[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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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 
[<SUP>35</SUP>S]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 C<INF>max</INF> = 
4320 ng/mL, T <INF>max</INF> = 1.2 hr, half-life = 4.1 hr, and AUC 
<INF>last</INF> = 30,500 hr<bullet>ng/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 GABA<INF>A</INF> 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<INF>50</INF> 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 E<INF>max</INF> of Drug Liking VAS scores of 76.1 
and 82, respectively and these were significantly higher than the 
placebo. The E<INF>max</INF> 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<INF>21</INF>H<INF>26</INF>N<INF>2</INF>O<INF>4</INF> 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<INF>max</INF> 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