Janssen Research & Development, LLC

Global Regulatory Affairs

1125 Trenton-Harbourton Road, P.O. Box 200
Titusville NJ 08560

February 26, 2015

Division of Dockets Management (HFA-305)

Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, Maryland MD 20852
RE:

Docket FDA 2015 -N-0045, International Drug Scheduling: Convention on

Psychotropic Substances; World Health Organization Scheduling
Recommendations for Ketamine and CND Proposal to Place Ketamine in
Schedule I of the 1971 Psychotropic Convention

Dear Sir/ Madam:

The Janssen pharmaceutical companies of the Johnson & Johnson family of
companies welcome the opportunity to provide to the Food and Drug
Administration (FDA) our comments in response to the FDA Federal Register
Notice, 80 Fed. Reg. 4283 (January 27, 2015) in the above-captioned matter.
Executive Summary
Ketamine has important approved anesthetic uses in humans and animals in the
United States, and is already appropriately regulated under Schedule III of the
Controlled Substances Act (CSA) (21 CFR. 1308.13(c)(7)). Given the approved
medical uses of ketamine products in the United States, as well as its relative low
potential for abuse, classification is contrary to the CSA and Drug Enforcement
Administration regulations. Drug regulation and scheduling, whether pursuant to
United States law or international treaty, should maintain a proper balance
between regulating to prevent or deter abuse and maintaining availability of
substances for medical purposes. The United States placement of ketamine on
Schedule III provides a good example of that appropriate balance of ketamines
medical importance against its abuse potential and actual low levels of abuse.
Given the heterogeneous distribution of ketamine abuse and appropriate national
governmental approaches to ketamine regulation, regional or national level
regulation appears to be more appropriate to address this issue. Potential new
medical uses of ketamine and its isomer esketamine for treatment resistant
depression (TRD) should be considered in any scheduling decision. New
medications to treat TRD would address an important unmet medical need as

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demonstrated by the FDA breakthrough therapy designation of esketamine in

TRD, and if approved, patients should not be subjected to additional barriers to
treatment. We respectfully request that the United States strongly oppose and vote
against any proposal or recommendation to classify ketamine under Schedule I of
the 1971 Convention.
I.

Introduction

The FDA has requested comments on United Nations (UN) Economic and Social
Council published recommendations for action to be taken by the UN Commission
on Narcotic Drugs (CND) at the March 2015 meeting, including a request from the
Chinese Government that the CND vote to place ketamine in Schedule I of the
Convention on Psychotropic Substances of 1971 (1971 Convention). The Council
recommended that the CND should decide whether it wishes to place ketamine in
Schedule I of the 1971 Convention or, if not, what other action, if any, might be
required. The World Health Organizations (WHO) recommendation to the CND
was that ketamine should not be scheduled under international treaties. We
understand that pursuant to 21 U.S.C. 811(d)(2)(B), the Department of Health
and Human Services (HHS) is required to request public comments and provide a
recommendation that is binding on representatives of the United States in
discussions and negotiations at the CND meeting in Vienna, Austria in March
2015.
Ketamine is used as an anesthetic in human and veterinary medicine, and is
considered a core medicine (defined as a minimum medical need for a basic health
care system) by the WHO (WHO Model List Essential Medicines 2011).
Ketamine is one of the most commonly used anesthetic agents in developing
countries because it is inexpensive, readily available and easy to use, and is the
only available anesthetic in most rural areas of developing countries (Ketcham
1990). 1 Scheduling ketamine may leave entire countries with no alternative
anesthesia for essential surgery (WHO Expert Peer Review 2, 2014). 2 Ketamine
1

The ease of parenteral administration gives ketamine a major advantage when anesthetic gases are
impossible to use due to limited equipment and lack of appropriately trained specialists (WHO Expert Peer
Review 3, 2014). In countries with limited resources and infrastructure, ketamine is an ideal anesthetic
because it is inexpensive, has a wide margin of safety when compared with other anesthetic agents (WHO
2014), and does not suppress the cardiorespiratory system (WHO 2012). According to the WHO Critical
Review of Ketamine, general medical practices in Africa rely on ketamine for anesthesia (WHO 2012).
2

