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California Research Advisory Panel
Results of Study with Smoked Marijuana
The Protocols. Three protocols were developed based on
experiences since March of 1980: Protocol IV, Revised Operational Protocol for Smoked
Marijuana, and Revised Protocol for Smoked Marijuana (Appendix IX).
The initial Smoked Marijuana Protocol (Protocol IV) was limited to
inpatients who were experienced marijuana smokers and receiving Cisplatin, Dacarbazine
and/or 5-Azacytadine.
In 1981, the Smoked Marijuana Protocol was modified to permit
outpatients and marijuana naive' patients to participate. In addition, patients receiving
radiation therapy were then allowed to use smoked marijuana.
In 1983, another revision was made to adapt to the limited number of
patients choosing to use smoked marijuana. This protocol allowed all patients, regardless
of their anticancer treatment, to have access to smoked marijuana. A standardized smoking
technique was described and the use of a water pipe was encouraged to modify the harshness
of the smoke which was a deterrent for patients using smoked marijuana in the previous
protocols.
Minimal Accrual. The marijuana cigarette protocol attracted only 119 patients,
less than five percent of the total number enrolled in the Cannabis Therapeutic Program.
Anecdotal reports suggested that reasons for the low accrual included a general objection
to smoking on the part of some patients, their oncologists, or their hospitals, and some
reluctance to use a drug associated with street use.
The characteristics of the NIDA cigarettes may have been a factor in discouraging
further use by experieced marijuana smokers. The cigarettes, even after proper storage,
were dry and gave an acrid smoke. Their potency was noticeably low at a time when street
marijuana was increasing greatly in potency and availability.
Data Collection. As each protocol was changed data forms were
also revised in an effort to increase enrollment by reducing any burden of
paperwork for investigators and patients. All data forms associated with the
various protocols are included in the appendices.
The report form included with the latest revision of the protocol (2/11/83)
requested only information which was considered essential and, for the purpose
of this evaluation, data from the previous forms were transcribed to the newer form
for consistency in coding. This point is elaborated in a following section on
validity of results.
Potency Increase. The potency of the marijuana cigarettes being
used was changed in April of 1983 from 1.2% to 2.8% THC content. This
increase was not considered in our analysis.
Patients. The Panel received 218 treatment episode reports for
119 total patients treated with smoked marijuana. Eight reports were received for 3
patients treated with both smoked marijuana and THC capsules. Twenty-one of the 119
patients had been previously treated under other Cannabis Therapeutic Program protocols.
Reports on 98 patients are therefore available for analysis of the 'first treatment
episode' on the Cannabis Therapeutic Program. Table U reflects characteristics of the 98
patients whose reports are analyzed and Table V summarizes the primary tumor sites.
Evaluation of the Antiemetic Properties. As shown in Table W,
only 4.1% of the patients reported mild or no nausea during their first smoked marijuana
protected treatment episode. And, 46.72 reported vomiting of 3 times or less during their
first treatment episode.
Overall assessment of the effectiveness was rated very or moderately successful by 58.7%. The relative effectiveness of smoked and orally ingested THC are similar. Table X includes the column on THC capsules from Table R for comparison. Anecdotal reports by a few patients who had used both marijuana cigarettes and THC, rated the effectiveness of the smoked marijuana as comparable to that of the oral THC used in this study.
Side Effects. Side effects are reported in Table Y which also
presents the data on THC alone (from Table S) for comparison. The slightly more intense
side effects after smoked marijuana are not surprising in view of its more rapid onset. Presumably,
they persisted for a shorter time but no such measurements were recorded in this study.
