Document ID: FDA-2016-N-2633-0001
Agency: fda
Document Type: Notice
Title: International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; 4-Methylethcathinone and Eleven Other Substances; Request for Comments
Posted Date: 2016-09-19T04:00Z

[Federal Register Volume 81, Number 181 (Monday, September 19, 2016)]
[Notices]
[Pages 64162-64164]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-22472]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-2633]

International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; 4-Methylethcathinone 
and Eleven Other Substances; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is requesting 
interested persons to submit comments concerning abuse potential, 
actual abuse, medical usefulness, trafficking, and impact of scheduling 
changes on availability for medical use of 12 drug substances. These 
comments will be considered in preparing a response from the United 
States to the World Health Organization (WHO) regarding the abuse 
liability and diversion of these drugs. WHO will use this information 
to consider whether to recommend that certain international 
restrictions be placed on these drugs. This notice requesting comments 
is required by the Controlled Substances Act (the CSA).

DATES: Submit either electronic or written comments by October 4, 2016.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-N-2633 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; 3,4-
dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700); 
Butyrfentanyl (Butyrylfentanyl); 4-Methylethcathinone (4-MEC); 3-
Methylmethcathinone (3-methyl-N-methylcathinone; 3-MMC); Ethylone (3,4-
methylenedioxy-N-ethylcathinone; bk-MDEA; MDEC); Pentedrone ([alpha]-
Methylaminovalerophenone); Ethylphenidate (EPH); Methiopropamine (MPA); 
MDMB-CHMICA; 5F-APINACA (5F-AKB48); JWH-073; XLR-11 (5-Fluoro UR-144, 
5F-UR-144); Request for Comments.'' Received comments will be placed in 
the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at http://www.regulations.gov or at 
the Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research, Controlled Substance Staff, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5150, Silver 
Spring, MD 20993-0002, 301-796-3156, email: james.hunter@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic 
Substances (Psychotropic Convention). Article 2 of the Psychotropic 
Convention provides that if a party to the convention or WHO has 
information about a substance, which in its opinion may require 
international control or change in such control, it shall so notify the 
Secretary-General of the United Nations (the U.N. Secretary-General) 
and provide the U.N. Secretary-General

[[Page 64163]]

with information in support of its opinion.
    Section 201 of the CSA (21 U.S.C. 811) (Title II of the 
Comprehensive Drug Abuse Prevention and Control Act of 1970) provides 
that when WHO notifies the United States under Article 2 of the 
Psychotropic Convention that it has information that may justify adding 
a drug or other substances to one of the schedules of the Psychotropic 
Convention, transferring a drug or substance from one schedule to 
another, or deleting it from the schedules, the Secretary of State must 
transmit the notice to the Secretary of Health and Human Services 
(Secretary of HHS). The Secretary of HHS must then publish the notice 
in the Federal Register and provide opportunity for interested persons 
to submit comments that will be considered by HHS in its preparation of 
the scientific and medical evaluations of the drug or substance.

II. WHO Notification

    The Secretary of HHS received the following notice from WHO (non-
relevant text removed):

Ref.: C.L.28.2015
    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and has the pleasure of 
informing that the Thirty-eighth Expert Committee on Drug Dependence 
(ECDD) will meet in Geneva from 14 to 18 November 2016 to review a 
number of substances with potential for dependence, abuse and harm 
to health, and will make recommendations to the U.N. Secretary-
General, on the need for and level of international control of these 
substances.
    At its 126th session in January 2010, the Executive Board 
approved the publication ``Guidance on the WHO review of 
psychoactive substances for international control'' (EB126/2010/
REC1, Annex 6) which requires the Secretariat to request relevant 
information from Ministers of Health in Member States to prepare a 
report for submission to the ECDD. For this purpose, a questionnaire 
was designed to gather information on the legitimate use, harmful 
use, status of national control and potential impact of 
international control for each substance under evaluation. Member 
States are invited to collaborate, as in the past, in this process 
by providing pertinent information as requested in the questionnaire 
and concerning substances under review.
    It would be appreciated if a person from the Ministry of Health 
could be designated as the focal point responsible for coordinating 
and answering the questionnaire. The designated focal point, and 
only this person, should access and complete the questionnaires:
    1. U-47700;
    2. Butyrfentanyl (Butyrylfentanyl);
    3. 4-Methylethcathinone (4-MEC);
    4. 3-Methylmethcathinone (3-methyl-N-methylcathinone; 3-MMC);
    5. Ethylone (3,4-methylenedioxy-N-ethylcathinone; bk-MDEA; 
MDEC);
    6. Pentedrone ([alpha]-Methylaminovalerophenone);
    7. Ethylphenidate (EPH);
    8. Methiopropamine (MPA);
    9. MDMB-CHMICA;
    10. 5F-APINACA (5F-AKB48);
    11. JWH-073;
    12. XLR-11 (5-Fluoro UR-144, 5F-UR-144).
    For ease of reference a PDF version of the questionnaire in 
English, French and Spanish may be downloaded from the link http://www.who.int/medicines/access/controlled-substances/ecdd/en/. Please 
note that these versions are for reference only and all 
questionnaires must be answered through the online system. Further 
clarification regarding the questionnaire may be obtained from the 
Secretariat by emailing: ecddsecretariat@who.int.
    Replies to the questionnaire must reach the Secretariat by 20 
September 2016 in order to facilitate analyses and preparation of 
the report before the planned meeting. Where there is a competent 
National Authority under the International Drug Control Treaties, it 
is kindly requested that the questionnaire be completed in 
collaboration with such body.
    The summary information from the questionnaire will be published 
online as part of the report on the Web site for the 38th ECDD 
linked to the Department of Essential Medicines and Health Products 
(EMP).
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.

