[Federal Register Volume 86, Number 73 (Monday, April 19, 2021)]
[Rules and Regulations]
[Pages 20284-20286]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-07884]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-665]


Schedules of Controlled Substances: Removal of Samidorphan 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 Acting Administrator 
of the Drug Enforcement Administration removes samidorphan (3-
carboxamido-4-hydroxy naltrexone) and its salts from the schedules 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. Prior to the effective date of this rule, samidorphan 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 samidorphan.

DATES: Effective April 19, 2021.

FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Drug & Chemical 
Evaluation Section, Diversion Control Division, Drug Enforcement 
Administration; Mailing Address: 8701 Morrissette Drive, Springfield, 
Virginia 22152; Telephone: (571) 362-3261.

SUPPLEMENTARY INFORMATION:

Legal Authority

    Under the Controlled Substances Act (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 part 
1308.
    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 Acting Administrator of 
the Drug Enforcement Administration (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 on the petition of any interested 
party. 21 U.S.C. 811(a)(3). This action was initiated by one petition 
to remove samidorphan 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 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 samidorphan.

Background

    Samidorphan (3-carboxamido-4-hydroxy naltrexone), is a chemical 
entity that is structurally similar to naltrexone, a mu ([micro])-
opioid receptor antagonist. Samidorphan (other developmental code 
names: RDC-0313 or ALKS 33) is a mu-opioid receptor antagonist with a 
weak partial agonist activity at the kappa- and delta-opioid receptors. 
According to HHS, products containing samidorphan are currently being 
developed for medical use. Samidorphan is currently controlled in 
schedule II of the CSA, as defined in 21 CFR 1308.12(b)(l), because it 
can be derived from opium alkaloids. On April 14, 2014, DEA received a 
petition to initiate proceedings to amend 21 CFR 1308.12(b)(1) so as to 
decontrol samidorphan from schedule II of the CSA. The petition 
complied with the requirements of 21 CFR 1308.43(b) and was accepted 
for filing. The petitioner contended that samidorphan has been 
characterized as an opioid receptor

[[Page 20285]]

antagonist, a class of drugs with no abuse potential.

DEA and HHS Eight Factor Analyses

    Pursuant to 21 U.S.C. 811(b), DEA gathered the necessary data on 
samidorphan and forwarded the data, the sponsor's petition, and a 
request for scheduling recommendation on samidorphan to HHS on April 
24, 2015.
    On January 9, 2020, DEA received from HHS a scientific and medical 
evaluation (dated December 19, 2019) conducted by the Food and Drug 
Administration (FDA) \1\ entitled ``Basis for the Recommendation to 
Remove Samidorphan (3-Carboxamido-4-Hydroxy Naltrexone) and its Salts 
from All Schedules of Control Under the Controlled Substances Act'' and 
a scheduling recommendation. Following consideration of the eight 
factors and findings related to the substance's abuse potential, 
legitimate medical use, and dependence liability, HHS recommended that 
samidorphan and its salts be removed from all schedules of control of 
the CSA. In response, DEA conducted its own eight factor analysis of 
samidorphan pursuant to 21 U.S.C. 811(c). Both DEA and HHS analyses are 
available in their entirety in the public docket of this rule (Docket 
Number DEA-665) at http://www.regulations.gov under ``Supporting and 
Related Material.''
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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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Determination To Decontrol Samidorphan

    After a review of the available data, including the scientific and 
medical evaluation and the recommendation to decontrol samidorphan from 
HHS, the Acting Administrator of DEA published in the Federal Register 
a notice of proposed rulemaking (NPRM) entitled ``Schedules of 
Controlled Substances: Removal of Samidorphan from Control'' which 
proposed removal of samidorphan and its salts from the schedules of the 
CSA. 85 FR 79450, December 10, 2020. The proposed rule provided an 
opportunity for interested persons to file a request for a hearing in 
accordance with DEA regulations by January 11, 2021. No requests for 
such a hearing were received by DEA. The NPRM also provided an 
opportunity for interested persons to submit written comments on the 
proposal on or before January 11, 2021.

Comments Received

    DEA received two comments on the proposed rule to remove 
samidorphan from control. Both commenters supported decontrol of 
samidorphan.

