[Federal Register Volume 62, Number 118 (Thursday, June 19, 1997)]
[Notices]
[Pages 33418-33424]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-16064]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97N-0221]
Benzodiazepines and Related Substances; Criteria for Scheduling
Recommendations Under the Controlled Substance Act; Notice of Public
Hearing
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public hearing.
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SUMMARY: The Food and Drug Administration (FDA) in conjunction with
other Federal agencies will convene a part 15 public hearing on
benzodiazepines and related substances. The purpose of the hearing is
to gather evidence in order to assess the abuse potential of
benzodiazepines and related compounds and to develop criteria that will
distinguish the substances in order to address their appropriate
scheduling under the Controlled Substance Act (the CSA).
DATES: The hearing will be held on Thursday and Friday, September 11
and 12, 1997, from 9 a.m. to 4 p.m. Written notice of participation
should be filed by August 14, 1997. The closing date for comments will
be October 17, 1997.
ADDRESSES: The public hearing will be held at the Renaissance Hotel,
999 Ninth St. NW., Washington, DC 20001-9000. Written notices of
participation and any comments are to be sent to the Dockets Management
Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm.
1-23, Rockville, MD 20857. Transcripts of the public hearing may be
requested in writing from the Freedom of Information Office (HFI-35),
Food and Drug Administration, 5600 Fishers Lane, rm. 12A-16, Rockville,
MD 20857, approximately 15 working days after the hearing, at a cost of
10 cents per page. The transcript of the public hearing, copies of data
and information submitted during the hearing, and any written comments
will be available for review at the Dockets Management Branch (address
above) between 9 a.m. and 4 p.m., Monday through Friday.
FOR FURTHER INFORMATION CONTACT: Nicholas P. Reuter, Office of Health
Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane, rm.
15-22, Rockville, MD 20857, 301-827-1696, FAX 301-443-0232, e-mail
``[email protected]''.
SUPPLEMENTARY INFORMATION:
I. Background
Benzodiazepines and related drug substances have consistently
ranked among the most widely prescribed drug products in the United
States. These products are used extensively as anxiolytics, sedatives,
and hypnotics. Concomitant with the widespread use of these products
have been concerns associated with benzodiazepine abuse, misuse, and
the level of domestic and international control applied to these
substances.
Benzodiazepines act upon the central nervous system (CNS). In
addition, benzodiazepine substances have the potential for abuse and
the capacity to produce physical and psychological dependence. As such,
benzodiazepine substances have been subject to domestic and
international drug control reviews. For the most part, until recently,
these international and domestic reviews have resulted in uniform
domestic and international controls. Essentially, all benzodiazepines
and related compounds are controlled domestically in schedule IV of the
CSA. In the most recent benzodiazepine-type substance domestic
scheduling review, Ambien (Zolpidem), was added to Schedule
IV of the CSA in 1993. Internationally, most benzodiazepines are
controlled in Schedule IV of the Convention on Psychotropic Substances,
1971 (the Convention). However, in 1990, the World Health Organization
(WHO) reviewed, but did not recommend control of, three benzodiazepine
substances (brotizolam, etizolam, and quazepam).
In response to a request from the Drug Enforcement Administration
(DEA), the Department of Health and Human Services (DHHS) is currently
evaluating the abuse liability of quazepam, a benzodiazepine controlled
in Schedule IV of the CSA. The DEA request followed a petition from the
company that manufactures a drug product containing quazepam as the
active ingredient (Doral). In its petition, the manufacturer
requests that quazepam be removed from Schedule IV of the CSA and
decontrolled.
A. International Reviews
Benzodiazepines and related substances are psychotropics and are
subject to the Convention. The domestic review and control of many
benzodiazepine substances has been directly influenced by international
scheduling actions. This is because the United States is expected to
control substances domestically to fulfill international scheduling
actions under the Convention. In addition, although the findings
necessary for control under the Convention and the CSA are not
identical, the schedule structure and issues surrounding the
international and domestic control actions on benzodiazepines are
similar and overlap. As discussed in section I.A.1., 2., and 3 of this
document, the international scheduling review policy has evolved
between the initial class reviews in the 1980's and the more recent
substance oriented assessments.
