[Federal Register Volume 80, Number 15 (Friday, January 23, 2015)]
[Rules and Regulations]
[Pages 3468-3470]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-01172]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-400]


Schedules of Controlled Substances: Removal of Naloxegol From 
Control

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 removes naloxegol ((5[alpha],6[alpha])-
17-allyl-6-((20-hydroxy-3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-
epoxymorphinon-3,14-diol) and its salts from the schedules of the 
Controlled Substances Act (CSA). This scheduling action is pursuant to 
the CSA which requires that such actions be made on the record after 
opportunity for a hearing through formal rulemaking. Prior to the 
effective date of this rule, naloxegol was a schedule II controlled 
substance because it can be derived from opium alkaloids. This action 
removes the regulatory controls and administrative, civil, and criminal 
sanctions applicable to controlled substances, including those specific 
to schedule II controlled substances, on persons who handle 
(manufacture, distribute, reverse distribute, dispense, conduct 
research, import, export, or conduct chemical analysis) or propose to 
handle naloxegol.

DATES: Effective Date: January 23, 2015.

FOR FURTHER INFORMATION CONTACT: Imelda L. Paredes, 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, but they 
are collectively referred to as the ``Controlled Substances Act'' or 
the ``CSA'' for the purposes of this action. The DEA publishes the 
implementing regulations for these statutes in title 21 of the Code of 
Federal Regulations (CFR), parts 1300 to 1321. 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 providing 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 drug or other 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 scheduled substances 
is published at 21 CFR 1308. 21 U.S.C. 812(a).
    Pursuant to 21 U.S.C. 811(a)(2), the Attorney General may, by rule, 
``remove any drug or other substance from the schedules if he finds 
that the drug or other substance does not meet the requirements for 
inclusion in any schedule.'' 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 his 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 by a petition from the drug sponsor 
to remove naloxegol from the list of scheduled controlled substances of 
the CSA, and is supported by, inter alia, a recommendation from the 
Assistant Secretary of the HHS and an evaluation of all relevant data 
by the DEA. This action removes the regulatory controls and 
administrative, civil, and criminal sanctions applicable to controlled 
substances, including those specific to schedule II controlled 
substances, on persons who handle or propose to handle naloxegol.
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    \1\ As discussed 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.
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Background

    Naloxegol, or PEG-naloxol, is a new molecular entity and is a 
polyethylene glycolyated (PEGylated) derivative of naloxone. Its 
chemical names are (5[alpha],6[alpha])-17-allyl-6-((20-hydroxy-
3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol or 
alpha-6mPEG7-O-naloxol. Naloxegol is an antagonist predominantly of 
peripheral mu opioid receptors. The Food and Drug Administration (FDA) 
approved naloxegol for marketing on September 16, 2014, under the brand 
name Movantik<SUP>TM</SUP>.\2\ It is indicated for the treatment of 
opioid-induced constipation (OIC) in adults with chronic non-cancer 
pain. Gastrointestinal adverse events (AEs) effects are commonly 
experienced by chronic users of opioid analgesics. Opioids delay 
gastric emptying and intestinal transport, which over time leads to 
debilitating constipation. OIC is caused by activation of the mu opioid 
receptor in the GI tract.
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    \2\ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails (last accessed Sept. 26, 
2014).
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DEA and HHS Eight Factor Analyses

    The DEA received a petition from the drug sponsor dated March 22, 
2012, requesting that the DEA amend 21 CFR 1308.12(b)(1) to exclude 
naloxegol as a schedule II controlled substance. The petitioner stated 
that naloxegol is a mu opioid receptor antagonist without mu opioid 
agonist or partial agonist properties. The DEA accepted the petition 
for filing on October 1, 2012.
    On February 7, 2013 the DEA forwarded to the HHS the data with the 
sponsor's petition along with a request for a scientific and medical 
evaluation and the HHS's recommendation as to whether or not naloxegol 
should be removed from the list of controlled substances. According to 
the HHS, the sponsor submitted a New Drug Application (NDA) for 
naloxegol on September 16, 2013. Based on the NDA, the HHS summarized 
that naloxegol is an antagonist of peripheral opioid receptors for the 
treatment of OIC.
    On August 8, 2014, the HHS provided to the DEA a scientific and 
medical evaluation document prepared by the FDA entitled ``Basis for 
the

[[Page 3469]]

Recommendation to Decontrol Naloxegol and its Salts from Schedule II 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 naloxegol and its salts 
be removed from schedule II of the CSA. In response, the DEA conducted 
its own eight factor analysis of naloxegol pursuant to 21 U.S.C. 
811(c). Both the DEA and HHS analyses are available in their entirety 
in the public docket of this rule (Docket Number DEA-400) at http://www.regulations.gov under ``Supporting and Related Material.''

Determination To Decontrol Naloxegol

    After a review of the available data, including the scientific and 
medical evaluation and the recommendation to decontrol naloxegol from 
HHS, the Deputy Administrator of the DEA published in the Federal 
Register a notice of proposed rulemaking (NPRM) entitled ``Schedules of 
Controlled Substances: Removal of Naloxegol from Control'' which 
proposed removal of naloxegol and its salts from the schedules of the 
CSA. 79 FR 64349, October 29, 2014. The proposed rule provided an 
opportunity for interested persons to file a request for a hearing in 
accordance with DEA regulations by November 28, 2014. 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 November 28, 2014.

Comments Received

    The DEA received seven comments on the proposed rule to decontrol 
naloxegol. Five commenters supported decontrol of naloxegol. Two 
commenters submitted comments not related to the proposed action.

Support

    Commenters in support of decontrolling naloxegol included two 
members of industry, a former intensive care unit (ICU) nurse, and two 
patient advocacy groups, all of whom expressed agreement with the DEA's 
findings that naloxegol does not possess abuse or dependence potential.
    DEA Response: The DEA appreciates the comments in support of this 
rulemaking.

