Mr. Chairman, thank you for the opportunity to testify on the role of the Food and Drug
Administration (FDA or Agency) in the scheduling of drugs under the Controlled Substances
Act (CSA), 21 U.S.C. § 811. We recognize and share your interest and concern in this
matter and before we begin, we wish to express our sympathy with all those affected,
especially the families of the two young women involved in the tragic incident in
Michigan. These types of incidents certainly highlight the problems with the use of
illicit substances. You have asked us today to focus on FDA's role in the scheduling
process and to specifically discuss three drug substances of interest to the Committee.
The primary role for FDA under the CSA is to provide the Secretary of the Department of
Health and Human Service (DHHS) with our scientific and medical evaluation of drugs. FDA's
consultative role stems from the provisions of the Comprehensive Drug Abuse Prevention and
Control Act (Act) of 1970. Pub. L. 91-512 (October 27, 1970). Such a role is consistent
with FDA's mission of public health protection. Under the Act, the Secretary of DHHS is
charged with evaluating certain medical and scientific factors and making recommendations
to the Attorney General as to whether the substance under review should be managed as a
controlled substance, or removed from control, and the appropriate level of control. Title
II of the Act, now fully incorporated into the CSA, establishes the factors and findings
determinative for control. The factors set forth under 21 U.S.C. § 811 allow the Attorney
General and, by delegation, the Drug Enforcement Administration (DEA), to schedule a drug
if she finds that the drug has a potential for abuse. The Attorney General also must take
into account whether the drug has a currently accepted medical use within the United
States and the extent to which the use of the drug may lead to physical or psychological
When evaluating a particular drug, the Attorney General must, under 21 U.S.C. § 811
(c), consider the following factors:
(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.
Before proceeding to control a drug under this process, the Attorney General also must
request from the Secretary of DHHS a scientific and medical evaluation of the drug and
make a recommendation as to whether the drug should be controlled and, if so, under what
schedule. In making such a recommendation, the Secretary of DHHS must take into
consideration factors (2), (3), (6), (7) and (8) and any scientific and medical
considerations involved in factors (1), (4) and (5) as described above.
After evaluating the eight factors, the Secretary must make a scheduling recommendation
based on the substances relative potential for abuse, its accepted medical use and
its capacity for producing physical and psychological dependence. Under the CSA,
substances in Schedule I have a high potential for abuse and no accepted medical use.
Substances in Schedule II have a high potential for abuse but do have an accepted medical
use. Substances in Schedules III-V have an accepted medical use and a relatively lower
potential for abuse.
The legislative history of the CSA is replete with hearings, discussion and statements
that the scientific and medical evaluation of DHHS is important and critical to the
process. The operative provisions of the CSA reflect that history. In particular, 21
U.S.C. § 811(b) states:
The recommendation of the Secretary to the Attorney General shall be binding on the
Attorney General as to such scientific and medical matters, and if the Secretary
recommends that a drug or other substance not be controlled, the Attorney General shall
not control the drug or other substance.
The Secretary of DHHS has delegated responsibility for DHHS's recommendation to the
Assistant Secretary of Health (ASH). The ASH, in turn, relies on FDA and the National
Institute on Drug Abuse (NIDA) to develop the medical and scientific evaluation and
consider the appropriate factors and scheduling criteria. Under an interagency Memorandum
of Understanding (MOU), FDA and NIDA cooperate in completing the medical review,
evaluation, and recommendation that DHHS conducts as part of the domestic drug scheduling
Proceedings to add, delete or change the schedule of a drug or other substance may be
initiated by DHHS, DEA or by petition from any interested person such as a drug
manufacturer, medical society, pharmacy association, public interest group or state and
local government. Typically, FDA will not begin its medical and scientific evaluation
until it receives, through the ASH, a formal request for such an evaluation from DEA. FDA
may also initiate such an evaluation. FDA typically will do so during the investigational
stages of drug development or at such time that an application to market a new drug is
received by FDA and the Agency believes that the substance may be a candidate for
scheduling under the CSA as provided for in 21 U.S.C. § 811(f) which states:
If, at the time a new drug application is submitted to the Secretary for any drug
having a stimulant, depressant, or hallucinogenic effect on the central nervous system, it
appears that such drug has an abuse potential, such information shall be forwarded by the
Secretary to the Attorney General.
PROCESS WITHIN FDA
The scientific and medical evaluation process is a complex one which is a part of the
balancing of the interests of various agencies. There is a critical need to protect the
public from the dangers posed by drugs and substances of abuse. At the same time, we
recognize that many drugs that have the potential for abuse also may be medically
beneficial and a large segment of the population might benefit from the optimization of
drug development. These interests can create a tension in the scheduling process.
