ANNOUNCEMENT OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES' GUIDANCE ON PROCEDURES FOR THE PROVISION OF MARIJUANA FOR MEDICAL RESEARCH
The intent of this document is to provide guidance to the biomedical research community who intend to study marijuana in scientifically valid investigations and well-controlled clinical trials on the procedures of the Department of Health and Human Services (HHS) for providing research-grade marijuana to sponsors.(i)
The production and distribution of marijuana for clinical research, is carefully restricted under a number of federal laws and international commitments. The manufacture, acquisition, and distribution of marijuana is subject to control under Schedule I of the Controlled Substances Act (CSA) (21 U.S.C. 801 et seq.), the most restrictive of the five federally regulated classes of controlled substances. Persons who wish to conduct research using Schedule I substances such as marijuana must obtain a special registration under the CSA from the Drug Enforcement Administration (21 U.S.C. 823(f)). To receive such a registration, a researcher must first be determined by HHS to be qualified and competent, and the proposed research must be determined by HHS to have merit (id.). Moreover, persons who intend to study marijuana for use in the cure, mitigation, treatment, or prevention of disease are subject to the "drug" and "new drug" provisions of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 et seq.).
The United States is also a party to the Single Convention on Narcotic Drugs, an international narcotics control treaty. Parties to the Single Convention have agreed to limit production, distribution, and possession of cannabis and cannabis resins to authorized medical and scientific purposes (Art. 4). In addition to these and other controls, Articles 23 and 28 of the Single Convention provide that if a country allows cultivation of the cannabis plant for research purposes, the country must establish a national agency to control the cultivation and distribution of the crop. Currently, the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH), oversees the cultivation of research-grade marijuana on behalf of the United States government.
An appropriate scientific study of a drug substance requires, among other things, that the substance used in the research must have a consistent and predictable potency, must be free of contamination, and must be available in sufficient amounts to support the needs of the study. NIDA allocates resources to cultivate a grade of marijuana that is suitable for research purposes. Recently, there has been considerable interest in determining, through scientifically valid investigations, whether cannabinoids can provide positive medical benefits. In February 1997, an NIH-sponsored workshop analyzed available scientific information and concluded that "in order to evaluate various hypotheses concerning the potential utility of marijuana in various therapeutic areas, more and better studies would be needed."(ii) Most recently, the Institute of Medicine issued a detailed report that supports the absolute need for evidence-based research into the effects of using marijuana and, in particular, the cannabinoid components of marijuana, for patients with specific disease conditions.(iii) Moreover, recent State-level public initiatives, including referenda in support of the medical use of marijuana, have generated additional interest in the medical community for high quality clinical investigation and comprehensive safety and effectiveness data.
Against this backdrop are the real concerns regarding the toxicity of smoked marijuana. Indeed, the IOM report emphasized that smoked marijuana is a crude drug delivery system that exposes patients to a significant number of harmful substances and that "if there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives." As such, the IOM recommended that clinical trials should be conducted with the goal of developing safe delivery systems.
HHS recognizes the need for objective evaluations of the potential merits of cannabinoids for medical uses. If a positive benefit is found, HHS also recognizes the need to stimulate development of alternative, safer dosage forms. Through this document, HHS is announcing procedures that are intended to facilitate the research needed to evaluate these pending public health questions by making research-grade marijuana available for well-designed studies on a cost-reimbursable basis.
II. Availability of Marijuana for Research Purposes
To facilitate research on the potential medical uses of cannabinoids, HHS has determined that it will make research-grade marijuana available on a cost- reimbursable basis, subject to the priorities and conditions described in section III, below.
HHS will also consider the extent to which a proposed study incorporates the trial design elements outlined by the participants in the 1997 NIH Workshop. Such studies are the most likely to yield high quality, scientifically valid data on the safety and effectiveness of cannabinoids. The goal of this program must be to determine whether cannabinoid components of marijuana administered through an alternative delivery system can meet the standards enumerated under the Federal Food, Drug, and Cosmetic Act for commercial marketing of a medical product (see e.g., 21 U.S.C. 355). As the IOM report stated, "Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug, but such trials could be a first step towards the development of rapid-onset, nonsmoked cannabinoid delivery systems."
III. Elements for Considering Proposed Studies
The focus of HHS's program is the support of quality research for the development of clinically meaningful data. HHS intends to make available a sufficient amount of research-grade marijuana to support those studies that are the most likely to yield usable, essential data. However, it should be noted that NIDA's supply of marijuana is subject to a number of constraints associated with the cultivation of a research-grade crop and that the supply at times may be variable.
