[Federal Register Volume 81, Number 242 (Friday, December 16, 2016)]
[Proposed Rules]
[Pages 91071-91082]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-30109]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is proposing 
a regulation to 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 (the 
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 proposes 
to place six bulk drug substances on the list. This proposed rule also 
identifies four bulk drug substances that FDA has considered and 
proposes not to include on the list. Additional substances nominated by 
the public for inclusion on this list are currently under consideration 
and will be the subject of a future rulemaking.

DATES: Submit either electronic or written comments on the bulk drug 
substances list by March 16, 2017. See section VI for the proposed 
effective date of a final rule based on this proposed rule.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-N-3464 for ``List of Bulk Drug Substances That Can Be Used To 
Compound Drug Products in Accordance With Section 503A of the Federal 
Food, Drug, and Cosmetic Act.'' Received comments will be placed in the 
docket and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at http://www.regulations.gov or at the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

[[Page 91072]]

     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: James Flahive, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5108, Silver Spring, MD 20993-0002, 301-
796-9293.

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations and Acronyms Commonly Used in This 
Document
III. Background
    A. Statutory and Regulatory Background
    B. Regulatory History of the 503A Bulks List
    C. Requests for Nominations
IV. Legal Authority
V. Description of the Proposed Rule
    A. Criteria for Evaluating Bulk Drug Substances for the 503A 
Bulks List
    B. Methodology for Developing the 503A Bulks List
    C. Substances Proposed for Inclusion on the 503A Bulks List
    D. Substances Considered and Not Proposed for Inclusion on the 
503A Bulks List
VI. Proposed Effective Date
VII. Analysis of Environmental Impact
VIII. Economic Analysis of Impacts
    A. Summary of the Costs of the Rule
    B. Summary of the Benefits of the Rule
    C. Summary of the Impact on Small Entities
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. References

I. Executive Summary

A. Purpose of the Proposed Rule

    FDA is proposing to amend its 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''). 
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 a USP or NF monograph 
or components of approved drug products.

B. Summary of the Major Provisions of the Proposed Rule

    FDA is proposing to establish the criteria by which bulk drug 
substances will be evaluated for inclusion on the 503A Bulks List. 
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), FDA is also proposing to include 
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 
(for topical use only); squaric acid dibutyl ester (for topical use 
only); and thymol iodide (for topical use only) and that four other 
substances not be included on the list: Oxitriptan, piracetam, silver 
protein mild, and tranilast.

C. Legal Authority

    Section 503A of the FD&C Act, in conjunction with our general 
rulemaking authority in section 701(a) of the FD&C Act (21 U.S.C. 
371(a)), serves as our principal legal authority for this proposed 
rule.

D. Costs and Benefits

    FDA is proposing to place six bulk substances on the 503A Bulks 
List and not to place four bulk substances on the 503A Bulks List. 
Because we lack sufficient information to quantify the costs and 
benefits of this proposed rule, we include a qualitative description of 
potential benefits and potential costs. We expect that the rule would 
affect compounding pharmacies and 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 and Acronyms Commonly Used in This Document

5-HTP 5-hydroxytryptophan
BLA Biologics License Application
CFR Code of Federal Regulations
CSA Controlled Substances Act
DPCP Diphenylcyclopropenone
DQSA Drug Quality and Security Act
FD&C Act Federal Food, Drug, and Cosmetic Act
FDA Food and Drug Administration
IND Investigational New Drug
NAG N-acetyl-D-glucosamine
NAICS North American Industry Classification System
NF National Formulary
NPRM Notice of Proposed Rulemaking
OTC Over-The-Counter
PCAC Pharmacy Compounding Advisory Committee
PHS Act Public Health Service Act
PRESTO Prevention of REStenosis with Tranilast and its Outcomes
RFA Regulatory Flexibility Analysis
SADBE Squaric acid dibutyl ester
SBA Small Business Administration
UGT1A1 Uridine diphosphate glucuronosyltransferase 1A1
UK United Kingdom
USP United States Pharmacopeia

III. Background

A. Statutory and Regulatory Background

    Section 503A of the FD&C Act (21 U.S.C. 353a) describes the 
conditions under which a compounded drug product may qualify for an 
exemption from certain sections of the FD&C Act. Those conditions 
include that a licensed pharmacist in a State-licensed pharmacy or 
Federal facility or a licensed physician compounds the drug product 
using bulk drug substances that: (1) Comply with the standards of an 
applicable USP or NF monograph,\1\ if a

[[Page 91073]]

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, that appear on the 503A Bulks List. See 
section 503A(b)(1)(A)(i) of the FD&C Act. This proposed rule proposes 
criteria for evaluating substances for inclusion on the 503A Bulks List 
and identifies six substances the Secretary proposes to place on the 
list. The Agency considered four other substances and is proposing not 
to include those substances on the 503A Bulks List. Additional 
substances are under evaluation, and new substances may be added to the 
list through subsequent rulemaking.
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    \1\ FDA has interpreted the statutory language ``applicable USP 
or NF monographs'' to refer to official USP or NF drug substance 
monographs. Therefore, a substance that is the subject of a dietary 
supplement monograph, but not a USP or NF drug substance monograph, 
does not satisfy the condition regarding bulk drug substances in 
section 503A(b)(1)(A)(i)(I) of the Act. Such a substance may only be 
used as a bulk drug substance under section 503A of the FD&C Act if 
it is a component of an FDA-approved drug product or is on the 503A 
Bulks List.
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    Section 503A adopts the definition of ``bulk drug substance'' in 
FDA's drug establishment registration and listing regulations, which 
was codified at Sec.  207.3(a)(4) (21 CFR 207.3(a)(4)) at the time 
section 503A was enacted. See section 503A(b)(1)(A) of the FD&C Act. 
Under the definition, bulk drug substance means any substance that is 
represented for use in a drug and that, when used in the manufacturing, 
processing, or packaging of a drug, becomes an active ingredient or a 
finished dosage form of the drug, but the term does not include 
intermediates used in the synthesis of such substances.
    On August 31, 2016, FDA published a final rule in the Federal 
Register to update its registration and listing regulations in part 207 
(21 CFR part 207), which included minor changes to the definition of 
bulk drug substance and moved the definition to Sec.  207.3 (see 81 FR 
60170). This definition becomes effective on November 29, 2016. As set 
forth in Sec.  207.3, ``bulk drug substance,'' as referenced in section 
503A(b)(1)(A) of the FD&C Act, means the same as ``active 
pharmaceutical ingredient'' as defined in Sec.  207.1(b). An ``active 
pharmaceutical ingredient'' is any substance that is intended for 
incorporation into a finished drug product and is intended to furnish 
pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the 
structure or any function of the body. Active pharmaceutical ingredient 
does not include intermediates used in the synthesis of the substance 
(Sec.  207.1).
    Inactive ingredients used in compounded drug products, such as 
flavorings, dyes, or diluents, need not appear on the 503A Bulks List 
to be eligible for use in compounding drug products and will not be 
included on the list.