1. The 1984 Review
The United Nations (UN) Commission on Narcotic Drugs added 33
benzodiazepine substances to Schedule IV of the Convention (NAR/CL.4/
1984; DND 421/12(1-7)) in March, 1984. The UN action followed an
extensive review by the WHO, which had recommended that all 33
substances be controlled in Schedule IV. The WHO considered the
following information in evaluating the need for international control:
(1) Chemical structure, receptor binding characteristics, sedative-
hypnotic, anticonvulsant, and anxiolytic profile of CNS effects;
(2) Animal data on psychological and physical dependence potential;
(3) Human experimental data on both dependence and abuse potential;
(4) Clinical data on dependence and public health problems;
(5) Epidemiological data on public health and social problems;
(6) Extent of abuse or likelihood of abuse and seriousness of
public health and social problems resulting from such abuse; and
(7) Utilization and usefulness in therapy.
The WHO found that for many of the 33 benzodiazepine substances, no
data were available other than for items (1) and (4) listed previously.
In recommending international control, however, the WHO determined that
if a
[[Page 33419]]
drug under review possessed characteristics fulfilling item (1) listed
previously, the drug had the capacity to produce a state of dependence
and the likelihood of abuse constituted a public health and social
problem warranting international control (48 FR 53754, November 29,
1983; see also 48 FR 23913, May 27, 1983).
After reviewing written comments and convening a public meeting on
the WHO recommendations, DHHS concluded that there was sufficient
evidence, in the form of significant actual abuse or trafficking data
or compelling preclinical and clinical abuse liability data on 18 of
the 33 substances that the WHO was recommending for control. DHHS was
not aware of similar data for the remaining 15 benzodiazepine
substances that the WHO was recommending for international control. In
essence, the United States disagreed with the WHO assessment that the
chemical and pharmacological similarity of all 33 benzodiazepine
substances were sufficient to warrant international scheduling.
2. The 1991 Review
The WHO reconsidered the international control of benzodiazepine
substances again in 1989. In 1989, a WHO expert committee (the Expert
Committee on Drug Dependence (ECDD)) reviewed four benzodiazepine
substances, midazolam, brotizolam, etizolam, and quazepam. The ECDD
recommended that only one of these substances, midazolam, be added to
Schedule IV of the CSA. According to the 26th ECDD report, midazolam's
control was based on the water solubility of midazolam's salts, and
evidence of actual abuse associated with midazolam (Ref. 1). In 1990,
the U.N. subsequently voted to add midazolam to Schedule IV of the
Convention.
In 1990, the ECDD examined the issue of differential scheduling
among the 34 benzodiazepine substances controlled in Schedule IV of the
Convention (33 initial substances plus midazolam). The United States
forwarded abuse liability, trafficking, and other pertinent data to the
WHO as part of this review (see 54 FR 38441, September 18, 1989, and 54
FR 42844, October 18, 1989). The ECDD considered extensive prereview
documents (Ref. 2) on each substance and again determined that three
benzodiazepine substances that were not controlled (brotizolam,
etizolam, and quazepam) should not be controlled because the ``degree
of seriousness of the public health and social problems associated with
the abuse of [these substances] was not great enough to warrant
international control (Ref. 3).''
The ECDD also considered the information available on the 34
benzodiazepine substances that were already controlled internationally.
The ECDD differentiated the 34 substances into the following 3
categories:
(1) Nineteen benzodiazepine substances were found to be
appropriately controlled at their present level (Schedule IV of the
Convention). The ECDD determined that they needed no further action.
The nineteen substances are:
Table 1--Nineteen Benzodiazepine Substances Considered Appropriately Controlled By The ECDD
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Substances
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Alprazolam Halazopam Nitrazepam
Bromazepam Ketazolam Oxazepam
Chlordiazepoxide Lorazepam Prazepam
Clobazam Lometazepam Temazepam
Clonazepam Medazepam Triazolam
Chlorazepate Midazolam
Flurazepam Nimetazepam
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(2) The ECDD found that the 13 substances below have high to
moderate therapeutic usefulness, with few or no reports of abuse or
illicit activity. The ECDD recommended that the WHO monitor the
substances to determine whether or not they should be considered for
descheduling:
Table 2 --Thirteen Benzodiazepine Substances Being Considered For Rescheduling By The ECDD
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Substances
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Camazepam Ethyl loflazepate Nordiazepam
Clotazepam Fludiazepam Oxazolam
Cloxazolam Haloxazolam Pinazepam
Delorazepam Loprazolam Tetrazepam
Estazolam
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(3) Finally, the ECDD recommended that two substances, diazepam and
flunitrazepam, should be monitored for appropriate scheduling. The ECDD
found that:
* * *in comparison with all other benzodiazepines reviewed,
diazepam and flunitrazepam showed a continuing higher incidence of
abuse and association with illicit activities. The higher abuse
potential of diazepam than that of several other benzodiazepine
anxiolytics has also been demonstrated in human experimental studies
and survey studies of drug abusers, supported by information
received from health professionals engaged in the treatment of drug
dependence.
