79450 Federal Register / Vol. 85, No. 238 / Thursday, December 10, 2020 / Proposed Rules

The Proposed Amendment PART 71—DESIGNATION OF CLASS A, § 71.1 [Amended] B, C, D, AND E AIRSPACE AREAS; AIR ■ 2. The incorporation by reference in In consideration of the foregoing, the TRAFFIC SERVICE ROUTES; AND 14 CFR 71.1 of FAA Order 7400.11E, Federal Aviation Administration REPORTING POINTS Airspace Designations and Reporting proposes to amend 14 CFR part 71 as Points, dated July 21, 2020 and effective follows: ■ 1. The authority citation for part 71 September 15, 2020, is amended as continues to read as follows: follows: Authority: 49 U.S.C. 106(f), 106(g); 40103, Paragraph 2066 United States Area 40113, 40120; E.O. 10854, 24 FR 9565, 3 CFR, Navigation Routes. 1959–1963 Comp., p. 389. * * * * *

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)

* * * * * analysis) or propose to handle submitted and there is no need to Issued in Washington, DC, on December 2, samidorphan. resubmit the same comment. • Paper comments: Paper comments 2020. DATES: Interested persons may file George Gonzalez, that duplicate an electronic submission written comments on this proposal in are not necessary and are discouraged. Acting Manager, Rules and Regulations accordance with 21 CFR 1308.43(g). Group. Should you wish to mail a comment in Electronic comments must be lieu of an electronic format, it should be [FR Doc. 2020–26947 Filed 12–9–20; 8:45 am] submitted, and written comments must sent via regular or express mail to: Drug BILLING CODE 4910–13–P be postmarked, on or before January 11, Enforcement Administration, Attention: 2021. Commenters should be aware that DEA Federal Register Representative/ the electronic Federal Docket DPW, 8701 Morrissette Drive, Management System will not accept DEPARTMENT OF JUSTICE Springfield, Virginia 22152. comments after 11:59 p.m. Eastern Time • Hearing requests: All requests for Drug Enforcement Administration on the last day of the comment period. hearing and waivers of participation Interested persons may file a request must be sent to: Drug Enforcement 21 CFR Part 1308 for hearing or waiver of participation Administration, Attn: Hearing Clerk/ pursuant to 21 CFR 1308.44 and in OALJ, 8701 Morrissette Drive, [Docket No. DEA–665] accordance with 21 CFR 1316.45, Springfield, Virginia 22152. 1316.47, 1316.48, or 1316.49, as FOR FURTHER INFORMATION CONTACT: Schedules of Controlled Substances: applicable. Requests for hearing, notices Removal of Samidorphan From Control Terrence L. Boos, Drug & Chemical of appearance, and waivers of an Evaluation Section, Diversion Control opportunity for a hearing or to AGENCY: Drug Enforcement Division, Drug Enforcement participate in a hearing must be Administration, Department of Justice. Administration; Mailing Address: 8701 received on or before January 11, 2021. ACTION: Notice of proposed rulemaking. Morrissette Drive, Springfield, Virginia ADDRESSES: To ensure proper handling 22152; Telephone: (571) 362–3261. SUMMARY: The Drug Enforcement of comments, please reference ‘‘Docket SUPPLEMENTARY INFORMATION: Administration (DEA) proposes to No. DEA–665’’ on all correspondence, remove samidorphan (3-carboxamido-4- including any attachments. Posting of Public Comments hydroxy ) and its salts from • Electronic comments: DEA Please note that all comments the schedules of the Controlled encourages that all comments be received in response to this docket are Substances Act (CSA). This scheduling submitted through the Federal considered part of the public record. action is pursuant to the CSA which eRulemaking Portal, which provides the They will, unless reasonable cause is requires that such actions be made on ability to type short comments directly given, be made available by DEA for the record after opportunity for a into the comment field on the web page public inspection online at http:// hearing through formal rulemaking. or to attach a file for lengthier www.regulations.gov. Such information Samidorphan is currently a schedule II comments. Please go to http:// includes personal identifying controlled substance because it can be www.regulations.gov and follow the information (such as your name, derived from alkaloids. This online instructions at that site for address, etc.) voluntarily submitted by action would remove the regulatory submitting comments. Upon completion the commenter. The Freedom of controls and administrative, civil, and of your submission you will receive a Information Act applies to all comments criminal sanctions applicable to Comment Tracking Number for your received. If you want to submit personal controlled substances, including those comment. Please be aware that identifying information (such as your specific to schedule II controlled submitted comments are not name, address, etc.) as part of your substances, on persons who handle instantaneously available for public comment, but do not want it to be made (manufacture, distribute, reverse view on Regulations.gov. If you have publicly available, you must include the distribute, dispense, conduct research, received a comment tracking number, phrase ‘‘PERSONAL IDENTIFYING import, export, or conduct chemical your comment has been successfully INFORMATION’’ in the first paragraph

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of your comment. You must also place the interest of the person in the products containing samidorphan are the personal identifying information proceeding and the objections or issues, currently being developed for medical you do not want made publicly if any, concerning which the person use. available in the first paragraph of your desires to be heard. Any waiver must Samidorphan is currently controlled comment and identify what information conform to the requirements of 21 CFR in Schedule II of the CSA, as defined in you want redacted. 1308.44(c) and 1316.49, including a 21 CFR 1308.12(b)(l), because it can be If you want to submit confidential written statement regarding the derived from opium alkaloids. On April business information as part of your interested person’s position on the 14, 2014, DEA received a petition to comment, but do not want it to be made matters of fact and law involved in any initiate proceedings to amend 21 CFR publicly available, you must include the hearing. 