Table U
Characteristics of Study Population
------------------------------------
n - 98
No. Percent
Sex ---- -------
Male 56 57.1
Female 42 42.9
Age Distribution
19 yrs or less 1 1.0
20 - 39 yrs 38 38.8
40 - 59 yrs 32 32.7
60 yrs or more 27 27.6
---------------------------------------------
Table V
Distribution of Patient Cancer History
by Primary Site
--------------------------------------
n 98
Primary Cancer Site Number Percent
------------------- ------ -------
Hodgkin's 5 5.1
Other lymphomas 3 3.1
Myeloid leukemia 2 2.0
Tongue 1 1.0
Esophagus 1 1.0
Liver and intrahepatic ... 3 3.1
Gallbladder and ducts 1 1.0
Pancreas 1 1.0
Retroperitoneal 2 2.0
Other and ill defined 1 1.0
Nasal cavities 1 1.0
Trachea, bronchi 18 18.4
Thymus, heart 3 3.1
Bone and articulations 5 5.1
Connective and .... 2 2.0
Melanoma of skin 4 4.1
Female breast 5 5.1
Ovary and other .... 14 14.3
Prostate 4 4.1
Testis 18 18.4
Bladder 2 2.0
Without specific 2 2.0
Table W
Comparative Ratings of Nausea and Vomiting
------------------------------------------
Smoked Marijuana THC used alone
n 98 n 257
Ratings of No. % No. %
Nausea
None 9 9.2 38 15.1
Mild 34 34.7 85 33.9
Moderate 36 36.7 73 29.1
Severe 17 17.3 55 21.9
Missing 2 2.0 6 2.3
Vomiting
None 19 19.4 89 35.3
1 - 3 times 36 36.7 69 27.4
4 - 6 times 18 18.4 35 13.9
> 6 times 24 24.5 59 23.4
Missing 1 1.0 5 1.9
-------------------------------------------------------
Table X
Comparative Ratings of Overall Effectiveness
-------------------------------------------
Smoked Marijuana THC used alone
n - 98 n - 257
No. % No. %
--- ----- --- -----
Not effective 26 26.8 62 24.7
Slightly 14 14.4 45 17.9
Moderately 40 41.2 68 27.1
Very 17 17.5 76 30.3
Missing 1 1.0 6 2.3
-------------------------------------------------------
Table Y
Comparative Ratings of Side Effects
----------------------------------
Smoked THC
Marijuana used
alone
n 98 n 257
No. No.
--- ----- --- -----
Incidence of
Side Effects
Dry mouth
Severe 4 4.3 4 1.6
Moderate 26 27.7 31 12.4
Mild 23 24.5 77 30.8
None 41 43.6 138 55.2
Missing 4 7
Tachycardia
Severe 2 2.1
Moderate 1 1.1 6 2.4
Mild 3 3.2 19 7.6
None 88 93.6 225 90
Missing 4 7
Ataxia
Severe 1 1.1 1 0.4
Moderate 9 9.6 4 1.6
Mild 6 6.4 26 10.4
None 78 83.0 219 87.6
Missing 4 7
Dizziness
Severe 4 4.3 5 2
Moderate 12 12.8 16 6.4
Mild 15 16.0 46 18.4
None 63 67.0 183 73.2
Missing 4 7
Orthostatic
hypotension
Severe 2 2.1 1 0.4
Moderate 2 2.1 4 1.6
Mild 3 3.2 27 10.8
None 67 71.3 218 87.2
Missing 4 7
Anxiety
Severe 3 3.2 7 2.8
Moderate 8 8.5 8 3.2
Mild 8 8.5 32 12.8
None 75 79.8 203 81.2
Missing 4 7
Table Y (Cont.)
Smoked THC
Marijuana used
alone
No. No.
