81_FR_29579 81 FR 29487 - Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V

81 FR 29487 - Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V

DEPARTMENT OF JUSTICE
Drug Enforcement Administration

Federal Register Volume 81, Issue 92 (May 12, 2016)

Page Range29487-29492
FR Document2016-11245

The Drug Enforcement Administration is placing the substance brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) (also referred to as BRV; UCB-34714; Briviact) (including its salts) into schedule V of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act, as revised by the Improving Regulatory Transparency for New Medical Therapies Act which was signed into law on November 25, 2015.

Federal Register, Volume 81 Issue 92 (Thursday, May 12, 2016)
[Federal Register Volume 81, Number 92 (Thursday, May 12, 2016)]
[Rules and Regulations]
[Pages 29487-29492]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-11245]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-435]


Schedules of Controlled Substances: Placement of Brivaracetam 
Into Schedule V

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Interim final rule, with request for comments.

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SUMMARY: The Drug Enforcement Administration is placing the substance 
brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) 
(also referred to as BRV; UCB-34714; Briviact) (including its salts) 
into schedule V of the Controlled Substances Act. This scheduling 
action is pursuant to the Controlled Substances Act, as revised by the 
Improving Regulatory Transparency for New Medical Therapies Act which 
was signed into law on November 25, 2015.

DATES: The effective date of this rulemaking is May 12, 2016. 
Interested persons may file written comments on this rulemaking in 
accordance with 21 CFR 1308.43(g). Electronic comments must be 
submitted, and written comments must be postmarked, on or before June 
13, 2016. 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, defined at 21 CFR 1300.01 as those ``adversely 
affected or aggrieved by any rule or proposed rule issuable pursuant to 
section 201 of the Act (21 U.S.C. 811),'' may file a request for 
hearing or waiver of hearing pursuant to 21 CFR 1308.44. Requests for 
hearing and waivers of an opportunity for a hearing or to participate 
in a hearing must be received on or before June 13, 2016.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-435'' on all correspondence, including any 
attachments.
     Electronic comments: The Drug Enforcement Administration 
encourages that all comments be submitted electronically through the 
Federal eRulemaking Portal, which provides the ability to type short 
comments directly into the comment field on the Web page or attach a 
file for lengthier comments. Please go to http://www.regulations.gov 
and follow the online instructions at that site for submitting 
comments. Upon completion of your submission, you will receive a 
Comment Tracking Number for your comment. Please be aware that 
submitted comments are not instantaneously available for public view on 
Regulations.gov. If you have received a Comment Tracking Number, your 
comment has been successfully submitted and there is no need to 
resubmit the same comment.
     Paper comments: Paper comments that duplicate the 
electronic submission are not necessary and are discouraged. Should you 
wish to mail a paper comment in lieu of an electronic comment, it 
should be sent via regular or express mail to: Drug Enforcement 
Administration, Attn: DEA Federal Register Representative/ODW, 8701 
Morrissette Drive, Springfield, VA 22152.
     Hearing requests: All requests for hearing and waivers of 
participation must be sent to: Drug Enforcement Administration, Attn: 
Administrator, 8701 Morrissette Drive, Springfield, Virginia 22152. All 
requests for hearing and waivers of participation should also be sent 
to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 8701 
Morrissette Drive, Springfield, Virginia 22152; and (2) Drug 
Enforcement Administration, Attn: DEA Federal Register Representative/
ODW, 8701 Morrissette Drive, Springfield, Virginia 22152.

FOR FURTHER INFORMATION CONTACT: Barbara J. Boockholdt, Office of 
Diversion Control, Drug Enforcement Administration; Mailing Address: 
8701 Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 
598-6812.

SUPPLEMENTARY INFORMATION:

Posting of Public Comments

    Please note that all comments received are considered part of the 
public record. They will, unless reasonable cause is given, be made 
available by the Drug Enforcement Administration (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 (FOIA) 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 of your comment. You must also 
place all of 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 the 
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, 
including the complete Department of Health and Human Services and Drug 
Enforcement Administration eight-factor analyses, to this interim final 
rule are available at http://www.regulations.gov for easy reference.

Request for Hearing, Notice of Appearance at Hearing, 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 (APA), 5 U.S.C. 551-559. 21 CFR 1308.41-1308.45; 21 CFR part 1316, 
subpart D. In accordance with 21 CFR 1308.44(a)-

[[Page 29488]]

(c), requests for a hearing, notices of appearance, and waivers of an 
opportunity for a hearing or to participate in a hearing may be 
submitted only by interested persons, defined as those ``adversely 
affected or aggrieved by any rule or proposed rule issuable pursuant to 
section 201 of the Act (21 U.S.C. 811).'' 21 CFR 1300.01. Requests for 
a hearing and notices of participation must conform to the requirements 
of 21 CFR 1308.44(a) or (b), 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 of an opportunity for a hearing must conform to the requirements 
of 21 CFR 1308.44(c) 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), the purpose and 
subject matter of the hearing are restricted to ``(A) find[ing] that 
such drug or other substance has a potential for abuse, and (B) 
mak[ing] with respect to such drug or other substance the findings 
prescribed by subsection (b) of section 812 of this title for the 
schedule in which such drug is to be placed. * * *'' Requests for a 
hearing and waivers of participation in the hearing should be submitted 
to DEA using the address information provided above.

Legal Authority

    The DEA implements and enforces titles II and III of the 
Comprehensive Drug Abuse Prevention and Control Act of 1970, as 
amended. 21 U.S.C. 801-971. Titles II and III are referred to as the 
``Controlled Substances Act'' and the ``Controlled Substances Import 
and Export Act,'' respectively, and are collectively referred to as the 
``Controlled Substances Act'' or the ``CSA'' for the purpose of this 
action. The DEA publishes the implementing regulations for these 
statutes in title 21 of the Code of Federal Regulations (CFR), chapter 
II. The CSA and its implementing regulations are designed to prevent, 
detect, and eliminate the diversion of controlled substances and listed 
chemicals into the illicit market while providing for the legitimate 
medical, scientific, research, and industrial needs of the United 
States. Controlled substances have the potential for abuse and 
dependence and are controlled to protect the public health and safety.
    Under the CSA, controlled substances are classified into one of 
five schedules based upon their potential for abuse, their currently 
accepted medical use in treatment in the United States, and the degree 
of dependence the substance may cause. 21 U.S.C. 812. The initial 
schedules of controlled substances established by Congress are found at 
21 U.S.C. 812(c), and the current list of all scheduled substances is 
published at 21 CFR part 1308.
    Pursuant to 21 U.S.C. 811(a)(1), the Attorney General may, by rule, 
``add to such a schedule or transfer between such schedules any drug or 
other substance if he * * * finds that such drug or other substance has 
a potential for abuse, and * * * makes with respect to such drug or 
other substance the findings prescribed by subsection (b) of section 
812 of this title for the schedule in which such drug is to be placed * 
* *'' The Attorney General has delegated this scheduling authority 
under 21 U.S.C. 811 to the Administrator of the DEA. 28 CFR 0.100.
    The CSA provides that scheduling of any drug or other substance may 
be initiated by the Attorney General (1) on her own motion; (2) at the 
request of the Secretary of Health and Human Services (HHS); or (3) on 
the petition of any interested party. 21 U.S.C. 811(a). This action 
imposes the regulatory controls and administrative, civil, and criminal 
sanctions of schedule V controlled substances for any person who 
handles or proposes to handle BRV.
    The Improving Regulatory Transparency for New Medical Therapies Act 
(Pub. L. 114-89) was signed into law on November 25, 2015. This law 
amended 21 U.S.C. 811 and states that in cases where a new drug is (1) 
approved by the Department of Health and Human Services (HHS) and (2) 
HHS recommends control in CSA schedule II-V, DEA shall issue an interim 
final rule scheduling the drug, within 90 days.
    The law further states that the 90-day timeframe starts the later 
of (1) the date DEA receives the HHS scientific and medical evaluation/
scheduling recommendation or (2) the date DEA receives notice of drug 
approval by HHS. In addition, the law specifies that the rulemaking 
shall become immediately effective as an interim final rule without 
requiring the DEA to demonstrate good cause therefor.
    Specifically, Public Law 114-89 revised section 201 of the CSA (21 
U.S.C. 811) by inserting after subsection (i) a new paragraph (j), 
which requires that with respect to a drug referred to in subsection 
(f), if the Secretary recommends that the Attorney General control the 
drug in schedule II, III, IV, or V pursuant to subsections (a) and (b), 
the Attorney General is required to, within 90 days, issue an interim 
final rule controlling the drug in accordance with such subsections and 
21 U.S.C. 812(b) using the specified procedures. For purposes of 
calculating the 90 days, Public Law 114-89 states that such date shall 
be the later of the date on which the Attorney General receives the 
scientific and medical evaluation and the scheduling recommendation 
from the Secretary in accordance with subsection (b), or the date on 
which the Attorney General receives notification from the Secretary 
that the Secretary has approved an application under section 505(c), 
512, or 571 of the Federal Food, Drug, and Cosmetic Act or section 
351(a) of the Public Health Service Act, or indexed a drug under 
section 572 of the Federal Food, Drug, and Cosmetic Act, with respect 
to the drug described in paragraph (1). Public Law 114-89 further 
stipulates that a rule issued by the Attorney General under paragraph 
(1) becomes immediately effective as an interim final rule without 
requiring the Attorney General to demonstrate good cause and requires 
that the interim final rule give interested persons the opportunity to 
comment and to request a hearing. After the conclusion of such 
proceedings, the Attorney General must issue a final rule in accordance 
with the scheduling criteria of subsections 21 U.S.C. 811(b), (c), and 
(d) of this section and 21 U.S.C. 812(b).