Parties to the Convention are obliged to prohibit any medical use of a Schedule I substance except by
"persons directly under control of the government, and even use for and by those persons is very restricted
(Art. 7). Restricting availability of ketamine under Schedule I could compromise health outcomes in
situations where ketamine would ordinarily be used. Providers in non-government institutions and
clinicians in remote areas, especially in resource poor settings, will be unable to use ketamine if it is placed
in Schedule I. Since many countries have no appropriate or affordable alternatives, scheduling ketamine
would force patients in those regions to forego lifesaving essential surgery (Ketcham 1990). In addition, as
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is also the primary anesthetic used in veterinary practice in the United States and
worldwide, and is used for the provision of analgesia in certain circumstances.
Limiting its availability would be a major loss to animal welfare, as well as have a
negative impact on the agricultural economy.3 Similarly, access for new medical
uses of ketamine and its enantiomer esketamine currently under investigation may
also be negatively impacted if the new uses are approved. Therefore, we strongly
request that HHS recommend that the United States oppose any action to schedule
ketamine as a Schedule I drug under the 1971 Convention. As described more
fully herein, we strongly support the WHOs recommendation that ketamine not
be scheduled under international treaties. In view of the well-accepted medical
uses for ketamine, placement in Schedule I, reserved for agents which have limited
medical uses, is not appropriate and would be disruptive and raise unnecessary
obstacles for human and veterinary medical practice.
II.

Ketamine Scheduling and Approved Uses in the United States

United States regulations implementing the CSA provide for scheduling of

ketamine, its salts, isomers, and salts of isomers as a psychotropic at Schedule III
(21 CFR 1308.13). Drugs scheduled as Schedule III have the following
findings:
(A) The drug or other substance has a potential for abuse less than the drugs
or other substances in schedules I and II.
(B) The drug or other substance has a currently accepted medical use in
treatment in the United States.
(C) Abuse of the drug or other substance may lead to moderate or low
physical dependence or high psychological dependence.
In the United States, ketamine is indicated for human use as the sole anesthetic
agent for diagnostic and surgical procedures that do not require skeletal muscle
relaxation, for the induction of anesthesia prior to the administration of other
general anesthetic agents, and to supplement low-potency agents, such as nitrous
oxide (Ketamine HCl USPI JHP). Ketamine is also indicated for use in animals: in
cats, for restraint or as the sole anesthetic agent for diagnostic or minor, brief,
noted in the 2014 WHO Expert Report, scheduling will likely lead to the decrease in availability and
accessibility of ketamine to the same level of other controlled medications, which would result in a public
health crisis (WHO Expert Peer Review 2, 2014).
3

In the critical review report for the 35th Expert Committee on Drug Dependence (ECDD), several
Member States indicated that ketamine is indispensable for its indications in veterinary medicine (WHO
Expert Peer Review 2, 2014).
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surgical procedures that do not require skeletal muscle relaxation, and in

subhuman primates for restraint (Ketamine HCl USPI Mylan).
Given the approved medical uses of ketamine products in the United States, a
Schedule I designation is not authorized by the CSA (21 CFR 812(b)(1)):
Except where control is required by United States obligations under
an international treaty, convention, or protocol, in effect on October
27, 1970, and except in the case of an immediate precursor, a drug or
other substance may not be placed in any schedule unless the
findings required for such schedule are made with respect to such
drug or other substance. The findings required for each of the
schedules are as follows:
(1) Schedule I.
(A) The drug or other substance has a high potential for abuse.
(B) The drug or other substance has no currently accepted
medical use in treatment in the United States.
(C) There is a lack of accepted safety for use of the drug or other
substance under medical supervision.
All drugs listed in Schedule I have no currently accepted medical use in treatment
in the United States and therefore may not be prescribed, administered, or
dispensed for medical use. In contrast, drugs listed in Schedules II through V all
have some accepted medical use and therefore may be prescribed, administered, or
dispensed for medical use.
Not dissimilar to the United States scheduling criteria, the WHO has developed
specific criteria to include a substance in a particular schedule. WHO has been
entrusted with the responsibility to make medical and scientific findings related to
a drugs abuse potential and its medical usefulness (UN Convention on
Psychotropic Substances 1971, Article 2(5)). For Schedule I under the 1971
Convention this applies to substances whose liability to abuse constitutes an
especially serious risk to public health and which have very limited, if any,
therapeutic usefulness (WHO Guidance on the WHO Review of Psychoactive
Substances for International Control, 2010). This is consistent with the 1971
Convention itself which prohibits all use except for scientific and very limited
medical purposes (UN Convention on Psychotropic Substances 1971, Article
7(a)).