--- ----- --- -----
Sedation
Severe 2 2.1 13 5.2
Moderate 25 26.6 46 18.4
Mild 22 23.4 101 40.4
None 45 47.9 90 36
Missing 4 7
Elated mood
Severe 1 1.1 6 2.4
Moderate 10 10.6 22 8.8
Mild 14 14.9 33 13.2
None 61 64.9 189 75.6
Missing 4 7
Confusion
Severe 4 4.3 2 0.8
Moderate 10 10.6 30 12
Mild 9 9.6 47 18.8
None 71 75.5 171 68.4
Missing 4 7
Distortion of
perception
Severe 3 3.2 2 0.8
Moderate 7 7.4 12 4.8
Mild 5 5.3 43 17.2
None 79 84.0 193 77.2
Missing 4 7
Fantasizing
Severe
Moderate 4 4.3 7 2.8
Mild 6 6.4 22 8.8
None 84 89.4 221 88.4
Missing 4 4.3 7
Depressed mood
Severe 3 3.2 3 1.2
Moderate 4 4.3 11 4.4
Mild 10 10.6 19 7.6
None 77 81.9 217 86.8
Missing 4 7
Panic or fear
Severe 3 3.2 3 1.2
Moderate 3 3.2 4 1.6
Mild 1 1.1 12 4.8
None 87 92.6 231 92.4
Missing 4 7
-------------------------------------------------------------------
Patient Drop-out Rates. Thirtyfour patients continued on to two
or more treatment episodes using smoked marijuana. Sixty-four patients dropped from the
study. The reasons for dropping are detailed below in Table Z.
Reliability Estimate of Results. There were three basic concerns
regarding the reliability of the marijuana protocol results: 1) the change in the data
forms, 2) the change in the protocols themselves, and 3) the change in the potency of the
marijuana cigarettes. Each of these may influence the kind of data reported.
Since the potency changed from 1.2% to 2.8% THC, any patients smoking
marijuana after April 1983, were smoking marijuana that was roughly twice as potent. This
may or may not have been considered by the prescribing physician and/or pharmacist in
calculating and marking the dosage. There was general confusion about how to calculate
dose. Sometimes the number of cigarettes used was listed. Also, patients not smoking the
entire dose may not have had this fact recorded, and there was variation in smoking
technique.
In 1983, eligibility requirements were changed to permit outpatients and
inexperienced marijuana smokers to participate. The smoking method was changed, increasing
the amount of time the smoke is held in the lungs. Water pipes were also permitted.
With each protocol change there were changes in the data forms. The
original data form had different labels on the side effect
Table Z
Reasons for Termination
After First Treatment Episode
--------------------------
n - 64
No. of Patients Percent
--------------- -------
Ineffective as
an antiemetic 17 26.6
Side effects
too severe 7 10.9
Expired or
completed treatment 32 50
Other 8 12.5
-------------------------------------------------------
categories (none, tolerable, intolerable). More than one treatment
episode could be reported on one form. Also, the patient reports had categories dealing
with mood. The next data form revision changed the category labels of side effects to
none, moderate and severe. One treatment episode was reported per form. Mood was deleted
from the patient reports. The final revision is the one sheet form.
The protocol directed that four doses of marijuana should be
administered prior to chemotherapy, but the data form also provided a place to enter the
actual number of 'doses prior' as 'other.' The patient evaluation form was discontinued
and the investigator (or his/her staff) evaluated the nausea, vomiting and overall
effectiveness. In tabulating the data the physician's assessment was used. The number of
side effect categories was increased to four: none, mild, moderate, and severe. The mean
value of patient reports was used. If it fell between categories, it was rounded up when
converted to the new form. The dosage level was a fixed choice.
The coding process attempted to take into consideration these changes
and standardized the data onto the one page data collection form (Treatment Report Form
A).
Protocol Exceptions (Pilot Protocols)
Protocols initially available under the Cannabis Therapeutic Program
were limited to antinauseant use of delta-9-tetrahydrocannabinol (THC) to patients
undergoing chemotherapy for cancer. In 1983, the Panel began to receive requests for THC
from physicians with patients who suffered intractable nausea and vomiting from conditions
other than chemotherapy. These patients did not meet the strict criteria of the
Panel's other protocols, but needed an alternative to the standard treatments available
for nausea and vomiting. THC was considered to be their antiemetic of last resort. The
"pilot protocols' provided a treatment option for desperate patients unresponsive to
standard treatments.