The FDA Office of Health Affairs (OHA) is responsible for the coordination of the DHHS
activities in preparation of the report and recommendation on scheduling. Internally, once
a scheduling request is referred to FDA, there is a review period during which FDA's
Center for Drug Evaluation and Research (CDER), with assistance from others within the
Agency, conducts a review of the drug. The data review includes review of the chemical
properties, pharmacology studies and clinical studies and reports related to the drug.
This evaluation involves the careful analysis of many kinds of data: data on chemical
synthesis and solubility; data on absorption and metabolism; information gathered from
studies designed to investigate whether animals develop physical dependence and will work
to self-administer the drug; and, whether an animal can distinguish a given drug from
other controlled substances. Interaction studies with other agents, including alcohol,
also may be evaluated. Human adverse events (relating to the drug's ability to cause
physical dependence, alter moods, cause hallucinations, etc.) are collected and reviewed
from clinical trial reports and from postmarketing experience if applicable.
In the case of a new drug under investigation, the data specific to the issue of abuse
potential may not already be developed by the sponsor unless there has been some reason to
suspect that it may indeed have abuse potential. These kinds of specialized studies are
not a routine aspect of the drug development process. The development of this information,
therefore, may take many years as studies are initiated and completed and as more clinical
trial experience becomes available.
FDA has an Advisory Committee, composed of non-FDA employees, available if necessary,
to review the data and provide recommendations to FDA concerning the medical and
scientific evaluation, abuse potential and the need for scheduling controls. The CDER
Division will then forward a recommendation for review by CDER's Center Director. Once the
recommendation is signed by the Center Director, it is reviewed by the Office of
Commissioner, including OHA. The recommendation is then forwarded for formal interagency
review, a process coordinated by OHA.
During this period, there are informal consultations with NIDA. Under the MOU, FDA
transmits the scheduling request from DEA upon receipt from DHHS to NIDA for concurrent
review. An interagency group, the Interagency Drug Scheduling Working Group (IDSWG), which
includes representatives from FDA, NIDA and the Substance Abuse and Mental Health Services
Administration (SAMHSA), convenes periodically to assess the status of the scheduling
review. Occasionally, the IDSWG will identify the need for additional abuse liability
testing, or, on rare occasions, a public hearing under Part 15 of FDA regulations.
The MOU, noted above, describes procedures for sharing information between the
agencies, and outlines FDAs role in preparing the initial recommendation and eight
factor "basis" document. Upon completion, the medical and scientific evaluation
and scheduling recommendation of FDA and NIDA are forwarded to the ASH who makes the final
determination on behalf of the Secretary. The medical and scientific evaluation and the
recommendation as to the appropriate schedule for the drug are then forwarded to the DEA.
Since the inception of the scheduling process in 1970, there have been dozens of
substances reviewed for control under the CSA. On average, DHHS completes its response to
a scheduling request within 8-10 months. In addition, FDA, DEA and NIDA meet monthly to
discuss issues of mutual concern in the drug abuse control area. The Interagency Committee
on Drug Control, formed in the early 1970s, provides a forum to discuss emerging drug
issues and monitor the status of ongoing activities within the agencies.
It should be noted that there are other scheduling mechanisms that I will not discuss
in detail but I do want to mention. Many substances were controlled under the CSA at the
time the law was enacted in 1970. Scheduling also can be accomplished by legislation. The
scheduling of Methaqualone (Qualuudes) and anabolic steroids are examples of legislative
control. In addition, there is scheduling to fulfill treaty obligations. Finally, DEA can
"emergency" schedule certain substances not subject to an investigational new
drug application, under certain conditions on a temporary basis if there is an imminent
hazard to the public health. 21 U.S.C. § 811(h)(1).
Ketamine, Rohypnol (Flunitrazepam) and GHB (Gamma-Hydroxybutyrate)
There are three drugs you requested that we specifically discuss in our testimony,
Ketamine, Rohypnol and GHB. These drugs have been the subject of abuse in varying degrees
for a number of years.
Ketamine is an anesthetic and has been approved both for
human and animal use as an anesthetic. It was approved both as a human and veterinary drug
in 1970. Ketamine has powerful analgesic and amnesic actions in humans and is typically
used in humans in pediatric and obstetric procedures and is prominently used in veterinary
procedures. Approximately 90% of the Ketamine legally sold today is for veterinary use. In
the 1980s, Ketamine emerged as a recreational street drug because consumption of large
doses cause reactions similar to those associated with use of PCP. Symptoms associated
with recreational use of ketamine include dream-like states and hallucinations. The Drug
Abuse Warning Network (DAWN) documented at least two Ketamine related deaths between 1993
and 1997 in which no other drugs, including alcohol, were used.