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Accordingly, placement of ketamine under Schedule I would be inconsistent with

United States law, the 1971 Convention and the WHO scheduling criteria.
III.

The CND Should Consider the United States Experience in Striking

an Appropriate Balance of Regulation and Medical Availability

Drug regulation and scheduling, whether pursuant to United States law or

international treaty, should maintain a proper balance between regulating to
prevent or deter abuse and maintaining availability of substances for medical
purposes. The federal CSA recognizes that scheduled drugs have a useful and
legitimate medical purpose and are necessary to maintain the health and welfare of
the American people (21 CFR 801(I)). The preamble to the 1971 Convention
states that use of psychotropic substances for medical and scientific purposes is
indispensable, and availability should not be unduly restricted. As an indication
of the importance of ketamine for health and welfare globally, ketamine is on the
WHO Model List of Essential Medicines and the Essential Medicines for
Children.4
Given the existing medical and veterinary use of ketamine, its classification under
Schedule III in the United States provides the necessary balance between medical
use and its abuse potential and actual low levels of abuse. Importantly, ketamine
abuse has not shown a tendency to increase between 2006 and 2013 in the United
States (SAMHSA 2013).
If ketamine were to be controlled under Schedule I of the 1971 Convention, then
additional controls may be necessary to fulfill United States obligations. Such
additional controls would impact the appropriate access to ketamine for patients in
the United States, in the form of stricter prescribing and dispensing limits and
manufacturing quotas. This may have detrimental effects on health outcomes.
a. Ketamine Abuse Potential

Ketamine has pharmacologic properties consistent with a drug with

abuse potential. As an N-methyl-D-aspartate (NMDA) receptor
4

The WHO defines essential medicines as those that satisfy the priority health care needs of the population.
They are selected with due regard to disease prevalence, evidence on efficacy and safety, and comparative
cost-effectiveness, and are intended to be available within the context of functioning health systems at all
times in adequate amounts, in the appropriate dosage forms, with assured quality, and at a price the
individual and the community can afford (WHO Essential Medicines and Health Products). The WHO
Model List of Essential Medicines was first published in 1977 and included 208 individual medicines
which together could provide safe, effective treatment for the majority of communicable and noncommunicable diseases. The list is updated every two years. Since 2007, a separate list for children up to
12 years (WHO Model List of Essential Medicines) has been released. The 18th edition for adults and the
4th edition for children were released in April 2013. Ketamine is included in both lists as an injectable
anesthetic.
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antagonist, it has reinforcing properties in animals and humans,

although these are probably weaker compared to higher-affinity
NMDA antagonists. Importantly, ketamine is not an opioid and is not
associated with serious opioid-related adverse events (eg, hypotension
and respiratory depression). Ketamine has a combination of stimulant,
depressant, hallucinogenic, and analgesic properties (US Dept. Justice
2004; WHO Ketamine Review 2006).
The WHO ECDD expert report (WHO Expert Peer Review 1, 2014)
notes that, while there are multiple reports of physical problems caused
by prolonged use of ketamine (or use in high doses), such as urinary
tract and biliary tract problems, there is no firm evidence regarding
dependence in recreational users. Reported deaths in users of ketamine
in the United States and the United Kingdom were in most cases due to
acute multidrug intoxications (WHO Expert Peer Review 2, 2014).
Ketamine is produced commercially in a number of countries.
Ketamine synthesis is a complex and time-consuming process, making
clandestine production impractical (US Dept. Justice 2004; WHO
Expert Peer Review 1, 2014). Levels of use in the general population
are therefore low, with higher levels in groups that have access (eg,
medical and veterinarian professionals) (WHO Expert Peer Review 2,
2014).
b. Ketamine Abuse Data