Support

    One commenter, a psychiatrist, clinical investigator and pain 
management expert, who participated as a principal investigator in 
clinical trials that examined the safety and efficacy of samidorphan 
and olanzapine combination product, stated that samidorphan counters 
weight gain associated with clinical use of olanzapine as antipsychotic 
medication and this combination product offers significant advancement 
relative to olanzapine alone, and thus supported this scheduling 
action.
    Another commenter, on behalf of the sponsor of a samidorphan and 
olanzapine combination drug product currently under review by FDA for 
marketing approval, stated that samidorphan when combined with 
olanzapine has the potential to improve the safety profile of 
olanzapine by mitigating the weight gain associated with olanzapine 
treatment without altering its antipsychotic efficacy. This commenter 
agreed with DEA's conclusion that samidorphan lacks abuse or dependence 
potential and stated that samidorphan and its salts should be removed 
from the CSA schedules. This commenter further mentioned that the 
samidorphan and olanzapine combination product, which is currently 
under review by FDA for marketing approval, is an important new 
therapeutic option for patients and any delay in its availability for 
therapeutic use would negatively affect stakeholders, and therefore 
this final rule should be made effective immediately.
    DEA Response: DEA appreciates the comments in support of this 
rulemaking.

Scheduling Conclusion

    Based on the consideration of all comments, the scientific and 
medical evaluation and accompanying recommendation of HHS, and based on 
DEA's consideration of its own eight-factor analysis, the Acting 
Administrator finds that these facts and all relevant data demonstrate 
that samidorphan 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 (E.O.) 12866 and the principles reaffirmed 
in E.O. 13563.

Executive Order 12988

    This regulation meets the applicable standards set forth in 
sections 3(a) and 3(b)(2) of E.O. 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 E.O. 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 E.O. 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 Acting 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 samidorphan from the list of schedules of the CSA. 
This action removes regulatory controls and administrative, civil, and 
criminal sanctions applicable to controlled substances for handlers and 
proposed handlers of samidorphan. Accordingly, it has the potential for 
some economic impact in the form of cost savings.
    This rule will affect all persons who would handle, or propose to 
handle,

[[Page 20286]]

samidorphan. Samidorphan is not currently available or marketed in any 
country. Due to the wide variety of unidentifiable and unquantifiable 
variables that potentially could influence the distribution and 
dispensing rates, if any, of samidorphan, DEA is unable to determine 
the number of entities and small entities which might handle 
samidorphan. In some instances where a controlled pharmaceutical drug 
is removed from the schedules of the CSA, DEA is able to quantify the 
estimated number of affected entities and small entities because the 
handling of the drug is expected to be limited to DEA registrants even 
after removal from the schedules. In such instances, DEA's knowledge of 
its registrant population forms the basis for estimating the number of 
affected entities and small entities. However, DEA does not have a 
basis to estimate whether samidorphan is expected to be handled by 
persons who hold DEA registrations, by persons who are not currently 
registered with DEA to handle controlled substances, or both. 
Therefore, DEA is unable to estimate the number of entities and small 
entities who plan to handle samidorphan.
    Although DEA does not have a reliable basis to estimate the number 
of affected entities and quantify the economic impact of this final 
rule, a qualitative analysis indicates that this rule is likely to 
result in some cost savings. Any person planning to handle samidorphan 
will realize cost savings in the form of saved DEA registration fees, 
and the elimination of physical security, recordkeeping, and reporting 
requirements. Because of these factors, DEA projects that this rule 
will not result in a significant economic impact on a substantial 
number of small entities.

Administrative Procedure Act

    DEA finds that good cause exists for adopting this rule as a final 
rule with an immediate effective date under 5 U.S.C. 553(d) because 
this final rule relieves a restriction.

Unfunded Mandates Reform Act of 1995

    On the basis of information contained in the RFA section above, 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 million 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 million 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, DEA is submitting 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), 956(b) unless otherwise 
noted.


0
2. In Sec.  1308.12, revise paragraph (b)(1) introductory text 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, naldemedine, nalmefene, 
naloxegol, naloxone, 6[beta]-naltrexol, naltrexone, and samidorphan, 
and their respective salts, but including the following:
* * * * *

D. Christopher Evans,
Acting Administrator.
[FR Doc. 2021-07884 Filed 4-16-21; 8:45 am]
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