Federal Register, Volume 85 Issue 238 (Thursday, December 10, 2020)

[Federal Register Volume 85, Number 238 (Thursday, December 10, 2020)]
[Proposed Rules]
[Pages 79450-79456]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-26812]

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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: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration (DEA) proposes to remove
samidorphan (3-carboxamido-4-hydroxy naltrexone) 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. Samidorphan is currently a schedule II controlled substance
because it can be derived from opium alkaloids. This action would
remove 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: Interested persons may file written comments on this proposal in
accordance with 21 CFR 1308.43(g). Electronic comments must be
submitted, and written comments must be postmarked, on or before
January 11, 2021. Commenters should be aware that the electronic
Federal Docket Management System will not accept comments after 11:59
p.m. Eastern Time on the last day of the comment period.
Interested persons may file a request for hearing or waiver of
participation pursuant to 21 CFR 1308.44 and in accordance with 21 CFR
1316.45, 1316.47, 1316.48, or 1316.49, as applicable. Requests for
hearing, notices of appearance, and waivers of an opportunity for a
hearing or to participate in a hearing must be received on or before
January 11, 2021.

ADDRESSES: To ensure proper handling of comments, please reference
``Docket No. DEA-665'' on all correspondence, including any
attachments.
Electronic comments: DEA encourages that all comments be
submitted through the Federal eRulemaking Portal, which provides the
ability to type short comments directly into the comment field on the
web page or to attach a file for lengthier comments. Please go to
http://www.regulations.gov and follow the online instructions at that
site for submitting comments. Upon completion of your submission you
will receive a Comment Tracking Number for your comment. Please be
aware that submitted comments are not instantaneously available for
public view on Regulations.gov. If you have received a comment tracking
number, your comment has been successfully submitted and there is no
need to resubmit the same comment.
Paper comments: Paper comments that duplicate an
electronic submission are not necessary and are discouraged. Should you
wish to mail a comment in lieu of an electronic format, it should be
sent via regular or express mail to: Drug Enforcement Administration,
Attention: DEA Federal Register Representative/DPW, 8701 Morrissette
Drive, Springfield, Virginia 22152.
Hearing requests: All requests for hearing and waivers of
participation must be sent to: Drug Enforcement Administration, Attn:
Hearing Clerk/OALJ, 8701 Morrissette Drive, Springfield, Virginia
22152.

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:

Posting of Public Comments

Please note that all comments received in response to this docket
are considered part of the public record. They will, unless reasonable
cause is given, be made available by DEA for public inspection online
at http://www.regulations.gov. Such information includes personal
identifying information (such as your name, address, etc.) voluntarily
submitted by the commenter. The Freedom of Information Act applies to
all comments received. If you want to submit personal identifying
information (such as your name, address, etc.) as part of your comment,
but do not want it to be made publicly available, you must include the
phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph

[[Page 79451]]

of your comment. You must also place the personal identifying
information you do not want made publicly available in the first
paragraph of your comment and identify what information you want
redacted.
If you want to submit confidential business information as part of
your comment, but do not want it to be made publicly available, you
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the
first paragraph of your comment. You must also prominently identify
confidential business information to be redacted within the comment.
Comments containing personal identifying information and
confidential business information identified as directed above will
generally be made publicly available in redacted form. If a comment has
so much confidential business information or personal identifying
information that it cannot be effectively redacted, all or part of that
comment may not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information
(such as name, address, and phone number) included in the text of your
electronic submission that is not identified as directed above as
confidential.
An electronic copy of this document and supplemental information to
this proposed rule are available at http://www.regulations.gov for easy
reference. DEA specifically solicits written comments regarding DEA's
economic analysis of the impact of these proposed changes. DEA requests
that commenters provide detailed descriptions in their comments of any
expected economic impacts, especially to small entities. Commenters
should provide empirical data to illustrate the nature and scope of
such impact.