1308.12(b)(1) so as to decontrol phrase ‘‘CONFIDENTIAL BUSINESS Please note that, pursuant to 21 U.S.C. samidorphan from schedule II of the INFORMATION’’ in the first paragraph 811(a)(2), the purpose of a hearing CSA. The petition complied with the of your comment. You must also would be to determine whether requirements of 21 CFR 1308.43(b) and prominently identify confidential samidorphan should be removed from was accepted for filing. The petitioner business information to be redacted the list of controlled substances based contended that samidorphan has been within the comment. on a finding that the drug does not meet characterized as an receptor Comments containing personal the requirements for inclusion in any antagonist, a class of drugs with no identifying information and confidential schedule. All requests for hearing and abuse potential. business information identified as waivers of participation must be sent to Proposed Determination To Decontrol directed above will generally be made DEA using the address information Samidorphan publicly available in redacted form. If a above, on or before the date specified comment has so much confidential above. Pursuant to 21 U.S.C. 811(b), on April business information or personal 24, 2015, DEA, having gathered the identifying information that it cannot be Legal Authority necessary data on samidorphan, effectively redacted, all or part of that The CSA provides that proceedings forwarded that data and the petition to comment may not be made publicly for the issuance, amendment, or repeal HHS 2 with a request for scientific and available. Comments posted to http:// of the scheduling of any drug or other medical evaluation and scheduling www.regulations.gov may include any substance may be initiated by the recommendation for samidorphan. On personal identifying information (such Attorney General (1) on his own motion, January 9, 2020, DEA received from as name, address, and phone number) (2) at the request of the Secretary of the HHS a scientific and medical evaluation included in the text of your electronic Department of Health and Human (dated December 19, 2019) conducted submission that is not identified as Services (HHS),1 or (3) on the petition by the Food and Drug Administration directed above as confidential. of any interested party. 21 U.S.C. 811(a). (FDA) entitled ‘‘Basis for the An electronic copy of this document This action was initiated by a petition Recommendation to Remove and supplemental information to this to remove samidorphan from the list of Samidorphan (3-Carboxamido-4- proposed rule are available at http:// scheduled controlled substances of the Hydroxy Naltrexone) and its Salts from www.regulations.gov for easy reference. CSA, and is supported by, inter alia, a All Schedules of Control Under the DEA specifically solicits written recommendation from the Assistant Controlled Substances Act’’ and a comments regarding DEA’s economic Secretary of HHS and an evaluation of scheduling recommendation. The analysis of the impact of these proposed all relevant data by DEA. If finalized, National Institute on Drug Abuse changes. DEA requests that commenters this action would remove the regulatory (NIDA) concurred with the scientific provide detailed descriptions in their controls and administrative, civil, and and medical evaluation conducted by comments of any expected economic criminal sanctions applicable to FDA. Based on the totality of the impacts, especially to small entities. controlled substances, including those available scientific data, samidorphan Commenters should provide empirical specific to schedule II controlled does not conform with the findings for data to illustrate the nature and scope of substances, on persons who handle or schedule II in 21 U.S.C. 812(b)(2) or in such impact. propose to handle samidorphan. any other schedule as set forth in 21 U.S.C. 812(b). Based on FDA’s scientific Request for Hearing, Notice of Background and medical review of the eight factors Appearance at or Waiver of Samidorphan (3-carboxamido-4- Participation in Hearing and findings related to the substance’s hydroxy naltrexone), is a chemical abuse potential, legitimate medical use, Pursuant to 21 U.S.C. 811(a), this entity that is structurally similar to and dependence liability, HHS action is a formal rulemaking ‘‘on the naltrexone, a mu (m)- recommended that samidorphan and its record after opportunity for a hearing.’’ antagonist. Samidorphan (other salts be removed from all schedules of Such proceedings are conducted developmental code names: RDC–0313 control of the CSA. pursuant to the provisions of the or ALKS 33) is a mu-opioid receptor The CSA requires DEA, as delegated Administrative Procedure Act (5 U.S.C. antagonist with a weak by the Attorney General,3 to determine 551–559). 21 CFR 1308.41–1308.45, and activity at the kappa (k)- and delta (d)- whether HHS’s scientific and medical 21 CFR part 1316 subpart D. In opioid receptors. According to HHS, evaluation, scheduling accordance with 21 CFR 1308.44 (a)–(c), recommendation, and all other relevant requests for hearing, notices of 1 As discussed in a memorandum of data constitute substantial evidence that appearance, and waivers of an understanding entered into by the Food and Drug a substance should be scheduled. 21 Administration (FDA) and NIDA, FDA acts as the opportunity for a hearing or to lead agency within the HHS in carrying out the participate in a hearing may be Secretary’s scheduling responsibilities under the 2 Administrative responsibilities for evaluating a submitted by interested persons. Such CSA, with the concurrence of NIDA. 50 FR 9518, substance for control under the CSA are performed requests or notices must conform to the March 8, 1985. The Secretary of the HHS has for HHS by the Food and Drug Administration delegated to the Assistant Secretary for Health of (FDA), with the concurrence of NIDA, according to requirements of 21 CFR 1308.44(a) or the HHS the authority to make domestic drug a Memorandum of Understanding (50 FR 9518; (b), and 1316.47 or 1316.48, as scheduling recommendations. 58 FR 35460, July 1, March 8, 1985). applicable, and include a statement of 1993. 3 28 CFR 0.100(b).

