Schedules of Controlled Substances: Removal of Samidorphan From Control
| Published date | 10 December 2020 |
| Citation | 85 FR 79450 |
| Record Number | 2020-26812 |
| Section | Proposed rules |
| Court | Drug Enforcement Administration,Justice Department |
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The Proposed Amendment
In consideration of the foregoing, the
Federal Aviation Administration
proposes to amend 14 CFR part 71 as
follows:
PART 71—DESIGNATION OF CLASS A,
B, C, D, AND E AIRSPACE AREAS; AIR
TRAFFIC SERVICE ROUTES; AND
REPORTING POINTS
■1. The authority citation for part 71
continues to read as follows:
Authority: 49 U.S.C. 106(f), 106(g); 40103,
40113, 40120; E.O. 10854, 24 FR 9565, 3 CFR,
1959–1963 Comp., p. 389.
§ 71.1 [Amended]
■2. The incorporation by reference in
14 CFR 71.1 of FAA Order 7400.11E,
Airspace Designations and Reporting
Points, dated July 21, 2020 and effective
September 15, 2020, is amended as
follows:
Paragraph 2066 United States Area
Navigation Routes.
* * * * *
Q–437 VILLS, NJ to SLANG, VT [New]
VILLS, NJ FIX (Lat. 39°18′03.87″ N, long. 075°06′37.89″ W)
DITCH, NJ FIX (Lat. 39°47′37.86″ N, long. 074°42′59.88″ W)
LUIGI, NJ FIX (Lat. 40°04′09.65″ N, long. 074°26′40.32″ W)
HNNAH, NJ FIX (Lat. 40°28′12.73″ N, long. 074°02′36.62″ W)
LLUND, NY FIX (Lat. 40°51′45.04″ N, long. 073°46′57.30″ W)
BIZEX, NY WP (Lat. 41°17′02.86″ N, long. 073°34′50.20″ W)
BINGS, NY WP (Lat. 42°00′33.26″ N, long. 073°30′01.81″ W)
WARUV, NY FIX (Lat. 42°45′52.14″ N, long. 073°34′41.41″ W)
SLANG, VT WP (Lat. 43°14′24.64″ N, long. 073°11′09.69″ W)
* * * * *
Issued in Washington, DC, on December 2,
2020.
George Gonzalez,
Acting Manager, Rules and Regulations
Group.
[FR Doc. 2020–26947 Filed 12–9–20; 8:45 am]
BILLING CODE 4910–13–P
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.
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
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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.
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).
3
28 CFR 0.100(b).
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.
Background
Samidorphan (3-carboxamido-4-
hydroxy naltrexone), is a chemical
entity that is structurally similar to
naltrexone, a mu (m)-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 (k)- and delta (d)-
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.
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
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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.
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.
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.
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
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.
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
[
35
S]GTPgS 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 mM) 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 mM,
samidorphan significantly decreased
contractility. But, samidorphan at 5 and
50 mM 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 C
max
= 4320 ng/mL, T
max
= 1.2 hr, half-life = 4.1 hr, and AUC
last
= 30,500 hr•ng/mL. In regard to
cardiac activity, the female and male
groups produced a slight decrease in
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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
GABA
A
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 ED
50
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
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This statement and the subsequent content in
this paragraph are based on the revised information
provided under MOU by FDA/Controlled Substance
Staff (CSS).
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.
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 E
max
of Drug Liking
VAS scores of 76.1 and 82, respectively
and these were significantly higher than
the placebo. The E
max
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
C
21
H
26
N
2
O
4
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 T
max
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]GTPgS 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
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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).
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
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
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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
■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.
■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,
naldemedine, nalmefene, naloxegol,
naloxone, 6b-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
DEPARTMENT OF TRANSPORTATION
National Highway Traffic Safety
Administration
49 CFR Part 571
[Docket No. NHTSA–2020–0109]
RIN 2127–AM04
Federal Motor Vehicle Safety
Standards: Test Procedures
AGENCY
: National Highway Traffic
Safety Administration (NHTSA),
Department of Transportation (DOT).
ACTION
: Advance notice of proposed
rulemaking (ANPRM).
SUMMARY
: NHTSA is issuing this
ANPRM to seek public comment on
whether any test procedures for any
Federal Motor Vehicle Safety Standards
(FMVSS) may be a candidate for
replacement, repeal, or modification, for
reasons other than for considerations
relevant only to automated driving
systems (ADS). This document is a
continuation of the Agency’s efforts to
improve the FMVSS and minimize
burdens. The Agency takes this action
in response to its review of the FMVSS
and to public comments solicited by
DOT in a 2017 notice on its regulatory
reform efforts. The commenters
requested that NHTSA amend test
procedures for air brakes and occupant
crash protection. NHTSA has also
identified some possible additional test
procedure issues and discusses them in
this Notice. In addition, this ANPRM
also seeks comments and supporting
information relating to any other test
procedures which may be a candidate
for replacement, repeal or modification,
not just those specifically discussed in
this Notice.
DATES
: Comments must be received no
later than February 8, 2021. See the
Public Participation heading of the
SUPPLEMENTARY INFORMATION
section of
this document for more information
about written comments.
ADDRESSES
: You may submit comments
to the docket number identified in the
heading of this document by any of the
following methods:
•Federal eRulemaking Portal: Go to
http://www.regulations.gov. Follow the
online instructions for submitting
comments.
•Mail: Docket Management Facility:
U.S. Department of Transportation, 1200
New Jersey Avenue SE, West Building
Ground Floor, Room W12–140,
Washington, DC 20590–0001
•Hand Delivery or Courier: 1200
New Jersey Avenue SE, West Building
Ground Floor, Room W12–140, between
9 a.m. and 5 p.m. ET, Monday through
Friday, except Federal holidays.
•Fax: 202–493–2251.
Instructions: For detailed instructions
on submitting comments and additional
information on the rulemaking process,
see the Public Participation heading of
the
SUPPLEMENTARY INFORMATION
section
of this document. Note that all
comments received will be posted
without change to http://
www.regulations.gov, including any
personal information provided. Please
see the ‘‘Privacy Act’’ heading below.
Privacy Act: Anyone is able to search
the electronic form of all comments
received into any docket by the name of
the individual submitting the comment
(or signing the comment, if submitted
on behalf of an association, business,
labor union, etc.). You may review
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