Request for Hearing, Notice of Appearance at or Waiver of Participation
in Hearing

Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking
``on the record after opportunity for a hearing.'' Such proceedings are
conducted pursuant to the provisions of the Administrative Procedure
Act (5 U.S.C. 551-559). 21 CFR 1308.41-1308.45, and 21 CFR part 1316
subpart D. In accordance with 21 CFR 1308.44 (a)-(c), requests for
hearing, notices of appearance, and waivers of an opportunity for a
hearing or to participate in a hearing may be submitted by interested
persons. Such requests or notices must conform to the requirements of
21 CFR 1308.44(a) or (b), and 1316.47 or 1316.48, as applicable, and
include a statement of the interest of the person in the proceeding and
the objections or issues, if any, concerning which the person desires
to be heard. Any waiver must conform to the requirements of 21 CFR
1308.44(c) and 1316.49, including a written statement regarding the
interested person's position on the matters of fact and law involved in
any hearing.
Please note that, pursuant to 21 U.S.C. 811(a)(2), the purpose of a
hearing would be to determine whether samidorphan should be removed
from the list of controlled substances based on a finding that the drug
does not meet the requirements for inclusion in any schedule. All
requests for hearing and waivers of participation must be sent to DEA
using the address information above, on or before the date specified
above.

Legal Authority

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 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 HHS and an evaluation of all relevant data by DEA. If finalized,
this action would remove 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.
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\1\ As discussed in a memorandum of understanding entered into
by the Food and Drug Administration (FDA) and NIDA, 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, March 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

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 ([kappa])- and delta
([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 antagonist, a class of drugs with no abuse potential.

Proposed Determination To Decontrol Samidorphan

Pursuant to 21 U.S.C. 811(b), on April 24, 2015, DEA, having
gathered the necessary data on samidorphan, forwarded that data and the
petition to HHS \2\ with a request for scientific and medical
evaluation and scheduling recommendation for samidorphan. 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)
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. The National Institute on Drug Abuse (NIDA) concurred
with the scientific and medical evaluation conducted by FDA. Based on
the totality of the available scientific data, samidorphan does not
conform with the findings for schedule II in 21 U.S.C. 812(b)(2) or in
any other schedule as set forth in 21 U.S.C. 812(b). Based on FDA's
scientific and medical review 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.
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\2\ Administrative responsibilities for evaluating a substance
for control under the CSA are performed for HHS by the Food and Drug
Administration (FDA), with the concurrence of NIDA, according to a
Memorandum of Understanding (50 FR 9518; March 8, 1985).
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The CSA requires DEA, as delegated by the Attorney General,\3\ to
determine whether HHS's scientific and medical evaluation, scheduling
recommendation, and all other relevant data constitute substantial
evidence that a substance should be scheduled. 21

[[Page 79452]]

