Part 5 of 5
What Special Issues Have To Be Considered in Conducting
Benefit and Risk Considerations
The risks of concern associated with the investigational use of marijuana differ depending on the patient populations being studied and with the proposed duration of administration. For example, there is a different level of risk of developing bacterial pneumonia associated with marijuana administration to immune-compromised patients compared with nonimmune-compromised subjects. On the other hand, some risks may decrease with continued use due to the rapid tolerance development to certain central nervous system (CNS) and cardiovascular effects of marijuana. Marijuana-experienced subjects may already have some level of tolerance to certain effects. Hence, it is critical to consider the side effects of marijuana, the proposed duration of administration, the previous and current level of marijuana use in the proposed study population, and any additional risks that may be conferred by the disease status of the population in the assessment of risks and the appropriate type and frequency of safety monitoring. Concerns regarding the long-term risks associated with smoking are less important in conditions where short-term use is being proposed or patients are terminally ill. However, such risks are of concern for conditions where chronic administration of smoked marijuana is likely. Regardless of whether short-term or long-term use is being studied, all clinical trials must monitor side effects.
Study Design Considerations
There are two basic types of control groups to be considered in designing studies of the medical use of smoked marijuana: placebo control and active control groups. A placebo control is important in studying clinical conditions where there is no known effective therapy. Placebo controls are also desirable in studies where the question is whether smoked marijuana is effective or whether it is equivalent to another drug, and many study designs utilize both placebo and active control groups. This allows a determination as to whether a valid conclusion can be drawn about the efficacy of the test drug by providing a measure of assay sensitivity for the study; i.e., did any treatment show superiority to placebo. This design also allows comparison of marijuana with a standard therapy. If an effective standard treatment exists, there are conditions such as chemotherapy-related nausea and vomiting in which it would be unethical to include a placebo control group. On the other hand, in single-dose analgesic studies a placebo group can be incorporated in the design if appropriate provision is made for administration of a "rescue" analgesic if the study medication proves ineffective. Adding a placebo group increases the complexity of the study design and the number of subjects required and presents ethical questions that must be confronted and answered on a study-by-study basis, but a study without a placebo group may yield uninterpretable results unless some other measure of assay sensitivity is incorporated in the study.
If smoked marijuana is being compared to a standard of care, placebo may not be needed if objective endpoints are being measured; e.g., number of vomiting episodes per day. Since many of the potential therapeutic uses of marijuana involve the use of the drug as an "add on" or adjunctive therapy administered concomitantly with a standard therapeutic regimen, a practical strategy for avoiding a placebo group is to administer the standard therapy to all patients in the study, and in addition administer marijuana to half the patients and a placebo marijuana to the other half. In that way, no patient would be deprived of standard effective therapy.
Some investigations address whether an effect is dose related. This type of design allows for the assessment of the dose range that produces therapeutic effects and the relationship between these effects and dose-related side effects. Although these designs do not exclude the addition of placebo groups, a placebo is often not used because the determination of a positive dose-response curve for an effect provides an internal measure of assay sensitivity. An obvious difficulty with this type of design for smoked marijuana is the inability to standardize dose delivery due to the inherent variability associated with pulmonary administration. One possible design is to compare self-titrated smoking with several fixed doses of THC capsules.
Selection of Patient Population
One proposed strategy, selecting subsets responsive to marijuana in an open manner (i.e., "enrichment design"), assumes that there may be subpopulations that are difficult to recognize, except on the basis of their prior putative response to marijuana. Once identified, such patients are randomly assigned to a study drug or control group and are evaluated in a prospective manner. This approach is useful in situations where responses are variable and/or modest, making it difficult to demonstrate an effect, and where it would be of interest to know if a drug was useful even in a subset of the patient population. However, the limitation of this approach is the difficulty of estimating the size of the population to which study results can be generalized.
Single-patient (N = 1) studies utilize multiple periods of a study drug-control, within-subject, crossover design. Evidence of efficacy in single patients can be determined in such designs, although carryover effects from the long plasma half-life of cannabinoids may confound interpretation of results.
Blinding or Masking Treatment Assignments
Selection of Clinical Endpoints
While blinding may not be as important in studies with clear objective endpoints, some potential indications for marijuana are in conditions that involve subjective responses, e.g., treating the symptoms and improving the quality of life in very sick or dying patients. Scientific evidence can be generated on the basis of subjective responses. These therapeutic areas should not be avoided on the grounds that studies involving objective endpoints would be easier to quantitate or would be more immune to bias.
Because of the importance of the questions of the medical utility of marijuana and the inherent difficulties in designing a definitive study with clinically important endpoints, a mechanism could be considered, such as a forum where experts in the subject areas and experts in clinical trial methodology, Government scientists, and applicable physicians and patients could engage in dialog regarding appropriate study designs prior to their adoption.
Possible Role of the NIH in Facilitating Clinical Evaluation of the Medical Utility of Marijuana
Adequate supplies of marijuana of various and consistent strengths and placebos should be made available to investigators. The NIH should consider using its facilities and influence to assure the availability of comparator compounds and appropriate placebos (e.g., active and identical placebo amitriptyline tablets to permit a randomized trial versus smoked marijuana/smoked marijuana placebo for the control of neuropathic pain).
