[Federal Register Volume 80, Number 218 (Thursday, November 12, 2015)]
[Rules and Regulations]
[Pages 69861-69864]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-28718]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-419F]


Schedules of Controlled Substances: Placement of Eluxadoline Into 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: With the issuance of this final rule, the Administrator of the 
Drug Enforcement Administration places the substance 5-[[[(2S)-2-amino-
3-[4-aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-
1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid 
(eluxadoline), including its salts, isomers, and salts of isomers, into 
schedule IV of the Controlled Substances Act. This scheduling action is 
pursuant to the Controlled Substances Act which requires that such 
actions be made on the record after opportunity for a hearing through 
formal rulemaking. This action imposes the regulatory controls and 
administrative, civil, and criminal sanctions applicable to schedule IV 
controlled substances on persons who handle (manufacture, distribute, 
dispense, import, export, engage in research, conduct instructional 
activities, or possess) or propose to handle eluxadoline.

DATES: Effective date: December 17, 2015.

FOR FURTHER INFORMATION CONTACT: John R. Scherbenske, Office of 
Diversion Control, Drug Enforcement Administration; Mailing Address: 
8701 Morrissette Drive, Springfield, Virginia 22152, Telephone: (202) 
598-6812.

SUPPLEMENTARY INFORMATION:

Legal Authority

    The Drug Enforcement Administration (DEA) implements and enforces 
titles II and III of the Comprehensive Drug Abuse Prevention and 
Control Act of 1970, as amended. 21 U.S.C. 801-971. Titles II and III 
are referred to as the ``Controlled Substances Act'' and the 
``Controlled Substances Import and Export Act,'' respectively, and are 
collectively referred to as the ``Controlled Substances Act'' or the 
``CSA'' for the purpose of this action. The DEA publishes the 
implementing regulations for these statutes in title 21 of the Code of 
Federal Regulations (CFR), chapter II. The CSA and its implementing 
regulations are designed to prevent, detect, and eliminate the 
diversion of controlled substances and listed chemicals into the 
illicit market while ensuring an adequate supply is available for the 
legitimate medical, scientific, research, and industrial needs of the 
United States. Controlled substances have the potential for abuse and 
dependence and are controlled to protect the public health and safety.
    Under the CSA, each controlled substance is classified into one of 
five schedules based upon its potential for abuse, its currently 
accepted medical use in treatment in the United States, and the degree 
of dependence the substance may cause. 21 U.S.C. 812. The initial 
schedules of controlled substances established by Congress are found at 
21 U.S.C. 812(c), and the current list of controlled substances is 
published at 21 CFR part 1308.
    Pursuant to 21 U.S.C. 811(a)(1), the Attorney General may, by rule, 
``add to such a schedule or transfer between such schedules any drug or 
other substance if he (A) finds that such drug or other substance has a 
potential for abuse, and (B) makes with respect to such drug or other 
substance the findings prescribed by [21 U.S.C. 812(b)] for the 
schedule in which such drug is to be placed * * *.'' The Attorney 
General has delegated scheduling authority under 21 U.S.C. 811 to the 
Administrator of the DEA. 28 CFR 0.100.
    The CSA provides that proceedings for the issuance, amendment, or 
repeal of the scheduling of any drug or other substance may be 
initiated by the Attorney General (1) on her own motion; (2) at the 
request of the Secretary of the Department of Health and Human Services 
(HHS); \1\ or (3) on the petition of any interested party. 21 U.S.C. 
811(a). This action was initiated at the request of the Assistant 
Secretary of the HHS and imposes the regulatory controls and 
administrative, civil, and criminal sanctions applicable to controlled 
substances, including those specific to schedule IV controlled 
substances, on persons who handle or propose to handle eluxadoline.
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    \1\ As set forth in a memorandum of understanding entered into 
by the Food and Drug Administration (FDA) and the National Institute 
on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS 
in carrying out the Secretary's scheduling responsibilities under 
the CSA, with the concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. The 
Secretary of the HHS has delegated to the Assistant Secretary for 
Health of the HHS the authority to make domestic drug scheduling 
recommendations. 58 FR 35460, July 1, 1993. Accordingly, all 
subsequent references to ``Secretary'' have been replaced with 
``Assistant Secretary.''
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Background

    Eluxadoline (5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6-
dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-
yl)ethyl]amino]methyl]-2-methoxybenzoic acid), is a new molecular 
entity with central nervous system opioid properties. Eluxadoline has 
mixed mu opioid receptor (MOR) and kappa opioid receptor (KOR) agonist 
and delta opioid receptor (DOR) antagonist properties. The Food and 
Drug Administration (FDA) approved eluxadoline (brand name ``VIBERZI'') 
as a prescription drug for the treatment of irritable bowel syndrome 
with diarrhea (IBS-D) on May 27, 2015.