Background

    Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] 
butanamide) (also referred to as BRV; UCB-34714; Briviact) is a new 
molecular entity with central nervous system (CNS) depressant 
properties. BRV is known to be a high affinity ligand for the synaptic 
vesicle protein, SV2A, which is found on excitatory synapses in the 
brain. On November 22, 2014, UCB Inc. (Sponsor) submitted three New 
Drug Applications (NDAs) to the U.S. Food and Drug Administration (FDA) 
for the tablet, oral, and intravenous formulations of BRV. The FDA 
accepted the NDA filings for BRV on January 21, 2015.
    On March 28, 2016 the DEA received notification that HHS/FDA 
approved BRV as an add-on treatment to other medications to treat 
partial onset seizures in patients age 16 years and older with 
epilepsy.

Determination to Schedule BRV

    Pursuant to 21 U.S.C. 811(a)(1), proceedings to add a drug or 
substance to those controlled under the CSA may be initiated by request 
of the Secretary

[[Page 29489]]

of the HHS.\1\ On September 8, 2015, the HHS provided the DEA with a 
scientific and medical evaluation document prepared by the FDA entitled 
``Basis for the Recommendation to Place Brivaracetam in Schedule V of 
the Controlled Substances Act.'' Pursuant to 21 U.S.C. 811(b), this 
document contained an eight-factor analysis of the abuse potential of 
BRV as a new drug, along with the HHS' recommendation to control BRV 
under schedule V of the CSA.
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    \1\ As set forth in a memorandum of understanding entered into 
by the HHS, the FDA, and the National Institute on Drug Abuse 
(NIDA), the FDA acts as the lead agency within the HHS in carrying 
out the Secretary's scheduling responsibilities under the CSA, with 
the concurrence of the NIDA. 50 FR 9518, Mar. 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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    In response, in December 2015, the DEA reviewed the scientific and 
medical evaluation and scheduling recommendation provided by the HHS, 
along with all other relevant data, and completed its own eight-factor 
review document pursuant to 21 U.S.C. 811(c). The DEA concluded that 
BRV met the 21 U.S.C. 812(b)(5) criteria for placement in schedule V of 
the CSA. Subsequently, on March 28, 2016, the DEA received notification 
that HHS/FDA approved three NDAs for BRV (see Background section).
    Pursuant to the provisions of the Improving Regulatory Transparency 
for New Medical Therapies Act (Pub. L. 114-89), and based on the HHS 
recommendation, NDA approvals by HHS/FDA, and DEA's determination, DEA 
is issuing this interim final rule to schedule brivaracetam ((2S)-2-
[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) (including its salts) 
as a controlled substance under the CSA.
    Included below is a brief summary of each factor as analyzed by the 
HHS and the DEA, and as considered by the DEA in its scheduling action. 
Please note that both the DEA and HHS analyses are available in their 
entirety under ``Supporting Documents'' in the public docket for this 
interim final rule at http://www.regulations.gov, under Docket Number 
``DEA-435.'' Full analysis of, and citations to, the information 
referenced in the summary may also be found in the supporting and 
related material.
    1. The Drug's Actual or Relative Potential for Abuse: BRV is a new 
chemical entity and has not been marketed in the United States or in 
any other country; information on actual abuse of BRV is not available. 
The HHS characterized BRV as related in its action to lacasamide and 
ezogabine, which are both schedule V CNS depressant anti-epileptics 
(AEDs). Based on data submitted by the Sponsor in their NDAs, the HHS 
indicated that administration of BRV in mice, rats, and dogs resulted 
in CNS depressant effects, including decreased locomotor activity and 
reactivity, motor incoordination, and ataxia.
    BRV is not self-administered in animals and, unlike schedule IV 
benzodiazepines and the schedule III AED perampanel, lacks 
pentobarbital-like (schedule II) discriminative stimulus and 
reinforcing effects (HHS review, 2015). In humans, BRV is most similar 
to the schedule V AEDs lacosamide, ezogabine, and pregabalin in 
producing positive subjective effects without producing sedation and 
withdrawal following drug discontinuation that is observed with 
schedule IV benzodiazepines. Based on this collective evidence, the HHS 
concluded that BRV has an abuse potential that is most similar to AEDs 
in schedule V.
    2. Scientific Evidence of the Drug's Pharmacological Effects, if 
Known: BRV selectively binds with high affinity to synaptic vesicle 
protein 2A (SV2A). It produces reverse inhibition caused by negative 
modulators of gamma aminobutyric acid (GABA) and glycine and inhibits 
sodium (Na+) channels. These sites appear to underlie pharmacological 
activity of BRV.
    In rats, BRV at high doses partially generalizes to the schedule IV 
benzodiazepine chlordiazepoxide. BRV, across a wide range of doses, 
neither initiates nor maintains self-administration in rats trained to 
self-administer cocaine. Human studies have reported that healthy 
individuals may experience euphoria, sedation, and a drunken-like 
feeling following BRV administration. When treatment-emergent adverse 
events (TEAEs) \2\ were pooled across several clinical BRV studies, the 
most common TEAEs were dizziness and sedative-related events such as 
fatigue, extreme drowsiness, and extreme weakness. In a human abuse 
potential study, the oral abuse potential, safety, tolerability, and 
pharmacokinetics of BRV (50 mg, 200 mg, and 1000 mg) were compared to 
1.5 and 3.0 mg of the schedule IV CNS depressant alprazolam (ALP) and 
placebo. When surveyed, for all doses of BRV, there was an increase of 
drug likability, feeling of a high, and taking the drug again in 
comparison to placebo. The HHS mentioned that individuals who took BRV 
had fewer sedative, euphoric, stimulant, dizziness, and overall 
negative subjective effects compared to ALP.
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    \2\ Treatment-emergent adverse event (TEAE): An event or 
unexpected medical occurrence (e.g. adverse event) which first 
appears during treatment with a drug or substance. TEAEs are 
typically absent prior to the onset of treatment or would have been 
exacerbated relative to pre-treatment conditions.
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    3. The State of Current Scientific Knowledge Regarding 
Brivaracetam: The chemical name for brivaracetam is (2S)-2-[(4R)-2-oxo-
4-propylpyrrolidin-1-yl] butanamide. Other names include BRV and UCB-
34714. The Chemical Abstract Services number (CAS #) of BRV is: 357336-
20-0. BRV is a racetam derivative.\3\ As the HHS noted, BRV does not 
have structural similarities to any other scheduled AED or to any major 
classes of abused sedative drugs with noted euphoric effects. Chemical 
synthesis of BRV is considered highly complex and includes several 
steps, reagents and specialized equipment.
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    \3\ Racetams are a class of drugs that have a pyrrolidoline 
center.
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    BRV is readily soluble in water at up to 700 mg/mL. In an in vitro 
oral tablet dissolution evaluation, BRV oral tablets were placed in a 
buffer (pH 6.4) for 16 hours. Approximately 86-96% of BRV was released 
after 16 hours in the buffer; 14-30% of BRV was released following 1 
hour and 40-66% BRV was released after 4 hours.
    Following oral ingestion, BRV is rapidly and completely absorbed. 
In healthy young males, the half-life of BRV was determined to be 
approximately 9 hours. According to the HHS, the half-life of BRV is 
decreased to 6 hours when a repeated oral dose of 800 mg/day BRV is 
administered. The HHS noted that BRV binds weakly to plasma proteins 
and is extensively metabolized through several pathways. Clearance 
through the kidneys represents 5-10% of the total clearance and only 3-
7% of the parent compound (BRV) was detected in the urine. The three 
main metabolites of BRV were detected in urine and according to the 
HHS, these metabolites are relatively inactive. One BRV metabolite was 
characterized as having a potency that was 20 times less than BRV, and 
this metabolite was not detected in human plasma and represented less 
than 3% of the dose in urine.
    4. Its History and Current Pattern of Abuse: As noted by the HHS, 
information on the history and current pattern of abuse of BRV is not 
available since this drug is currently not marketed in any country. A 
review of the animal and human data indicates that BRV has an abuse 
potential similar to other schedule V AEDs. If BRV were to be

[[Page 29490]]

approved for medical use, the HHS indicated that BRV would be abused 
for its euphoric properties and other abuse-related TEAEs that were 
reported in human clinical studies. Based on the available information, 
the HHS concluded that the history and pattern of abuse of BRV will be 
similar to other schedule V CNS depressants.
    5. The Scope, Duration, and Significance of Abuse: As noted by the 
HHS, information on the scope, duration, and significance of abuse of 
BRV is not available since this drug is currently not marketed in any 
country. Results from animal and human studies suggest that there is 
abuse potential associated with BRV and if marketed in the United 
States, it is likely that BRV will be abused similar to other AEDs that 
are CNS depressants. The HHS stated that it is unlikely that epileptic 
individuals (the population expected to take this drug) will abuse BRV. 
The HHS concluded that based on abuse potential similarities between 
BRV and other schedule V AEDs, it is likely that the scope, duration, 
and significance of abuse of BRV will be similar to these compounds.
    6. What, if any, Risk There is to the Public Health: The HHS 
characterized BRV's drug abuse potential to be similar to schedule V 
AEDs. As such, the public health risk with BRV will also be similar to 
other schedule V AEDs. The HHS noted that if BRV were approved for 
medical use, it would be abused for its rewarding properties. In 
healthy volunteers administered 600 mg or higher of BRV, cognitive and 
motor impairment and sedation were observed. It is unknown how BRV 
would interact in combination with other CNS depressants and if the 
sedative effects would be additive or even a lethal combination. In an 
interaction study with BRV and intravenous ethanol in healthy 
individuals, it was determined that BRV enhanced the effects of 
ethanol.
    7. Its Psychic or Physiological Dependence Liability: BRV has 
limited psychological dependence and does not appear to have physical 
dependence. When rats were administered BRV for 30 days, no signs of 
physical dependence were noted in comparison to the schedule IV 
comparator, chlordiazepoxide. Similarly, in human clinical studies with 
healthy volunteers, there were no reports or adverse events that noted 
physical dependence or a withdrawal syndrome associated with BRV use. 
The low potential for physical dependence observed with BRV is 
consistent with other schedule V AEDs. There is limited evidence for 
psychological dependence with BRV. Clinical studies have reported 
individuals experiencing increasing euphoria with increasing doses of 
BRV. Tolerance does not appear to develop with respect to BRV treatment 
on epileptic seizure reduction.
    8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled under the CSA: BRV is not an immediate precursor of 
any controlled substance.
    Conclusion: After considering the scientific and medical evaluation 
conducted by the HHS, the HHS' recommendation, and its own eight-factor 
analysis, the DEA has determined that these facts and all relevant data 
constitute substantial evidence of a potential for abuse of BRV. As 
such, the DEA hereby schedules BRV as a controlled substance under the 
CSA.