B. Regulatory History of the 503A Bulks List

    Section 503A of the FD&C Act was enacted in 1997. In the Federal 
Register of April 7, 1998 (63 FR 17011), FDA invited all interested 
persons to nominate bulk drug substances for inclusion on the 503A 
Bulks List. In 1998, FDA received nominations for 41 different drug 
substances. Ten of these drug substances were the subject of an 
applicable USP or NF monograph or were components of FDA-approved drugs 
and did not need to go on the list to be used in compounding. After 
evaluating the nominated drug substances and consulting with the PCAC 
as required by section 503A(c)(2), FDA published a proposed rule 
listing 20 drug substances for potential inclusion on the initial 
section 503A Bulks List (64 FR 996, January 7, 1999) (the 1999 Proposed 
503A Bulks List). The proposed rule also described 10 nominated drug 
substances that were still under consideration for the 503A Bulks List. 
The PCAC reconvened in May 1999 to discuss bulk drug substances 
included in the proposed rule, in addition to other bulk drug 
substances (see 64 FR 19791, April 22, 1999).
    In February 2001, the U.S. Court of Appeals for the Ninth Circuit 
held that certain provisions of section 503A of the FD&C Act were 
unconstitutional restrictions on commercial speech. (See Western States 
Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001).) Furthermore, the 
Ninth Circuit held that the advertising and solicitation provisions 
could not be severed from the rest of section 503A and, as a result, 
found section 503A of the FD&C Act to be invalid in its entirety. In 
April 2002, the U.S. Supreme Court affirmed the Ninth Circuit's 
decision that the advertising and solicitation provisions were 
unconstitutional; it did not, however, rule on the severability of 
section 503A of the FD&C Act. (See Thompson v. Western States Med. 
Ctr., 535 U.S. 357 (2002).) In 2008, the U.S. Court of Appeals for the 
Fifth Circuit held that compounded drugs are subject to regulation by 
FDA, and that the advertising and solicitation provisions are severable 
from the rest of section 503A of the FD&C Act. (See Medical Ctr. Pharm. 
v. Mukasey, 536 F.3d 383 (5th Cir. 2008).)
    Following a fungal meningitis outbreak in September 2012, FDA 
sought legislation to, among other things, resolve the split in the 
Circuits to clarify that section 503A of the FD&C Act was valid 
nationwide. On November 27, 2013, President Obama signed the Drug 
Quality and Security Act (Pub. L. 113-54) (DQSA), which contains 
important provisions relating to the oversight of human drug product 
compounding. Among other things, the DQSA removed from section 503A of 
the FD&C Act the provisions that had been held unconstitutional by the 
U.S. Supreme Court in 2002. By removing these provisions, the DQSA 
clarified that section 503A of the FD&C Act applies nationwide.

C. Requests for Nominations

    Because of the amount of time that had passed between the 
publication of the 1999 proposed rule and the enactment of the DQSA, 
FDA felt it was necessary to begin again to develop the 503A Bulks 
List. In the Federal Register of December 4, 2013 (78 FR 72841), FDA 
published a notice withdrawing the 1999 proposed rule and inviting all 
interested persons to nominate bulk drug substances for inclusion on 
the 503A Bulks List.
    Over 2,000 substances were nominated. However, many of those 
nominations were for a substance that is the subject of an applicable 
USP or NF monograph or a component of an FDA-approved drug, were not 
for substances used in compounding as active ingredients, or did not 
include sufficient information for FDA to evaluate whether the 
substances should be proposed for inclusion on the 503A Bulks List. To 
improve the efficiency of the process for developing the 503A Bulks 
List, FDA reopened the nomination process in July 2014 (79 FR 37747, 
July 2, 2014) and provided a more detailed description about what 
information should be included in a nomination to support the Agency's 
evaluation. FDA stated that bulk drug substances that were previously 
nominated would not be further considered unless they were renominated 
and the new nominations were adequately supported. Substances that were 
already eligible for use in compounding or that were not adequately 
supported would not be placed on the list.
    In response to that solicitation, approximately 740 unique 
substances were nominated. Of those substances, approximately 315 are 
components of an FDA-approved drug product or the

[[Page 91074]]

subject of an applicable USP or NF monograph. Such substances can be 
used in compounding under section 503A(b)(1)(A)(i)(I) and (II) of the 
FD&C Act and, therefore, are not eligible for inclusion on the 503A 
Bulks List.
    At least one of the nominated substances is a finished drug product 
that was nominated by its brand name. Finished drug products are not 
eligible for the 503A Bulks List because they do not meet the 
definition of a bulk drug substance in Sec.  207.3(4).
    At least one of the nominated substances is a biological product 
subject to approval in a biologics license application (BLA) under 
section 351 of the Public Health Service (PHS) Act (42 U.S.C. 262) when 
used for the indication proposed in the nomination. This substance is 
not eligible for the 503A Bulks List because biological products 
subject to approval in a BLA under section 351 of the PHS Act are not 
eligible for the exemptions in section 503A of the FD&C Act. No 
biological products subject to approval in a BLA will be considered for 
the 503A Bulks List.
    At least four of the nominated substances appear on the list 
published by FDA of substances that have been withdrawn or removed from 
the market because the drug products or components of the drug products 
have been found to be unsafe or not effective (section 503A(b)(1)(C) of 
the FD&C Act) (Withdrawn or Removed List). Such substances cannot be 
used in compounding under section 503A of the FD&C Act, and therefore, 
are not eligible for inclusion on the 503A Bulks List.
    One of the nominated substances has no currently accepted medical 
use and is included on Schedule I of the Controlled Substances Act 
(CSA) (21 U.S.C. 812(c)). The CSA does not allow possession or 
distribution of Schedule I substances (see 21 U.S.C. 841(a)(1) and 
829), except for research purposes (see 21 U.S.C. 823(f)), and Schedule 
I substances will not be considered for the 503A Bulks List. Those 
desiring to do research on a Schedule I substance may apply to do so 
under an investigational new drug (IND) application.
    Of the substances that are not components of an approved drug 
product or the subject of an applicable USP or NF monograph, finished 
drug products, biological products subject to licensure in a BLA, and 
do not appear on the Withdrawn or Removed List or Schedule I of the 
CSA, about 350 substances were nominated with insufficient supporting 
evidence for FDA to evaluate them.
    The remaining substances may be eligible for inclusion on the 503A 
Bulks List and were nominated with sufficient supporting information 
for FDA to evaluate them. Ten of those substances have been evaluated 
and are discussed in section V. The rest will be discussed in future 
notices of proposed rulemaking (NPRMs) after they have been evaluated. 
Once the Agency completes its review of the substances that were 
nominated for the 503A Bulks List with adequate supporting information 
under the July 2, 2014, request for nominations, FDA will consider 
additional substances nominated for inclusion on the list if they are 
eligible and adequate supporting information is submitted to permit FDA 
to meaningfully evaluate them (see section III).
    With regard to the substances nominated with sufficient supporting 
information for FDA to evaluate them, including the 10 nominated 
substances discussed in this proposed rule, FDA generally does not 
intend to take regulatory action against a State-licensed pharmacy, 
Federal facility, or licensed physician for compounding a drug product 
using a bulk drug substance that is not the subject of an applicable 
USP or NF monograph or a component of an FDA-approved drug product, 
provided that the other conditions in section 503A and the FD&C Act are 
met, until the substance is addressed in a final rule. FDA is not 
applying this interim policy to a nominated substance however, if the 
Agency has identified the substance as posing a significant safety 
risk,\2\ or if the substance was nominated without adequate support. 
For further information on this subject, see the guidance for industry 
entitled ``Interim Policy on Compounding Using Bulk Drug Substances 
Under Section 503A of the Federal Food, Drug, and Cosmetic Act'' (Ref. 
1). As described in the guidance, the following categories of bulk drug 
substances are identified on FDA's Web site at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM467373.pdf: (1) The substances nominated with 
sufficient supporting information that are under evaluation, (2) the 
substances nominated with sufficient supporting information but with 
which FDA has identified significant safety risks relating to the use 
of these bulk drug substances in compounding, and (3) the substances 
nominated with insufficient supporting evidence for FDA to evaluate 
them.
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    \2\ This is not a determination regarding whether the substances 
will be added to the 503A Bulks list. FDA intends to make that 
determination after notice and comment rulemaking, as set forth in 
this proposal.
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IV. Legal Authority

