Document ID: FDA-2016-N-3464-0029
Agency: fda
Document Type: Rule
Title: 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
Posted Date: 2019-02-19T05:00Z

[Federal Register Volume 84, Number 33 (Tuesday, February 19, 2019)]
[Rules and Regulations]
[Pages 4696-4710]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-02367]

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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.

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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

[[Page 4697]]

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, 240-402-6223, 
Rosilend.Lawson@fda.hhs.gov.

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

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       Abbreviation/ acronym                    What it means
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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.
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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

[[Page 4698]]

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

[[Page 4699]]

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-

[[Page 4700]]

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\
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    \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,

[[Page 4701]]

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

[[Page 4702]]

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.

[[Page 4703]]

    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

[[Page 4704]]

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

[[Page 4705]]

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

[[Page 4706]]

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

[[Page 4707]]

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

[[Page 4708]]

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.

[[Page 4709]]

                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,

[[Page 4710]]

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