Determination of Appropriate Schedule

    The CSA outlines the findings required to place a drug or other 
substance in any particular schedule (I, II, III, IV, or V). 21 U.S.C. 
812(b). After consideration of the analysis and recommendation of the 
Assistant Secretary for Health of the HHS and review of all available 
data, the Acting Administrator of the DEA, pursuant to 21 U.S.C. 
812(b)(5), finds that:
    1. BRV has a low potential for abuse relative to the drugs or other 
substances in schedule IV. The overall abuse potential of BRV is 
comparable to schedule V controlled substances such as ezogabalin, 
pregabalin, and lacosamide;
    2. With FDA's approval of the new drug applications, BRV has a 
currently accepted medical use in the United States as adjunctive 
treatment of partial onset seizures in epileptic individuals ages 16 
and older; and
    3. Human and animal studies demonstrate that BRV has limited 
psychological dependence and does not appear to have physical 
dependence. There was no evidence of physical dependence associated 
with BRV in human and animal studies since there have been no reports 
of withdrawal syndromes or other physical dependence effects. Based on 
these data, abuse of BRV may lead to limited psychological dependence 
similar to schedule V AEDs but less than that of drugs in schedule IV.
    Based on these findings, the Acting Administrator of the DEA 
concludes that brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-
yl] butanamide) (also referred to as BRV; UCB-34714; Briviact), 
including its salts, warrants control in schedule V of the CSA. 21 
U.S.C. 812(b)(5).

Requirements for Handling Brivaracetam

    BRV is subject to the CSA's schedule V regulatory controls and 
administrative, civil, and criminal sanctions applicable to the 
manufacture, distribution, reverse distribution, dispensing, importing, 
exporting, research, and conduct of instructional activities and 
chemical analysis with, and possession involving schedule V substances, 
including the following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, dispenses, imports, exports, engages in research, 
or conducts instructional activities or chemical analysis with, or 
possesses) BRV, or who desires to handle BRV, must be registered with 
the DEA to conduct such activities pursuant to 21 U.S.C. 822, 823, 957, 
and 958 and in accordance with 21 CFR parts 1301 and 1312. Any person 
who currently handles BRV, and is not registered with the DEA, must 
submit an application for registration and may not continue to handle 
BRV, unless the DEA has approved that application for registration, 
pursuant to 21 U.S.C. 822, 823, 957, and 958, and in accordance with 21 
CFR parts 1301 and 1312.
    2. Disposal of stocks. Any person who does not desire or is not 
able to obtain a schedule V registration must surrender all quantities 
of currently held BRV, or may transfer all quantities of currently held 
BRV to a person registered with the DEA in accordance with 21 CFR part 
1317, in additional to all other applicable federal, state, local, and 
tribal laws.
    3. Security. BRV is subject to schedule III-V security requirements 
and must be handled and stored pursuant to 21 U.S.C. 821, 823, and 
871(b), and in accordance with 21 CFR 1301.71-1301.93.
    4. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of BRV must comply with 21 U.S.C. 825 and 958(e), 
and be in accordance with 21 CFR part 1302.
    5. Inventory. Every DEA registrant who possesses any quantity of 
BRV must take an inventory of BRV on hand, pursuant to 21 U.S.C. 827 
and 958, and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    Any person who becomes registered with the DEA must take an initial 
inventory of all stocks of controlled substances (including BRV) on 
hand on the date the registrant first engages in the handling of 
controlled substances, pursuant to 21 U.S.C. 827 and 958, and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.

[[Page 29491]]

    After the initial inventory, every DEA registrant must take a new 
inventory of all stocks of controlled substances (including BRV) on 
hand every two years, pursuant to 21 U.S.C. 827 and 958, and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    6. Records and Reports. Every DEA registrant must maintain records 
and submit reports for BRV, or products containing BRV, pursuant to 21 
U.S.C. 827 and 958(e), and in accordance with 21 CFR parts 1304, 1312, 
and 1317.
    7. Prescriptions. All prescriptions for BRV or products containing 
BRV must comply with 21 U.S.C. 829, and be issued in accordance with 21 
CFR parts 1306 and 1311, subpart C.
    8. Importation and Exportation. All importation and exportation of 
BRV must be in compliance with 21 U.S.C. 952, 953, 957, and 958, and in 
accordance with 21 CFR part 1312.
    9. Liability. Any activity involving BRV not authorized by, or in 
violation of, the CSA or its implementing regulations, is unlawful, and 
may subject the person to administrative, civil, and/or criminal 
sanctions.

Regulatory Analyses

Administrative Procedure Act

    Public Law 114-89 was signed into law, amending 21 U.S.C. 811. This 
amendment provides that in cases where a new drug is (1) approved by 
the Department of Health and Human Services (HHS) and (2) HHS 
recommends control in CSA schedule II-V, the DEA shall issue an interim 
final rule scheduling the drug within 90 days. Additionally, the law 
specifies that the rulemaking shall become immediately effective as an 
interim final rule without requiring the DEA to demonstrate good cause. 
Therefore, the DEA has determined that the notice and comment 
requirements of section 553 of the APA, 5 U.S.C. 553, do not apply to 
this scheduling action.

Executive Orders 12866, Regulatory Planning and Review, and 13563, 
Improving Regulation and Regulatory Review

    In accordance with Public Law 114-89, this scheduling action is 
subject to formal rulemaking procedures performed ``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 procedures 
and criteria for scheduling a drug or other substance. Such actions are 
exempt from review by the Office of Management and Budget (OMB) 
pursuant to section 3(d)(1) of Executive Order 12866 and the principles 
reaffirmed in Executive Order 13563.

Executive Order 12988, Civil Justice Reform

    This regulation meets the applicable standards set forth in 
sections 3(a) and 3(b)(2) of Executive Order 12988 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 Executive Order 13132. The rule does not have 
substantial direct effects on the States, on the relationship between 
the national government and the States, or on 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 Executive Order 13175. It 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

    In accordance with 5 U.S.C. 603(a), ``[w]henever an agency is 
required by [5 U.S.C. 553], or any other law, to publish general notice 
of proposed rulemaking for any proposed rule, or publishes a notice of 
proposed rulemaking for an interpretive rule involving the internal 
revenue laws of the United States, the agency shall prepare and make 
available for public comment an initial regulatory flexibility 
analysis.'' As noted in the above discussion regarding applicability of 
the Administrative Procedure Act, the DEA has determined that the 
notice and comment requirements of section 553 of the APA, 5 U.S.C. 
553, do not apply to this scheduling action. Consequently, the RFA does 
not apply to this interim final rule.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., the DEA has determined and certifies 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 UMRA of 1995.

Paperwork Reduction Act of 1995

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act of 1995. 44 U.S.C. 3501-
3521. This action would not impose recordkeeping or reporting 
requirements on State or local governments, individuals, businesses, or 
organizations. An agency may not conduct or sponsor, and a person is 
not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

Congressional Review Act

    This rule is not a major rule as defined by section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act (CRA)). This rule will not result in: An 
annual effect on the economy of $100,000,000 or more; a major increase 
in costs or prices for consumers, individual industries, Federal, 
State, or local government agencies, or geographic regions; or 
significant adverse effects on competition, employment, investment, 
productivity, innovation, or on the ability of U.S.-based companies to 
compete with foreign based companies in domestic and export markets. 
However, pursuant to the CRA, the DEA has submitted a copy of this 
interim final rule to both Houses of Congress and to the Comptroller 
General.

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, the DEA amends 21 CFR part 1308:

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), unless otherwise noted.


0
2. Amend Sec.  1308.15 by redesignating paragraphs (e)(1) through 
(e)(3) as paragraphs (e)(2) through (e)(4) and adding new paragraph 
(e)(1) to read as follows:


Sec.  1308.15  Schedule V.

* * * * *
    (e) * * *

[[Page 29492]]



(1) Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]       2710
 butanamide) (also referred to as BRV; UCB-34714; Briviact)
 (including its salts).........................................
 