    As described in the Background section, section 503A of the FD&C 
Act describes the conditions that must be satisfied for human drug 
products compounded by a licensed pharmacist or licensed physician to 
be exempt from three sections of the FD&C Act (sections 501(a)(2)(B), 
502(f)(1), and 505 (21 U.S.C. 351(a)(2)(B), 352(f)(1), and 355)). One 
of the conditions that must be satisfied for a compounded drug to 
qualify for the exemptions under section 503A of the FD&C Act is that a 
licensed pharmacist in a State-licensed pharmacy or Federal facility or 
a licensed physician compounds the drug product using bulk drug 
substances that: (1) Comply with the standards of an applicable USP or 
NF monograph, if a monograph exists, and the USP chapter on pharmacy 
compounding; (2) if such a monograph does not exist, are drug 
substances that are components of drugs approved by the Secretary; or 
(3) if such a monograph does not exist and the drug substance is not a 
component of a drug approved by the Secretary, that appear on the 503A 
Bulks List. See section 503A(b)(1)(A)(i) of the FD&C Act. Section 
503A(c)(1) of the FD&C Act also states that the Secretary shall issue 
regulations to implement section 503A, and that before issuing 
regulations to implement section 503A(b)(1)(A)(i)(III) pertaining to 
the 503A bulks list, among other sections, the Secretary shall convene 
and consult an advisory committee on compounding unless the Secretary 
determines that the issuance of such regulations before consultation is 
necessary to protect the public health. Section 503A(c)(2) of the FD&C 
Act requires the Secretary to issue the regulations in consultation 
with the USP, and to include in the regulation the criteria for such 
substances that shall include historical use, reports in peer reviewed 
journals, 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 proposed rule.

V. Description of the Proposed Rule

    FDA is proposing to add Sec.  216.23 to title 21 of the Code of 
Federal Regulations (CFR) to set forth criteria to evaluate bulk drug 
substances for inclusion on the 503A Bulks List. Additionally, after 
considering 10 bulk drug substances for the 503A Bulks List,

[[Page 91075]]

FDA proposes to codify the initial 503A Bulks List to include 6 of the 
bulk drug substances that were considered and to identify 4 substances 
that were considered and would not be placed on the list. The criteria 
and the bulk drug substances considered for inclusion on the list are 
described in the paragraphs that follow.

A. Criteria for Evaluating Bulk Drug Substances for the 503A Bulks List

    Section 503A(c)(2) of the FD&C Act provides that the criteria for 
determining which substances should appear on the 503A Bulks List shall 
include historical use, reports in peer reviewed medical literature, or 
other criteria the Secretary of Health and Human Services may identify. 
Consistent with the July 2, 2014, Federal Register notice (79 FR 37747) 
soliciting nominations for this list, and as presented to and discussed 
with the PCAC in February 2015 (Ref. 2), FDA proposes that the 
following criteria be used to evaluate the nominated substances:
     The physical and chemical characterization of the 
substance;
     Any safety issues raised by the use of the substance in 
compounded drug products;
     The available evidence of effectiveness or lack of 
effectiveness of a drug product compounded with the substance, if any 
such evidence exists; and
     Historical use of the substance in compounded drug 
products, including information about the medical condition(s) the 
substance has been used to treat and any references in peer-reviewed 
medical literature.
    In evaluating candidates for the 503A Bulks List under these 
criteria, the Agency proposes to use a balancing test. Specifically, 
the Agency proposes to consider each criterion in the context of the 
others and balance them, on a substance-by-substance basis, to decide 
whether a particular substance is appropriate for inclusion on the 503A 
Bulks List.
    Under the first criterion, the physical and chemical 
characterization of the substance, FDA would consider each substance's 
purity, identity, and quality. Based on attributes such as the 
substance's molecular structure, stability, melting point, appearance, 
likely impurities, and solubilities, FDA would determine whether the 
substance can be identified consistently based on its physical and 
chemical characteristics. If a substance cannot be well characterized 
chemically and physically, the Agency proposes that this criterion 
weigh against its inclusion on the 503A Bulks List because there can be 
no assurance that its properties and toxicities, when used in 
compounding, would be the same as the properties and toxicities 
reported in the literature and considered by the Agency.
    Under the second criterion, FDA would consider the safety issues 
raised by the use of each substance in pharmacy compounding. Based on 
FDA's review of the substances nominated to date, 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. Thus, in evaluating list candidates, the Agency is likely to 
have at its disposal very limited information, or in some cases no 
information, of the type and quality that is ordinarily required and 
evaluated as part of the drug approval process.
    To evaluate the safety of the substances then, the Agency proposes 
to rely on available information, including reports in peer-reviewed 
medical literature, about each substance's pharmacology, acute 
toxicity, repeat dose toxicity, mutagenicity, developmental and 
reproductive toxicity, and carcinogenicity. The Agency would also rely 
on reports and abstracts in the literature about adverse reactions the 
substances have caused in humans. In applying the safety criterion, FDA 
also proposes to consider the availability of approved drug products or 
drug products that follow an OTC monograph (OTC monograph products). 
The existence of approved drug products or OTC monograph products would 
likely weigh against inclusion on the proposed list when the toxicity 
of a particular substance appears to be significant or where there are 
other safety concerns associated with the use of the substance in 
compounded drug products.
    Under the third criterion, FDA proposes to consider the available 
evidence of the substance's effectiveness or lack of effectiveness for 
a particular use, including reports in peer-reviewed medical 
literature, if any such evidence exists. In the new drug approval 
process, applicants are required to demonstrate effectiveness under the 
substantial evidence standard described in section 505(d) of the FD&C 
Act. FDA recognizes that few, if any, of the candidates for the 503A 
Bulks List will have been studied in adequate and well-controlled 
investigations sufficient to satisfy this standard. Thus, in its 
balancing of the relevant criteria, the Agency would take into account 
whatever relevant evidence concerning effectiveness is available.
    For example, for substances that have been widely used for a long 
period of time, the literature may include anecdotal reports of 
effectiveness for a particular use or reports of one or more trials 
suggesting possible effectiveness. Conversely, the literature may 
contain anecdotal or clinical evidence that a particular bulk drug 
substance was not effective for a particular use (negative 
effectiveness data). When evaluating a bulk drug substance that is 
proposed for the treatment of a less serious illness, FDA would 
generally be more concerned about the safety of the substance than 
about its effectiveness. Thus, the availability of minimal 
effectiveness data, or the existence of mere anecdotal reports, would 
be less likely to preclude inclusion of the substance on the list. 
However, for a bulk drug substance that is proposed to treat a more 
serious or life-threatening disease, there may be more serious 
consequences associated with ineffective therapy, particularly when 
there are approved drug products or OTC monograph products. In those 
cases, the existence of approved drug products or OTC monograph 
products would likely weigh against inclusion on the proposed list, and 
the availability of minimal effectiveness data, or the presence of 
negative effectiveness data, would weigh more heavily against placement 
on the list in FDA's balancing of the relevant criteria.
    Under the fourth criterion, the historical use of the substance in 
pharmacy compounding, FDA proposes to consider the length of time the 
substance has been used in pharmacy compounding, the medical conditions 
it has been used to treat, how widespread its use has been, including 
use in other countries, and any references in peer-reviewed medical 
literature. The Agency proposes that the longer a substance has been 
used in pharmacy compounding and the broader its use, the more this 
criterion will weigh in favor of inclusion of the substance on the 
list.