For protocols submitted by non-NIH funded sources, institutional peer-review is strongly recommended prior to submission to HHS. After submission, the scientific merits of each protocol will be evaluated through a Public Health Service interdisciplinary review process. This process will take into consideration a number of factors, including the scientific quality of the proposed study, the quality of the organization's peer-review process, and the objectives of the proposed research. For example:
The extent to which the protocol incorporates the elements of good clinical and laboratory research;
The extent to which the protocol describes an adequate and well-controlled clinical study to evaluate the safety and effectiveness of marijuana and its constituent cannabinoids in the treatment of a serious or life threatening condition;
The extent to which the protocol describes an adequate and well-controlled clinical study to evaluate the safety and effectiveness of marijuana and its constituent cannabinoids for a use for which there are no alternative therapies;
The extent to which the protocol describes a biopharmaceutical study designed to support the development of a dosage form alternative to smoking;
The extent to which the protocol describes high-quality research designed to address basic, unanswered scientific questions about the effects of marijuana and its constituent cannabinoids or about the safety or toxicity of smoked marijuana.
In the event that supplies become limited, marijuana will be made available in the order of priority described below.
1. Protocols that have been reviewed and funded by NIH.
2. Protocols sponsored or conducted by other governmental organizations.
3. Protocols sponsored or conducted by other sources.
The sponsor of a proposed protocol must be able to demonstrate the ability to fully reimburse NIDA's contractor for the cost of research-grade marijuana supplied through the completion of the study. In addition, researchers who propose to conduct investigations in humans must be able to fulfill the Food and Drug Administration's investigational new drug (IND) requirements and must obtain a valid registration from the Drug Enforcement Administration (DEA) for research with Schedule I drugs.
IV. Marijuana Trial Design Elements
A clinical study involving marijuana should include certain core elements, many of which reflect recommendations made by the 1997 NIH Workshop. A study that incorporates the NIH Workshop recommendations will be expected to yield useful data and therefore, will be more likely to be eligible to receive marijuana under the HHS program. The full report can be accessed on the Internet at http://www.nih.gov/news/medmarijuana/MedicalMarijuana.htm. HHS will consider if additional guidelines are needed on the essential elements of clinical trial design for medical marijuana studies.
HHS also notes that within each of the categories described in section III, preference will be given to those protocols that are designed around specific safety or efficacy endpoints. Protocols for open-ended or "ongoing" trials that do not include ending dates are not likely to be eligible to receive marijuana. In addition, proposed protocols must be determined to be acceptable under FDA's standards for authorizing the clinical study of investigational new drugs, which state in part:
FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety. Therefore, although FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA's review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.
21 CFR 312.22(a).
Finally, HHS intends to direct its program toward multi-patient clinical studies. As previously determined by the Public Health Service, single- patient requests for marijuana raised a number of concerns including the fact that the single-patient IND process would not produce useful scientific information and we do not foresee that they would be supported under this program.
V. Procedures for Obtaining Research-Grade Marijuana
Researchers who intend to conduct clinical studies of marijuana should first make an inquiry to NIDA to determine the availability and costs of marijuana. Such an inquiry must address the considerations outlined in sections III and IV of this document for establishing research priority.
Because research-grade marijuana will be provided to researchers on a cost- reimbursable basis only, researchers also will be expected to include a plan for ensuring timely reimbursement for all costs associated with the cultivation and delivery of the marijuana.
In addition, specific information (including full justification) should be provided as to the number and potency of marijuana cigarettes or bulk marijuana needed, and the timing of the intended use of the marijuana.
This information must be updated annually with NIDA in order that adequate supplies can be maintained and future needs estimated. Continued provision of marijuana is subject to availability and to continued compliance with these policies and procedures and with all applicable statutes and regulations. This information and requests to NIDA concerning availability and costs should be sent to:
Drug Supply and Analytical Services
National Institute on Drug Abuse
6001 Executive Blvd Bethesda, MD 20892
If NIDA determines that marijuana is available to support the study, NIDA will provide the researcher with authorization to reference NIDA's marijuana Drug Master File (DMF).
If the researcher is proposing a study in humans, after obtaining the right of reference to the DMF, the researcher must proceed through the FDA process for filing an IND application under 21 CFR part 312. Information on the requirements for obtaining an IND can be found on the FDA web site at http://www.fda.gov.
In addition, all researchers must obtain from DEA registration to conduct research using a Schedule I controlled substance. Information on the requirements for obtaining a DEA registration for research with marijuana can be obtained following the process outlined in 21 CFR part 1301.
This procedure will apply to the provision, through NIDA, of marijuana cigarettes (of varying THC content, including placebo), as well as bulk marijuana. HHS will apply this procedure beginning on December 1, 1999. HHS will re-evaluate these procedures periodically and determine within five years whether or not the procedures should be continued. Requests for marijuana may be submitted prior to that time. However, shipments should not be expected before then and definitive information regarding costs may not be available until that time.
i Once implemented, this document will represent HHS's current approach with respect to biomedical research involving marijuana. It does not create or confer any rights for or on any person and does not operate to bind HHS or the public. An alternative approach may be used if such an approach would satisfy all applicable legal requirements.
ii Workshop on the Medical Utility of Marijuana: Report to the Director, National Institutes of Health. National Institutes of Health, February 19-21, 1997.
iii "Marijuana and Medicine: Assessing the Science Base", Institute of Medicine, March 17, 1999.15) 845-1132