News & Events
Scheduling of Drugs Under the Controlled Substances Act
Nicholas Reuter, M.P.H.
Associate Director for Domestic and International Drug Control
Office of Health Affairs
Food and Drug Administration
Department of Health and Human Services
the Subcommittee on Oversight and Investigations
House Committee on Commerce
March 11, 1999
RELEASE ONLY UPON DELIVERY
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 dependence.
When evaluating a particular drug, the Attorney General must, under 21 U.S.C. § 811 (c), consider the following factors:
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 substance's 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 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 process.
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:
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 FDA's 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 complex.
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 DEA's request, the Department has continued to gather and evaluate scientific data on GHB's 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 GHB's 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 FDA's 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.