B. Methodology for Developing the 503A Bulks List

    FDA reviewed the substances addressed in this proposed rule in the 
context of adequately supported nominated uses. In certain 
circumstances, FDA also reviewed substances in the context of 
unnominated or inadequately supported uses because, for example, such 
uses appear to be widespread, are intended to treat serious conditions, 
or pose serious risks to patients. The

[[Page 91076]]

information that FDA assessed to evaluate the substances addressed in 
this proposed rule under each of the proposed evaluation criteria was 
obtained from publicly available sources, including peer-reviewed 
medical literature. Some of this information was referenced in the 
nominations, and the remainder FDA gathered through independent 
searches of medical and pharmaceutical databases. FDA did not review 
raw data. The nature, quantity, and quality of the information FDA 
assessed varied considerably from substance to substance. In some 
cases, there were very little data. For other substances, reports in 
the literature were more plentiful and sometimes comprised hundreds or 
thousands of articles. In those cases, generally the Agency limited its 
review to a sample of the best literature sources available (e.g., 
review articles in widely known, peer-reviewed journals; meta-analyses; 
reports of randomized controlled trials).
    FDA's evaluation of the nominated substances was, necessarily, far 
less rigorous and less comprehensive than the Agency's review of drugs 
as part of the new drug approval process. The new drug approval process 
is conducted based on extensive data compiled and submitted with new 
drug and abbreviated new drug applications, which are not available for 
the nominated substances. Additionally, the Agency's review during the 
drug approval process includes premarketing evaluation of a specific 
drug formulation, the sponsor's chemistry and manufacturing controls, 
and the establishments where approved drugs will be manufactured. In 
contrast, these bulk drug substances will be evaluated only for 
possible use in compounded drugs.
    Therefore, the proposed inclusion of a drug substance on the 503A 
Bulks List should not, in any way, be equated with or considered an FDA 
approval, endorsement, or recommendation of any drug compounded using 
the substance. Nor should it be assumed that a drug compounded using 
the substances on the proposed list has been proven to be safe and 
effective under the standards required for Agency approval. Any person 
who represents that a compounded drug made with a bulk drug substance 
that appears on this list is 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 FD&C Act.
    On February 23 and 24, 2015, and on June 17, 2015, FDA consulted 
with the PCAC created under section 503A(c)(1) of the FD&C Act, about 
the criteria proposed to evaluate substances nominated for the list and 
about the 10 substances that are addressed in this proposed rule (Refs. 
2-4). The Agency has considered all of the PCAC's recommendations in 
developing this proposed rule, and the Agency intends to continue to 
consult with the PCAC in evaluating future candidates for the 503A 
Bulks List. The first 10 substances evaluated are addressed in this 
proposed rule. Going forward, FDA intends to publish NPRMs proposing 
additional substances be placed on the list or not placed on the list 
on a rolling basis as evaluations are completed. Depending on the 
length of time it takes to complete a rulemaking, multiple rulemakings 
may be ongoing simultaneously.
    Section 503A of the FD&C Act requires that FDA create the 503A 
Bulks List by regulation, in consultation with the USP. See section 
503A(c)(2) of the FD&C Act. To this end, FDA has been periodically 
meeting with USP and discussing the 503A Bulks List (Refs. 5 and 6). 
After publication of this NPRM, the public will have an opportunity to 
comment on the proposed rule. After considering the comments on this 
proposed rule submitted to the docket, FDA will issue the 503A Bulks 
List as a final rule, which will be codified in the CFR. The final 
version of the rule may include all, none, or only some of the 
substances proposed here for inclusion on the 503A Bulks List, 
depending on the comments received, and will also identify those 
substances the Agency has determined should not be placed on the list. 
The Agency may amend the 503A Bulks List to add or delete substances 
after further notice and comment rulemaking.
    Individuals and organizations may petition FDA to amend the list 
(to add or delete bulk drug substances) at any time after the final 
rule is published (see 21 CFR 10.30). Individuals and organizations may 
also nominate new substances for the 503A Bulks List or comment on 
nominated substances that have not yet been addressed in an NPRM via 
Docket No. FDA-2015-N-3534 while that docket is open.

C. Substances Proposed for Inclusion on the 503A Bulks List

    Under section 503A(c)(2) of the FD&C Act, FDA is proposing that the 
following six bulk drug substances, which are neither the subject of a 
current applicable USP or NF monograph nor components of FDA-approved 
drugs, be included on the 503A Bulks List, and the drug products 
compounded with those substances may qualify for the exemptions 
provided for in section 503A of the FD&C Act (i.e., from sections 
501(a)(2)(B), 502(f)(1), and 505 of the FD&C Act). When a salt or ester 
of an active moiety is listed, only that particular salt or ester may 
be used. The base compound and other salts or esters of the same active 
moiety must be evaluated separately for eligibility for the 503A Bulks 
List. Additionally, when a bulk drug substance is included on the 503A 
Bulks List subject to certain restrictions (for example, for a 
particular route of administration (e.g., topical)), only dosage forms 
for that route of administration may be compounded with that bulk drug 
substance.
    The following bulk drug substances are being proposed for the 503A 
Bulks List, to appear in Sec.  216.23(a) of Title 21 of the CFR:
1. Brilliant Blue G
    Brilliant Blue G, also known as Coomassie Brilliant Blue G-250,\3\ 
was evaluated for use as a dye used in staining for visualization 
during ophthalmic procedures. It is well characterized physically and 
chemically. There are potential mutagenic and carcinogenic concerns 
associated with Brilliant Blue G; however, those concerns are mitigated 
in clinical use because the dye is immediately washed out of the eye 
after administration, and tissue that is stained with the dye is 
removed as part of the surgical procedure. Published clinical trials 
provide some evidence for efficacy of Brilliant Blue G in staining the 
internal limiting membrane. Brilliant Blue has had relatively 
widespread use for staining the internal limiting membrane during 
retinal surgery for approximately 10 years. There is one product that 
is FDA-approved for staining the internal limiting membrane and the 
anterior capsule.
---------------------------------------------------------------------------