The ECDD's differentiation of the controlled benzodiazepines and
the recommendation for not controlling three substances were based on
an evaluation of information in the following areas:
a. Human pharmacokinetic studies:
Onset of action, elimination time, and duration of effect after
both single and repeated administrations may be important determinants
of the dependence potential of individual substances. Active
metabolites may contribute to the overall effects of a substance.
b. Preclinical studies:
(1) Drug discrimination.
(2) Physical dependence.
(3) Self-administration.
c. Clinical studies:
(1) Categorization of subjective effects in persons with histories
of drug abuse.
[[Page 33420]]
(2) Determination of euphoriant, liking, and reinforcing effects in
persons with histories of drug abuse.
(3) Assessment of physical dependence.
d. Epidemiological data and information on illicit activities:
(1) Utilization data.
(2) Reports of extent and nature of actual abuse.
(3)Survey data.
(4) Drug seizures.
(5) Reports of clandestine manufacture.
(6) Diversion from illicit sources.
e. Clinical usefulness and breadth of therapeutic indications:
In sum, the international review, culminating in 1991, strongly
suggests that criteria can be developed and applied to differentiate
the abuse liability of individual benzodiazepine substances.
Importantly, the ECDD suggested that these criteria should be used
collectively and that no one criterion could or should be used as a
sole determinate for control.
3. The 1995 Review
In 1994 and 1995, the ECDD considered five benzodiazepine
substances or benzodiazepine-related substances for possible changes in
their control status under the Convention.
a. Brotizolam. The ECDD recommended that brotizolam should be added
to Schedule IV of the Convention. This recommendation was based on
studies that demonstrate that brotizolam is a short-acting hypnotic
with a mean elimination half life of 4 to 5 hours. The ECDD also found
that brotizolam produces mild-to-severe withdrawal symptoms that
indicate that the substance has a moderate dependence potential similar
to other benzodiazepine hypnotics. Brotizolam was found to have an
appreciable abuse liability based on the actual abuse problems in two
countries.
b. Flunitrazepam. The ECDD differentiated flunitrazepam from other
benzodiazepines, including diazepam, and recommended that it be up-
scheduled from Schedule IV to Schedule III of the Convention. The ECDD
based its recommendation on flunitrazepam's effects on the central
nervous system, on flunitrazepam's dependence potential, and on its
actual abuse.
The ECDD found that flunitrazepam's pharmacology and central
nervous system effects were different than other benzodiazepines:
Flunitrazepam has typical benzodiazepine effects, with a greater
sedative-hypnotic potency than diazepam or chlordiazepoxide.
Flunitrazepam binds with high affinity to central benzodiazepine
receptors and is rapidly absorbed after oral administration. The
elimination half-life of flunitrazepam following a single oral dose
ranges between 9 and 25 hours in humans. Accumulation occurs with
chronic administration (Ref. 4).
Further, the ECDD was able to distinguish flunitrazepam from other
benzodiazepine substances on the basis of its dependence producing
characteristics:
Drug preference studies in opioid users, however, have shown
that flunitrazepam and diazepam stand out from other benzodiazepines
by producing a strong positive reinforcing effect in these subjects.
Flunitrazepam is estimated to have a moderate abuse potential which
may be higher than that of other benzodiazepines. The rapid onset
and longer duration of action, coupled with the stronger sedative-
hypnotic effects, may contribute to its higher abuse potential (Ref.
5).