U.S.C. 811(b). DEA reviewed the scientific and medical evaluation and
scheduling recommendation provided by HHS, and all other relevant data,
and completed its own eight-factor review document on samidorphan
pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each
factor as analyzed by HHS and DEA, and as considered by DEA in this
proposal to remove samidorphan from the schedules of the CSA. Please
note that both DEA and HHS analyses are available in their entirety
under ``Supporting and Related Material'' of the public docket for this
rule at http://www.regulations.gov under docket number DEA-665.
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\3\ 28 CFR 0.100(b).
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1. The Drug's Actual or Relative Potential for Abuse.
The first factor that must be considered is the actual or relative
potential for abuse of samidorphan. The term ``abuse'' is not defined
in the CSA. However, the legislative history of the CSA suggests the
following points in determining whether a particular drug or substance
has a potential for abuse: \4\
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\4\ Comprehensive Drug Abuse Prevention and Control Act of 1970,
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N.
4566, 4603.
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a. Whether there is evidence that individuals are taking the drug
or drugs containing such a substance in amounts sufficient to create a
hazard to their health or to the safety of other individuals or to the
community.
As stated by HHS, samidorphan is not readily available or marketed
in any country, so there is a lack of evidence to date regarding
samidorphan diversion, illicit manufacturing, or use outside of
clinical trials. There are no anecdotal reports of samidorphan abuse in
the published literature or in drug abuse discussion platforms (e.g.,
PubMed, erowid.org).
b. Whether there is significant diversion of the drug or drugs
containing such a substance from legitimate drug channels.
According to HHS, there were no reports of diversion of samidorphan
in clinical trials conducted with this substance. DEA further notes
that there are no reports of law enforcement encounters of samidorphan
in the National Forensic Laboratory Information System (NFLIS),\5\ the
System to Retrieve Information from Drug Evidence (STRIDE) \6\ and
STARLiMS \7\ (Queried October 14, 2020). Thus, there is no evidence of
diversion of samidorphan.
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\5\ The NFLIS is a national forensic laboratory reporting system
that systematically collects results from drug chemistry analyses
conducted by State and local forensic laboratories in the United
States.
\6\ STRIDE is a database of drug exhibits sent to DEA
laboratories for analysis. Exhibits from the database are from DEA,
other federal agencies, and some local law enforcement agencies.
\7\ STARLiMS is a laboratory information management system that
systematically collects results from drug chemistry analyses
conducted by DEA laboratories. On October 1, 2014, STARLiMS replaced
STRIDE as the DEA laboratory drug evidence data system of record.
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c. Whether individuals are taking the drug or drugs containing such
a substance on their own initiative rather than on the basis of medical
advice from a practitioner licensed by law to administer such drugs in
the course of his professional practice.
According to HHS, there is no evidence of individuals taking
samidorphan on their own initiative. DEA notes that a review of
scientific literature, STRIDE, STARLiMS, and NFLIS databases revealed
no history of abuse of samidorphan. Thus, there is no evidence that
individuals are taking samidorphan on their own initiative rather than
on the basis of medical advice from a practitioner licensed by law to
administer the same. There are no anecdotal reports of samidorphan
abuse in the published literature or in drug discussion platforms
(e.g., PubMed, erowid.org, bluelight.org).
d. Whether the drug or drugs containing such a substance are new
drugs so related in their action to a substance already listed as
having a potential for abuse to make it likely that it 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 they have a substantial capability of creating hazards to the
health of the user or to the safety of the community.
According to HHS, actions of samidorphan are not related to a
substance already listed as having a potential for abuse. There is no
evidence that individuals are taking samidorphan to create a hazard to
their health or to the safety of other individuals or to the community.
Samidorphan is not currently marketed and there is no evidence of
diversion of samidorphan from legitimate drug channels. There is no
evidence that individuals are taking samidorphan on their own
initiative without medical advice. Samidorphan is not related in its
action to any known substance with abuse liability. Substances such as
naloxone and naltrexone, with pharmacological effects of mu-opioid
receptor antagonists similar to that of samidorphan, have been
decontrolled under the CSA. Thus, these data collectively indicate that
samidorphan has no potential for abuse.
2. Scientific Evidence of the Drug's Pharmacological Effects, If
Known.

Preclinical studies

In Vitro Studies

According to HHS, opioid receptor binding and functional studies
with samidorphan have been conducted in vitro in cloned human opioid
receptors expressed in Chinese hamster ovary (CHO) cells. These studies
showed that samidorphan binds to human mu- and kappa-opioid receptors
with sub-nanomolar Ki values of 0.052 nM and 0.23 nM, respectively.
Samidorphan also binds to the delta-opioid receptors with nanomolar
affinity (Ki of 2.7 nM). These values demonstrate that, like the opioid
receptor antagonist naltrexone, samidorphan has a high affinity for the
mu- and kappa-opioid receptors. A cellular functional study with
[³⁵S]GTP[gamma]S assay in CHO cells further showed that
samidorphan has subnanomolar antagonist activity at the mu-opioid
receptor and is comparable to that of naltrexone.

Safety Pharmacology Studies

According to the HHS' review, several safety studies were conducted
to determine the cardiovascular, respiratory, and neurological effects
of the drug and can help determine if samidorphan has depressant,
stimulant, or other psychoactive effects related to abuse potential.