    \3\ While there are other substances referred to by the name 
``Brilliant Blue,'' only Coomassie Brilliant Blue G-250 (CAS RN 
6104-58-1, UNII M1ZRX790SI) was evaluated, and the Agency is 
proposing only that substance for inclusion on the 503A Bulks List. 
The other substances referred to as ``Brilliant Blue'' would have to 
be nominated and separately evaluated for consideration for 
inclusion on the 503A Bulks List.
---------------------------------------------------------------------------

    FDA proposed to the PCAC that Brilliant Blue G be included on the 
503A Bulks List (Ref. 7), and at its meeting on June 17, 2015, the PCAC 
voted to include Brilliant Blue G on the list (Ref. 4). The proposed 
rule would place Brilliant Blue G on the 503A Bulks List.
2. Cantharidin
    Cantharidin, which is obtained from various species of blister 
beetle, was

[[Page 91077]]

evaluated for topical use \4\ in the treatment of warts and molluscum 
contagiosum. It is well characterized physically and chemically. 
Cantharidin is extremely toxic, due to its potential for severe 
irritation. However, clinical data accumulated since 1958 indicate 
that, with careful use under physician direction, toxicities observed 
with cantharidin, are no worse than and sometimes less severe than 
those seen with other destructive modalities in the treatment of 
molluscum contagiosum and warts. Evidence of some efficacy of 
cantharidin in the treatment of warts and molluscum contagiosum has 
been reported in the literature. It appears to have been widely used to 
treat molluscum contagiosum and warts since the 1950s. There are no 
approved prescription or OTC monograph products for molluscum 
contagiosum. For warts, there are no prescription drug products 
approved for use outside of the genital area. A variety of OTC 
monograph products containing salicylic acid are available.
---------------------------------------------------------------------------

    \4\ Except where specified otherwise, ``topical use'' means for 
application on the skin only and does not include oral, 
intravaginal, or ophthalmic use.
---------------------------------------------------------------------------

    FDA proposed to the PCAC that cantharidin be included on the 503A 
Bulks List for topical use only (Ref. 8). At the PCAC meeting on 
February 24, 2015, the PCAC voted to include cantharidin on the list 
(Ref. 3). Because the supported nominations and the Agency's review 
were limited to the topical use of this substance, the proposed rule 
would place cantharadin on the 503A Bulks List for topical use only.
3. Diphenylcyclopropenone (DPCP)
    DPCP was evaluated for topical use in the treatment of alopecia 
areata and nongenital warts. It is well characterized physically and 
chemically but degrades readily by hydrolysis in an alcoholic base or 
exposure to light. Known safety concerns about the use of DPCP are 
limited to reported adverse effects primarily due to its action as a 
contact sensitizer to elicit contact dermatitis. Evidence of some 
efficacy of DPCP in the treatment of alopecia areata and recalcitrant 
nongenital warts has been reported in the literature. DPCP has been 
used to treat resistant non-genital warts and alopecia areata for over 
30 years. The only FDA-approved drug product indicated for the 
treatment of alopecia areata is intralesional injection of 
corticosteroid suspensions. For warts, there are no approved 
prescription drug products outside of the genital area. A variety of 
OTC monograph products are available containing salicylic acid at 
percentages varying from 17 to 40 percent.
    FDA proposed to the PCAC that DPCP be included on the 503A Bulks 
List (Ref. 8). At its meeting on February 24, 2015, the PCAC voted to 
include DPCP on the list (Ref. 3). Because the supported nominations 
and the Agency's review were limited to the topical use of this 
substance, the proposed rule would place DPCP on the 503A Bulks List 
for topical use only.
4. N-acetyl-D-glucosamine (NAG)
    NAG, also known as acetyl-D glucosamine or N-acetyl glucosamine, 
was evaluated for topical use in the treatment of hyperpigmentation and 
other skin conditions. It is well characterized physically and 
chemically. Topical use of NAG has been associated with relatively 
minor and infrequent side effects. Studies have indicated that NAG may 
be effective for reducing diffuse and local facial hyperpigmentation. 
NAG has been used topically for the treatment of hyperpigmentation 
since the mid-2000s. There are FDA-approved drug products indicated for 
the treatment of hyperpigmentation and other skin conditions, which are 
not serious or life-threatening conditions.
    FDA proposed to the PCAC that NAG be included on the 503A Bulks 
List for topical use only (Ref. 7). At the PCAC meeting on June 17, 
2015, the PCAC voted to include NAG on the list (Ref. 4). Because the 
supported nominations and the Agency's review were limited to the 
topical use of this substance, the proposed rule would place NAG on the 
503A Bulks List for topical use only.
5. Squaric Acid Dibutyl Ester (SADBE)
    SADBE was evaluated for topical use in the treatment of alopecia 
areata and recalcitrant nongenital warts. It is well characterized 
physically and chemically but hydrolyzes readily in the presence of 
water. The adverse effects from use of SADBE are primarily related to 
its action as contact sensitizer. Evidence of some efficacy of SADBE in 
the treatment of recalcitrant nongenital warts and alopecia areata has 
been reported in the literature. SADBE has been used in the treatment 
of resistant nongenital warts and alopecia areata for 30 to 40 years. 
The only FDA-approved drug product indicated for the treatment of 
alopecia areata is intralesional injection of corticosteroid 
suspensions. For warts, there are no prescription drug products 
approved for use outside of the genital area. A variety of OTC 
monograph products are available containing salicylic acid at 
percentages varying from 17 to 40 percent.
    FDA proposed to the PCAC that SADBE be included on the 503A Bulks 
List (Ref. 8). At its meeting on February 24, 2015, the PCAC voted to 
include SADBE on the list (Ref. 3). Because the supported nominations 
and the Agency's review were limited to the topical use of this 
substance, the proposed rule would place SADBE on the 503A Bulks List 
for topical use only.
6. Thymol Iodide
    Thymol iodide was evaluated for use as a topical treatment for 
ulcerations and skin infections, as well as an intrapleural treatment 
for pleural effusions. It is well characterized physically and 
chemically. Reports indicate that it has been used without major 
complications. Literature reports some efficacy of thymol iodide for 
pleural effusions, which are serious and can be life-threatening 
conditions. Data regarding the effectiveness of thymol iodide in 
compounding for topical use on wounds or ulcers in various skin 
conditions is limited; however, these skin conditions generally are not 
serious or life-threatening. Thymol iodide has been in use for over 100 
years. Regarding use as an antiseptic in surgery and use as an external 
application to wounds or ulcers in various skin conditions, approved 
and OTC monograph products are available. There are also FDA-approved 
products available to treat malignant pleural effusions.
    FDA proposed to the PCAC that thymol iodide be included on the 503A 
Bulks List (Ref. 8). At its meeting on February 23, 2015, the PCAC 
voted to include thymol iodide on the list (Ref. 2). Because the 
supported nominations were limited to the topical use of this 
substance, and because pleural effusions are serious and potentially 
life-threatening conditions for which there are approved products 
available, the proposed rule would place thymol iodide on the 503A 
Bulks List for topical use only.