Request for Immediate Effective Date

    Four of the commenters specifically requested that a rule 
decontrolling naloxegol be issued with an immediate effective date. 
Commenters stated that an immediate effective date was warranted 
because naloxegol does not have an abuse potential and is a new 
therapeutic option for opioid-induced constipation with no alternatives 
currently on the market. Additionally, a commenter distinguished this 
particular instance of decontrolling a substance that is not yet 
commercially available and thus would not result in burdens on the 
healthcare system or law enforcement from other DEA actions to control 
a substance which necessitated lead time for registrants to make 
necessary preparations for compliance.
    DEA Response: 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). In accordance with 
21 CFR 1308.45, the DEA finds that the absence of comparative effective 
therapeutic treatments for OIC with similar or less adverse effects 
than naloxegol, coupled with the fact that this is an action for 
decontrol, support the finding that conditions of public health require 
this action to be effective immediately upon publication in the Federal 
Register. Due to adverse side effects, the majority of treatment 
alternatives currently available for OIC have restricted clinical 
application. By comparison, the side effects of naloxegol have been 
shown to be generally mild and reversible. The addition of the 
polyethylene glycol group decreases the capacity of naloxegol from 
crossing the blood-brain barrier as compared to naloxone and is 
therefore expected to limit the potential for interference with 
centrally mediated opioid analgesia.
    In making the determination to make this rule immediately 
effective, the DEA took into consideration the effects of immediate 
implementation. The DEA agrees that making this rule immediately 
effective is in the best interest of the public health and will not 
burden registrants, the healthcare system, or law enforcement. The DEA 
notes that its decision to make this rule immediately effective aligns 
with the exceptions to the 30-day effective date requirement of the 
Administrative Procedure Act (APA). One of the APA's exceptions to the 
30-day effective date is for a substantive rule granting or recognizing 
an exemption or which relieves a restriction. 5 U.S.C. 553(d)(3).

Scheduling Conclusion

    Based on the consideration of all comments, the scientific and 
medical evaluation and accompanying recommendation of the HHS, and 
based on the DEA's consideration of its own eight-factor analysis, the 
Administrator finds that these facts and all relevant data demonstrate 
that naloxegol does not meet the requirements for inclusion in any 
schedule, and will be removed from control under the CSA.

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 (OMB) 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 Federal 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. This 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 (5 U.S.C. 601-612) (RFA), has reviewed this 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 rule is to 
remove naloxegol from the list of schedules of the CSA. This action

[[Page 3470]]

removes regulatory controls and administrative, civil, and criminal 
sanctions applicable to controlled substances for handlers and proposed 
handlers of naloxegol. Accordingly, it has the potential for some 
economic impact in the form of cost savings.
    Naloxegol is a new molecular entity and is not currently available 
or marketed in any country. According to publicly available information 
reviewed by the DEA, naloxegol is anticipated to enjoy patent 
protection for an extended period of time before generic equivalents 
may be manufactured and marketed in the United States. Although the 
number of manufacturers of naloxegol may initially be limited, there is 
potential for numerous handlers in various business activities, e.g., 
distributors, hospitals/clinics, pharmacies, practitioners, etc.
    This rule will affect all persons who would handle, or propose to 
handle, naloxegol. Due to the wide variety of unidentifiable and 
unquantifiable variables that potentially could influence the 
distribution and dispensing rates of new molecular entities, the DEA is 
unable to determine the number of entities and small entities which 
might handle naloxegol. However, the DEA estimates that all persons who 
would handle, or propose to handle, naloxegol are currently registered 
with the DEA to handle schedule II controlled substances. Therefore, 
the 1.5 million (1,469,418 as of September 2014) controlled substance 
registrations, representing approximately 426,714 entities, would be 
the maximum number of entities affected by this rule. The DEA estimates 
that 417,302 (97.8%) of 426,714 affected entities are ``small 
entities'' in accordance with the RFA and Small Business Administration 
size standards.
    The DEA estimates all controlled substances registrants handle both 
controlled and non-controlled substances and these registrants are 
expected to handle naloxegol. Additionally, since prospective naloxegol 
handlers are likely to handle other schedule II controlled substances, 
the cost savings they would receive as a result of the de-control of 
naloxegol would be nominal. As naloxegol handlers are likely to handle 
other schedule II controlled substances, they will need to maintain 
their DEA registration and keep the same security, reporting, and 
recordkeeping processes, equipment, and facilities in place and would 
experience only a nominal reduction in security, reporting, inventory, 
recordkeeping, and labeling costs.
    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 426,714 of which 417,302 are estimated to be small 
entities. Since the affected entities are expected to handle other 
schedule II controlled substances and maintain security, reporting, and 
recordkeeping facilities and processes consistent with schedule II 
controlled substances handling requirements, the DEA estimates any 
economic impact (cost savings) will be nominal. Because of these facts, 
this rule will not result in a significant economic impact on a 
substantial number of small entities.

Unfunded Mandates Reform Act of 1995

    On the basis of information contained in the ``Regulatory 
Flexibility Act'' section above, 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

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act, 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.

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. In Sec.  1308.12, revise the introductory text of paragraph (b)(1) 
to read as follows:


Sec.  1308.12  Schedule II.

* * * * *
    (b) * * *
    (1) Opium and opiate, and any salt, compound, derivative, or 
preparation of opium or opiate excluding apomorphine, thebaine-derived 
butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, 
and naltrexone, and their respective salts, but including the 
following:
* * * * *

    Dated: January 16, 2015.
Michele M. Leonhart,
Administrator.
[FR Doc. 2015-01172 Filed 1-22-15; 8:45 am]
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