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U.S.C. 811(b). DEA reviewed the STARLiMS 7 (Queried October 14, 2. Scientific Evidence of the Drug’s scientific and medical evaluation and 2020). Thus, there is no evidence of Pharmacological Effects, If Known. scheduling recommendation provided diversion of samidorphan. Preclinical studies by HHS, and all other relevant data, and c. Whether individuals are taking the completed its own eight-factor review drug or drugs containing such a In Vitro Studies substance on their own initiative rather document on samidorphan pursuant to According to HHS, opioid receptor than on the basis of medical advice 21 U.S.C. 811(c). Included below is a binding and functional studies with from a practitioner licensed by law to brief summary of each factor as samidorphan have been conducted in administer such drugs in the course of analyzed by HHS and DEA, and as vitro in cloned human opioid receptors considered by DEA in this proposal to his professional practice. According to HHS, there is no expressed in Chinese hamster ovary remove samidorphan from the (CHO) cells. These studies showed that schedules of the CSA. Please note that evidence of individuals taking samidorphan on their own initiative. samidorphan binds to human mu- and both DEA and HHS analyses are kappa-opioid receptors with sub- available in their entirety under DEA notes that a review of scientific literature, STRIDE, STARLiMS, and nanomolar Ki values of 0.052 nM and ‘‘Supporting and Related Material’’ of 0.23 nM, respectively. Samidorphan the public docket for this rule at http:// NFLIS databases revealed no history of abuse of samidorphan. Thus, there is no also binds to the delta-opioid receptors www.regulations.gov under docket with nanomolar affinity (Ki of 2.7 nM). number DEA–665. evidence that individuals are taking samidorphan on their own initiative These values demonstrate that, like the 1. The Drug’s Actual or Relative opioid naltrexone, Potential for Abuse. rather than on the basis of medical advice from a practitioner licensed by samidorphan has a high affinity for the The first factor that must be mu- and kappa-opioid receptors. A considered is the actual or relative law to administer the same. There are no anecdotal reports of samidorphan cellular functional study with potential for abuse of samidorphan. The [35S]GTPgS assay in CHO cells further term ‘‘abuse’’ is not defined in the CSA. abuse in the published literature or in drug discussion platforms (e.g., showed that samidorphan has However, the legislative history of the subnanomolar antagonist activity at the CSA suggests the following points in PubMed, erowid.org, bluelight.org). d. Whether the drug or drugs mu-opioid receptor and is comparable determining whether a particular drug containing such a substance are new to that of naltrexone. or substance has a potential for abuse: 4 drugs so related in their action to a a. Whether there is evidence that Safety Pharmacology Studies substance already listed as having a individuals are taking the drug or drugs potential for abuse to make it likely that According to the HHS’ review, several containing such a substance in amounts it will have the same potentiality for safety studies were conducted to sufficient to create a hazard to their abuse as such drugs, thus making it determine the cardiovascular, health or to the safety of other reasonable to assume that there may be respiratory, and neurological effects of individuals or to the community. significant diversions from legitimate the drug and can help determine if As stated by HHS, samidorphan is not channels, significant use contrary to or samidorphan has depressant, stimulant, readily available or marketed in any without medical advice, or that they or other psychoactive effects related to country, so there is a lack of evidence have a substantial capability of creating abuse potential. to date regarding samidorphan hazards to the health of the user or to Cardiovascular and Respiratory Effects diversion, illicit manufacturing, or use the safety of the community. outside of clinical trials. There are no According to HHS, actions of According to HHS, a study evaluating anecdotal reports of samidorphan abuse samidorphan are not related to a in vitro effects of samidorphan (0.5, 5, in the published literature or in drug substance already listed as having a and 50 mM) on the QT-interval, QRS abuse discussion platforms (e.g., potential for abuse. There is no evidence duration, contractility and maximum PubMed, erowid.org). that individuals are taking samidorphan rate of contraction was conducted in b. Whether there is significant to create a hazard to their health or to isolated retrograde perfused rabbit heart diversion of the drug or drugs the safety of other individuals or to the preparation. Results showed that, at the containing such a substance from community. Samidorphan is not lowest concentration, 0.5 mM, legitimate drug channels. currently marketed and there is no samidorphan significantly decreased According to HHS, there were no evidence of diversion of samidorphan contractility. But, samidorphan at 5 and reports of diversion of samidorphan in from legitimate drug channels. There is 50 mM concentrations did not clinical trials conducted with this no evidence that individuals are taking significantly affect contractility. substance. DEA further notes that there samidorphan on their own initiative An animal study revealed the are no reports of law enforcement without medical advice. Samidorphan is cardiovascular and pulmonary effects of encounters of samidorphan in the not related in its action to any known orally administered (per os or PO) National Forensic Laboratory substance with abuse liability. samidorphan (0.5, 3, and 10 mg/kg Information System (NFLIS),5 the Substances such as and doses) in beagle dogs. The high doses of System to Retrieve Information from naltrexone, with pharmacological effects samidorphan resulted in several cases of Drug Evidence (STRIDE) 6 and of mu-opioid receptor antagonists emesis and excessive salivation. For similar to that of samidorphan, have pharmacokinetic (PK) measurements, 4 Comprehensive Drug Abuse Prevention and been decontrolled under the CSA. Thus, animals were given either a low dose of Control Act of 1970, H.R. Rep. No. 91–1444, 91st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4603. these data collectively indicate that 0.5 mg/kg or a high dose of 20 mg/kg of 5 The NFLIS is a national forensic laboratory samidorphan has no potential for abuse. samidorphan. Male dogs given a single reporting system that systematically collects results PO dose of samidorphan had average PK from drug chemistry analyses conducted by State 7 STARLiMS is a laboratory information measurements of Cmax = 4320 ng/mL, T and local forensic laboratories in the United States. management system that systematically collects max = 1.2 hr, half-life = 4.1 hr, and AUC 6 STRIDE is a database of drug exhibits sent to results from drug chemistry analyses conducted by • DEA laboratories for analysis. Exhibits from the DEA laboratories. On October 1, 2014, STARLiMS last = 30,500 hr ng/mL. In regard to database are from DEA, other federal agencies, and replaced STRIDE as the DEA laboratory drug cardiac activity, the female and male some local law enforcement agencies. evidence data system of record. groups produced a slight decrease in

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systolic blood pressure (an average mu-opioid receptor because it blocked tested at 0.0136, 0.0408, and 0.068 mg/ insignificant decrease of 17 to 26 mm the analgesic effects of the mu-opioid kg/injection, the animals did not Hg) and no significant differences in receptor agonist without respond at levels seen with the positive cardiac contractility or body producing analgesic effects of its own. control, morphine. Therefore, it was temperature. Based on the results, this Abuse Liability Studies concluded that samidorphan did not investigation reported no observed produce reinforcing effects similar to adverse effects at the level of 10 mg/kg Effects on Ethanol Self-Administration that of morphine in rats. However, the in beagle dogs. In the same study, According to HHS, a self- total number of infusions of samidorphan at any of the doses tested administration study in male Wistar rats samidorphan was statistically higher did not cause any significant effects on was conducted to determine if than the vehicle. According to HHS, this respiratory rate, tidal volume, and samidorphan has effects similar to that could have been the result of the minute volume. inadequate extinction due to the According to HHS’ review, of other opioid receptor antagonists reintroduction of the training drug samidorphan reversed cardiac and such as naltrexone in reducing ethanol respiratory effects produced by drinking behavior. Rats were trained to between doses of samidorphan; this continuous intravenous infusion (IV) of self-administer ethanol on a fixed ratio could have artificially inflated the , a mu-opioid receptor agonist, (FR) 2 schedule of reinforcement. Effects responding of samidorphan because in beagle dogs and Cynomolgus of samidorphan (0 to 3 mg/kg, SC) animals never fully underwent monkeys. Overall, samidorphan does administered 30 minutes prior to the extinction. As a result, a second self- not appear to produce mu-opioid placement of the rats into the test cages administration study with as the receptor agonist related cardiac or on ethanol drinking behavior were training drug using FR5 and a pulmonary effects. studied. Naltrexone, the positive control progressive schedule of reinforcement drug (3 or 6 mg/kg, SC), was only able was conducted. There was no Central Nervous System Effects to decrease lever responding by reintroduction of the training drug According to HHS, central nervous approximately 75 percent. The highest between doses of samidorphan with an system effects of samidorphan (3.5, 35, dose of samidorphan (3 mg/kg, SC) additional referred arm of naltrexone. or 350 mg/kg, PO) on functional decreased lever responding by The result showed that the number of observational battery in a study approximately 50 percent. According to samidorphan (0.068 mg/kg/injection) conducted in Sprague-Dawley rats are HHS, these data demonstrate that injections, similar to naltrexone, was most consistent with that of depressants pretreatment with samidorphan can significantly higher than the number of decrease, but not eliminate, the such as , cannabinoids, and saline injections, but was significantly reinforcing effects of 10 percent ethanol GABAA channel modulators. lower than that of heroin. A progressive Unlike mu-opioid receptor agonists and these results are consistent with ratio schedule of reinforcement is used that typically produce analgesic effects that of other mu-opioid receptor to determine the reinforcing efficacy of in assays on thermal and inflammatory antagonists such as naltrexone, which is painful stimulation, samidorphan indicated for the treatment of alcohol a drug by measuring the break point. A produced no measurable analgesic dependence. breakpoint is defined as the number of effects. In the hot plate test in male operant responses (lever presses) at Sprague-Dawley rats, samidorphan did Drug Discrimination Studies which the subject ceases self- not produce thermal analgesia when Drug discrimination assays in animals administration of the reinforcer. Results administered subcutaneously (SC) at can be used to predict if a test drug will of the study using the PR schedule of doses of 0.003 to 0.1 mg/kg or when have abuse potential in humans. reinforcement were similar to that of the administered intraperitoneally at doses According to HHS, a drug FR5 study: All doses of samidorphan in the range of 0.01 to 30 mg/kg. discrimination study was conducted to tested produced breakpoints that were However, samidorphan blocked test the stimulus effects of samidorphan significantly lower than heroin and only morphine-induced (15 mg/kg, SC) in rats trained to discriminate the the highest dose of samidorphan (0.068 analgesia in rats with ED50 values of stimulus effects of subcutaneously mg/kg/injection) was significantly 0.01 mg/kg (SC administration) and 0.3 administered morphine (3 mg/kg) to its higher than saline. Importantly, mg/kg (PO administration), respectively. vehicle (0.9 percent sodium chloride for naltrexone, tested at the same doses as Its blockade of morphine’s analgesic injection, USP) in a two-lever operant samidorphan, produced results similar effects lasted for approximately 4 hours. chamber on a FR10 schedule of to that of samidorphan. According to Because morphine is known to produce reinforcement. Samidorphan (0.1, 0.3, 1 HHS, these studies suggest that its analgesic effects as an agonist of the or 3 mg/kg) did not generalize to the samidorphan has a profile similar to mu-opioid receptor, this study suggests morphine cue. Samidorphan did not that of naltrexone and does not produce that samidorphan blocks this affect lever press response rates statistically significant reinforcing mechanism of action similar to other indicating that the rats were not effects. mu-opioid receptor antagonists, such as incapacitated by the drug. These data naloxone and naltrexone, which also indicate that samidorphan does not Intra-Cranial Self-Stimulation Study possess this blockade effect. produce a discriminative cue similar to Intracranial self-stimulation (ICSS) is In a tail-flick assay used to measure that of morphine (at 3 mg/kg). thermal-nociception, the result showed a behavioral study that can be used to that administered subcutaneously Self-Administration Studies evaluate brain rewarding or aversive samidorphan did not produce analgesia HHS cited two self-administration effects of drugs. HHS provided an ICSS up to the highest dose tested of 10 mg/ studies assessing the reinforcing effects study report of samidorphan in rats. kg. Furthermore, samidorphan of samidorphan in rats. In the first Following implantation with permanent antagonized morphineinduced anti- study, rats were trained to lever press on indwelling electrodes in the right nociception when administered either a FR5 schedule for intravenous self- medial forebrain at the level of the SC or PO. These data indicate that administration of morphine (0.56 mg/ lateral hypothalamus, the animals were samidorphan acts as an antagonist at the kg/injection). When samidorphan was trained to respond (i.e., lever press) to

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receive brain stimulation.8 Baseline Drug Again, and Alertness. The study (RDC–0313–02; molecular weight is ICSS training generated a frequency also took PK measurements to 504.53 g/mol). Samidorphan is a response curve where increasing the determine a correlation between blood derivative of naltrexone and it shares intensity of brain stimulation increased levels and time of onset of the PD structural similarity with naltrexone. A the rate of lever pressing. After baseline assessment. The positive controls, multi-step process of samidorphan ICSS levels were established, rats were (40 mg) and (30 synthesis starts with naltrexone, with an administered several doses of mg), produced the Emax of Drug Liking end product of its malate salt. samidorphan. The subcutaneous VAS scores of 76.1 and 82, respectively According to HHS, samidorphan is administration of samidorphan at doses and these were significantly higher than rapidly absorbed both orally and of 0.03, 0.1, 0.3, and 1.0 mg/kg did not the placebo. The Emax drug liking scores sublingually. The Tmax is approximately shift the frequency response curve following 10 and 30 mg samidorphan 60 minutes after orally dosing, with a relative to baseline and did not change were not significantly different from the half-life of six to eight hours depending the maximum rate of responding. This placebo or naltrexone (100 mg). on the dose. The plasma levels of study indicates that samidorphan does Euphoric mood was indicated as an AE samidorphan increase linearly with not affect the brain reward pathway in in 30 subjects (53.6 percent) for each dose and it rapidly distributes rats. oxycodone and in 30 subjects (52.6 throughout the body. Samidorphan is percent) for pentazocine. The 30 and 10 metabolized into two main products, Clinical Abuse Liability Studies mg doses of samidorphan produced a RDC–9986 (N-dealkylated metabolite) The HHS review describes two euphoric mood as an AE in 9 (15 and RDC–1066 (N-oxide metabolite), studies to assess the abuse potential of percent) and 7 (12.3 percent) subjects, and they can be detected in human samidorphan in human subjects. The respectively; however, 5 subjects (8.6 plasma at greater than 10 percent of the first one, a randomized, double-blind, percent) reported when total drug-related exposure. Both RDC– placebo and positive control, crossover receiving naltrexone, and 5 subjects (8.8 9986 and RDC–1066 have nanomolar study was to compare samidorphan (2.5, percent) reported euphoria when affinity for the mu-, kappa-, and delta- 10, and 20 mg, PO), oxycodone (15 and receiving the placebo. There were no opioid receptors. RDC–9986 is an 30 mg, PO), and the placebo in 41 