DEA and HHS Eight Factor Analyses

    On May 5, 2015, the HHS provided the DEA with a scientific and 
medical evaluation document prepared by the FDA entitled ``Basis for 
the Recommendation to Place Eluxadoline in Schedule IV of the 
Controlled Substances Act.'' After considering the eight factors in 21 
U.S.C. 811(c), including consideration of the substance's abuse 
potential, legitimate medical use, and dependence liability, the 
Assistant Secretary of the HHS recommended that eluxadoline be 
controlled in schedule IV of the CSA. In response, the DEA completed 
its own eight-factor analysis of eluxadoline. Both the DEA and HHS 
analyses and other relevant documents are available in their entirety 
in the public docket of this rule (Docket Number DEA-419) at http://www.regulations.gov under ``Supporting Documents.'' \2\
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    \2\ Although the published notice of proposed rulemaking stated 
that such items had been placed into the docket on regulations.gov, 
the Administration discovered in preparing this final rule that the 
HHS analysis had in fact not been posted. However, that document was 
available for review at DEA. The DEA posted the cited analysis to 
regulations.gov upon discovery of the error.
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Determination to Schedule Eluxadoline

    After a review of the available data, including the scientific and 
medical evaluation and the scheduling recommendation from the HHS, the 
Administrator of the DEA published in the Federal Register a notice of 
proposed rulemaking (NPRM) entitled ``Schedules of Controlled 
Substances: Placement of Eluxadoline into Schedule

[[Page 69862]]

IV'' which proposed placement of eluxadoline in schedule IV of the CSA. 
80 FR 48044, August 11, 2015. The proposed rule provided an opportunity 
for interested persons to file a request for hearing in accordance with 
DEA regulations by September 10, 2015. No requests for such a hearing 
were received by the DEA. The NPRM also provided an opportunity for 
interested persons to submit written comments on the proposal on or 
before September 10, 2015.

Comments Received

    The DEA received two comments on the proposed rule to schedule 
eluxadoline. One commenter supported controlling eluxadoline as a 
schedule IV controlled substance. One commenter opposed the control of 
eluxadoline as a schedule IV substance, and suggested it be controlled 
as a schedule V substance instead.
    Support for the Proposed Rule. One commenter agreed with the DEA's 
proposal to control eluxadoline as a schedule IV controlled substance, 
and stated that the public health (specifically, an unmet medical need) 
necessitates an immediate effective date for the final order 
controlling eluxadoline.
    DEA Response. The DEA appreciates the comment in support of this 
rulemaking. Generally, DEA scheduling actions are effective 30 days 
from the date of publication of the final rule in the Federal Register. 
21 CFR 1308.45; see also 5 U.S.C. 553(d). The DEA believes that 
providing 30 days for this rule to become effective is both expeditious 
and sufficient to allow handlers to comply with regulatory requirements 
for handling Schedule IV controlled substances. Both the HHS' and the 
DEA's scientific and medical analyses, the data collectively suggest 
that eluxadoline does have sufficient abuse potential and the DEA does 
not agree that eluxadoline's effective date should be the date of 
publication of the final rule.
    Opposition to the Proposed Rule. One commenter opposed the proposal 
to control eluxadoline as a schedule IV controlled substance, stating 
``I do not think that eluxadoline meets the factor [5] requirements for 
scheduling under schedule IV due to there being no general widespread 
use throughout other countries.'' The commenter also stated that the 
best approach would be to place eluxadoline in schedule V, rather than 
schedule IV.
    DEA Response. Although eluxadoline is a new chemical entity and 
information on actual abuse is not currently available, there is a 
sufficient factual basis to meet the requirements of Factor 5 (the 
scope, duration, and significance of abuse). The legislative history of 
the CSA provides guidance regarding the assessment of a new drug's 
potential for abuse. The legislative history of the CSA provides that a 
substance may have a potential for abuse if: ``The drug or drugs 
containing such a substance are new drugs so related in their action to 
a drug or drugs already listed as having a potential for abuse to make 
it likely that the drug will have the same potentiality for abuse as 
such drugs, thus making it reasonable to assume that there may be 
significant diversions from legitimate channels, significant use 
contrary to or without medical advice, or that it has a substantial 
capability of creating hazards to the health of the user or to the 
safety of the community.'' Comprehensive Drug Abuse Prevention and 
Control Act of 1970, H.R. Rep. No. 91-1444 (1970); as reprinted in 1970 
U.S.C.C.A.N. 4566, 4601. As discussed in the HHS and the DEA eight-
factor analyses, both pre-clinical and clinical studies indicate 
eluxadoline shares pharmacological similarities with schedule IV drugs 
such as butorphanol and pentazocine and has similar abuse potential.
    In addition, the HHS and DEA eight-factor analyses support the 
finding that the overall abuse potential of eluxadoline is comparable 
to schedule IV substances such as pentazocine and butorphanol. This 
indicates that placement in schedule IV is appropriate rather than 
schedule V.