D. Substances Considered and Not Proposed for Inclusion on the 503A 
Bulks List

    FDA is proposing that four of the bulk drug substances that it has 
evaluated not be included on the 503A Bulks List. Bulk drug substances 
that are considered for the 503A Bulks list but not placed on the list 
cannot be used to compound drug products that would qualify for the 
exemptions in section 503A. If a prescribing practitioner nevertheless 
believes that a patient should be treated with a drug product 
compounded from such a bulk drug substance, it may be possible to 
obtain

[[Page 91078]]

the drug under an IND. For information about the requirements for 
proceeding under an IND, visit FDA's Web site at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm.
    The four bulk drug substances that have been evaluated and that FDA 
is not proposing to place on the list, and the reasons for that 
proposal, are as follows:
1. Oxitriptan
    Oxitriptan, also known as 5-hydroxytryptophan (5-HTP), was 
evaluated as a treatment for depression and insomnia. It is a 
hydroxylated form of a naturally occurring amino acid, tryptophan. 
Oxitriptan is well characterized physically and chemically. However, 
there are significant safety concerns related to its use. Based upon 
its mechanism of action, concomitant use of oxitriptan with 
antidepressant drugs could result in serotonin syndrome, a serious and 
life-threatening drug interaction. Additionally, medications used to 
treat depression have been linked to an increase in suicidal thinking 
and behavior. There are no data to suggest that oxitriptan would be 
free of similar risks, and compounded drugs do not include labeling 
that would adequately warn physicians and patients of such risks. Other 
potential adverse reactions include moderate gastrointestinal effects, 
which are common upon administration of oxitriptan.
    Data supporting the efficacy of oxitriptan for depression are 
limited, and there is no evidence to support long-term efficacy of 
oxitriptan for the treatment of this chronic disease. Depression is a 
serious and potentially life-threatening condition, and there are 
multiple FDA-approved antidepressants that have been shown to be safe 
and effective in their approved forms that are appropriately labeled. 
Regarding the use of oxitriptan to treat insomnia, the clinical trials 
examining insomnia were too poorly designed and/or executed to assess 
efficacy. There are multiple FDA-approved drug products available for 
the treatment of insomnia. The length of time oxitriptan has been used 
in compounding is uncertain, although it has been discussed in 
scientific journals dating back approximately 40 years.
    On balance, the physiochemical characteristics, the safety 
concerns, lack of evidence of effectiveness, and historical use of 
oxitriptan weigh against inclusion of this substance on the 503A Bulks 
List. In particular, the Agency's proposal regarding this substance is 
based on the seriousness of the safety concerns related to the use of 
oxitriptan for depression in lieu of, or causing a delay in the use of 
an approved product, the lack of adequate warnings that would inform 
patients and prescribers of the risks associated with taking an 
oxitriptan product, and the availability of approved drug products for 
the treatment of depression, a potentially life-threatening condition. 
FDA proposed to the PCAC that this substance not be included on the 
503A Bulks List (Ref. 7). At its meeting on June 17, 2015, the PCAC 
voted not to include oxitriptan on the list (Ref. 4). The proposed rule 
would not place oxitriptan on the 503A Bulks List.
2. Piracetam
    Piracetam was evaluated as a treatment for enhancing cognitive 
skills in treating a variety of cognitive disorders, including 
Alzheimer's disease. It has also been studied for treatment of 
coagulation disorders and vertigo. It is well characterized physically 
and chemically. Piracetam is approved in the United Kingdom (UK) as a 
prescription drug for the adjunctive treatment of cortical myoclonus. 
The labeling of the UK product identifies that the drug is renally 
excreted, that the dosage should be adjusted in the presence of renal 
disease, and that it is contraindicated in end-stage renal disease. 
Piracetam acts by multiple mechanisms to prolong bleeding time and is 
therefore not recommended for use by individuals with medical 
conditions that prolong bleeding time or that are taking concomitant 
anticoagulants or other medications that prolong bleeding (Ref. 9). 
Piracetam is not recommended for women who are pregnant, planning to 
become pregnant, or breastfeeding, because, according to the UK 
product's labeling, the drug has been shown to cross the placenta and 
be excreted in human milk. It is also recommended that individuals 
required to restrict their salt intake avoid piracetam (id.).
    Piracetam was assessed for the treatment of mild cognitive 
impairment, a potential component of Alzheimer's disease, in a large, 
well-conducted, controlled clinical trial that failed to demonstrate 
efficacy. Studies of the efficacy of piracetam for other indications 
have been inconclusive, many of which were poorly designed or executed, 
or used flawed statistical methods to analyze the results. Piracetam's 
regulatory approval in the UK for the treatment of cortical myoclonus, 
which is not among the uses for which piracetam was nominated, was 
based on a single center, retrospective review of 40 patients treated 
with piracetam (id.). FDA-approved products are available for treatment 
of the conditions, and conditions related to, those for which piracetam 
was nominated, for example, for Alzheimer's disease, which is 
frequently preceded by mild cognitive impairment. Regarding historical 
use, piracetam has been available for approximately 40 years.
    On balance, the physiochemical characteristics, safety concerns, 
inconclusive evidence of effectiveness, and historical use of piracetam 
weigh against inclusion of this substance on the list. In particular, 
the Agency's proposal regarding this substance is based on the limited 
evidence of benefit associated with piracetam, the seriousness of the 
conditions for which piracetam was nominated to be used, and the 
availability of safe and effective FDA-approved medications for many of 
these uses. FDA proposed to the PCAC that this substance not be 
included on the 503A Bulks List (Ref. 8). At its meeting on February 
24, 2015, the PCAC voted not to include piracetam on the list (Ref. 3). 
The proposed rule would not place piracetam on the 503A Bulks List.
3. Silver Protein Mild
    Silver protein mild, also known as mild silver protein, was 
evaluated for use as an anti-infective agent for ophthalmic use. Silver 
protein mild is not well characterized because the term ``silver 
protein mild'' is used to refer to a variety of different drug 
products. There are also safety concerns associated with the use of 
silver protein mild. It can cause argyria, which is a permanent ashen-
gray discoloration of the skin, conjunctiva, and internal organs. 
Regarding effectiveness, silver protein mild has been found to be 
inferior to another treatment in clinical trials. A number of FDA-
approved anti-infective agents for ophthalmic use are available and 
have been shown to be both safe and effective. While it has a long 
history of use, dating back to the early 1900s, the use of silver 
protein mild declined dramatically after the introduction of FDA-
approved ocular anti-infectives.
    On balance, the physiochemical characteristics, safety issues, 
questionable effectiveness, and historical use of silver protein mild 
weigh against inclusion of this substance on the 503A Bulks List. In 
particular, the Agency's proposal is based on the facts that silver 
protein mild is not well characterized, that in clinical trials it has 
been found to be inferior to another treatment and