Because of the broad range of potential uses of marijuana cutting across many NIH Institutes, a centralized mechanism should be considered to facilitate the design, approval, and conduct of trials supported by the NIH. Consideration should be given to supporting mechanisms whereby experts in multiple areas and physicians and patients could engage in dialog regarding study designs prior to their commencement. In addition, to permit the most rapid and accurate determination of marijuana's medical utility, the NIH should coordinate with efforts in individual States and by research organizations also conducting peer-reviewed research studying marijuana (e.g., American Cancer Society, Multiple Sclerosis Society). The NIH should also work closely with the Drug Enforcement Administration (DEA) and the U.S. Food and Drug Administration (FDA) to ensure that FDA regulations are followed and that clinical trials supported are adequate for submission as part of an FDA approval package should marijuana prove effective for a particular indication.
The NIH should use its resources and influence to rapidly develop a smoke-free inhaled delivery system for marijuana or THC. This effort will remove a significant health hazard during clinical testing and future potential use. This will also bring this research effort in line with other Government initiatives to curtail cigarette smoking, the number-one preventable cause of premature death and disability in America. Until this is done, the testing of smoked marijuana would be difficult in smoke-free healthcare and municipal facilities. In addition, study of smoked marijuana in private facilities such as community medical offices or patients' homes, where smoking is not prohibited, would still present an environmental hazard of secondhand smoke for healthcare workers and family members. "Taking the smoke" out of an inhaled dosage form of marijuana or THC would remove an important obstacle to the accurate determination of inhaled marijuana's beneficial and deleterious effects.
The Effect of Controlled Substances Scheduling on Marijuana Research
(Although not discussed at the meeting, this section is provided as background regarding research with Schedule I substances.)
In addition to the requirements of the U.S. Food and Drug Administration (FDA) and sponsoring organizations such as the National Institutes of Health (NIH) concerning the conduct of clinical research, U.S. investigators are subject to specific FDA and Drug Enforcement Agency (DEA) regulations concerning research with controlled substances. Under the Controlled Substances Act (21 USC 822 (a)(1)) and implementing DEA regulations, persons conducting clinical research with any controlled substance must register with the DEA, keep specific types of records, and periodically report to the DEA. Marijuana is currently classified at the highest (most restrictive) level as a Schedule I drug (no accepted medical use, high potential for abuse). Attempts by various petitioners to have marijuana rescheduled have not been successful.
Therefore, there is at least one extra layer (many States have their own laws modeled after the Controlled Substances Act (CSA), which add further complexity) for any investigator undertaking clinical trials with controlled substances. In the case of research conducted under an Investigational New Drug Application (IND), recordkeeping requirements are exempt from the CSA but must be kept in accordance with the Food, Drug and Cosmetic Act (FDCA). Under the FDCA, a sponsor or investigator must make its records concerning shipment, delivery, receipt, and disposition available for inspection and copying at DEA's request. Additionally, FDA regulations require that sponsors and investigators conducting clinical trials take special precautions to prevent diversion, including storage in a secure place with limited access. In the case of some investigator sites, this may require acquisition of a safe and/or other physical space changes and/or procedures to insure security and accountability of the substance.
The CSA also mandates reporting procedures when conducting research with controlled substances. A DEA registration for controlled substances also authorizes (within specified limits) the manufacture and distribution of the substances. If a researcher engages in manufacture or distribution, then he or she is held to the reporting standard of manufacturers and distributors. Presumably, the manufacturer/distributor reporting requirements would not apply in most studies, as the source of marijuana would be the National Institute on Drug Abuse (NIDA) and most studies would not be using the plant material to manufacture other forms or products.
Where research studies of Schedule I substances are not conducted under an IND, the DEA requires a copy of the research protocol be submitted for approval and identify in the registration applications the extent to which the research will involve manufacture or importation. Where research is conducted under an IND, however, the sponsor need only provide the DEA with a copy of the IND and a statement of security precautions. The FDA has ultimate authority to decide whether the research may proceed either under its jurisdiction over INDs (FDCA) or in the case of non-IND research, under the CSA (21CFR1301.42). Where non-IND research is undertaken, the FDA must consult with the DEA concerning the adequacy of the applicant's diversion control procedures. If a researcher desires to increase the amount of Schedule I material it has previously received permission to use, it must apply to the DEA for the increase, and the DEA will forward the request to the FDA for approval/denial, taking into account DEA comments on the adequacy of the researcher's security against diversion control.
Some States may have their own registration requirements for Schedule I substances above and beyond the Federal requirements. Each researcher must check his or her own State authorities to see if other regulatory requirements need to be met. Given the small amounts of research material used by researchers in comparison to the additional regulatory burden and time delays, many researchers have been discouraged from pursuing research with these substances. Indeed, one of the recommendations of the Institute of Medicine Report entitled The Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector (National Academy Press, Washington, DC 1995, pp. 168-171) was that the current regulatory system be modified to remove barriers to undertaking clinical research with controlled substances.
William T. Beaver, M.D.