Scheduling Conclusion

    Based on consideration of all comments, the scientific and medical 
evaluation and accompanying recommendation of the HHS, and the DEA's 
consideration of its own eight-factor analysis, the Administrator finds 
that these facts and all relevant data demonstrate substantial evidence 
of potential for abuse of eluxadoline. As such, the DEA is scheduling 
eluxadoline as a controlled substance under the CSA.

Determination of Appropriate Schedule

    The CSA establishes five schedules of controlled substances known 
as schedules I, II, III, IV, and V. The CSA outlines the findings 
required for placing a drug or other substance in any particular 
schedule. 21 U.S.C. 812(b). After consideration of the analysis and 
recommendation of the Assistant Secretary for Health of the HHS and 
review of all available data, the Administrator of the DEA, pursuant to 
21 U.S.C. 812(b)(4), finds that:
    (1) 5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6-dimethylphenyl]-1-
oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-
methoxybenzoic acid (eluxadoline) has a low potential for abuse 
relative to the drugs or other substances in schedule III. The overall 
abuse potential of eluxadoline is comparable to schedule IV substances 
such as pentazocine and butorphanol;
    (2) 5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6-dimethylphenyl]-1-
oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-
methoxybenzoic acid (eluxadoline) has a currently accepted medical use 
in treatment in the United States. Recently, the FDA approved 
eluxadoline as a prescription drug for the treatment of IBS-D. 
Therefore, eluxadoline has a currently accepted medical use in 
treatment in the United States; and
    (3) Abuse of 5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6-
dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-
yl)ethyl]amino]methyl]-2-methoxybenzoic acid (eluxadoline) may lead to 
limited psychological dependence similar to that of schedule IV drugs, 
but less than that of schedule III drugs.
    Based on these findings, the Administrator of the DEA concludes 
that eluxadoline, including its salts, isomers, and salts of isomers, 
warrants control in schedule IV of the CSA. 21 U.S.C. 812(b)(4).

Requirements for Handling Eluxadoline

    Upon the effective date of this final rule, any person who handles 
eluxadoline is subject to the CSA's schedule IV regulatory controls and 
administrative, civil, and criminal sanctions applicable to the 
manufacture, distribution, dispensing, importing, exporting, engagement 
in research, and conduct of instructional activities, of schedule IV 
controlled substances including the following:
    1. Registration. Any person who handles (manufactures, distributes, 
dispenses, imports, exports, engages in research, or conducts 
instructional activities with) eluxadoline, or who desires to handle 
eluxadoline, must be registered with the DEA to conduct such 
activities, pursuant to 21 U.S.C. 822, 823, 957, and 958, and in 
accordance with 21 CFR parts 1301 and 1312 as of December 14, 2015. Any 
person who currently handles eluxadoline and is not registered with the 
DEA must submit an application for registration and may not continue to 
handle eluxadoline as of December 14, 2015 unless the DEA has approved 
that application, pursuant to 21 U.S.C. 822, 823, 957, and 958, and