Cardiovascular and Respiratory Effects

According to HHS, a study evaluating in vitro effects of
samidorphan (0.5, 5, and 50 [micro]M) on the QT-interval, QRS duration,
contractility and maximum rate of contraction was conducted in isolated
retrograde perfused rabbit heart preparation. Results showed that, at
the lowest concentration, 0.5 [micro]M, samidorphan significantly
decreased contractility. But, samidorphan at 5 and 50 [micro]M
concentrations did not significantly affect contractility.
An animal study revealed the cardiovascular and pulmonary effects
of orally administered (per os or PO) samidorphan (0.5, 3, and 10 mg/kg
doses) in beagle dogs. The high doses of samidorphan resulted in
several cases of emesis and excessive salivation. For pharmacokinetic
(PK) measurements, animals were given either a low dose of 0.5 mg/kg or
a high dose of 20 mg/kg of samidorphan. Male dogs given a single PO
dose of samidorphan had average PK measurements of Cmax =
4320 ng/mL, T max = 1.2 hr, half-life = 4.1 hr, and AUC
last = 30,500 hrng/mL. In regard to cardiac
activity, the female and male groups produced a slight decrease in

[[Page 79453]]

systolic blood pressure (an average insignificant decrease of 17 to 26
mm Hg) and no significant differences in cardiac contractility or body
temperature. Based on the results, this investigation reported no
observed adverse effects at the level of 10 mg/kg in beagle dogs. In
the same study, samidorphan at any of the doses tested did not cause
any significant effects on respiratory rate, tidal volume, and minute
volume.
According to HHS' review, samidorphan reversed cardiac and
respiratory effects produced by continuous intravenous infusion (IV) of
fentanyl, a mu-opioid receptor agonist, in beagle dogs and Cynomolgus
monkeys. Overall, samidorphan does not appear to produce mu-opioid
receptor agonist related cardiac or pulmonary effects.

Central Nervous System Effects

According to HHS, central nervous system effects of samidorphan
(3.5, 35, or 350 mg/kg, PO) on functional observational battery in a
study conducted in Sprague-Dawley rats are most consistent with that of
depressants such as opioids, cannabinoids, and GABAA channel
modulators.
Unlike mu-opioid receptor agonists that typically produce analgesic
effects in assays on thermal and inflammatory painful stimulation,
samidorphan produced no measurable analgesic effects. In the hot plate
test in male Sprague-Dawley rats, samidorphan did not produce thermal
analgesia when administered subcutaneously (SC) at doses of 0.003 to
0.1 mg/kg or when administered intraperitoneally at doses in the range
of 0.01 to 30 mg/kg. However, samidorphan blocked morphine-induced (15
mg/kg, SC) analgesia in rats with ED50 values of 0.01 mg/kg
(SC administration) and 0.3 mg/kg (PO administration), respectively.
Its blockade of morphine's analgesic effects lasted for approximately 4
hours. Because morphine is known to produce its analgesic effects as an
agonist of the mu-opioid receptor, this study suggests that samidorphan
blocks this mechanism of action similar to other mu-opioid receptor
antagonists, such as naloxone and naltrexone, which also possess this
blockade effect.
In a tail-flick assay used to measure thermal-nociception, the
result showed that administered subcutaneously samidorphan did not
produce analgesia up to the highest dose tested of 10 mg/kg.
Furthermore, samidorphan antagonized morphineinduced anti-nociception
when administered either SC or PO. These data indicate that samidorphan
acts as an antagonist at the mu-opioid receptor because it blocked the
analgesic effects of the mu-opioid receptor agonist morphine without
producing analgesic effects of its own.