* * * * *

    Dated: May 6, 2016.
Chuck Rosenberg,
Acting Administrator.
[FR Doc. 2016-11245 Filed 5-11-16; 8:45 am]
BILLING CODE 4410-09-P



                                                                    Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations                                         29487

                                                et seq.; 22 U.S.C. 7210; E.O. 13026, 61 FR              opportunity for a hearing or to                       Administration (DEA) for public
                                                58767, 3 CFR, 1996 Comp., p. 228; E.O.                  participate in a hearing must be                      inspection online at http://
                                                13222, 66 FR 44025, 3 CFR, 2001 Comp., p.               received on or before June 13, 2016.                  www.regulations.gov. Such information
                                                783; Notice of August 7, 2015, 80 FR 48233                                                                    includes personal identifying
                                                (August 11, 2015).                                      ADDRESSES: To ensure proper handling
                                                                                                        of comments, please reference ‘‘Docket                information (such as your name,
                                                Supplement No. 1 to Part 774—                           No. DEA–435’’ on all correspondence,                  address, etc.) voluntarily submitted by
                                                [Amended]                                               including any attachments.                            the commenter. The Freedom of
                                                                                                          • Electronic comments: The Drug                     Information Act (FOIA) applies to all
                                                ■ 21. In Supplement No. 1 to Part 774                                                                         comments received. If you want to
                                                                                                        Enforcement Administration encourages
                                                (the Commerce Control List), ECCN                                                                             submit personal identifying information
                                                                                                        that all comments be submitted
                                                1C981 is removed.                                                                                             (such as your name, address, etc.) as
                                                                                                        electronically through the Federal
                                                  Dated: May 5, 2016.                                   eRulemaking Portal, which provides the                part of your comment, but do not want
                                                Eric L. Hirschhorn,                                     ability to type short comments directly               it to be made publicly available, you
                                                Under Secretary for Industry and Security.              into the comment field on the Web page                must include the phrase ‘‘PERSONAL
                                                [FR Doc. 2016–11047 Filed 5–11–16; 8:45 am]             or attach a file for lengthier comments.              IDENTIFYING INFORMATION’’ in the
                                                                                                        Please go to http://www.regulations.gov               first paragraph of your comment. You
                                                BILLING CODE 3510–33–P
                                                                                                        and follow the online instructions at                 must also place all of the personal
                                                                                                        that site for submitting comments. Upon               identifying information you do not want
                                                                                                        completion of your submission, you will               made publicly available in the first
                                                DEPARTMENT OF JUSTICE                                                                                         paragraph of your comment and identify
                                                                                                        receive a Comment Tracking Number for
                                                Drug Enforcement Administration                         your comment. Please be aware that                    what information you want redacted.
                                                                                                        submitted comments are not                               If you want to submit confidential
                                                                                                        instantaneously available for public                  business information as part of your
                                                21 CFR Part 1308
                                                                                                        view on Regulations.gov. If you have                  comment, but do not want it to be made
                                                [Docket No. DEA–435]
                                                                                                        received a Comment Tracking Number,                   publicly available, you must include the
                                                                                                        your comment has been successfully                    phrase ‘‘CONFIDENTIAL BUSINESS
                                                Schedules of Controlled Substances:                                                                           INFORMATION’’ in the first paragraph
                                                Placement of Brivaracetam Into                          submitted and there is no need to
                                                                                                        resubmit the same comment.                            of your comment. You must also
                                                Schedule V                                                                                                    prominently identify the confidential
                                                                                                          • Paper comments: Paper comments
                                                AGENCY:  Drug Enforcement                               that duplicate the electronic submission              business information to be redacted
                                                Administration, Department of Justice.                  are not necessary and are discouraged.                within the comment.
                                                                                                                                                                 Comments containing personal
                                                ACTION: Interim final rule, with request                Should you wish to mail a paper
                                                                                                                                                              identifying information and confidential
                                                for comments.                                           comment in lieu of an electronic
                                                                                                                                                              business information identified as
                                                                                                        comment, it should be sent via regular
                                                                                                                                                              directed above will generally be made
                                                SUMMARY:    The Drug Enforcement                        or express mail to: Drug Enforcement
                                                                                                                                                              publicly available in redacted form. If a
                                                Administration is placing the substance                 Administration, Attn: DEA Federal                     comment has so much confidential
                                                brivaracetam ((2S)-2-[(4R)-2-oxo-4-                     Register Representative/ODW, 8701                     business information or personal
                                                propylpyrrolidin-1-yl] butanamide)                      Morrissette Drive, Springfield, VA                    identifying information that it cannot be
                                                (also referred to as BRV; UCB–34714;                    22152.                                                effectively redacted, all or part of that
                                                Briviact) (including its salts) into                      • Hearing requests: All requests for
                                                                                                                                                              comment may not be made publicly
                                                schedule V of the Controlled Substances                 hearing and waivers of participation
                                                                                                                                                              available. Comments posted to http://
                                                Act. This scheduling action is pursuant                 must be sent to: Drug Enforcement
                                                                                                                                                              www.regulations.gov may include any
                                                to the Controlled Substances Act, as                    Administration, Attn: Administrator,
                                                                                                                                                              personal identifying information (such
                                                revised by the Improving Regulatory                     8701 Morrissette Drive, Springfield,
                                                                                                                                                              as name, address, and phone number)
                                                Transparency for New Medical                            Virginia 22152. All requests for hearing
                                                                                                                                                              included in the text of your electronic
                                                Therapies Act which was signed into                     and waivers of participation should also
                                                                                                                                                              submission that is not identified as
                                                law on November 25, 2015.                               be sent to: (1) Drug Enforcement
                                                                                                                                                              directed above as confidential.
                                                DATES: The effective date of this                       Administration, Attn: Hearing Clerk/LJ,                  An electronic copy of this document
                                                rulemaking is May 12, 2016. Interested                  8701 Morrissette Drive, Springfield,                  and supplemental information,
                                                persons may file written comments on                    Virginia 22152; and (2) Drug                          including the complete Department of
                                                this rulemaking in accordance with 21                   Enforcement Administration, Attn: DEA                 Health and Human Services and Drug
                                                CFR 1308.43(g). Electronic comments                     Federal Register Representative/ODW,                  Enforcement Administration eight-factor
                                                must be submitted, and written                          8701 Morrissette Drive, Springfield,                  analyses, to this interim final rule are
                                                comments must be postmarked, on or                      Virginia 22152.                                       available at http://www.regulations.gov
                                                before June 13, 2016. Commenters                        FOR FURTHER INFORMATION CONTACT:                      for easy reference.
                                                should be aware that the electronic                     Barbara J. Boockholdt, Office of
                                                Federal Docket Management System                        Diversion Control, Drug Enforcement                   Request for Hearing, Notice of
                                                will not accept comments after 11:59                    Administration; Mailing Address: 8701                 Appearance at Hearing, or Waiver of
                                                p.m. Eastern Time on the last day of the                Morrissette Drive, Springfield, Virginia              Participation in Hearing
                                                comment period.                                         22152; Telephone: (202) 598–6812.                       Pursuant to 21 U.S.C. 811(a), this
                                                   Interested persons, defined at 21 CFR                SUPPLEMENTARY INFORMATION:                            action is a formal rulemaking ‘‘on the
jstallworth on DSK7TPTVN1PROD with RULES




                                                1300.01 as those ‘‘adversely affected or                                                                      record after opportunity for a hearing.’’
                                                aggrieved by any rule or proposed rule                  Posting of Public Comments                            Such proceedings are conducted
                                                issuable pursuant to section 201 of the                   Please note that all comments                       pursuant to the provisions of the
                                                Act (21 U.S.C. 811),’’ may file a request               received are considered part of the                   Administrative Procedure Act (APA), 5
                                                for hearing or waiver of hearing                        public record. They will, unless                      U.S.C. 551–559. 21 CFR 1308.41–
                                                pursuant to 21 CFR 1308.44. Requests                    reasonable cause is given, be made                    1308.45; 21 CFR part 1316, subpart D.
                                                for hearing and waivers of an                           available by the Drug Enforcement                     In accordance with 21 CFR 1308.44(a)–


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                                                29488               Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations

                                                (c), requests for a hearing, notices of                 treatment in the United States, and the               within 90 days, issue an interim final
                                                appearance, and waivers of an                           degree of dependence the substance                    rule controlling the drug in accordance
                                                opportunity for a hearing or to                         may cause. 21 U.S.C. 812. The initial                 with such subsections and 21 U.S.C.
                                                participate in a hearing may be                         schedules of controlled substances                    812(b) using the specified procedures.
                                                submitted only by interested persons,                   established by Congress are found at 21               For purposes of calculating the 90 days,
                                                defined as those ‘‘adversely affected or                U.S.C. 812(c), and the current list of all            Public Law 114–89 states that such date
                                                aggrieved by any rule or proposed rule                  scheduled substances is published at 21               shall be the later of the date on which
                                                issuable pursuant to section 201 of the                 CFR part 1308.                                        the Attorney General receives the
                                                Act (21 U.S.C. 811).’’ 21 CFR 1300.01.                     Pursuant to 21 U.S.C. 811(a)(1), the               scientific and medical evaluation and
                                                Requests for a hearing and notices of                   Attorney General may, by rule, ‘‘add to               the scheduling recommendation from
                                                participation must conform to the                       such a schedule or transfer between
                                                                                                                                                              the Secretary in accordance with
                                                requirements of 21 CFR 1308.44(a) or                    such schedules any drug or other
                                                                                                                                                              subsection (b), or the date on which the
                                                (b), as applicable, and include a                       substance if he * * * finds that such
                                                                                                        drug or other substance has a potential               Attorney General receives notification
                                                statement of the interest of the person in
                                                                                                        for abuse, and * * * makes with respect               from the Secretary that the Secretary has
                                                the proceeding and the objections or
                                                                                                        to such drug or other substance the                   approved an application under section
                                                issues, if any, concerning which the
                                                person desires to be heard. Any waiver                  findings prescribed by subsection (b) of              505(c), 512, or 571 of the Federal Food,
                                                of an opportunity for a hearing must                    section 812 of this title for the schedule            Drug, and Cosmetic Act or section
                                                conform to the requirements of 21 CFR                   in which such drug is to be placed                    351(a) of the Public Health Service Act,
                                                1308.44(c) including a written statement                * * *’’ The Attorney General has                      or indexed a drug under section 572 of
                                                regarding the interested person’s                       delegated this scheduling authority                   the Federal Food, Drug, and Cosmetic
                                                position on the matters of fact and law                 under 21 U.S.C. 811 to the                            Act, with respect to the drug described
                                                involved in any hearing.                                Administrator of the DEA. 28 CFR                      in paragraph (1). Public Law 114–89
                                                   Please note that pursuant to 21 U.S.C.               0.100.                                                further stipulates that a rule issued by
                                                811(a), the purpose and subject matter                     The CSA provides that scheduling of                the Attorney General under paragraph
                                                of the hearing are restricted to ‘‘(A)                  any drug or other substance may be                    (1) becomes immediately effective as an
                                                find[ing] that such drug or other                       initiated by the Attorney General (1) on              interim final rule without requiring the
                                                substance has a potential for abuse, and                her own motion; (2) at the request of the             Attorney General to demonstrate good
                                                (B) mak[ing] with respect to such drug                  Secretary of Health and Human Services                cause and requires that the interim final
                                                or other substance the findings                         (HHS); or (3) on the petition of any                  rule give interested persons the
                                                prescribed by subsection (b) of section                 interested party. 21 U.S.C. 811(a). This              opportunity to comment and to request
                                                812 of this title for the schedule in                   action imposes the regulatory controls                a hearing. After the conclusion of such
                                                which such drug is to be placed. * * *’’                and administrative, civil, and criminal               proceedings, the Attorney General must
                                                Requests for a hearing and waivers of                   sanctions of schedule V controlled                    issue a final rule in accordance with the
                                                participation in the hearing should be                  substances for any person who handles                 scheduling criteria of subsections 21
                                                submitted to DEA using the address                      or proposes to handle BRV.                            U.S.C. 811(b), (c), and (d) of this section
                                                information provided above.                                The Improving Regulatory                           and 21 U.S.C. 812(b).
                                                                                                        Transparency for New Medical
                                                Legal Authority                                         Therapies Act (Pub. L. 114–89) was                    Background
                                                   The DEA implements and enforces                      signed into law on November 25, 2015.
                                                titles II and III of the Comprehensive                  This law amended 21 U.S.C. 811 and                       Brivaracetam ((2S)-2-[(4R)-2-oxo-4-
                                                Drug Abuse Prevention and Control Act                   states that in cases where a new drug is              propylpyrrolidin-1-yl] butanamide)
                                                of 1970, as amended. 21 U.S.C. 801–971.                 (1) approved by the Department of                     (also referred to as BRV; UCB–34714;
                                                Titles II and III are referred to as the                Health and Human Services (HHS) and                   Briviact) is a new molecular entity with
                                                ‘‘Controlled Substances Act’’ and the                   (2) HHS recommends control in CSA                     central nervous system (CNS)
                                                ‘‘Controlled Substances Import and                      schedule II–V, DEA shall issue an                     depressant properties. BRV is known to
                                                Export Act,’’ respectively, and are                     interim final rule scheduling the drug,               be a high affinity ligand for the synaptic
                                                collectively referred to as the                         within 90 days.                                       vesicle protein, SV2A, which is found
                                                ‘‘Controlled Substances Act’’ or the                       The law further states that the 90-day             on excitatory synapses in the brain. On
                                                ‘‘CSA’’ for the purpose of this action.                 timeframe starts the later of (1) the date            November 22, 2014, UCB Inc. (Sponsor)
                                                The DEA publishes the implementing                      DEA receives the HHS scientific and                   submitted three New Drug Applications
                                                regulations for these statutes in title 21              medical evaluation/scheduling                         (NDAs) to the U.S. Food and Drug
                                                of the Code of Federal Regulations                      recommendation or (2) the date DEA                    Administration (FDA) for the tablet,
                                                (CFR), chapter II. The CSA and its                      receives notice of drug approval by                   oral, and intravenous formulations of
                                                implementing regulations are designed                   HHS. In addition, the law specifies that              BRV. The FDA accepted the NDA filings
                                                to prevent, detect, and eliminate the                   the rulemaking shall become                           for BRV on January 21, 2015.
                                                diversion of controlled substances and                  immediately effective as an interim final                On March 28, 2016 the DEA received
                                                listed chemicals into the illicit market                rule without requiring the DEA to
                                                                                                                                                              notification that HHS/FDA approved
                                                while providing for the legitimate                      demonstrate good cause therefor.
                                                                                                           Specifically, Public Law 114–89                    BRV as an add-on treatment to other
                                                medical, scientific, research, and
                                                                                                        revised section 201 of the CSA (21                    medications to treat partial onset
                                                industrial needs of the United States.
                                                                                                        U.S.C. 811) by inserting after subsection             seizures in patients age 16 years and
                                                Controlled substances have the potential
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                                                                                                        (i) a new paragraph (j), which requires               older with epilepsy.
                                                for abuse and dependence and are
                                                controlled to protect the public health                 that with respect to a drug referred to in            Determination to Schedule BRV
                                                and safety.                                             subsection (f), if the Secretary
                                                   Under the CSA, controlled substances                 recommends that the Attorney General                    Pursuant to 21 U.S.C. 811(a)(1),
                                                are classified into one of five schedules               control the drug in schedule II, III, IV,             proceedings to add a drug or substance
                                                based upon their potential for abuse,                   or V pursuant to subsections (a) and (b),             to those controlled under the CSA may
                                                their currently accepted medical use in                 the Attorney General is required to,                  be initiated by request of the Secretary


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                                                                    Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations                                                   29489

