|
|
Question 4.
What Special Issues Have To
Be Considered in Conducting Clinical Trials of the Therapeutic Uses of Marijuana?
Benefit and Risk Considerations
There are a number of guidelines and specific issues related to smoked
marijuana that are
important in planning trial designs and carrying out clinical studies. The
current state of
knowledge regarding the efficacy of smoked marijuana for a given
disease/condition should be
taken into account in designing clinical protocols. Investigators should give
consideration to the
range of potential questions that could be addressed and propose to address the
most pertinent
question(s) with the most appropriate study designs. This strategy should
enhance the possibility
of National Institutes of Health (NIH) funding support. In some instances, the
initial question to
be addressed may be whether smoked marijuana is efficacious in the
treatment/management of a
clinical condition. Such a proposed study may be a validation of clinical
anecdotes or be
proposed from basic research findings that suggest a potential benefit. In
either case, the
question should be formulated as a testable hypothesis. In other instances, the
more germane
question may be whether smoked marijuana possesses specific advantages over
dronabinol
capsules or other pharmacological therapies, has additional therapeutic effects
in combination
with standard therapies, has benefit in patients refractory to standard
medications, or has benefit
primarily in marijuana-experienced patients.
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
Beyond the benefit and risk considerations, there are some general and
specific study design
issues regarding the evaluation of the therapeutic effects of smoked marijuana.
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
The selection of the patient population to be studied, and the inclusion
/exclusion criteria for the
defined population, are another critical set of decisions. Design choices
include patients who are
the general population of patients with the disorder, or one of the following
groups: nonresponders
or incomplete responders to other therapies, patients selected in open-trial
designs who responded
to marijuana, and naive versus experienced marijuana smokers.
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
The issue of "blinding" or "masking" marijuana cigarettes was discussed at
some length. Blinding
may be difficult, even with identical-looking placebo cigarettes. Experienced
marijuana users
may be able to discern from the subjective effects whether they received active
or placebo
cigarettes. Nonetheless, there should be an effort to mask treatment assignment
from both the
patient and investigator, i.e., the double-blind technique. The effectiveness of
blinding can be
evaluated to some extent by querying patients after the study about their guess
as to the identity
of their treatment. In order to maintain double-blind conditions when comparing
smoked
marijuana with a control treatment in tablet or capsule form, a double-dummy
technique is used.
The marijuana treatment group would receive active marijuana plus dummy tablets
or capsules,
while the control group would receive dummy marijuana (i.e., with little or no
THC) plus active
tablets or capsules.
Selection of Clinical Endpoints
The choice of clinical endpoints for evaluation of potential efficacy should
be guided by the desire
to obtain objective data, if such endpoints can be obtained and are clinically
relevant. Examples
of such endpoints would be the number of vomiting episodes associated with a
particular
chemotherapy, intraocular pressure (IOP) measurements in glaucoma trials, and
weight gain and
percent changes in body composition in AIDS-wasting syndrome studies. The
frequency of
measurements should be dictated by the clinical condition being studied.
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
There are several mechanisms whereby the NIH can facilitate clinical trials
with 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.
Go to the Medical Marijuana Menu
Go to the HIV & Nutrition Menu
Go to the HIVpositive.us Main Menu