Abuse Liability Studies

Effects on Ethanol Self-Administration

According to HHS, a self-administration study in male Wistar rats
was conducted to determine if samidorphan has effects similar to that
of other opioid receptor antagonists such as naltrexone in reducing
ethanol drinking behavior. Rats were trained to self-administer ethanol
on a fixed ratio (FR) 2 schedule of reinforcement. Effects of
samidorphan (0 to 3 mg/kg, SC) administered 30 minutes prior to the
placement of the rats into the test cages on ethanol drinking behavior
were studied. Naltrexone, the positive control drug (3 or 6 mg/kg, SC),
was only able to decrease lever responding by approximately 75 percent.
The highest dose of samidorphan (3 mg/kg, SC) decreased lever
responding by approximately 50 percent. According to HHS, these data
demonstrate that pretreatment with samidorphan can decrease, but not
eliminate, the reinforcing effects of 10 percent ethanol and these
results are consistent with that of other mu-opioid receptor
antagonists such as naltrexone, which is indicated for the treatment of
alcohol dependence.

Drug Discrimination Studies

Drug discrimination assays in animals can be used to predict if a
test drug will have abuse potential in humans. According to HHS, a drug
discrimination study was conducted to test the stimulus effects of
samidorphan in rats trained to discriminate the stimulus effects of
subcutaneously administered morphine (3 mg/kg) to its vehicle (0.9
percent sodium chloride for injection, USP) in a two-lever operant
chamber on a FR10 schedule of reinforcement. Samidorphan (0.1, 0.3, 1
or 3 mg/kg) did not generalize to the morphine cue. Samidorphan did not
affect lever press response rates indicating that the rats were not
incapacitated by the drug. These data indicate that samidorphan does
not produce a discriminative cue similar to that of morphine (at 3 mg/
kg).

Self-Administration Studies

HHS cited two self-administration studies assessing the reinforcing
effects of samidorphan in rats. In the first study, rats were trained
to lever press on a FR5 schedule for intravenous self-administration of
morphine (0.56 mg/kg/injection). When samidorphan was tested at 0.0136,
0.0408, and 0.068 mg/kg/injection, the animals did not respond at
levels seen with the positive control, morphine. Therefore, it was
concluded that samidorphan did not produce reinforcing effects similar
to that of morphine in rats. However, the total number of infusions of
samidorphan was statistically higher than the vehicle. According to
HHS, this could have been the result of the inadequate extinction due
to the reintroduction of the training drug between doses of
samidorphan; this could have artificially inflated the responding of
samidorphan because animals never fully underwent extinction. As a
result, a second self-administration study with heroin as the training
drug using FR5 and a progressive schedule of reinforcement was
conducted. There was no reintroduction of the training drug between
doses of samidorphan with an additional referred arm of naltrexone. The
result showed that the number of samidorphan (0.068 mg/kg/injection)
injections, similar to naltrexone, was significantly higher than the
number of saline injections, but was significantly lower than that of
heroin. A progressive ratio schedule of reinforcement is used to
determine the reinforcing efficacy of a drug by measuring the break
point. A breakpoint is defined as the number of operant responses
(lever presses) at which the subject ceases self-administration of the
reinforcer. Results of the study using the PR schedule of reinforcement
were similar to that of the FR5 study: All doses of samidorphan tested
produced breakpoints that were significantly lower than heroin and only
the highest dose of samidorphan (0.068 mg/kg/injection) was
significantly higher than saline. Importantly, naltrexone, tested at
the same doses as samidorphan, produced results similar to that of
samidorphan. According to HHS, these studies suggest that samidorphan
has a profile similar to that of naltrexone and does not produce
statistically significant reinforcing effects.

Intra-Cranial Self-Stimulation Study

Intracranial self-stimulation (ICSS) is a behavioral study that can
be used to evaluate brain rewarding or aversive effects of drugs. HHS
provided an ICSS study report of samidorphan in rats. Following
implantation with permanent indwelling electrodes in the right medial
forebrain at the level of the lateral hypothalamus, the animals were
trained to respond (i.e., lever press) to