The actual rates of ketamine abuse in the United States and worldwide
are low. Of the 64 countries who responded to the 2008 WHO
questionnaire for the preparation of the 35th WHO ECDD, 16 countries
reported on the use of ketamine in a harmful way, with reported
lifetime use of less than 2% (WHO Critical Review Ketamine 2012).
The 2013 National Survey on Drug Use and Health (NSDUH),
administered by the Office of Applied Studies of the Substance Abuse
and Mental Health Services Administration (SAMHSA), found that
nonmedical use of ketamine was low relative to other drugs of abuse.
Lifetime nonmedical use was reported by 0.9% to 1% of the
population, compared to the rates of 39% to 42% for marijuana, 13% to
15% for cocaine, and 5% to 6% for methamphetamine over the same
time period. There was no tendency for increased lifetime use in the
younger age groups between 2006 and 2013 (in persons 12 to 17 years
of age, the use remained unchanged, from 0.3% in 2006 to 0.2% in

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2013, and in persons 18 to 25 years of age, it steadily decreased from

2.8% in 2006 to 1.5% in 2013) (SAMHSA 2013).
The Drug Abuse Warning Network (DAWN 2011) survey reported that
ketamine accounted for a very minor proportion of drug-related
emergency department visits. Such visits for ketamine in 2009-2011
were consistently at the levels below 0.01% of the total emergency
department visits associated with illicit drug use (WHO Critical Review
Ketamine 2012).
Abuse of ketamine appears to be heterogeneously distributed, with
higher levels reported in specific regions/countries (WHO Critical
Review Ketamine 2006). Thus, regional or national level regulation
appears to be more appropriate to address this issue, as evidenced in the
governments comments solicited by the WHO in 2014 (UN Economic
and Social Council 2014). In fact, local measures are taken to curb its
misuse. In 2009, a total of 55 governments reported that ketamine had
been placed on the list of substances controlled under national
legislation intended to regulate its availability (WHO Expert Peer
Review 2, 2014).
However, such local action does not warrant placement of ketamine in
Schedule I of the 1971 Convention and, in fact, demonstrates that such
action would be detrimental to the public health.
c. Many Countries support Regional or National Level Regulation
Rather than International Scheduling to Achieve the Right
Balance
The UN Secretary-General solicited comments on economic, social,
legal, administrative or other factors relevant to the possible scheduling
of ketamine and received input from 26 governments as of December
2014. Only two countries supported Schedule I (Italy and the Republic
of Moldova). Several governments (e.g., Czech Republic, Hungary,
Latvia, Poland, Russian Federation, and Ukraine) objected specifically
to Schedule I classification, raising concerns about significant possible
consequences to veterinary practice, and the use of ketamine as an
anesthetic, and indicating that international control under Schedule II,
III or IV would be acceptable. A number of governments (including
Austria, Belgium, Ecuador, Germany, Latvia, Mexico, Netherlands,
and Switzerland), objected to scheduling altogether, citing existing
local regulations and suggesting that regional control measures could
be taken wherever relevant problems with the substance were observed.
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The comments cited the need to find the appropriate balance between
the level of controls required to mitigate misuse and the protection of
legitimate use (UN Economic and Social Council 2014).
IV.