non- reports of abuse of the drug or diversion agonist at all three opioid receptors dependent recreational opioid users. in the study. HHS concludes that whereas RDC–1066 showed antagonist The primary pharmacodynamic (PD) samidorphan produces stimulus effects activity at the mu-opioid receptor as assessment was At the Moment Drug similar to the placebo and naltrexone assessed by the [35S]GTPgS functional Liking measured by a visual analog and does not have abuse potential. DEA assay. DEA further notes that scale (VAS), with secondary endpoints notes that a recent peer-reviewed samidorphan has been reported to have that measured Overall Drug Liking, Take published clinical report describes that high bioavailability following both Drug Again, and Alertness, all on a samidorphan, similar to a placebo and sublingual and oral administration, it is bipolar VAS. High, Good Effects and naltrexone, lacks abuse potential. not subject to extensive first-pass Bad Effects were measured on a In summary, data from in vitro studies metabolism, and the PK parameters are unipolar VAS. Oxycodone at 30 and 15 showed that samidorphan is a mu- not affected by food or age in health mg doses produced mean Drug Liking opioid receptor antagonist with weak volunteers. scores of 81 and 73.3, respectively and partial agonist activity at the kappa- and In summary, samidorphan shares these scores were significantly higher delta-opioid receptors. Data from in vivo chemical structural features with mu- than the placebo. All three doses of studies further supported this opioid antagonists such as naltrexone. It samidorphan produced At the Moment conclusion; samidorphan blocked the is synthesized from the non-controlled Drug Liking, Overall Drug Liking, and analgesic effects of the mu-opioid substance naltrexone. Samidorphan exhibits high oral bioavailability and is Take Drug Again scores that were not receptor agonist morphine and the rapidly absorbed. Clinical studies significantly different from the placebo respiratory depressive effects of suggest that samidorphan was generally (50 to 51). There was one report (2.1 fentanyl. Samidorphan neither well-tolerated following single and percent) of euphoria as an adverse event produced a discriminative cue similar to multiple doses. RDC–9986 and RDC– (AE) after taking samidorphan (20 mg) that of morphine nor had reinforcing 1066, the two main metabolites of versus 11 reports (22.4 percent) effects in in vivo abuse liability studies samidorphan, though they bind to following the positive control in animals. Data from two clinical abuse potential studies suggested that opioid receptors, do not contribute oxycodone dose (30 mg). This study samidorphan does not produce drug significantly to pharmacodynamics of concluded that samidorphan does not liking scores similar to oxycodone (a samidorphan. produce PD measurements that are mu-opioid receptor agonist) or 4. Its History and Current Pattern of consistent with abuse potential. pentazocine (a kappa-opioid receptor Abuse. A second abuse potential study was agonist); instead, drug liking scores According to HHS, samidorphan has conducted by using a placebo (PO), produced by samidorphan were similar not been marketed in any country and samidorphan (10 and 30 mg, PO), to the negative controls, placebo and thus information about the history and oxycodone (40 mg, PO), pentazocine (30 naltrexone. Overall, these data support current pattern of its abuse is not mg, IV), and naltrexone (100 mg, IV) in the conclusion that samidorphan does available. Preclinical and clinical 42 healthy non-dependent recreational not have abuse liability. studies evaluating abuse potential of opioid users. The primary PD 3. The State of Current Scientific samidorphan did not show any abuse- assessment was At the Moment Drug Knowledge Regarding the Drug or Other related signals (see Factor 1 and 2, DEA Liking measured by the bipolar VAS, Substance. and HHS Eight Factor Analyses). with secondary endpoints that Samidorphan’s molecular formula is Instead, samidorphan showed effects measured Overall Drug Liking, Take C21H26N2O4 with a molecular weight of similar to those of mu-opioid 370.44 g/mol. Currently, there are two antagonists, a class of drugs not known 8 This statement and the subsequent content in this paragraph are based on the revised information salt forms, a hydrochloric acid salt to have abuse potential. The opioid provided under MOU by FDA/Controlled Substance (RDC–0313–01; molecular weight is antagonists, naloxone and naltrexone, Staff (CSS). 406.90 g/mol) and a malic acid salt were both originally schedule II

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substances as ‘‘ derivatives,’’ and will not lead to psychological This final rule is not an E.O. 13771 both are synthesized from . dependence. Similar to naltrexone (see regulatory action pursuant to E.O. 12866 However, because they lacked opioid Factor 2, DEA and HHS Eight Factor and OMB guidance.9 agonist activity, these were decontrolled Analyses), samidorphan would not be Executive Order 12988, Civil Justice in 1974 (naloxone), and in 1975 expected to produce psychological Reform (naltrexone). More recently, the opioid dependence, and no evidence of This regulation meets the applicable antagonist , a FDA-approved psychological dependence was observed standards set forth in sections 3(a) and drug for the treatment of opioid induced in clinical studies. constipation, was decontrolled in 2015. 3(b)(2) of E.O. 12988 Civil Justice In addition, as mentioned earlier (see 8. Whether the Substance is an Reform to eliminate drafting errors and Factor 1, DEA and HHS Eight Factor Immediate Precursor of a Substance ambiguity, minimize litigation, provide Analyses), NFLIS, STRIDE, and Already Controlled Under the CSA. a clear legal standard for affected STARLiMS had no mentions of Samidorphan is not considered an conduct, and promote simplification samidorphan. immediate precursor of any controlled and burden reduction. 