[[Page 79454]]

receive brain stimulation.\8\ Baseline ICSS training generated a
frequency response curve where increasing the intensity of brain
stimulation increased the rate of lever pressing. After baseline ICSS
levels were established, rats were administered several doses of
samidorphan. The subcutaneous administration of samidorphan at doses of
0.03, 0.1, 0.3, and 1.0 mg/kg did not shift the frequency response
curve relative to baseline and did not change the maximum rate of
responding. This study indicates that samidorphan does not affect the
brain reward pathway in rats.
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\8\ This statement and the subsequent content in this paragraph
are based on the revised information provided under MOU by FDA/
Controlled Substance Staff (CSS).
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Clinical Abuse Liability Studies

The HHS review describes two studies to assess the abuse potential
of samidorphan in human subjects. The first one, a randomized, double-
blind, placebo and positive control, crossover study was to compare
samidorphan (2.5, 10, and 20 mg, PO), oxycodone (15 and 30 mg, PO), and
the placebo in 41 non-dependent recreational opioid users. The primary
pharmacodynamic (PD) assessment was At the Moment Drug Liking measured
by a visual analog scale (VAS), with secondary endpoints that measured
Overall Drug Liking, Take Drug Again, and Alertness, all on a bipolar
VAS. High, Good Effects and Bad Effects were measured on a unipolar
VAS. Oxycodone at 30 and 15 mg doses produced mean Drug Liking scores
of 81 and 73.3, respectively and these scores were significantly higher
than the placebo. All three doses of samidorphan produced At the Moment
Drug Liking, Overall Drug Liking, and Take Drug Again scores that were
not significantly different from the placebo (50 to 51). There was one
report (2.1 percent) of euphoria as an adverse event (AE) after taking
samidorphan (20 mg) versus 11 reports (22.4 percent) following the
positive control oxycodone dose (30 mg). This study concluded that
samidorphan does not produce PD measurements that are consistent with
abuse potential.
A second abuse potential study was conducted by using a placebo
(PO), samidorphan (10 and 30 mg, PO), oxycodone (40 mg, PO),
pentazocine (30 mg, IV), and naltrexone (100 mg, IV) in 42 healthy non-
dependent recreational opioid users. The primary PD assessment was At
the Moment Drug Liking measured by the bipolar VAS, with secondary
endpoints that measured Overall Drug Liking, Take Drug Again, and
Alertness. The study also took PK measurements to determine a
correlation between blood levels and time of onset of the PD
assessment. The positive controls, oxycodone (40 mg) and pentazocine
(30 mg), produced the Emax of Drug Liking VAS scores of 76.1
and 82, respectively and these were significantly higher than the
placebo. The Emax drug liking scores following 10 and 30 mg
samidorphan were not significantly different from the placebo or
naltrexone (100 mg). Euphoric mood was indicated as an AE in 30
subjects (53.6 percent) for oxycodone and in 30 subjects (52.6 percent)
for pentazocine. The 30 and 10 mg doses of samidorphan produced a
euphoric mood as an AE in 9 (15 percent) and 7 (12.3 percent) subjects,
respectively; however, 5 subjects (8.6 percent) reported euphoria when
receiving naltrexone, and 5 subjects (8.8 percent) reported euphoria
when receiving the placebo. There were no reports of abuse of the drug
or diversion in the study. HHS concludes that samidorphan produces
stimulus effects similar to the placebo and naltrexone and does not
have abuse potential. DEA notes that a recent peer-reviewed published
clinical report describes that samidorphan, similar to a placebo and
