[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                                                             
----------------------------------------------------------------------------------------------------------------

    (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                                                
----------------------------------------------------------------------------------------------------------------
                                                                                                                
Bromazepam                              Ethyl loflazepate                       Nimetazepam                     
Camazepam                               Fludiazepam                             Nitrazepam                      
Clobazam                                Flunitrazepam                           Ordiazepam                      
Clotazepam                              Haloxazolam                             Oxazolam                        
Cloxazolam                              Ketazolam                               Pinazepam                       
Delorazepam                             Loprazolam                              Tetrazepam                      
Estazolam                               Lormetazepam                            Medazepam                       
----------------------------------------------------------------------------------------------------------------

    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