                                                of the HHS.1 On September 8, 2015, the                  action to lacasamide and ezogabine,                    BRV, there was an increase of drug
                                                HHS provided the DEA with a scientific                  which are both schedule V CNS                          likability, feeling of a high, and taking
                                                and medical evaluation document                         depressant anti-epileptics (AEDs). Based               the drug again in comparison to
                                                prepared by the FDA entitled ‘‘Basis for                on data submitted by the Sponsor in                    placebo. The HHS mentioned that
                                                the Recommendation to Place                             their NDAs, the HHS indicated that                     individuals who took BRV had fewer
                                                Brivaracetam in Schedule V of the                       administration of BRV in mice, rats, and               sedative, euphoric, stimulant, dizziness,
                                                Controlled Substances Act.’’ Pursuant to                dogs resulted in CNS depressant effects,               and overall negative subjective effects
                                                21 U.S.C. 811(b), this document                         including decreased locomotor activity                 compared to ALP.
                                                contained an eight-factor analysis of the               and reactivity, motor incoordination,                     3. The State of Current Scientific
                                                abuse potential of BRV as a new drug,                   and ataxia.                                            Knowledge Regarding Brivaracetam:
                                                along with the HHS’ recommendation to                      BRV is not self-administered in                     The chemical name for brivaracetam is
                                                control BRV under schedule V of the                     animals and, unlike schedule IV                        (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-
                                                CSA.                                                    benzodiazepines and the schedule III                   yl] butanamide. Other names include
                                                   In response, in December 2015, the                   AED perampanel, lacks pentobarbital-                   BRV and UCB–34714. The Chemical
                                                DEA reviewed the scientific and                         like (schedule II) discriminative                      Abstract Services number (CAS #) of
                                                medical evaluation and scheduling                       stimulus and reinforcing effects (HHS                  BRV is: 357336–20–0. BRV is a racetam
                                                recommendation provided by the HHS,                     review, 2015). In humans, BRV is most                  derivative.3 As the HHS noted, BRV
                                                along with all other relevant data, and                 similar to the schedule V AEDs                         does not have structural similarities to
                                                completed its own eight-factor review                   lacosamide, ezogabine, and pregabalin                  any other scheduled AED or to any
                                                document pursuant to 21 U.S.C. 811(c).                  in producing positive subjective effects               major classes of abused sedative drugs
                                                The DEA concluded that BRV met the                      without producing sedation and                         with noted euphoric effects. Chemical
                                                21 U.S.C. 812(b)(5) criteria for                        withdrawal following drug                              synthesis of BRV is considered highly
                                                placement in schedule V of the CSA.                     discontinuation that is observed with                  complex and includes several steps,
                                                Subsequently, on March 28, 2016, the                    schedule IV benzodiazepines. Based on                  reagents and specialized equipment.
                                                DEA received notification that HHS/                     this collective evidence, the HHS                         BRV is readily soluble in water at up
                                                FDA approved three NDAs for BRV (see                    concluded that BRV has an abuse                        to 700 mg/mL. In an in vitro oral tablet
                                                Background section).                                    potential that is most similar to AEDs in              dissolution evaluation, BRV oral tablets
                                                   Pursuant to the provisions of the                    schedule V.                                            were placed in a buffer (pH 6.4) for 16
                                                Improving Regulatory Transparency for                      2. Scientific Evidence of the Drug’s                hours. Approximately 86–96% of BRV
                                                New Medical Therapies Act (Pub. L.                      Pharmacological Effects, if Known: BRV                 was released after 16 hours in the buffer;
                                                114–89), and based on the HHS                           selectively binds with high affinity to                14–30% of BRV was released following
                                                recommendation, NDA approvals by                        synaptic vesicle protein 2A (SV2A). It                 1 hour and 40–66% BRV was released
                                                HHS/FDA, and DEA’s determination,                       produces reverse inhibition caused by                  after 4 hours.
                                                DEA is issuing this interim final rule to               negative modulators of gamma                              Following oral ingestion, BRV is
                                                schedule brivaracetam ((2S)-2-[(4R)-2-                  aminobutyric acid (GABA) and glycine                   rapidly and completely absorbed. In
                                                oxo-4-propylpyrrolidin-1-yl]                            and inhibits sodium (Na+) channels.                    healthy young males, the half-life of
                                                butanamide) (including its salts) as a                  These sites appear to underlie                         BRV was determined to be
                                                controlled substance under the CSA.                     pharmacological activity of BRV.                       approximately 9 hours. According to the
                                                   Included below is a brief summary of                    In rats, BRV at high doses partially                HHS, the half-life of BRV is decreased
                                                each factor as analyzed by the HHS and                  generalizes to the schedule IV                         to 6 hours when a repeated oral dose of
                                                the DEA, and as considered by the DEA                   benzodiazepine chlordiazepoxide. BRV,                  800 mg/day BRV is administered. The
                                                in its scheduling action. Please note that              across a wide range of doses, neither                  HHS noted that BRV binds weakly to
                                                both the DEA and HHS analyses are                       initiates nor maintains self-                          plasma proteins and is extensively
                                                available in their entirety under                       administration in rats trained to self-                metabolized through several pathways.
                                                ‘‘Supporting Documents’’ in the public                  administer cocaine. Human studies have                 Clearance through the kidneys
                                                docket for this interim final rule at                   reported that healthy individuals may                  represents 5–10% of the total clearance
                                                http://www.regulations.gov, under                       experience euphoria, sedation, and a                   and only 3–7% of the parent compound
                                                Docket Number ‘‘DEA–435.’’ Full                         drunken-like feeling following BRV                     (BRV) was detected in the urine. The
                                                analysis of, and citations to, the                      administration. When treatment-                        three main metabolites of BRV were
                                                information referenced in the summary                   emergent adverse events (TEAEs) 2 were                 detected in urine and according to the
                                                may also be found in the supporting and                 pooled across several clinical BRV                     HHS, these metabolites are relatively
                                                related material.                                       studies, the most common TEAEs were                    inactive. One BRV metabolite was
                                                   1. The Drug’s Actual or Relative                     dizziness and sedative-related events                  characterized as having a potency that
                                                Potential for Abuse: BRV is a new                       such as fatigue, extreme drowsiness,                   was 20 times less than BRV, and this
                                                chemical entity and has not been                        and extreme weakness. In a human                       metabolite was not detected in human
                                                marketed in the United States or in any                 abuse potential study, the oral abuse                  plasma and represented less than 3% of
                                                other country; information on actual                    potential, safety, tolerability, and                   the dose in urine.
                                                abuse of BRV is not available. The HHS                  pharmacokinetics of BRV (50 mg, 200                       4. Its History and Current Pattern of
                                                characterized BRV as related in its                     mg, and 1000 mg) were compared to 1.5                  Abuse: As noted by the HHS,
                                                                                                        and 3.0 mg of the schedule IV CNS                      information on the history and current
                                                  1 As set forth in a memorandum of understanding
                                                                                                        depressant alprazolam (ALP) and                        pattern of abuse of BRV is not available
                                                entered into by the HHS, the FDA, and the National
                                                                                                        placebo. When surveyed, for all doses of               since this drug is currently not marketed
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                                                Institute on Drug Abuse (NIDA), the FDA acts as the
                                                lead agency within the HHS in carrying out the                                                                 in any country. A review of the animal
                                                Secretary’s scheduling responsibilities under the         2 Treatment-emergent adverse event (TEAE): An
                                                                                                                                                               and human data indicates that BRV has
                                                CSA, with the concurrence of the NIDA. 50 FR            event or unexpected medical occurrence (e.g.           an abuse potential similar to other
                                                9518, Mar. 8, 1985. The Secretary of the HHS has        adverse event) which first appears during treatment
                                                delegated to the Assistant Secretary for Health of      with a drug or substance. TEAEs are typically          schedule V AEDs. If BRV were to be
                                                the HHS the authority to make domestic drug             absent prior to the onset of treatment or would have
                                                scheduling recommendations. 58 FR 35460, July 1,        been exacerbated relative to pre-treatment               3 Racetams are a class of drugs that have a

                                                1993.                                                   conditions.                                            pyrrolidoline center.



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                                                29490               Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations

                                                approved for medical use, the HHS                       Clinical studies have reported                        Requirements for Handling
                                                indicated that BRV would be abused for                  individuals experiencing increasing                   Brivaracetam
                                                its euphoric properties and other abuse-                euphoria with increasing doses of BRV.                   BRV is subject to the CSA’s schedule
                                                related TEAEs that were reported in                     Tolerance does not appear to develop                  V regulatory controls and
                                                human clinical studies. Based on the                    with respect to BRV treatment on                      administrative, civil, and criminal
                                                available information, the HHS                          epileptic seizure reduction.                          sanctions applicable to the manufacture,
                                                concluded that the history and pattern                     8. Whether the Substance is an                     distribution, reverse distribution,
                                                of abuse of BRV will be similar to other                Immediate Precursor of a Substance                    dispensing, importing, exporting,
                                                schedule V CNS depressants.                             Already Controlled under the CSA: BRV                 research, and conduct of instructional
                                                   5. The Scope, Duration, and                          is not an immediate precursor of any                  activities and chemical analysis with,
                                                Significance of Abuse: As noted by the                  controlled substance.                                 and possession involving schedule V
                                                HHS, information on the scope,                             Conclusion: After considering the
                                                duration, and significance of abuse of                                                                        substances, including the following:
                                                                                                        scientific and medical evaluation                        1. Registration. Any person who
                                                BRV is not available since this drug is                 conducted by the HHS, the HHS’                        handles (manufactures, distributes,
                                                currently not marketed in any country.                  recommendation, and its own eight-
                                                Results from animal and human studies                                                                         reverse distributes, dispenses, imports,
                                                                                                        factor analysis, the DEA has determined               exports, engages in research, or
                                                suggest that there is abuse potential                   that these facts and all relevant data
                                                associated with BRV and if marketed in                                                                        conducts instructional activities or
                                                                                                        constitute substantial evidence of a                  chemical analysis with, or possesses)
                                                the United States, it is likely that BRV                potential for abuse of BRV. As such, the
                                                will be abused similar to other AEDs                                                                          BRV, or who desires to handle BRV,
                                                                                                        DEA hereby schedules BRV as a                         must be registered with the DEA to
                                                that are CNS depressants. The HHS                       controlled substance under the CSA.
                                                stated that it is unlikely that epileptic                                                                     conduct such activities pursuant to 21
                                                individuals (the population expected to                 Determination of Appropriate Schedule                 U.S.C. 822, 823, 957, and 958 and in
                                                take this drug) will abuse BRV. The                                                                           accordance with 21 CFR parts 1301 and
                                                                                                           The CSA outlines the findings                      1312. Any person who currently
                                                HHS concluded that based on abuse                       required to place a drug or other
                                                potential similarities between BRV and                                                                        handles BRV, and is not registered with
                                                                                                        substance in any particular schedule (I,              the DEA, must submit an application for
                                                other schedule V AEDs, it is likely that                II, III, IV, or V). 21 U.S.C. 812(b). After
                                                the scope, duration, and significance of                                                                      registration and may not continue to
                                                                                                        consideration of the analysis and                     handle BRV, unless the DEA has
                                                abuse of BRV will be similar to these                   recommendation of the Assistant
                                                compounds.                                                                                                    approved that application for
                                                                                                        Secretary for Health of the HHS and                   registration, pursuant to 21 U.S.C. 822,
                                                   6. What, if any, Risk There is to the
                                                                                                        review of all available data, the Acting              823, 957, and 958, and in accordance
                                                Public Health: The HHS characterized
                                                                                                        Administrator of the DEA, pursuant to                 with 21 CFR parts 1301 and 1312.
                                                BRV’s drug abuse potential to be similar
                                                                                                        21 U.S.C. 812(b)(5), finds that:                         2. Disposal of stocks. Any person who
                                                to schedule V AEDs. As such, the public
                                                health risk with BRV will also be similar                  1. BRV has a low potential for abuse               does not desire or is not able to obtain
                                                to other schedule V AEDs. The HHS                       relative to the drugs or other substances             a schedule V registration must surrender
                                                noted that if BRV were approved for                     in schedule IV. The overall abuse                     all quantities of currently held BRV, or
                                                medical use, it would be abused for its                 potential of BRV is comparable to                     may transfer all quantities of currently
                                                rewarding properties. In healthy                        schedule V controlled substances such                 held BRV to a person registered with the
                                                volunteers administered 600 mg or                       as ezogabalin, pregabalin, and                        DEA in accordance with 21 CFR part
                                                higher of BRV, cognitive and motor                      lacosamide;                                           1317, in additional to all other
                                                impairment and sedation were                               2. With FDA’s approval of the new                  applicable federal, state, local, and tribal
                                                observed. It is unknown how BRV                         drug applications, BRV has a currently                laws.
                                                would interact in combination with                      accepted medical use in the United                       3. Security. BRV is subject to schedule
                                                other CNS depressants and if the                        States as adjunctive treatment of partial             III–V security requirements and must be
                                                sedative effects would be additive or                   onset seizures in epileptic individuals               handled and stored pursuant to 21
                                                even a lethal combination. In an                        ages 16 and older; and                                U.S.C. 821, 823, and 871(b), and in
                                                interaction study with BRV and                             3. Human and animal studies                        accordance with 21 CFR 1301.71–
                                                intravenous ethanol in healthy                          demonstrate that BRV has limited                      1301.93.
                                                individuals, it was determined that BRV                 psychological dependence and does not                    4. Labeling and Packaging. All labels,
                                                enhanced the effects of ethanol.                        appear to have physical dependence.                   labeling, and packaging for commercial
                                                   7. Its Psychic or Physiological                      There was no evidence of physical                     containers of BRV must comply with 21
                                                Dependence Liability: BRV has limited                   dependence associated with BRV in                     U.S.C. 825 and 958(e), and be in
                                                psychological dependence and does not                   human and animal studies since there                  accordance with 21 CFR part 1302.
                                                appear to have physical dependence.                     have been no reports of withdrawal                       5. Inventory. Every DEA registrant
                                                When rats were administered BRV for                     syndromes or other physical                           who possesses any quantity of BRV
                                                30 days, no signs of physical                           dependence effects. Based on these data,              must take an inventory of BRV on hand,
                                                dependence were noted in comparison                     abuse of BRV may lead to limited                      pursuant to 21 U.S.C. 827 and 958, and
                                                to the schedule IV comparator,                          psychological dependence similar to                   in accordance with 21 CFR 1304.03,
                                                chlordiazepoxide. Similarly, in human                   schedule V AEDs but less than that of                 1304.04, and 1304.11.
                                                clinical studies with healthy volunteers,               drugs in schedule IV.                                    Any person who becomes registered
                                                there were no reports or adverse events                    Based on these findings, the Acting                with the DEA must take an initial
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                                                that noted physical dependence or a                     Administrator of the DEA concludes                    inventory of all stocks of controlled
                                                withdrawal syndrome associated with                     that brivaracetam ((2S)-2-[(4R)-2-oxo-4-              substances (including BRV) on hand on
                                                BRV use. The low potential for physical                 propylpyrrolidin-1-yl] butanamide)                    the date the registrant first engages in
                                                dependence observed with BRV is                         (also referred to as BRV; UCB–34714;                  the handling of controlled substances,
                                                consistent with other schedule V AEDs.                  Briviact), including its salts, warrants              pursuant to 21 U.S.C. 827 and 958, and
                                                There is limited evidence for                           control in schedule V of the CSA. 21                  in accordance with 21 CFR 1304.03,
                                                psychological dependence with BRV.                      U.S.C. 812(b)(5).                                     1304.04, and 1304.11.