naltrexone, lacks abuse potential.
In summary, data from in vitro studies showed that samidorphan is a
mu-opioid receptor antagonist with weak partial agonist activity at the
kappa- and delta-opioid receptors. Data from in vivo studies further
supported this conclusion; samidorphan blocked the analgesic effects of
the mu-opioid receptor agonist morphine and the respiratory depressive
effects of fentanyl. Samidorphan neither produced a discriminative cue
similar to that of morphine nor had reinforcing effects in in vivo
abuse liability studies in animals. Data from two clinical abuse
potential studies suggested that samidorphan does not produce drug
liking scores similar to oxycodone (a mu-opioid receptor agonist) or
pentazocine (a kappa-opioid receptor agonist); instead, drug liking
scores produced by samidorphan were similar to the negative controls,
placebo and naltrexone. Overall, these data support the conclusion that
samidorphan does not have abuse liability.
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance.
Samidorphan's molecular formula is
C21H26N2O4 with a molecular
weight of 370.44 g/mol. Currently, there are two salt forms, a
hydrochloric acid salt (RDC-0313-01; molecular weight is 406.90 g/mol)
and a malic acid salt (RDC-0313-02; molecular weight is 504.53 g/mol).
Samidorphan is a derivative of naltrexone and it shares structural
similarity with naltrexone. A multi-step process of samidorphan
synthesis starts with naltrexone, with an end product of its malate
salt.
According to HHS, samidorphan is rapidly absorbed both orally and
sublingually. The Tmax is approximately 60 minutes after
orally dosing, with a half-life of six to eight hours depending on the
dose. The plasma levels of samidorphan increase linearly with each dose
and it rapidly distributes throughout the body. Samidorphan is
metabolized into two main products, RDC-9986 (N-dealkylated metabolite)
and RDC-1066 (N-oxide metabolite), and they can be detected in human
plasma at greater than 10 percent of the total drug-related exposure.
Both RDC-9986 and RDC-1066 have nanomolar affinity for the mu-, kappa-,
and delta-opioid receptors. RDC-9986 is an agonist at all three opioid
receptors whereas RDC-1066 showed antagonist activity at the mu-opioid
receptor as assessed by the [\35\S]GTP[gamma]S functional assay. DEA
further notes that samidorphan has been reported to have high
bioavailability following both sublingual and oral administration, it
is not subject to extensive first-pass metabolism, and the PK
parameters are not affected by food or age in health volunteers.
In summary, samidorphan shares chemical structural features with
mu-opioid antagonists such as naltrexone. It is synthesized from the
non-controlled substance naltrexone. Samidorphan exhibits high oral
bioavailability and is rapidly absorbed. Clinical studies suggest that
samidorphan was generally well-tolerated following single and multiple
doses. RDC-9986 and RDC-1066, the two main metabolites of samidorphan,
though they bind to opioid receptors, do not contribute significantly
to pharmacodynamics of samidorphan.
4. Its History and Current Pattern of Abuse.
According to HHS, samidorphan has not been marketed in any country
and thus information about the history and current pattern of its abuse
is not available. Preclinical and clinical studies evaluating abuse
potential of samidorphan did not show any abuse-related signals (see
Factor 1 and 2, DEA and HHS Eight Factor Analyses). Instead,
samidorphan showed effects similar to those of mu-opioid antagonists, a
class of drugs not known to have abuse potential. The opioid
antagonists, naloxone and naltrexone, were both originally schedule II