Finally, the ECDD found that flunitrazepam was reported to be the
most [widely] abused benzodiazepine by opioid abusers in Europe, Asia,
and Oceania. The health problems associated with the abuse of
flunitrazepam ``include deaths directly or indirectly related to its
use, drug dependence, withdrawal syndrome, paranoia, amnesia, and other
psychiatric disorders.'' Although information available indicated that
both diazepam and flunitrazepam were associated with a higher incidence
of ``illicit activities'' when the ECDD factored in the amounts
manufactured and potency, flunitrazepam could be distinguished with
respect to both seizures of the drug and the number of cases.
c. Zolpidem. The ECDD noted that Zolpidem is a ligand that binds
specifically to the 1 benzodiazepine receptor. The
committee characterized Zolpidem as a short-acting hypnotic that does
not alter significantly natural sleep characteristics. The ECDD
characterized zolpidem's abuse liability as minimal, which may be
attributable to its short marketing history. The ECDD did not recommend
further review of this substance.
d. Zopiclone. The ECDD noted that zopiclone is a hypnotic
pharmacologically similar to benzodiazepines, binding to central, but
not peripheral benzodiazepine, receptors. The ECDD rated zopiclone's
dependence potential as comparable to benzodiazepines; however, its
abuse liability could not be considered significant because there were
so few reports of abuse despite availability in 40 countries. The ECDD
did not recommend further review for control.
e. Triazolam. The ECDD determined that no scheduling recommendation
was required for triazolam, but they suggested continued monitoring of
abuse-related adverse reactions.
B. Domestic Control Actions
There are 36 benzodiazepine substances controlled domestically in
Schedule IV the CSA. For the most part, these substances have been
added to Schedule IV in groups.
(1) Six benzodiazepine substances were controlled in 1975 (40 FR
23998, June 4, 1975). These substances are: Chlordiazepoxide,
clonazepam, clorazepate, diazepam, flurazepam, and oxazepam.
(2) An additional six benzodiazepine substances were controlled in
Schedule IV between 1976 and 1984. These substances are: Prazepam (41
FR 55176, December 17, 1976), lorazepam (42 FR 54546, October 7, 1977),
temazepam (46 FR 20671, April 7, 1981), halazepam (46 FR 53407, October
29, 1981), alprazolam (46 FR 55688, November 12, 1981), and triazolam
(47 FR 57694, December 28, 1982).
The twelve substances listed under section II.B.(1) and (2) of this
document had been approved for marketing by FDA prior to their control
under the CSA, and prior to the international review that led to the
initial international control of 33 benzodiazepine substances in 1984.
These substances were the subject of scientific and medical reviews and
scheduling recommendations by DHHS, as required under 21 U.S.C. 811(a))
of the CSA.
For the most part, the reviews and findings were similar, and did
not reflect the application of criteria that would differentiate the
individual substances.
(3) Twenty-one benzodiazepine substances were controlled
``temporarily'' in Schedule IV of the CSA in 1984 (49 FR 39307, October
5, 1984). These substances were not reviewed under the scheduling
provisions of 21 U.S.C. 811(a) of the CSA. Instead, the substances were
controlled domestically in schedule IV under the temporary control
provisions of section 201(d) (4) of the CSA. DEA noted that the
temporary scheduling order for each substance shall remain in effect
until the process of permanent scheduling is completed under 21 U.S.C.
811(a) and (b) of the CSA (Ref. 6) None of the substances are marketed
in the United States at this time. The 21 substances are:
[[Page 33421]]
Table 3--Twenty-One Benzodiazipine Substances Controlled Under Section 201(d)(4) Of The CSA
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Substances
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Bromazepam Ethyl loflazepate Nimetazepam
Camazepam Fludiazepam Nitrazepam
Clobazam Flunitrazepam Ordiazepam
Clotazepam Haloxazolam Oxazolam
Cloxazolam Ketazolam Pinazepam
Delorazepam Loprazolam Tetrazepam
Estazolam Lormetazepam Medazepam
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There was no attempt to examine the abuse liability of these
substances individually. Indeed, in recommending the Schedule IV
control to DEA, the Assistant Secretary for Health stated that
``[p]lacement of the following drug substances in Schedule IV would
also control them similarly to other benzodiazepines already marketed
in this country'' (Ref. 7).
(4) Two substances, midazolam and quazepam, were added to Schedule
IV in 1986 (51 FR 10190, March 25, 1986). As discussed in section I.A.2
of this document, midazolam was controlled internationally in 1991.
(5) Zolpidem is the most recent benzodiazepine related substance to
be controlled domestically. This substance was added to Schedule IV in
1993, following its review and approval by FDA and following a
comprehensive medical and scientific evaluation by DHHS (58 FR 7186,
February 5, 1993).