Potential New Medical Uses for Ketamine and its Enantiomer

Esketamine Should Be Considered in Any Scheduling Decision

In addition to its established use as an anesthetic and analgesic, ketamine has

demonstrated promising results in early clinical trials for uses in psychiatry. There
is currently heightened interest in the scientific community regarding the use of
ketamine in the treatment of major depressive disorder (MDD) (DeWilde 2015).
Major depressive disorder is a serious, recurrent, and disabling psychiatric illness,
and is the leading cause of disability worldwide (WHO Depression Fact Sheet
2012; Vos 2010). About 30% of patients fail to achieve remission despite
treatment with multiple antidepressant medications, and are considered to have
TRD (Rush 2006; Fava 2003). In patients who respond to antidepressants, the
time to onset of effect is typically 4 to 7 weeks, during which time patients
continue to suffer from their symptoms and continue to be at risk of self-harm, as
well as being impacted by the associated harm to their personal and professional
lives (Rush 2006; Saveanu 2015). Therefore, there is a significant need to develop
novel treatments based upon relevant pathophysiologic pathways underlying MDD
for the rapid relief of symptoms of depression, especially in patients with TRD
(DeWilde 2015).
Ketamine is approved and widely used for the induction and maintenance of
anesthesia via intramuscular (IM) or intravenous (IV) administration (Ketamine
HCl USPI JHP). The desired analgesic-anesthetic effects of ketamine and
esketamine are attributed to the blockade of ionotropic NMDA glutamate
receptors.
Monoamines (serotonin, norepinephrine, and/or dopamine) are only modulatory
transmitters; therefore, conventional monoaminergic antidepressants would not be
expected to robustly affect synaptic transmission, activity-dependent release of
brain-derived neurotrophic factor (BDNF), or synaptogenesis (Duman 2012). In
contrast, the mechanism of action of ketamine is distinct from conventional
antidepressants and ketamine profoundly affects fast excitatory glutamate
transmission, increases BDNF release, and stimulates synaptogenesis (Duman
2012).
Most literature reports of the antidepressant effects of ketamine describe
studies using IV administration of the racemate, with a few exceptions (Cusin
2012). Janssen is developing esketamine for antidepressant therapy. Moreover,
intranasal administration is being investigated instead of IV administration, since
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intranasal administration can offer better convenience and ease of use for patients
(McGirr 2015; Opler 2015).
Janssen has completed several Phase 1 and 2 studies with esketamine and
ketamine. Data from a Phase 2 study conducted by Janssen have shown that IV
esketamine has a similar, rapid, and robust antidepressant effect as that seen with
IV ketamine.
In November 2013, the FDA granted Breakthrough Therapy designation to
esketamine for TRD. A breakthrough therapy is a drug (1) intended alone or in
combination with one or more other drugs to treat a serious or life threatening
disease or condition and (2) preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over existing therapies on one or more
clinically significant endpoints, such as substantial treatment effects observed
early in clinical development (FDA SIA Section 902).
In light of the evidence showing that esketamine can be an effective treatment for
patients with TRD, the promising results from early studies in this population, and
the FDAs recognition of the importance to patients of this potential new treatment
by granting Breakthrough Therapy designation, there is a heightened level of
interest among government bodies, academic institutions and the pharmaceutical
industry to confirm these early findings in future studies.
As previously mentioned, Janssen is currently investigating an intranasal
formulation of esketamine in TRD. The Janssen development program includes an
ongoing Phase 2 trial of intranasal esketamine in subjects with TRD, with plans to
initiate several global Phase 3 studies in 2015. Should the planned Phase 3 studies
confirm the earlier evidence that TRD patients can benefit from intranasal
esketamine and with an acceptable safety and tolerability profile, Janssen would
seek to make this medicine available to patients worldwide by submitting
marketing applications for approval in the United States and other regions.
Given the promising studies and potential for increased medical use of
ketamine and, if approved, esketamine, placement of ketamine under Schedule I of
the 1971 Convention may have a detrimental impact for ongoing and planned
research with ketamine and esketamine. For example, if Janssens investigational
formulation containing esketamine were approved for use in TRD, this would
represent a new treatment for patients who desperately need more effective
options to treat this illness, thus fulfilling an unmet medical need. Restricting or
eliminating the availability of this drug, if approved, would subject these patients
to additional barriers to obtaining treatment deemed necessary by their health care
professional.

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V.

Conclusion and Requested Action

We respectfully request that the United States strongly oppose scheduling of

ketamine and vote against any recommendation or proposal to schedule ketamine
under Schedule I of the 1971 Convention.
Sincerely,
Signature:

Husseini Manji

Husseini Manji (Feb 26, 2015)

Email: hmanji@its.jnj.com
Title: Global Therapeutic Area Head

Husseini Manji

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