharma SA, 2007. A multicenter, randomized, double-blind,
placebo-controlled, parallel-group study of the efficacy and safety
of 9600 and 4800 mg/day piracetam (oral 800 mg tablets, b.i.d.)
taken for 12 months by subjects suffering from mild cognitive
impairment (MCI) Brussels: UCB, Inc. Clinical Study Summary;
available at https://www.ucb.com/_up/ucb_com_patients/documents/N01001_CSS_20070907.pdf.
* 15. Food and Drug Administration, Transcript of the February 24,
2015, Meeting of the Pharmacy Compounding Advisory Committee;
available at https://wayback.archive-it.org/7993/20170404155242/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM444501.pdf.
* 16. Food and Drug Administration Supplemental Review of Topical
Tranilast, April 25, 2016.
* 17. Economic Analysis of Impacts, 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, 21 CFR part
216 is 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. Add Sec.  216.23 to subpart 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 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) N-acetyl-D-glucosamine (for topical use only).
    (5) Squaric acid dibutyl ester (for topical use only).
    (6) Thymol iodide (for topical use only).
    (b) After balancing the criteria set forth in paragraph (c) of this
section, FDA has determined that the following bulk drug substances
will not be included on the list of substances that can be used in
compounding set forth in paragraph (a) of this section:
    (1) Oxitriptan.
    (2) Piracetam.
    (3) Silver Protein Mild.
    (4) Tranilast.
    (c) FDA will use the following criteria in evaluating substances
considered for inclusion on the list set forth in paragraph (a) of this
section:
    (1) The physical and chemical characterization of the substance;
    (2) Any safety issues raised by the use of the substance in
compounded drug products;
    (3) The available evidence of the effectiveness or lack of
effectiveness of a drug product compounded with the substance, if any
such evidence exists; and
    (4) 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.
    (d) Based on evidence currently available, there are inadequate
data to demonstrate the safety or efficacy of any drug product
compounded using any of the drug substances listed in paragraph (a) of
this section, or to establish general recognition of the safety or
effectiveness of any such drug product. Any person who represents that
a compounded drug made with a bulk drug substance that appears on this
list is FDA approved, or otherwise endorsed by FDA generally or for a
particular indication, will cause the drug to be misbranded under
section 502(a) and/or 502(bb) of the Federal Food, Drug, and Cosmetic
Act.

    Dated: February 11, 2019.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2019-02367 Filed 2-15-19; 8:45 am]
BILLING CODE 4164-01-P