Zolpidem is a novel nonbenzodiazepine related hypnotic, that
possesses an imidazopyridine structure. Although Zolpidem is chemically
not a benzodiazepine and appears to have some distinct receptor binding
activity at one identified benzodiazepine receptor, its pharmacology,
psychological, and physical dependence liability do not appear overall
to be any less than the other benzodiazepines that are currently listed
in Schedule IV of the CSA.
In recommending Schedule IV control for zolpidem DHHS found that:
Zolpidem's potential for abuse is equal to or greater than
triazolam's and the other benzodiazepines which are in Schedule IV.
Zolpidem elicits many of the same pharmacological responses of the
benzodiazepines. Its short duration of action and rapid onset
enhance the likelihood that zolpidem would be a drug of abuse. In
addition, zolpidem's water solubility, which is not a feature of
most of the other marketed benzodiazepines, offers potentially an
additional factor that could lead to greater abuse, by way of
diversion and extraction of the drug substance for injection * * *.
There are actual reports of abuse and dependence. The psychological
and physical dependence capacity can be inferred from preclinical
data and clinical pharmacology studies which describe tolerance
development, drug discrimination properties, self-administration
experiments, and adverse reaction reports from other countries.
(6) Flunitrazepam was added to Schedule IV of the CSA in 1984,
along with 20 other benzodiazepine substances that had been reviewed
and controlled as a class. In 1995, the U.N. moved flunitrazepam from
Schedule IV to Schedule III of the Convention on Psychotropic
Substances. The U. S. Government supported this action.
Flunitrazepam is the active ingredient in Rohypnol, that has been
the subject of escalating abuse and trafficking in the United States in
recent months. DEA initiated a review on flunitrazepam to determine if
stricter controls are warranted to deter abuse and trafficking of this
substance.
In response to a request from the Administrator of DEA, DHHS
evaluated the abuse liability of flunitrazepam in accordance with the
eight factors determinate of control under the CSA. In January 1997,
DHHS concluded that the preclinical and clinical abuse liability
research findings and the actual abuse of flunitrazepam do not
significantly distinguish it from other benzodiazepines currently
determined by DHHS to have a low abuse liability and controlled in
Schedule IV. Furthermore, the same science suggests that the abuse
liability of flunitrazepam is significantly less than that of the
Schedule II barbiturates. Thus, DHHS advised DEA that the abuse
potential of this drug, based on the factors applied by DHHS, is
consistent with control under Schedule IV. In light of these findings,
DHHS recommended that there be no change in the current scheduling of
flunitrazepam under Schedule IV of the CSA.
(7) DHHS is currently evaluating the abuse liability of quazepam, a
benzodiazepine controlled in Schedule IV of the CSA. Quazepam is the
active ingredient in Doral, which was approved for marketing
in the United States in December 1985 and has been commercially
available in the United States since March 1990. Quazepam was added to
Schedule IV of the CSA in March 1986. In May 1992, the manufacturer of
Doral submitted a petition requesting that quazepam be
removed from Schedule IV of the CSA and decontrolled.
The petitioner contends that quazepam should be decontrolled
because the substance has no significant potential for abuse and does
not lead to limited physical or psychological dependence. According to
the petitioner, quazepam's abuse and dependence characteristics are
influenced by its unique combination of pharmacologic and
pharmacogenetic properties. Quazepam is relatively selective to the
BZ1 (-1) receptor (as is zolpidem, previously).
And, quazepam is highly lipophilic with long acting metabolites that
may further reduce rebound insomnia and the risk of dependence. The
petitioner argues that some studies suggest that quazepam, in contrast
to other benzodiazepines, only partially suppresses the intermediate to
severe withdrawal signs produced after barbital administration (Ref.
8).
III. Discussion
Notwithstanding the exceptions noted in section I.A. 3 of this
document, most currently controlled benzodiazepine substances were
reviewed and controlled between 1983 and 1993 without differentiation.
However, recent studies have suggested that benzodiazepine substances
may be distinguishable by pharmacologic properties that influence their
abuse liability characteristics.