GENEVA, 8 August 2016

    HHS received an extension from WHO that replies to the 
questionnaire must reach the Secretariat by October 11, 2016. FDA has 
verified the Web site addresses contained in the WHO notice, as of the 
date this document publishes in the Federal Register, but Web sites are 
subject to change over time.

III. Substances Under WHO Review

    U-47700 is a synthetic opioid drug developed in the 1970s. U-47700 
is structurally related to the opioid AH-7921. U-47700 is selective for 
the [micro]-opioid receptor. U-47700 has never been studied on humans, 
but would be expected to produce effects similar to those of other 
potent opioid agonists, including strong analgesia, sedation, euphoria, 
constipation, itching, and respiratory depression which could be 
harmful or fatal. Overdoses and overdose fatalities have been directly 
attributed to U-47700 misuse. There have been reports of U-47700 being 
encountered in counterfeit pills. On September 7, 2016, the Drug 
Enforcement Administration issued a notice of intent to temporarily 
schedule U-47700 into schedule I pursuant to the temporary scheduling 
provisions of the Controlled Substances Act.
    Butyrfentanyl (butyrylfentanyl) is a synthetic opioid and analog of 
fentanyl. Fentanyl is controlled in Schedule II of the CSA, and an 
active ingredient in drug products approved for medical use and 
marketed in the United States. Butyrylfentanyl has a pharmacological 
profile similar to that of fentanyl and other [micro]-opioid receptor 
agonists. Risks associated with abuse of butyrylfentanyl include 
development of substance use disorder, overdose, and death similar to 
that of other [micro]-opioid agonists. The U.S. Drug Enforcement 
Administration (DEA) is aware of at least 40 confirmed fatalities 
associated with butyrylfentanyl. It has no approved medical use in the 
United States. On May 12, 2016, butyrylfentanyl was temporarily placed 
into Schedule I of the CSA for 2 years upon finding that it posed an 
imminent hazard to the public safety. The Attorney General, though, may 
extend this temporary scheduling for up to 1 year.
    4-Methylethcathinone (4-MEC), 3-Methylmethcathinone (3-methyl-N-
methylcathinone; 3-MMC): 3-methyl-methcathinone (3-MMC), pentedrone, 
and ethylone (3,4-methylenedioxy-N-ethylcathinone; bk-MDEA; MDEC) are 
synthetic cathinones that are structurally and pharmacologically 
similar to amphetamine, 3-4 methylenedioxymethamphetamine (MDMA), 
cathinone, and other related substances. These substances are central 
nervous system stimulants with psychoactive properties similar to 
Schedule I and II amphetamine type substances. Public health risks 
associated with the use of synthetic cathinones suggest that these 
substances are associated with cardiac, psychiatric, and neurological 
symptoms that may lead to emergency department admissions, violent 
behaviors causing harm to self or others, or death. 4-MEC, 3-MMC, 
pentedrone, and ethylone have no known medical use in the United 
States. On March 7, 2014, the DEA published a final order in the 
Federal Register amending 21 CFR 1308.11(h) to temporarily place 4-MEC 
and pentedrone into Schedule I of the CSA pursuant to the temporary 
scheduling provisions of 21 U.S.C. 811(h). On March 4, 2016, the 
temporary Schedule I status of 4-MEC and pentedrone was extended for 1 
year, or until permanent scheduling is completed. Permanent scheduling 
for 4-MEC and pentedrone was initiated on March 4, 2016, upon 
publication of the notice of proposed rulemaking. As a positional 
isomer of 4-methylmethcathinone, 3-MMC is considered a Schedule I 
substance under the CSA. In the United States,