[[Page 79455]]

substances as ``opiate derivatives,'' and both are synthesized from
thebaine. However, because they lacked opioid agonist activity, these
were decontrolled in 1974 (naloxone), and in 1975 (naltrexone). More
recently, the opioid antagonist naloxegol, a FDA-approved drug for the
treatment of opioid induced constipation, was decontrolled in 2015. In
addition, as mentioned earlier (see Factor 1, DEA and HHS Eight Factor
Analyses), NFLIS, STRIDE, and STARLiMS had no mentions of samidorphan.
5. The Scope, Duration, and Significance of Abuse.
As stated by HHS, information about the scope, duration, and
significance of samidorphan abuse is not available because it has not
been marketed in any country. As mentioned in Factor 4 (DEA and HHS
Eight Factor Analyses), a comprehensive review and research on
available databases performed by both HHS and DEA revealed no reports
of abuse of samidorphan. Data from preclinical and clinical studies
showed no evidence of abuse potential for samidorphan. As stated by
HHS, samidorphan upon its approval and availability for marketing is
unlikely to be abused.
6. What, if any, Risk There is to the Public Health.
Based on the data and scientific information of preclinical and
clinical study data reviewed by both HHS and DEA, there are no signals
that indicate that samidorphan has abuse potential (see Factor 1 and 2,
DEA and HHS Eight Factor Analyses). Currently, there is no evidence of
drug dependence, abuse, and diversion. Thus, there is likely to be
little or no risk of abuse and public health risk from samidorphan if
it becomes available on the market.
7. Its Psychic or Physiological Dependence Liability.
According to HHS, several long-term toxicology studies were
conducted using samidorphan in rats and dogs lasting 13, 26, or 39
weeks at doses of 250, 50, and 10 mg/kg/day. The animals were
continually monitored after the study for withdrawal signs, such as
weight changes, food consumption, morbidity, mortality, and locomotion
effects. These studies did not find any behaviors or physical
manifestations that were different from the control groups, indicating
that samidorphan lacks potential to produce physical dependence. Data
from these clinical studies showed no signals related to withdrawal or
physical dependence.
The lack of samidorphan's ability to function as a positive
reinforcer in self-administration studies in animals suggests that the
use of samidorphan will not lead to psychological dependence. Similar
to naltrexone (see Factor 2, DEA and HHS Eight Factor Analyses),
samidorphan would not be expected to produce psychological dependence,
and no evidence of psychological dependence was observed in clinical
studies.
8. Whether the Substance is an Immediate Precursor of a Substance
Already Controlled Under the CSA.
Samidorphan is not considered an immediate precursor of any
controlled substance listed under the CSA as defined by 21 U.S.C.
802(23).

Conclusion

Based on consideration of the scientific and medical evaluation and
accompanying recommendation of HHS, and based on DEA's consideration of
its own eight-factor analysis, DEA finds that these facts and all
relevant data demonstrate that samidorphan does not possess abuse or
dependence potential. According to HHS, medical product formulations
containing samidorphan are under development. However, the finding that
samidorphan lacks abuse potential would, irrespective of other
findings, permit decontrol of samidorphan prior to or in the absence of
an FDA action under 21 U.S.C. 355(c). Therapeutic and supratherapeutic
doses of samidorphan did not produce physical or psychological
dependence both in non-clinical (in rats and dogs) and in clinical
studies. Accordingly, DEA finds that samidorphan does not meet the
requirements for inclusion in any schedule, and should be removed from
control under the CSA.

Regulatory Analyses

Executive Orders 12866, 13563, and 13771, Regulatory Planning and
Review, Improving Regulation and Regulatory Review, and Reducing
Regulation and Controlling Regulatory Costs

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
removing a drug or other substance from the list of controlled
substances. Such actions are exempt from review by 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.
This final rule is not an E.O. 13771 regulatory action pursuant to
E.O. 12866 and OMB guidance.\9\
---------------------------------------------------------------------------

\9\ Office of Mgmt. & Budget, Exec. Office of The President,
Interim Guidance Implementing Section 2 of the Executive Order of
January 30, 2017 Titled ``Reducing Regulation and Controlling
Regulatory Costs'' (Feb. 2, 2017).
---------------------------------------------------------------------------

Executive Order 12988, Civil Justice Reform

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, Federalism

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, Consultation and Coordination With Indian Tribal
Governments

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 (RFA) (5 U.S.C. 601-612), has reviewed this proposed
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 will remove 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.
If finalized, the proposed rule will affect all persons who would
handle, or propose to handle samidorphan. Samidorphan is not currently
available or marketed in any country. Due to the wide variety of
unidentifiable and unquantifiable variables that potentially

[[Page 79456]]

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. As noted above, DEA is specifically
soliciting comments on the economic impact of this proposed rule. DEA
will revise this section if warranted after consideration of any
comments received. 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.

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 $100,000,000 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.

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 proposed to be
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 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, naldemedine, nalmefene,
naloxegol, naloxone, 6[beta]-naltrexol, naltrexone, and samidorphan,
and their respective salts, but including the following:
* * * * *

Timothy J. Shea,
Acting Administrator.
[FR Doc. 2020-26812 Filed 12-9-20; 8:45 am]
BILLING CODE 4410-09-P