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                                                                    Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations                                            29491

                                                   After the initial inventory, every DEA               principles reaffirmed in Executive Order              private sector, of $100,000,000 or more
                                                registrant must take a new inventory of                 13563.                                                (adjusted for inflation) in any one year.’’
                                                all stocks of controlled substances                                                                           Therefore, neither a Small Government
                                                                                                        Executive Order 12988, Civil Justice
                                                (including BRV) on hand every two                                                                             Agency Plan nor any other action is
                                                                                                        Reform
                                                years, pursuant to 21 U.S.C. 827 and                                                                          required under UMRA of 1995.
                                                958, and in accordance with 21 CFR                         This regulation meets the applicable
                                                                                                        standards set forth in sections 3(a) and              Paperwork Reduction Act of 1995
                                                1304.03, 1304.04, and 1304.11.
                                                   6. Records and Reports. Every DEA                    3(b)(2) of Executive Order 12988 to                     This action does not impose a new
                                                registrant must maintain records and                    eliminate drafting errors and ambiguity,              collection of information requirement
                                                submit reports for BRV, or products                     minimize litigation, provide a clear legal            under the Paperwork Reduction Act of
                                                containing BRV, pursuant to 21 U.S.C.                   standard for affected conduct, and                    1995. 44 U.S.C. 3501–3521. This action
                                                827 and 958(e), and in accordance with                  promote simplification and burden                     would not impose recordkeeping or
                                                21 CFR parts 1304, 1312, and 1317.                      reduction.                                            reporting requirements on State or local
                                                   7. Prescriptions. All prescriptions for              Executive Order 13132, Federalism                     governments, individuals, businesses, or
                                                BRV or products containing BRV must                                                                           organizations. An agency may not
                                                comply with 21 U.S.C. 829, and be                         This rulemaking does not have                       conduct or sponsor, and a person is not
                                                issued in accordance with 21 CFR parts                  federalism implications warranting the                required to respond to, a collection of
                                                1306 and 1311, subpart C.                               application of Executive Order 13132.                 information unless it displays a
                                                   8. Importation and Exportation. All                  The rule does not have substantial                    currently valid OMB control number.
                                                importation and exportation of BRV                      direct effects on the States, on the
                                                must be in compliance with 21 U.S.C.                    relationship between the national                     Congressional Review Act
                                                952, 953, 957, and 958, and in                          government and the States, or on the
                                                                                                                                                                 This rule is not a major rule as
                                                accordance with 21 CFR part 1312.                       distribution of power and
                                                                                                                                                              defined by section 804 of the Small
                                                   9. Liability. Any activity involving                 responsibilities among the various
                                                                                                                                                              Business Regulatory Enforcement
                                                BRV not authorized by, or in violation                  levels of government.
                                                                                                                                                              Fairness Act of 1996 (Congressional
                                                of, the CSA or its implementing                         Executive Order 13175, Consultation                   Review Act (CRA)). This rule will not
                                                regulations, is unlawful, and may                       and Coordination With Indian Tribal                   result in: An annual effect on the
                                                subject the person to administrative,                   Governments                                           economy of $100,000,000 or more; a
                                                civil, and/or criminal sanctions.                                                                             major increase in costs or prices for
                                                                                                          This rule does not have tribal
                                                Regulatory Analyses                                     implications warranting the application               consumers, individual industries,
                                                                                                        of Executive Order 13175. It does not                 Federal, State, or local government
                                                Administrative Procedure Act                                                                                  agencies, or geographic regions; or
                                                                                                        have substantial direct effects on one or
                                                   Public Law 114–89 was signed into                    more Indian tribes, on the relationship               significant adverse effects on
                                                law, amending 21 U.S.C. 811. This                       between the Federal government and                    competition, employment, investment,
                                                amendment provides that in cases                        Indian tribes, or on the distribution of              productivity, innovation, or on the
                                                where a new drug is (1) approved by the                 power and responsibilities between the                ability of U.S.-based companies to
                                                Department of Health and Human                          Federal government and Indian tribes.                 compete with foreign based companies
                                                Services (HHS) and (2) HHS                                                                                    in domestic and export markets.
                                                recommends control in CSA schedule                      Regulatory Flexibility Act                            However, pursuant to the CRA, the DEA
                                                II–V, the DEA shall issue an interim                       In accordance with 5 U.S.C. 603(a),                has submitted a copy of this interim
                                                final rule scheduling the drug within 90                ‘‘[w]henever an agency is required by [5              final rule to both Houses of Congress
                                                days. Additionally, the law specifies                   U.S.C. 553], or any other law, to publish             and to the Comptroller General.
                                                that the rulemaking shall become                        general notice of proposed rulemaking                 List of Subjects in 21 CFR Part 1308
                                                immediately effective as an interim final               for any proposed rule, or publishes a
                                                rule without requiring the DEA to                       notice of proposed rulemaking for an                    Administrative practice and
                                                demonstrate good cause. Therefore, the                  interpretive rule involving the internal              procedure, Drug traffic control,
                                                DEA has determined that the notice and                  revenue laws of the United States, the                Reporting and recordkeeping
                                                comment requirements of section 553 of                  agency shall prepare and make available               requirements.
                                                the APA, 5 U.S.C. 553, do not apply to                  for public comment an initial regulatory                For the reasons set out above, the DEA
                                                this scheduling action.                                 flexibility analysis.’’ As noted in the               amends 21 CFR part 1308:
                                                                                                        above discussion regarding applicability
                                                Executive Orders 12866, Regulatory
                                                                                                        of the Administrative Procedure Act, the              PART 1308—SCHEDULES OF
                                                Planning and Review, and 13563,
                                                                                                        DEA has determined that the notice and                CONTROLLED SUBSTANCES
                                                Improving Regulation and Regulatory
                                                                                                        comment requirements of section 553 of
                                                Review
                                                                                                        the APA, 5 U.S.C. 553, do not apply to                ■ 1. The authority citation for 21 CFR
                                                  In accordance with Public Law 114–                    this scheduling action. Consequently,                 part 1308 continues to read as follows:
                                                89, this scheduling action is subject to                the RFA does not apply to this interim                  Authority: 21 U.S.C. 811, 812, 871(b),
                                                formal rulemaking procedures                            final rule.                                           unless otherwise noted.
                                                performed ‘‘on the record after
                                                opportunity for a hearing,’’ which are                  Unfunded Mandates Reform Act of 1995                  ■ 2. Amend § 1308.15 by redesignating
                                                conducted pursuant to the provisions of                   In accordance with the Unfunded                     paragraphs (e)(1) through (e)(3) as
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                                                5 U.S.C. 556 and 557. The CSA sets                      Mandates Reform Act (UMRA) of 1995,                   paragraphs (e)(2) through (e)(4) and
                                                forth the procedures and criteria for                   2 U.S.C. 1501 et seq., the DEA has                    adding new paragraph (e)(1) to read as
                                                scheduling a drug or other substance.                   determined and certifies that this action             follows:
                                                Such actions are exempt from review by                  would not result in any Federal
                                                the Office of Management and Budget                     mandate that may result ‘‘in the                      § 1308.15   Schedule V.
                                                (OMB) pursuant to section 3(d)(1) of                    expenditure by State, local, and tribal               *       *    *    *       *
                                                Executive Order 12866 and the                           governments, in the aggregate, or by the                  (e) * * *