DHHS has evaluated Ketamine three times pursuant to requests from DEA for a medical and
scientific evaluation and has forwarded a scheduling recommendation each time. The first
time was in 1981; the second in 1986 and recently in 1998. Each time a recommendation was
made to DEA from DHHS that Ketamine be placed in Schedule III of the CSA. Each time a
request for a recommendation was made, FDA had to review current medical and scientific
data to ensure that the Schedule III recommendation was appropriate. To date these
recommendations have not been finalized.
Rohypnol (flunitrazepam) is an unapproved drug in the United States
, although it is
approved in Europe and is used in over 60 countries. The drug belongs to the class of
drugs known as benzodiazepines (such as Valium, Halcion, Xanax, and Versed ) and is used
outside the United States
as a treatment for relief of insomnia, to induce sedation and as
a pre-anesthetic. The drug can cause anterograde amnesia, thus, individuals may not
remember certain events they experienced while under the effects of the drug. This effect
is presumably what has lead to the drug's use in sexual assaults. Without the ability to
recall the sexual assault or rape, the victim is hindered in assisting law enforcement
officials in providing information leading to the prosecution of the perpetrator. For
these reasons, one of the street names for Rohypnol is "the forget me pill." The
drug is tasteless, odorless and dissolves easily in carbonated beverages. The sedative and
toxic effects of Rohypnol also are aggravated by the concurrent use of alcohol. Even
without alcohol, doses as small as 1 milligram can incapacitate a victim for 8-12 hours.
Rohypnol is not approved or available for medical use in the United States
, but it is
temporarily controlled in Schedule IV pursuant to a treaty obligation under the 1971
Convention on Psychotropic Substances. At the time flunitrazepam was placed temporarily in
Schedule IV (November 5, 1984), there was no evidence of abuse or trafficking of the drug
in the United States
In March 1996, DEA requested that DHHS conduct a scientific and medical evaluation and
provide a permanent scheduling recommendation for Rohypnol. DHHS provided a recommendation
to DEA in January 1997 that it remain in Schedule IV. This action has not been finalized.
FDA continues to work with the United States
Customs Service (Customs) and DEA to
control the illegal importation of Rohypnol into the United States
through smuggling from
other countries. FDA issued an import bulletin in December 1995 and the Agency continues
to work to help control the illegal entry of the drug.
GHB is an unapproved drug in the United States
and currently is not scheduled under the
CSA. It is approved in other countries for use as an anesthetic in humans. The drug is a
central nervous system depressant that can induce deep sleep. GHB is presently the subject
of several investigational new drug applications (IND) and is being studied for commercial
development in the United States
. FDA designated GHB as an orphan drug in 1987 for the
treatment of patients with narcolepsy and the constellation of symptoms of cataplexy,
sleep paralysis, hypnagogic hallucinations and automatic behavior. FDA also has issued
orphan product grants for the study of GHB in the treatment of narcolepsy. Orphan Medical,
Inc., has submitted an IND to FDA to review the use of GHB in the diagnosis and /or
treatment of narcolepsy.
At the same time, GHB also is being abused as an intoxicant, depressant, euphoriant,
growth hormone releasing agent and as an agent in sexual assaults. Unlike the two drugs
discussed above, GHB poses a particularly acute law enforcement problem in that it can be
easily synthesized by individuals with a limited knowledge of chemistry. Gamma
Butyrolactone (GBL) and Sodium Hydroxide are the chemicals necessary to make GHB. Both of
these chemicals are readily purchased from numerous chemical supply houses. Also, the
recipe to manufacture the drug can be obtained easily over the Internet.
FDA has been involved in evaluating the reports of abuse of GHB and investigating the
adverse events suffered as a result of the abuses. Since it was established in 1992, FDA's
Office of Criminal Investigations (OCI) has tried to take aggressive enforcement actions
against the manufacture and interstate distribution of GHB. OCI's investigative
initiatives are directed at large scale interstate manufacturers and distributors
including Internet web site vendors. Working with the Office of Chief Counsel and CDER,
OCI has developed investigative and prosecution strategies that have been highly effective
in identifying and convicting violators. From 1993 until the present, OCI has worked
closely with CDER and FDA's National Forensic Chemistry Center to develop an expertise in
the safe handling and processing of GHB when collected as evidence. Also, OCI, CDER and
the Department of Justice have developed and maintained a list of scientific experts
available to testify in court proceedings. OCI also utilizes its expertise and resources
to assist state and local police departments in conducting numerous investigations. As a
part of our systemic efforts to combat abuse of GHB, FDA/OCI has initiated and supported a
number of federal and state prosecutions throughout the United States
related to the
illegal manufacture and distribution of the drug. To date the government has obtained over