[[Page 64164]]

ethylone has been sold as the street drug ``Molly'' and encountered as 
a replacement for methylone. As a positional isomer of the controlled 
drug butylone, ethylone is considered a Schedule I controlled substance 
under the CSA.
    Ethylphenidate (EPH) is structurally related to methylphenidate. 
Methylphenidate is controlled in Schedule IV of the CSA, and an active 
ingredient in drug products approved for medical use and marketed in 
the United States. Ethylphenidate is not approved for medical use in 
the United States. Ethylphenidate is structurally related to 
methylphenidate are being marketed as novel psychoactive substances 
with psychoactive effects similar to methylphenidate, therefore posing 
similar health risks to the users. Ethylphenidate is a controlled 
substance in several European countries, and is not a controlled 
substance in the United States under the CSA.
    Methiopropamine (MPA) is a structural analogue of the Schedule II 
controlled substance methamphetamine. Pharmacologically, it functions 
as a norepinephrine-dopamine reuptake inhibitor and, secondarily, as a 
serotonin reuptake inhibitor. MPA is a thiophene based analog of 
methamphetamine. It has stimulant properties as an inhibitor of 
dopamine, norepinephrine transporters in the central nervous system. 
MPA was critically reviewed by the WHO at its 36th meeting of the 
Expert Committee on Drug Dependence in June 2014. It is not approved 
for medical use or controlled in the United States under the CSA, but 
is a controlled substance in the United Kingdom.
    MDMB-CHMICA is an indole-based synthetic cannabinoid that is a 
potent full agonist at CB1 receptors and mimics functionally 
(biologically) the effects of the structurally unrelated delta-9-
tetrahydrocannabinol (THC), a Schedule I substance, and the main active 
ingredient of marijuana. Synthetic cannabinoids are marketed under the 
guise of ``herbal incense,'' and promoted by drug traffickers as legal 
alternatives to marijuana. MDMB-CHMICA use is associated with serious 
adverse events including death in several European countries. There are 
no commercial or approved medical uses for MDMB-CHMICA. MDMB-CHMICA is 
not controlled under the CSA, but may be treated as a ``controlled 
substance analogue'' under the CSA pursuant to 21 U.S.C 802(32)(A) and 
813, and is a controlled substance in the State of Louisiana.
    5F-APINACA (5F-AKB48) is a synthetic cannabinoid belonging to a 
chemical structural class with an indazole core. In vitro studies show 
that it binds to the cannabinoid CB1 receptors and displays agonist 
properties in functional assays, suggesting that it would share in vivo 
effects with delta-9-THC and various synthetic cannabinoids. There are 
no commercial or medical uses for 5F-APINACA. Synthetic cannabinoids 
are marketed under the guise of ``herbal incense,'' and promoted by 
drug traffickers as legal alternatives to marijuana. SF-APINACA is not 
a controlled substance under the CSA, but may be treated as a 
``controlled substance analogue'' under the CSA pursuant to 21 U.S.C. 
802(32)(A) and 813.
    JWH-073 is an indole-based synthetic cannabinoid agonist without 
the classical cannabinoid chemical structure. Pharmacology studies have 
been conducted on this substance. Behavioral pharmacology studies show 
that JWH-073 has delta-9-THC-like activity in animals. Synthetic 
cannabinoids are marketed under the guise of ``herbal incense,'' and 
promoted by drug traffickers as legal alternatives to marijuana. On 
March 1, 2011, JWH-073 was temporarily controlled in Schedule I and on 
July 9, 2012, JWH-073 was permanently controlled as a Schedule I 
substance under the CSA.
    XLR-11 (5-Fluoro-UR-144, 5F-UR-144) is an indole-based synthetic 
cannabinoid and acts as an agonist at cannabinoid CB1 receptors. Animal 
studies indicate that it mimics functionally (biologically) the effects 
of the structurally unrelated delta-9-THC, a Schedule I substance, and 
the main active ingredient of marijuana and numerous other Schedule I 
synthetic cannabinoids. Synthetic cannabinoids are marketed under the 
guise of ``herbal incense,'' and promoted by drug traffickers as legal 
alternatives to marijuana. On May 16, 2013, XLR-11 was temporarily 
placed under Schedule I and on May 11, 2016, XLR11 was permanently 
controlled as a Schedule I substance under the CSA.

IV. Opportunity To Submit Domestic Information

    As required by section 201(d)(2)(A) of the CSA, FDA, on behalf of 
the Department of Health and Human Services (HHS), invites interested 
persons to submit comments regarding the 12 named drugs. Any comments 
received will be considered by HHS when it prepares a scientific and 
medical evaluation of these drugs. HHS will forward a scientific and 
medical evaluation of these drugs to WHO, through the Secretary of 
State, for WHO's consideration in deciding whether to recommend 
international control/decontrol of any of these drugs. Such control 
could limit, among other things, the manufacture and distribution 
(import/export) of these drugs and could impose certain recordkeeping 
requirements on them.
    Although FDA is, through this notice, requesting comments from 
interested persons which will be considered by HHS when it prepares an 
evaluation of these drugs, HHS will not now make any recommendations to 
WHO regarding whether any of these drugs should be subjected to 
international controls. Instead, HHS will defer such consideration 
until WHO has made official recommendations to the Commission on 
Narcotic Drugs, which are expected to be made in early 2017. Any HHS 
position regarding international control of these drugs will be 
preceded by another Federal Register notice soliciting public comments, 
as required by section 201(d)(2)(B) of the CSA.

V. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: September 14, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-22472 Filed 9-16-16; 8:45 am]
 BILLING CODE 4164-01-P