3468 Federal Register / Vol. 80, No. 15 / Friday, January 23, 2015 / Rules and Regulations 

1As 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. 

2http://www.accessdata.fda.gov/scripts/cder/

drugsatfda/

index.cfm?fuseaction=Search.DrugDetails (last 

accessed Sept. 26, 2014). 

with the sulfur content limits of ASTM 

C1396–14a and must be accompanied 

by a general certification of compliance 

(GCC). 

Alberta E. Mills, 

Acting Secretary, Consumer Product Safety 

Commission. 

[FR Doc. 2015–01051 Filed 1–22–15; 8:45 am] 

BILLING CODE 6355–01–P 

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. 

SUMMARY: With the issuance of this final 

rule, the Administrator of the Drug 

Enforcement Administration removes 

naloxegol ((5a,6a)-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. 

Background 

Naloxegol, or PEG-naloxol, is a new 

molecular entity and is a polyethylene 

glycolyated (PEGylated) derivative of 

naloxone. Its chemical names are 

(5a,6a)-17-allyl-6-((20-hydroxy3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)- 

4,5-epoxymorphinon-3,14-diol or alpha6mPEG7-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 

MovantikTM.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. 

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 


emcdonald on DSK67QTVN1PROD with RULES
Federal Register / Vol. 80, No. 15 / Friday, January 23, 2015 / Rules and Regulations 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 


emcdonald on DSK67QTVN1PROD with RULES
3470 Federal Register / Vol. 80, No. 15 / Friday, January 23, 2015 / Rules and Regulations 

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 foreignbased 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 

■ 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. 

■ 2. In § 1308.12, revise the introductory 

text of paragraph (b)(1) to read as 

follows: 

§ 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] 

BILLING CODE 4410–09–P 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 5 

[Docket No. USCG–1999–6712] 

RIN 1625–AB66 

Revision of Auxiliary Regulations 

AGENCY: Coast Guard, DHS. 

ACTION: Final rule. 

SUMMARY: The Coast Guard is amending 

and reorganizing the regulations that 

govern the operation and administration 

of the Coast Guard Auxiliary, a 

uniformed, volunteer, non-military 

organization chartered by Congress. The 

amendments conform the regulatory 

language to changes in the laws 

governing the Coast Guard Auxiliary; 

clarify the Auxiliary’s organization, 

status, and role in Coast Guard 


emcdonald on DSK67QTVN1PROD with RULES