A review of the clinical literature shows that benzodiazepines and
other sedative/hypnotics may be differentiated with respect to their
abuse liability and ``attractiveness'' to abusers. For example, a
series of placebo-controlled, double-blind studies that compared the
reinforcing/subjective effects of different benzodiazepines across a
range of doses in sedative abusers found that there were meaningful
differences among these compounds (Ref. 9). Specifically, lorazepam and
diazepam appear to have high abuse liability, while oxazepam,
[[Page 33422]]
halazepam, and chlordiazepoxide have less potential for abuse than
diazepam (Refs. 10 and 11). Diazepam has one of the most rapid onsets
of action of all marketed benzodiazepines; in contrast, halazepam and
oxazepam are among the slowest to produce effects. Thus, it has been
suggested that the differentiation among benzodiazepines may be based
on their pharmacokinetic profiles (fast versus slow onset of behavioral
or subjective effects) (Refs. 9 and 12).
In addition, there is some evidence in the scientific literature
that the results of self-administration studies in animals may differ
for different benzodiazepines. These studies have often been used to
compare the potential for psychological dependence on drug substances.
Further, some benzodiazepine substances have been reported to produce
marked, severe withdrawal syndromes in animals (including seizures).
Other benzodiazepines have been reported to produce relatively mild
withdrawal syndromes.
In sum, recent research suggests that benzodiazepines may be
distinguishable on the basis of their specific potential for abuse. It
is not clear, however, how valid these distinctions are and how
reliably benzodiazepines can be differentiated on this basis. Further,
there are also questions regarding how these characteristics should
influence the type of restrictions and controls that may be applied to
these substances. It is possible that, based on pharmacologic and abuse
liability characteristics, some benzodiazepine substances warrant a
higher level of control. For others, these characteristics could
support a lesser level of control or perhaps decontrol. The purpose of
this hearing will be to generate evidence with which to relate a
substance's abuse characteristics with the legal criteria determinative
for control.
A. Criteria for and Procedures for Scheduling Reviews
Under the CSA, the Secretary of DHHS is charged with evaluating
medical and scientific factors and recommending to DEA whether the
substance under review should be controlled or removed as a controlled
substance and the appropriate level of control (if control is
necessary). Under an interagency memorandum of understanding (Ref. 13),
FDA and the National Institute on Drug Abuse (NIDA) participate in the
medical review, evaluation, and recommendations that DHHS conducts as
part of the domestic drug scheduling process.
The CSA establishes the factors and findings determinative for the
control of substances in the United States. The factors set forth under
21 U.S.C. 811(a), (b), and (c) of the CSA are:
(1) Its actual or relative potential for abuse.
(2) Scientific evidence of its pharmacological effect, if known.
(3) The state of current scientific knowledge regarding the drug or
other substance.
(4) Its history or current pattern of abuse.
(5) The scope, duration, and significance of abuse.
(6) What, if any, risk there is to the public health.
(7) Its psychic or physiological dependence liability.
(8) Whether the substance is an immediate precursor of a substance
already controlled under this title.
To be controlled in any of the five schedules established by the
CSA, the substance must meet certain findings relative to its potential
for abuse as well as the physical and psychological dependence
associated with such abuse (21 U.S.C. 811(c)). Currently, all
benzodiazepine substances are controlled domestically in Schedule IV.
The findings necessary for control in Schedule IV are:
(1) The drug or other substance has a low potential for abuse
relative to other drugs or substances in Schedule III.
(2) The drug or other substance has a currently accepted medical
use in treatment in the United States.
(3) The drug or other substance may lead to limited physical
dependence or psychological dependence relative to the drugs or other
substances in Schedule III.
B. Need for Meaningful Criteria
There are currently 36 benzodiazepine and related substances
controlled in Schedule IV of the CSA. Of these, 15 are approved and
marketed for medical use in the United States. A cursory review of the
substances on this list suggests that there may be differences in their
pharmacology. There may also be differences in the onset and duration
of action. In addition, substances may differ in their abuse liability
characteristics, including the ability to develop tolerance and produce
dependence. These differences may be reflected in epidemiological data
relating to abuse, as well as the illicit use and trafficking of the
substances.
It is important that a substance's abuse potential and dependence
producing characteristics are reflected in the substance's control
under the CSA. This permits drug abuse control resources to be focused
appropriately.
The criteria will be useful in identifying the types of information
and scientific evidence needed to assess or differentiate the abuse
potential for benzodiazepine and related compounds. These criteria will
provide guidance to the industry about the types of studies to pursue
and submit to address the abuse potential section of a new drug
application. Moreover, the guidance developed will aid in evaluating
the type of control necessary for such substances. As such, FDA and
NIDA anticipate that the criteria and guidance will stimulate the
development of drug products with lower abuse potential.