5. The Scope, Duration, and substance listed under the CSA as Executive Order 13132, Federalism Significance of Abuse. defined by 21 U.S.C. 802(23). As stated by HHS, information about This rulemaking does not have the scope, duration, and significance of Conclusion federalism implications warranting the samidorphan abuse is not available application of E.O. 13132. The rule does because it has not been marketed in any Based on consideration of the not have substantial direct effects on the country. As mentioned in Factor 4 (DEA scientific and medical evaluation and States, on the relationship between the and HHS Eight Factor Analyses), a accompanying recommendation of HHS, Federal Government and the States, or comprehensive review and research on and based on DEA’s consideration of its the distribution of power and available databases performed by both own eight-factor analysis, DEA finds responsibilities among the various HHS and DEA revealed no reports of that these facts and all relevant data levels of government. abuse of samidorphan. Data from demonstrate that samidorphan does not Executive Order 13175, Consultation preclinical and clinical studies showed possess abuse or dependence potential. and Coordination With Indian Tribal no evidence of abuse potential for According to HHS, medical product Governments samidorphan. As stated by HHS, formulations containing samidorphan This rule does not have tribal samidorphan upon its approval and are under development. However, the implications warranting the application availability for marketing is unlikely to finding that samidorphan lacks abuse be abused. of E.O. 13175. This rule does not have potential would, irrespective of other substantial direct effects on one or more 6. What, if any, Risk There is to the findings, permit decontrol of Public Health. Indian tribes, on the relationship samidorphan prior to or in the absence Based on the data and scientific between the Federal Government and information of preclinical and clinical of an FDA action under 21 U.S.C. Indian tribes, or on the distribution of study data reviewed by both HHS and 355(c). Therapeutic and power and responsibilities between the DEA, there are no signals that indicate supratherapeutic doses of samidorphan Federal Government and Indian tribes. did not produce physical or that samidorphan has abuse potential Regulatory Flexibility Act (see Factor 1 and 2, DEA and HHS Eight psychological dependence both in non- Factor Analyses). Currently, there is no clinical (in rats and dogs) and in clinical The Acting Administrator, in evidence of drug dependence, abuse, studies. Accordingly, DEA finds that accordance with the Regulatory and diversion. Thus, there is likely to be samidorphan does not meet the Flexibility Act (RFA) (5 U.S.C. 601– little or no risk of abuse and public requirements for inclusion in any 612), has reviewed this proposed rule health risk from samidorphan if it schedule, and should be removed from and by approving it certifies that it will becomes available on the market. control under the CSA. not have a significant economic impact 7. Its Psychic or Physiological on a substantial number of small Dependence Liability. Regulatory Analyses entities. The purpose of this rule is to remove samidorphan from the list of According to HHS, several long-term Executive Orders 12866, 13563, and schedules of the CSA. This action will toxicology studies were conducted 13771, Regulatory Planning and Review, remove regulatory controls and using samidorphan in rats and dogs Improving Regulation and Regulatory administrative, civil, and criminal lasting 13, 26, or 39 weeks at doses of Review, and Reducing Regulation and 250, 50, and 10 mg/kg/day. The animals sanctions applicable to controlled Controlling Regulatory Costs were continually monitored after the substances for handlers and proposed study for withdrawal signs, such as In accordance with 21 U.S.C. 811(a), handlers of samidorphan. Accordingly, weight changes, food consumption, this scheduling action is subject to it has the potential for some economic morbidity, mortality, and locomotion formal rulemaking procedures done ‘‘on impact in the form of cost savings. If finalized, the proposed rule will effects. These studies did not find any the record after opportunity for a affect all persons who would handle, or behaviors or physical manifestations hearing,’’ which are conducted pursuant that were different from the control propose to handle samidorphan. to the provisions of 5 U.S.C. 556 and Samidorphan is not currently available groups, indicating that samidorphan 557. The CSA sets forth the criteria for lacks potential to produce physical or marketed in any country. Due to the removing a drug or other substance from dependence. Data from these clinical wide variety of unidentifiable and the list of controlled substances. Such studies showed no signals related to unquantifiable variables that potentially withdrawal or physical dependence. actions are exempt from review by The lack of samidorphan’s ability to Office of Management and Budget 9 Office of Mgmt. & Budget, Exec. Office of The function as a positive reinforcer in self- (OMB) pursuant to section 3(d)(1) of President, Interim Guidance Implementing Section Executive Order (E.O.) 12866 and the 2 of the Executive Order of January 30, 2017 Titled administration studies in animals ‘‘Reducing Regulation and Controlling Regulatory suggests that the use of samidorphan principles reaffirmed in E.O. 13563. Costs’’ (Feb. 2, 2017).