[[Page 91079]]

numerically inferior to no treatment at all, and that chronic use may 
result in permanent discoloration of the conjunctiva, cornea, and/or 
lens. FDA proposed to the PCAC that this substance not be included on 
the 503A Bulks List (Ref. 8). At its meeting on February 23, 2015, the 
PCAC voted not to include silver protein mild on the list (Ref. 2). The 
proposed rule would not place silver protein mild on the 503A Bulks 
List.
4. Tranilast
    Tranilast, an antiallergenic agent, was evaluated for the treatment 
of allergic disorders, arthritis, dry eye syndrome, keloids, and 
hypertrophic scars. It is approved in South Korea and Japan for the 
treatment of asthma, keloids, and hypertrophic scarring, and as an 
ophthalmic solution for allergic conjunctivitis. It is well 
characterized physically and chemically. However, there are significant 
safety concerns associated with its systemic administration. In a well-
controlled clinical trial with nearly 12,000 participants (the 
Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) 
Trial) (Ref. 10), tranilast was associated with significantly elevated 
liver enzymes (three times the upper limit of normal) in 11 percent of 
patients within 1 to 3 months of drug initiation, as well as anemia, 
renal failure, rash, and dysuria.\5\ Liver toxicity is of particular 
concern because many of the conditions for which tranilast was 
nominated are chronic conditions. While there is some evidence that 
tranilast may be effective for allergic disorders, evidence of 
effectiveness for other uses is either not available or inconclusive. 
For allergy, arthritis, and ophthalmic indications, there are numerous 
FDA-approved and OTC monograph products. The length of time tranilast 
has been used in compounding is uncertain, although it has been 
discussed in scientific journals dating back approximately 40 years.
---------------------------------------------------------------------------

    \5\ During the PCAC meeting on June 17, 2015, the PRESTO trial 
was criticized by one of the tranilast nominators as having 
insufficiently accounted for the medical history of the subjects, 
among other things (see Ref. 4). To the contrary, the five-arm trial 
design appears to have been properly controlled for the patients' 
various medical conditions, and signals of liver toxicity were 
consistent across arms (see Ref. 10).
---------------------------------------------------------------------------

    On balance, the physiochemical characteristics, safety concerns, 
lack of evidence of effectiveness, and historical use of tranilast 
weigh against inclusion of this substance on the 503A Bulks List, 
particularly given the seriousness of the safety concerns related to 
hepatotoxicity of tranilast and contraindications in pregnant and 
breastfeeding women, the availability of approved products for most of 
the proposed uses, and the lack of evidence that tranilast is 
effective. FDA proposed to the PCAC that this substance not be included 
on the 503A Bulks List (Ref. 7). However, at its meeting on June 17, 
2015, the PCAC voted to include tranilast on the list for topical use 
only (Ref. 4).
    Subsequent to that meeting, FDA reviewed the topical use of 
tranilast further. It obtained the label of the Japanese tranilast 
product, RIZABEN, but found no information on the transdermal 
absorption or other pharmacokinetics of tranilast when applied 
topically to healthy or diseased human skin (Ref. 11). The labeling of 
the Japanese product identifies a number of safety concerns, including 
a contraindication in pregnant women, especially during the first 
trimester of pregnancy, and in those who might be pregnant, due to 
evidence of teratogenicity in animal studies (id.). The labeling also 
states that tranilast is detected in breast milk and should be avoided 
by breastfeeding women. In addition, the RIZABEN label lists a drug 
interaction with warfarin and identifies a number of serious adverse 
events, particularly those that are hematologic in nature (leukopenia, 
thrombocytopenia, anemia, hemolytic anemia), associated with the oral 
use of tranilast. Safety information regarding other routes of 
administration is limited.
    FDA also noted evidence that some increases in some liver function 
tests (bilirubin) are explained by tranilast inhibition of uridine 
diphosphate glucuronosyltransferase 1A1 (UGT1A1) especially in patients 
with a genotype for Gilbert's Disease. Increases in liver transaminases 
observed with tranilast are not typically seen with inhibition of 
UGT1A1. It is speculated that tranilast impairs the metabolism of drugs 
that are metabolized by UGT1A1. If these drugs are associated with 
transaminase elevations, inhibiting the drug's metabolism may lead to 
liver transaminitis.
    As was found in the Agency's initial review and presented to the 
PCAC, there is no persuasive information available regarding the safety 
or effectiveness of topical tranilast. FDA has identified only two 
reports in the literature describing the efficacy and safety of 
tranilast administered topically for the treatment of keloids and 
hypertrophic scars (Refs. 12 and 13). One of those studies was an open-
label trial, and the other was a case series. Between the two studies, 
only five patients were exposed to topical tranilast.
    As stated previously, FDA has serious concerns about the safety of 
tranilast when administered orally. The Agency has insufficient 
information about the systemic absorption of topical tranilast 
formulations to determine whether topical administration of the drug 
product would present the same safety concerns. Given the lack of 
information available about the safety and efficacy of topical 
tranilast, and safety concerns related to the oral use of this product, 
the proposed rule would not place tranilast on the 503A Bulks List.

VI. Proposed Effective Date

    The Agency proposes that any final rule based on this proposal will 
become effective 30 days after the date of publication of the final 
rule in the Federal Register.

VII. Analysis of Environmental Impact

    FDA has 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.

VIII. Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, 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). We 
have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the proposed rule. We believe that this 
proposed rule is not a significant regulatory action as defined by 
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because we find little evidence that a substantial number of 
small entities would be affected by the proposed rule or that the 
economic impact on each affected small entity would be significant, we 
propose to certify that the proposed rule will not 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

[[Page 91080]]

prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $146 million, using the most current (2015) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

                                                  Table 1--Economic Data: Costs and Benefits Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                           Discount rate  Period covered
            Category               Primary estimate    Low estimate    High estimate  Units year dollars        (%)           (years)          Notes
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Benefits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized $ mil/year.  Not Estimated       ..............  ..............  ..................               7              10  ..............
                                   (N.E.).
Annualized Monetized $ mil/year.  N.E...............  ..............  ..............  ..................               3              10  ..............
Annualized Quantified...........  N.E...............  ..............  ..............  ..................               7  ..............  ..............
Annualized Quantified...........  N.E...............  ..............  ..............  ..................               3  ..............  ..............
Qualitative.....................  Not including four  ..............  ..............  ..................  ..............  ..............  ..............
                                   bulk drug
                                   substances from
                                   the 503A Bulks
                                   List would limit
                                   the use of
                                   potentially
                                   ineffective or
                                   unsafe unapproved
                                   drugs.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                          Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annualized Monetized $ mil/year.  N.E...............  ..............  ..............  ..................               7              10  ..............
Annualized Monetized $ mil/year.  N.E...............  ..............  ..............  ..................               3              10  ..............
Annualized Quantified...........  $118 to $235 one-   ..............  ..............  2014..............               7  ..............  ..............
                                   time per firm
                                   costs.
Annualized Quantified...........  $118 to $235 one-   ..............  ..............  2014..............               3  ..............  ..............
                                   time per firm
                                   costs.
Qualitative.....................  ..................  ..............  ..............  ..................  ..............  ..............  ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Transfers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Federal Annualized Monetized $    ..................  ..............  ..............  ..................               7  ..............  ..............
 mil/year.
Federal Annualized Monetized $    ..................  ..............  ..............  ..................               3  ..............  ..............
 mil/year.
From/To.........................  From:.............  ..............  ..............  To:...............  ..............  ..............  ..............
Other Annualized $ mil/year.....  N.E...............  ..............  ..............  ..................               7  ..............  ..............
Other Annualized Monetized $ mil/ N.E...............  ..............  ..............  ..................               3  ..............  ..............
 year.