FDA and NIDA are inviting the pharmaceutical industry, academia,
regulatory entities, law enforcement entities, consumer, and other
entities to participate in this hearing.
IV. Public Hearing Topics
In order to promote a more useful discussion at the public hearing,
FDA and NIDA developed a list of questions and issues. This list is not
intended to be exclusive, and presentations and comments on other
issues related to the criteria for controlling benzodiazepines and
related substances are encouraged. The list follows:
(1) Is it possible to distinguish benzodiazepine and related
substances on the basis of their abuse potential and dependence
producing effects? If so, would such distinctions be useful in
determining what level of control is appropriate under the CSA for a
given benzodiazepine or related substance?
(2) Different types of data and information are traditionally used
in making decisions on scheduling of substances under the CSA that can
be grouped into four broad classes:
(a) Preclinical studies of abuse-related phenomena;
(b) Clinical studies of abuse-related phenomena (physiological
dependence, subjective effects, psychological dependence, acute
toxicity, tolerance, etc.);
(c) Epidemiologic studies of use and abuse of drugs; and
(d) Information gathered from various law enforcement agencies.
Within each of these broad classes there exists an array of types
of pharmacological procedures and tests that are used to collect
information relevant to abuse liability assessments.
(i) Are there preclinical test paradigms that can be meaningful and
useful in distinguishing the abuse liability of benzodiazepine and
related substances?
[[Page 33423]]
(ii) Are there clinical abuse liability studies that can be useful
for assessing and distinguishing the abuse potential of
benzodiazepines?
(iii) Are there pharmacodynamic characteristics (intrinsic
efficacy, binding of subtypes of benzodiazepine receptors) and
pharmacokinetic properties (e.g., its onset and duration of action, its
active metabolites, etc.) that reliably distinguish among
benzodiazepine and related substances with regard to their abuse or
potential for abuse? If so, how does a benzodiazepine or related
substances pharmacodynamic and pharmacokinetic properties influence its
abuse or potential for abuse?
(iv) Are there reliable methods for using epidemiological, actual
abuse, and trafficking data to distinguish among benzodiazepines for
scheduling purposes? How should intentional overdose and suicide data
be considered in this analysis?
(v) Are there other sources of information that can be used in
assessing and distinguishing the abuse potential of benzodiazepine
substances?
(vi) Are there test methods and procedures that have better
predictive validity than others in assessing and distinguishing the
abuse potential of benzodiazepines?
(3) What information should be included in the drug abuse/
dependence portion of the benzodiazepine product labeling? Are there
instances where a label warning could obviate the need for scheduling?
Should the product's labeled indication (e.g., chronic insomnia,
depression, anxiety, epilepsy, adjunct to anesthesia, etc.) influence
the abuse potential and dependence potential assessment?
V. Scope of Hearing
The purpose of this hearing is to generate evidence and information
that will aid in developing criteria to evaluate the abuse liability
characteristics of benzodiazepines. It is not the purpose of this
hearing to evaluate and make recommendations on the control of specific
substances, including substances that are the subject of current
scheduling petitions.
VI. Notice of Hearing Under 21 CFR Part 15
As discussed in sections III., IV., and V of this document, FDA
believes the format and procedures of a public hearing, at which
interested persons can testify, will best elicit the information needed
to develop meaningful criteria for determining the appropriate level of
control under the CSA for benzodiazepine and related substances.
Accordingly, the Commissioner of Food and Drugs, is announcing a public
hearing under part 15 (21 CFR part 15).
The public hearing is scheduled to begin at 9 a.m. at the
Renaissance Hotel (address above), on September 11 and 12, 1997. The
presiding officer, Stuart L. Nightingale, Associate Commissioner for
Health Affairs, Food and Drug Administration, will be accompanied by a
panel from FDA, the National Institutes of Health, DEA, and other DHHS
employees with relevant expertise. The procedures governing the hearing
are found at part 15.
Persons who wish to participate are requested to file a notice of
participation with the Dockets Management Branch (address above) on or
before August 14, 1997. To ensure timely handling, the outer envelope
should be clearly marked with Docket No. 97N-0221 and the phrase
``Benzodiazepine Scheduling Criteria Hearing.'' The notice of
participation should contain the interested person's name, address,
telephone number, any business or organizational affiliation of the
person desiring to make a presentation, a brief summary of the
presentation, and the approximate time requested for the presentation.