[[Page 69863]]

in accordance with 21 CFR parts 1301 and 1312.
    2. Security. Eluxadoline is subject to schedule III-V security 
requirements and must be handled and stored pursuant to 21 U.S.C. 823 
and in accordance with 21 CFR 1301.71-1301.93, as of December 14, 2015.
    3. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of eluxadoline must comply with 21 U.S.C. 825 and 
958(e) and be in accordance with 21 CFR part 1302, as of December 14, 
2015.
    4. Inventory. Every DEA registrant who possesses any quantity of 
eluxadoline on the effective date of this final rule must take an 
inventory of all stocks of eluxadoline on hand as of December 14, 2015, 
pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR 
1304.03, 1304.04, and 1304.11(a), (d), and (e).
    Any person who becomes registered with the DEA after November 12, 
2015 must take an initial inventory of all stocks of controlled 
substances (including eluxadoline) on hand on the date the registrant 
first engages in the handling of controlled substances, pursuant to 21 
U.S.C. 827 and 958 and in accordance with 21 CFR 1304.03, 1304.04, and 
1304.11(a), (b), and (e).
    After the initial inventory, every DEA registrant must take a new 
inventory of all stocks of controlled substances (including 
eluxadoline) on hand every two years, pursuant to 21 U.S.C. 827 and 
958, and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    5. Records. All DEA registrants must maintain records with respect 
to eluxadoline pursuant to 21 U.S.C. 827 and 958(e), and in accordance 
with 21 CFR parts 1304 and 1312 and Sec.  1307.11, as of December 14, 
2015.
    6. Prescriptions. All prescriptions for eluxadoline or products 
containing eluxadoline must comply with 21 U.S.C. 829, and be issued in 
accordance with 21 CFR part 1306 and subpart C of 21 CFR part 1311 as 
of December 14, 2015.
    7. Importation and Exportation. All importation and exportation of 
eluxadoline must be in compliance with 21 U.S.C. 952, 953, 957, and 
958, and be in accordance with 21 CFR part 1312 as of December 14, 
2015.
    8. Liability. Any activity involving eluxadoline not authorized by, 
or in violation of, the CSA, occurring as of December 14, 2015 is 
unlawful, and may subject the person to administrative, civil, and/or 
criminal proceedings.

Regulatory Analyses

Executive Orders 12866 and 13563

    In accordance with 21 U.S.C. 811(a), this scheduling action is 
subject to formal rulemaking procedures done ``on the record after 
opportunity for a hearing,'' which are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for 
scheduling a drug or other substance. Such actions are exempt from 
review by the Office of Management and Budget pursuant to section 
3(d)(1) of Executive Order 12866 and the principles reaffirmed in 
Executive Order 13563.

Executive Order 12988

    This regulation meets the applicable standards set forth in 
sections 3(a) and 3(b)(2) of Executive Order 12988 Civil Justice Reform 
to eliminate drafting errors and ambiguity, minimize litigation, 
provide a clear legal standard for affected conduct, and promote 
simplification and burden reduction.

Executive Order 13132

    This rulemaking does not have federalism implications warranting 
the application of Executive Order 13132. The rule does not have 
substantial direct effects on the States, on the relationship between 
the national government and the States, or the distribution of power 
and responsibilities among the various levels of government.

Executive Order 13175

    This rule does not have tribal implications warranting the 
application of Executive Order 13175. The rule does not 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.