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                                                29492                  Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations

                                                (1) Brivaracetam ((2S)-2-[(4R)-2-                            FOR FURTHER INFORMATION CONTACT:                      substance under section 505 of the
                                                  oxo-4-propylpyrrolidin-1-yl]                           Barbara J. Boockholdt, Office of                          Federal Food, Drug, and Cosmetic Act
                                                  butanamide) (also referred to as                       Diversion Control, Drug Enforcement                       (FDCA), 21 U.S.C. 355. 21 U.S.C.
                                                  BRV; UCB–34714; Briviact) (in-                         Administration; Mailing Address: 8701                     811(h)(1). The Attorney General has
                                                  cluding its salts) ...........................    2710 Morrissette Drive, Springfield, Virginia                  delegated her scheduling authority
                                                *       *       *       *       *                        22152; Telephone: (202) 598–6812.                         under 21 U.S.C. 811 to the
                                                                                                         SUPPLEMENTARY INFORMATION:                                Administrator of the DEA. 28 CFR
                                                  Dated: May 6, 2016.                                                                                              0.100.
                                                Chuck Rosenberg,                                             Legal Authority
                                                Acting Administrator.                                                                                              Background
                                                                                                                The Drug Enforcement
                                                [FR Doc. 2016–11245 Filed 5–11–16; 8:45 am]                  Administration (DEA) implements and                      Section 201(h)(4) of the CSA, 21
                                                BILLING CODE 4410–09–P                                       enforces titles II and III of the                     U.S.C. 811(h)(4), requires the
                                                                                                             Comprehensive Drug Abuse Prevention                   Administrator to notify the Secretary of
                                                                                                             and Control Act of 1970, as amended. 21               the Department of Health and Human
                                                DEPARTMENT OF JUSTICE                                        U.S.C. 801–971. Titles II and III are                 Services (HHS) of his intention to
                                                                                                             referred to as the ‘‘Controlled                       temporarily place a substance into
                                                Drug Enforcement Administration                              Substances Act’’ and the ‘‘Controlled                 schedule I of the CSA.1 The
                                                                                                             Substances Import and Export Act,’’                   Administrator transmitted the notice of
                                                21 CFR Part 1308                                             respectively, and are collectively                    intent to place butyryl fentanyl and
                                                                                                             referred to as the ‘‘Controlled                       beta-hydroxythiofentanyl into schedule
                                                [Docket No. DEA–434F]                                        Substances Act’’ or the ‘‘CSA’’ for the               I on a temporary basis to the Assistant
                                                                                                             purpose of this action. The DEA                       Secretary by letter dated December 21,
                                                Schedules of Controlled Substances:                                                                                2015. The Assistant Secretary
                                                                                                             publishes the implementing regulations
                                                Temporary Placement of Butyryl                                                                                     responded to this notice by letter dated
                                                                                                             for these statutes in title 21 of the Code
                                                Fentanyl and Beta-Hydroxythiofentanyl                                                                              January 13, 2016, and advised that
                                                                                                             of Federal Regulations (CFR), chapter II.
                                                Into Schedule I                                              The CSA and its implementing                          based on review by the Food and Drug
                                                AGENCY:  Drug Enforcement                                    regulations are designed to prevent,                  Administration (FDA), there are
                                                Administration, Department of Justice.                       detect, and eliminate the diversion of                currently no investigational new drug
                                                                                                             controlled substances and listed                      applications or approved new drug
                                                ACTION: Final order.
                                                                                                             chemicals into the illicit market while               applications for butryl fentanyl or beta-
                                                SUMMARY:    The Administrator of the Drug                    ensuring an adequate supply is available              hydroxythiofentanyl. The Assistant
                                                Enforcement Administration is issuing                        for the legitimate medical, scientific,               Secretary also stated that the HHS has
                                                this final order to temporarily schedule                     research, and industrial needs of the                 no objection to the temporary placement
                                                the synthetic opioids, N-(1-                                 United States. Controlled substances                  of butryl fentanyl or beta-
                                                phenethylpiperidin-4-yl)-N-                                  have the potential for abuse and                      hydroxythiofentanyl into schedule I of
                                                phenylbutyramide, also known as N-(1-                        dependence and are controlled to                      the CSA. The DEA has taken into
                                                phenethylpiperidin-4-yl)-N-                                  protect the public health and safety.                 consideration the Assistant Secretary’s
                                                phenylbutanamide, (butyryl fentanyl)                            Under the CSA, every controlled                    comments as required by 21 U.S.C.
                                                and N-[1-[2-hydroxy-2-(thiophen-2-                           substance is classified into one of five              811(h)(4). Neither butryl fentanyl nor
                                                yl)ethyl]piperidin-4-yl]-N-                                  schedules based upon its potential for                beta-hydroxythiofentanyl is currently
                                                phenylpropionamide, also known as N-                         abuse, its currently accepted medical                 listed in any schedule under the CSA,
                                                [1-[2-hydroxy-2-(2-thienyl)ethyl]-4-                         use in treatment in the United States,                and no exemptions or approvals are in
                                                piperidinyl]-N-phenylpropanamide,                            and the degree of dependence the drug                 effect for butryl fentanyl or beta-
                                                (beta-hydroxythiofentanyl), and their                        or other substance may cause. 21 U.S.C.               hydroxythiofentanyl under section 505
                                                isomers, esters, ethers, salts and salts of                  812. The initial schedules of controlled              of the FDCA, 21 U.S.C. 355. The DEA
                                                isomers, esters and ethers, into schedule                    substances established by Congress are                has found that the control of butryl
                                                I pursuant to the temporary scheduling                       found at 21 U.S.C. 812(c), and the                    fentanyl and beta-hydroxythiofentanyl
                                                provisions of the Controlled Substances                      current list of all scheduled substances              in schedule I on a temporary basis is
                                                Act. This action is based on a finding by                    is published at 21 CFR part 1308.                     necessary to avoid an imminent hazard
                                                                                                                Section 201 of the CSA, 21 U.S.C. 811,             to public safety, and as required by 21
                                                the Administrator that the placement of
                                                                                                             provides the Attorney General with the                U.S.C. 811(h)(1)(A), a notice of intent to
                                                butyryl fentanyl and beta-
                                                                                                             authority to temporarily place a                      temporarily schedule butryl fentanyl
                                                hydroxythiofentanyl into schedule I of
                                                                                                             substance into schedule I of the CSA for              and beta-hydroxythiofentanyl was
                                                the Controlled Substances Act is
                                                                                                             two years without regard to the                       published in the Federal Register on
                                                necessary to avoid an imminent hazard
                                                                                                             requirements of 21 U.S.C. 811(b) if she               March 23, 2016. 81 FR 15485.
                                                to the public safety. As a result of this
                                                                                                             finds that such action is necessary to                   To find that placing a substance
                                                order, the regulatory controls and
                                                                                                             avoid an imminent hazard to the public                temporarily into schedule I of the CSA
                                                administrative, civil, and criminal
                                                                                                             safety. 21 U.S.C. 811(h)(1). In addition,             is necessary to avoid an imminent
                                                sanctions applicable to schedule I
                                                                                                             if proceedings to control a substance are             hazard to the public safety, the
                                                controlled substances will be imposed
                                                                                                             initiated under 21 U.S.C. 811(a)(1), the
                                                on persons who handle (manufacture,
                                                                                                             Attorney General may extend the                         1 As discussed in a memorandum of
                                                distribute, reverse distribute, import,                                                                            understanding entered into by the Food and Drug
                                                                                                             temporary scheduling for up to one
                                                export, engage in research, conduct
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                                                                                                                                                                   Administration (FDA) and the National Institute on
                                                                                                             year. 21 U.S.C. 811(h)(2).                            Drug Abuse (NIDA), the FDA acts as the lead agency
                                                instructional activities or chemical                            Where the necessary findings are                   within the HHS in carrying out the Secretary’s
                                                analysis, or possess), or propose to                         made, a substance may be temporarily                  scheduling responsibilities under the CSA, with the
                                                handle, butyryl fentanyl and beta-                           scheduled if it is not listed in any other            concurrence of NIDA. 50 FR 9518, Mar. 8, 1985.
                                                hydroxythiofentanyl.                                         schedule under section 202 of the CSA,                The Secretary of the HHS has delegated to the
                                                                                                                                                                   Assistant Secretary for Health of the HHS the
                                                DATES:This final order is effective on                       21 U.S.C. 812, or if there is no                      authority to make domestic drug scheduling
                                                May 12, 2016.                                                exemption or approval in effect for the               recommendations. 58 FR 35460, July 1, 1993.



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Document Created: 2016-05-12 01:07:30
Document Modified: 2016-05-12 01:07:30
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionRules and Regulations
ActionInterim final rule, with request for comments.
DatesThe effective date of this rulemaking is May 12, 2016. Interested persons may file written comments on this rulemaking in accordance with 21 CFR 1308.43(g). Electronic comments must be submitted, and written comments must be postmarked, on or before June 13, 2016. 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.
ContactBarbara J. Boockholdt, Office of
FR Citation81 FR 29487 
CFR AssociatedAdministrative Practice and Procedure; Drug Traffic Control and Reporting and Recordkeeping Requirements

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