FDA may ask that groups having similar interests consolidate their
comments as part of a panel. FDA will allocate the time available for
the hearing among the persons who properly file notices of
participation. If time permits, FDA may allow interested persons
attending the hearing who did not submit a notice of participation in
advance to make an oral presentation at the conclusion of the hearing.
Persons who find that there is insufficient time to submit the
required information in writing may give oral notice of participation
by calling Nicholas Reuter (telephone number above) no later than
August 29, 1997. Those persons who give oral notice of participation
should also submit written notice containing the information described
above to the Dockets Management Branch by the close of business
September 7, 1997.
After reviewing the notices of participation and accompanying
information, FDA will schedule each appearance and notify each
participant by mail or telephone of the time allotted to the persons
and the approximate time the person's oral presentation is scheduled to
begin. The hearing schedule will be available at the hearing, and after
the hearing it will be placed on file in the Dockets Management Branch.
To provide time for all interested persons to submit data,
information, or views on this subject, the administrative record of the
hearing will remain open until October 17, 1997. Persons who wish to
provide additional materials for consideration are to file these
materials with the Dockets Management Branch (address above). To ensure
timely handling, the outer envelope should be clearly marked with
Docket No. 97N-0221 and the phrase ``Benzodiazepine Scheduling Criteria
Hearing.''
The hearing is informal, and the rules of evidence do not apply. No
participant may interrupt the presentation of another participant. Only
the presiding officers and panel members may question any person during
or at the conclusion of a presentation.
Public hearings, including hearings under part 15, are subject to
FDA's guideline (21 CFR part 10, subpart C) concerning the policy and
procedures for electronic media coverage of FDA's public administrative
proceedings. Under 21 CFR 10.205, representatives of the electronic
media may be permitted, subject to certain limitations, to videotape,
film, or otherwise record FDA's public administrative proceedings,
including presentations by participants.
To the extent that the conditions for the hearing, as described in
this notice, conflict with any provisions set out in part 15, this
notice acts as a suspension, modification, or waiver of those
provisions as specified in 21 CFR 15.30(h).
VII. References
The following information has been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. World Health Organization, Expert Committee for Drug
Dependence, 26th Report.
2. World Health Organization, Pre-Review Data Sheets.
3. World Health Organization, Expert Committee for Drug
Dependence, 27th Report.
4. World Health Organization, Expert Committee for Drug
Dependence, 29th Report.
5. World Health Organization, Expert Committee for Drug
Dependence, 29th Report.
6. Proposed Rule, Federal Register of August 1, 1984, 49 FR
30748.
7. Letter from Assistant Secretary for Health to Administrator,
Drug Enforcement Administration, dated May 1, 1984.
8. Yanagita, T., ``Dependence Potential of the Benzodiazepines:
Use of Animal Models for Assessment,'' Clinical Neuropharmacology, 8
(S1):S118-s-122, 1985.
9. Griffiths, R. R. and B. Wolf, ``Relative Abuse Liability of
Difference
[[Page 33424]]
Benzodiazepines in Drug Abusers,'' Journal of Clinical
Psychopharmacology, 10:237-243, 1990.
10. Griffiths, R. R. and J. D. Roache, ``Abuse Liability of
Benzodiazepines: A Review of Human Studies Evaluation Subjective
and/or Reinforcing Effects,'' In: The Benzodiazepines: Current
Standards for Medical Practice, edited by D. E. Smith and D. R.
Wesson, MTP Press Limited: Lancaster, England, pp. 1535-1541, 1985.
11. Funderburk, F. R. et al., ``Relative Abuse Liability of
Lorazepam and Diazapam: An Evaluation in Recreational Drug Users,''
Drug and Alcohol Dependence, 22:215-222, 1988.
12. Juergens, S. M., ``Benzodiazepines and Addiction,'' Recent
Advances in Addictive Disorders, 16:75-86, 1993.
13. Memorandum of Understanding With the National Institute on Drug
Abuse, and the FDA, dated March 3, 1985 (50 FR 9518).
Dated: June 12, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-16064 Filed 6-16-97; 2:51 pm]
BILLING CODE 4160-01-F