[[Page 91081]]

 
From/To.........................  From: Producers of  ..............  ..............  To: Producers of    ..............  ..............  ..............
                                   bulk drug                                           alternative
                                   substances not                                      treatments,
                                   proposed for                                        consumers, using
                                   inclusion and                                       these treatments
                                   compounding                                         and payers for
                                   pharmacies using                                    these treatments.
                                   these substances.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                         Effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local, and/or Tribal
 Government: No effect.
Small Business: Unknown effect..
Wages: No effect................
Growth: No effect...............
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The Economic Analysis of Impacts of the proposed rule performed in 
accordance with Executive Order 12866, Executive Order 13563, the 
Regulatory Flexibility Act, and the Unfunded Mandates Reform Act is 
available at http://www.regulations.gov under the docket number for 
this proposed rule (Ref. 14) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm. We invite 
comments on this analysis.

A. Summary of the Costs of the Rule

    We lack data on the scope of the current use of the affected bulk 
drug substances and the number of firms that would be affected by the 
rule. Without this information, we cannot quantify the total potential 
costs of the proposed rule. Potential costs include administrative 
costs, additional costs for consumers and payers if alternative 
therapies are more costly than the affected compounded drug products, 
and a potential loss of producer surplus if producers use additional 
resources in response to the rule. We estimate that each affected firm 
would spend 1 to 2 hours on administrative costs to read and understand 
the rule. The average hourly wage for a pharmacist in 2014 equals about 
$57, or $114 including 100 percent overhead. Thus, each affected firm 
would incur administrative costs that range from $118 to $235. We 
request comment on the potential costs and number of firms affected by 
the proposed rule.

B. Summary of the Benefits of the Rule

    The benefits of the rule are unquantified. We include a qualitative 
discussion of potential benefits. For consumers who switch to more 
effective treatments, there would be benefits as consumers experience 
better health outcomes than they do currently.

C. Summary of the Impact on Small Entities

    The Regulatory Flexibility Act requires a Regulatory Flexibility 
Analysis (RFA) unless the Agency can certify that the proposed rule 
would have no significant impact on a substantial number of small 
entities. The Small Business Administration (SBA) establishes 
thresholds for small entities by North American Industry Classification 
System (NAICS); the SBA considers small any entity below these 
thresholds. Firms affected by the proposed rule would fall into three 
major industries, NAICS 325412 Pharmaceutical Preparation 
Manufacturing, NAICS 424210 Drugs and Druggists' Sundries Merchant 
Wholesalers, and NAICS 446110 Pharmacies and Drug Stores. The 
thresholds for these industries are 750 employees for NAICS 325412, 100 
employees for NAICS 424210, and annual sales of $27.5 million for NAICS 
446110.
    We lack data on the number or size of manufacturers, wholesalers, 
and compounding pharmacies that would be affected by the proposed rule. 
Moreover, we find little evidence of widespread use of four bulk drug 
substances not proposed for inclusion on the 503A Bulks List. This 
suggests that the impact of the rule would likely not be significant on 
small entities. Because we find little evidence that a substantial 
number of small entities would be affected by the proposed rule or that 
the economic impact on each affected small entity would be significant, 
we believe that the proposed rule would not have a significant economic 
impact on a substantial number of small entities, but the impacts are 
uncertain. We request detailed comments and data on the number of small 
entities that would be affected by the proposed rule, as well as data 
on the economic impact of the proposed rule on these small entities.

IX. Paperwork Reduction Act of 1995

    The submission of comments on this proposed rule would be 
submissions in response to a Federal Register notice, in the form of 
comments, which are excluded from the definition of ``information'' 
under 5 CFR 1320.3(h)(4) of Office of Management and Budget regulations 
on the Paperwork Reduction Act (i.e., facts or opinions submitted in 
response to general solicitations of comments from the public, 
published in the Federal Register or other publications, regardless of 
the form or format thereof, provided that no person is required to 
supply specific information pertaining to the commenter, other than 
that necessary for self-identification, as a condition of the Agency's 
full consideration of the

[[Page 91082]]

comment). The proposed rule contains no other collection of 
information.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the proposed rule, if finalized, would not contain policies that would 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Accordingly, we 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. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

    1. FDA, ``Guidance for Industry: Interim Policy on Compounding 
Using Bulk Drug Substances Under Section 503A of the Federal Food, 
Drug, and Cosmetic Act,'' (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469120.pdf), 
2016.
    2. FDA, Transcript of the February 23, 2015, Meeting of the 
Pharmacy Compounding Advisory Committee (Afternoon Session), 2015, 
(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM444500.pdf).
    3. FDA, Transcript of the February 24, 2015, Meeting of the 
Pharmacy Compounding Advisory Committee, 2015, (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM444501.pdf).
    4. Transcript of the June 17, 2015, Meeting of the Pharmacy 
Compounding Advisory Committee (Afternoon Session), 2015, (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM458513.pdf).
    5. Memorandum to File on FDA Consultations with USP, September 
26, 2016.
    6. Letter from USP to FDA, October 7, 2016.
    7. FDA Briefing Document for the June 17-18, 2015, Meeting of 
the Pharmacy Compounding Advisory Committee, 2015, (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM449535.pdf).
    8. FDA Briefing Document for the February 23-24, 2015, Meeting 
of the Pharmacy Compounding Advisory Committee, 2015, (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PharmacyCompoundingAdvisoryCommittee/UCM433804.pdf).
    9. Obeso, J. A., et al., ``Piracetam in the Treatment of 
Different Types of Myoclonus,'' Clinical Neuropharmacology, 11(6): 
529-536, 1988.
    10. Holmes, D.R., Jr., M. Savage, J.M. LaBlanche, et al., 
``Results of Prevention of REStenosis with Tranilast and its 
Outcomes (PRESTO) Trial,'' Circulation, 106(10): 1243-1250, 2002.
    11. FDA Supplemental Review of Topical Tranilast, April 25, 
2016.
    12. Shigeki, S., T. Murakami, N. Yata, and Y. Ikuta, ``Treatment 
of Keloid and Hypertrophic Scars by Iontophoretic Transdermal 
Delivery of Tranilast,'' Scandinavian Journal of Plastic and 
Reconstructive Surgery and Hand Surgery, 31(2): 151-159, 1997.
    13. Banov, D., F. Banov, and A.S. Bassani, ``Case Series: The 
Effectiveness of Fatty Acids From Pracaxi Oil in a Topical Silicone 
Base for Scar and Wound Therapy,'' Dermatology and Therapy, 4(2): 
259-269, 2014.
    14. Economic Analysis of Impacts.

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, the 
Food and Drug Administration proposes to amend 21 CFR part 216 as 
follows:

PART 216--HUMAN DRUG COMPOUNDING

0
1. The authority citation for part 216 is revised to read as follows:

    Authority: 21 U.S.C. 351, 352, 353a, 353b, 355, and 371.

0
2. The heading for part 216 is revised to read as set forth above.
0
3. Section 216.23 is added 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.
    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 (for topical use only).
    Squaric acid dibutyl ester (for topical use only).
    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:
    Oxitriptan.
    Piracetam.
    Silver Protein Mild.
    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: December 9, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-30109 Filed 12-15-16; 8:45 am]
BILLING CODE 4164-01-P