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could influence the distribution and under the Paperwork Reduction Act, 44 Federal Motor Vehicle Safety Standards dispensing rates, if any, of samidorphan, U.S.C. 3501–3521. This action would (FMVSS) may be a candidate for DEA is unable to determine the number not impose recordkeeping or reporting replacement, repeal, or modification, for of entities and small entities which requirements on State or local reasons other than for considerations might handle samidorphan. In some governments, individuals, businesses, or relevant only to automated driving instances where a controlled organizations. systems (ADS). This document is a pharmaceutical drug is removed from continuation of the Agency’s efforts to List of Subjects in 21 CFR Part 1308 the schedules of the CSA, DEA is able improve the FMVSS and minimize to quantify the estimated number of Administrative practice and burdens. The Agency takes this action affected entities and small entities procedure, Drug traffic control, in response to its review of the FMVSS because the handling of the drug is Reporting and recordkeeping and to public comments solicited by expected to be limited to DEA requirements. DOT in a 2017 notice on its regulatory registrants even after removal from the For the reasons set out above, 21 CFR reform efforts. The commenters schedules. In such instances, DEA’s part 1308 is proposed to be amended to requested that NHTSA amend test knowledge of its registrant population read as follows: procedures for air brakes and occupant forms the basis for estimating the crash protection. NHTSA has also number of affected entities and small PART 1308—SCHEDULES OF identified some possible additional test entities. However, DEA does not have a CONTROLLED SUBSTANCES procedure issues and discusses them in basis to estimate whether samidorphan this Notice. In addition, this ANPRM is expected to be handled by persons ■ 1. The authority citation for 21 CFR also seeks comments and supporting who hold DEA registrations, by persons part 1308 continues to read as follows: information relating to any other test who are not currently registered with Authority: 21 U.S.C. 811, 812, 871(b), procedures which may be a candidate DEA to handle controlled substances, or 956(b), unless otherwise noted. for replacement, repeal or modification, both. Therefore, DEA is unable to ■ 2. In § 1308.12, revise the introductory not just those specifically discussed in estimate the number of entities and text of paragraph (b)(1) to read as this Notice. small entities who plan to handle follows: DATES: Comments must be received no samidorphan. later than February 8, 2021. See the Although DEA does not have a § 1308.12 Schedule II. Public Participation heading of the reliable basis to estimate the number of * * * * * SUPPLEMENTARY INFORMATION section of affected entities and quantify the (b) * * * this document for more information economic impact of this final rule, a (1) Opium and opiate, and any salt, about written comments. qualitative analysis indicates that this compound, derivative, or preparation of rule is likely to result in some cost ADDRESSES: You may submit comments opium or opiate excluding to the docket number identified in the savings. As noted above, DEA is apomorphine, thebaine-derived specifically soliciting comments on the heading of this document by any of the , , , following methods: economic impact of this proposed rule. , , naloxegol, • DEA will revise this section if warranted Federal eRulemaking Portal: Go to naloxone, 6b-naltrexol, naltrexone, and http://www.regulations.gov. Follow the after consideration of any comments samidorphan, and their respective salts, received. Any person planning to online instructions for submitting but including the following: comments. handle samidorphan will realize cost • savings in the form of saved DEA * * * * * Mail: Docket Management Facility: U.S. Department of Transportation, 1200 registration fees, and the elimination of Timothy J. Shea, physical security, recordkeeping, and New Jersey Avenue SE, West Building Acting Administrator. Ground Floor, Room W12–140, reporting requirements. [FR Doc. 2020–26812 Filed 12–9–20; 8:45 am] Because of these factors, DEA projects Washington, DC 20590–0001 BILLING CODE 4410–09–P • that this rule will not result in a Hand Delivery or Courier: 1200 significant economic impact on a New Jersey Avenue SE, West Building substantial number of small entities. Ground Floor, Room W12–140, between DEPARTMENT OF TRANSPORTATION 9 a.m. and 5 p.m. ET, Monday through Unfunded Mandates Reform Act of 1995 Friday, except Federal holidays. On the basis of information contained National Highway Traffic Safety • Fax: 202–493–2251. in the ‘‘RFA’’ section above, DEA has Administration Instructions: For detailed instructions determined and certifies pursuant to the on submitting comments and additional Unfunded Mandates Reform Act of 1995 49 CFR Part 571 information on the rulemaking process, (UMRA), 2 U.S.C. 1501 et seq., that this [Docket No. NHTSA–2020–0109] see the Public Participation heading of action would not result in any federal the SUPPLEMENTARY INFORMATION section RIN 2127–AM04 mandate that may result ‘‘in the of this document. Note that all expenditure by State, local, and tribal Federal Motor Vehicle Safety comments received will be posted governments, in the aggregate, or by the Standards: Test Procedures without change to http:// private sector, of $100,000,000 or more www.regulations.gov, including any (adjusted for inflation) in any one year AGENCY: National Highway Traffic personal information provided. Please * * *.’’ Therefore, neither a Small Safety Administration (NHTSA), see the ‘‘Privacy Act’’ heading below. Government Agency Plan nor any other Department of Transportation (DOT). Privacy Act: Anyone is able to search action is required under provisions of ACTION: Advance notice of proposed the electronic form of all comments UMRA. rulemaking (ANPRM). received into any docket by the name of the individual submitting the comment Paperwork Reduction Act SUMMARY: NHTSA is issuing this (or signing the comment, if submitted This action does not impose a new ANPRM to seek public comment on on behalf of an association, business, collection of information requirement whether any test procedures for any labor union, etc.). You may review

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