Regulatory Flexibility Act

    The Administrator, in accordance with the Regulatory Flexibility 
Act (RFA), 5 U.S.C. 601-612, has reviewed this final rule and by 
approving it certifies that it will not have a significant economic 
impact on a substantial number of small entities. The purpose of this 
final rule is to place eluxadoline, including its salts, isomers, and 
salts of isomers, into schedule IV of the CSA. No less restrictive 
measures (i.e., non-control, or control in schedule V) enable the DEA 
to meet its statutory obligations under the CSA. In preparing this 
certification, the DEA has assessed economic impact by size category 
and has considered costs with respect to the various DEA registrant 
business activity classes.
    Eluxadoline is a new molecular entity which has not yet been 
marketed in the United States or any other country. The DEA has no 
basis to determine the level of contracted or outsourced manufacturing 
activities or the breadth of the distribution network. Furthermore, due 
to the wide variety of unidentifiable and unquantifiable variables that 
could potentially influence the dispensing and distribution rates of 
new pharmaceutical drugs, the DEA is unable to determine the number of 
potential small entities that might handle eluxadoline. However, the 
DEA estimates that all persons who would handle, or propose to handle, 
eluxadoline are currently registered with the DEA to handle schedule IV 
controlled substances, because it is a pharmaceutical controlled 
substance intended for medical treatment. Accordingly, the number of 
DEA registrations authorized to handle schedule IV controlled 
substances is a reasonable estimate for the maximum number of 
eluxadoline handlers. Therefore, the DEA estimates that 1.6 million 
(1,554,254 as of June 2015) controlled substance registrations, 
representing approximately 427,584 entities, would be the maximum 
number of entities affected by this final rule. The DEA estimates that 
418,141 (97.8%) of 427,584 affected entities are ``small entities'' in 
accordance with the RFA and SBA size standards.
    The DEA anticipates that prospective eluxadoline handlers already 
handle other schedule IV controlled substances and that the cost impact 
as a result of placing eluxadoline in schedule IV would be nominal. As 
the anticipated eluxadoline handlers already handle other schedule IV 
controlled substances, they already have DEA registrations and the 
required security and recordkeeping processes, equipment, and 
facilities in place, and would only require a nominal increase in 
security, inventory, recordkeeping and labeling costs.
    As discussed above, while the DEA does not have a basis to estimate 
the number of affected entities, the DEA estimates that the maximum 
number of affected entities is 427,584 of which 418,141 are estimated 
to be small entities. Since the affected entities are expected to 
handle other schedule IV controlled substances and maintain security 
and recordkeeping facilities and processes consistent with schedule IV 
controlled substances, the DEA estimates any economic impact will be 
nominal.
    Because of these facts, this final rule will not result in a 
significant economic

[[Page 69864]]

impact on a substantial number of small entities.

Unfunded Mandates Reform Act of 1995

    The DEA has determined and certifies pursuant to the Unfunded 
Mandates Reform Act of 1995 (UMRA), 2 U.S.C. 1501 et seq., that this 
action would not result in 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 for 
inflation) in any one year * * *'' Therefore, neither a Small 
Government Agency Plan nor any other action is required under 
provisions of UMRA.

Paperwork Reduction Act of 1995

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act of 1995. 44 U.S.C. 3501-
3521. This action would not impose recordkeeping or reporting 
requirements on State or local governments, individuals, businesses, or 
organizations. An agency may not conduct or sponsor, and a person is 
not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

Congressional Review Act

    This rule is not a major rule as defined by section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act (CRA)). This rule will not result in: an 
annual effect on the economy of $100,000,000 or more; a major increase 
in costs or prices for consumers, individual industries, Federal, 
State, or local government agencies, or geographic regions; or 
significant adverse effects on competition, employment, investment, 
productivity, innovation, or on the ability of United States-based 
companies to compete with foreign-based companies in domestic and 
export markets. However, pursuant to the CRA, the DEA has submitted a 
copy of this final rule to both Houses of Congress and to the 
Comptroller General.

Administrative Procedure Act

    The APA requires the publication of a substantive rule to be made 
not less than 30 days before its effective date. 5 U.S.C. 553(d). 
However, one exception is ``as otherwise provided by the agency for 
good cause found and published with the rule.'' As fully discussed 
above in response to the comment suggesting an immediate effective 
date, an immediate effective date is necessary in this case because 
there are limited therapeutic options currently available to patients 
with IBS-D and the eluxadoline NDA received priority review with FDA. 
Therefore, it is unnecessary to delay the effective date of this final 
rule by 30 days, and this rule shall take effect immediately upon 
publication.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.

    For the reasons set out above, 21 CFR part 1308 is amended to read 
as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as 
follows:

    Authority: 21 U.S.C. 811, 812, 871(b), unless otherwise noted.


0
2. Amend Sec.  1308.14 by adding paragraph (g)(3) to read as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (g) * * *
    (3) Eluxadoline (5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6-
dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-
yl)ethyl]amino]methyl]-2-methoxybenzoic acid) (including its optical 
isomers) and its salts, isomers, and salts of isomers (9725).

    Dated: November 5, 2015.
Chuck Rosenberg,
Acting Administrator.
[FR Doc. 2015-28718 Filed 11-10-15; 8:45 am]
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