33 GHB-related convictions nationwide.
Our technical and investigative assistance is invaluable to the approximately 20 states
that have enacted legislation to make GHB a controlled substance. In March 1997, the OCI
San Diego Field Office conducted a training seminar for federal, state and local law
enforcement agencies who were responsible for controlling the rapid growth in the use and
abuse of GHB in Southern California. In July 1997, OCI continued to assist state and local
law enforcement efforts when its San Francisco Resident Office conducted a GHB training
seminar for law enforcement personnel in Northern California.
OCI also has responded to a request from DEA's Office of Drug Diversion, Drug and
Chemical Evaluation for all available information related to the synthesis, tracking,
usage and other illicit commerce involving GHB. The recent surge in the popularity of GHB
and its precursors (GBL or 1, 4 butanediol) has made combating its illegal use
increasingly difficult. Investigations are resource intensive and the laws used to
prosecute distribution under the Federal Food Drug and Cosmetic Act are relatively
FDA has issued several alerts and warnings concerning GHB. FDA also has worked with
Customs to stop the importation of GHB and in May 1992, FDA issued an Import Alert
providing for automatic detention of the product.
Most recently, FDA moved to alert consumers not to purchase or consume products, some
of which are labeled as dietary supplements, that contain GBL. When taken orally, GBL is
converted in the body to GHB. FDA pressed the companies that manufacture these products to
cease the manufacture and distribution of these products and to voluntarily recall them.
As of this date, all of the manufacturers that were contacted agreed to cease the
manufacture and distribution of their GBL-containing products. All but one has agreed to
recall the products. The Agency had received reports of serious health problems -- some
that are potentially life-threatening -- associated with the use of these products.
Although some of these products were labeled as dietary supplements, the products were,
and are, illegally marketed unapproved new drugs. They are promoted with fantastic and
unsubstantiated claims to build muscles, improve physical performance, enhance sex, reduce
stress and induce sleep.
GBL related products have been associated with reports to FDA of at least 55 adverse
health events, including one death. In 19 cases, the individuals became unconscious or
comatose and several required intubation for assisted breathing. Other reported effects
included seizures, vomiting, slow breathing and slow heart rate. There have been reports
of at least five children under 18 years of age who have been injured or who have suffered
these kinds of effects.
As a result of the increased abuse of GHB, DEA requested in September 1997 that DHHS
conduct a scientific and medical evaluation of GHB and submit a scheduling recommendation
for GHB. In response to DEAs request, the Department has continued to gather and
evaluate scientific data on GHBs potential for abuse. These activities have
proceeded in conjunction with the OCI enforcement actions and the ongoing clinical
investigation of GHB for the treatment of narcolepsy.
In December 1998, FDA determined that the sponsor could provide GHB under a treatment
IND. Once under a treatment IND, the product may then be legally prescribed to appropriate
patients before general marketing is allowed. Treatment INDs are a means of facilitating,
even before general marketing of the product, the availability of promising new drugs to
desperately ill patients for whom no other therapy is available. FDA approves treatment
INDs if there is preliminary or presumptive evidence of drug efficacy and the drug is
intended to treat a serious or life-threatening disease, or if there is no comparable
alternative drug or therapy available to treat that stage of the disease in the intended
patient population. The drug also must be considered safe for its intended use under a
physician's care. Patients who receive the drug under the treatment IND are not eligible
to be in the definitive clinical trials, which must be well underway, if not almost
finished. These ongoing investigations may allow FDA to learn more about GHBs
relative potential for abuse, to aid in the scheduling review and to develop additional
information for the product labeling.
FDA is completing its evaluation and recommendation on GHB to DHHS. As part of the
review, the Agency is determining if GHB's abuse potential is "high" relative to
substances controlled currently in Schedules I and II (such as heroin, PCP, LSD,
marijuana, etc.) or if its abuse potential is closer to anabolic steroids or
benzodiazepines, currently controlled in Schedule III and IV.
Increasingly, our citizens have had to face the increasing availability and abuse of
drugs and other substances. In FDAs dual role as the evaluator of products that
promote public health and evaluator of substances that present a danger to the public, we
will use the best available scientific data to make the speediest and best decisions. We
are committed to optimizing our interactions with our critical partners federal,
state and local officials, scientific, clinical and industrial. There is no question that
FDA needs to move quickly to assist in the evaluation of these drugs and substances so
that scheduling under the CSA can move forward.
Thank you for the opportunity to testify.