By the end of the study, 29 patients, all seriously ill, had been
approved to receive THC as an antiemetic treatment of last resort. Two patients did not
receive drug treatment.. A total of 28 reports of treatment episodes were received; one
patient received two THC treatments. Conditions for which THC was tried as an antiemetic
included acute leukemia, acute myelocytic leukemia, bone marrow transplant, terminal
melanoma, terminal breast cancer, AIDS, multiple sclerosis, etc.
In summary, physicians rated the overall antiemetic effectiveness of THC
as very effective for fourteen treatments, moderately effective for five treatments,
slightly effective for two treatments and not effective for seven treatments. Other
notable THC benefits reported included improved appetites, an increased ability to
participate in family functions and an overall improvement in spirits. No serious side
effects were reported.
Results of the Controlled Study Protocols
THC plus Transdermal Scopolamine. A two arm placebo controlled
study was intended to test the hypothesis that antiemetic therapy with THC would be
optimized by combining its use with transdermal scopolamine, (Transderm V). The purpose of
the study was to determine antiemetic efficacy, side effects and drop out rate of the
combination regimen versu's THC alone using the cumulative, low dose regimen. The
investigation was limited to 5 investigators at selected clinical sites. The Panel hoped
to establish statistical significance early by means of sequential analysis, anticipating
30 to 50 patients.
The Transderm V Protocol began in late 1983, and continued into 1986.
Sixty-five patients were enrolled in this study. However, no conclusion about efficacy was
possible by the end of the Cannabis Therapeutic Program, since only ten of the 65 patients
who enrolled met the stringent study criteria and completed both arms of the study.
THC in Combination with Dexamethasone. The Dexamethasone Protocol
like the Transderm Protocol above was also a two arm placebo controlled study. It was
intended to test the hypothesis that antiemetic therapy with THC would be optimized by
combining its use with dexamethasone.
The Dexamethasone Protocol also was initiated in late 1983, and
continued into 1984; however, of the four patients who entered the study only one patient
completed the necessary two trials.
Delta-8-tetrahydrocannabinol (delta-8-THC), a synthetic
cannabinoid, is not present in natural marijuana. It is similar in action to delta-9-THC,
the oral THC administered in the Cannabis Therapeutic Program, but some reports in the
medical literature suggested that it caused fewer central nervous system side effects than
delta-9-THC. Because side effects may limit the maximum tolerated dose and may deter some
patients from continuing THC therapy even though it may be relieving nausea and vomiting,
such properties of delta-8-THC could offer a major advantage. The Panel was encouraged in
the effort by Dr. Perez-Reyes, author of some of the studies referred to above.
The Panel engaged Dr. Perez Reyes to consult in developing a pilot
research project on the effects of delta-8-THC as an., antiemetic. 'In October 1983, the
Panel submitted an investigational New Drug Application (IND 124,094) to the U.S. Food and
Drug Administration. Patients were first enrolled in October 1983.
Only ten patients were enrolled in this study. Results on this small
number cannot be interpreted except anecdotally. The drug was used on two patients over a
longterm period resulting in the following comments:
Patient D received 26 treatment episodes over a 10 month period. After
her initial three treatments, during which the patient rated delta-8-THC moderately or
very effective, the drug dosing schedule was modified to a single 20mg. dose. The patient
continued to benefit. For the next 20 treatment episodes with this modified dose, she
rated the drug very effective for 17 treatments, had no or only mild nausea and vomiting,
and suffered only dry mouth and sedation as side effects. (Overall effectiveness ratings
were missing from three treatment episodes.) However, during treatment episode number 23,
the patient experienced anxiety and said she felt 'funny or crazy.' To minimize these
effects, the dose was lowered to 10mg. for treatments 24 to 26. The-drug was rated very
effective for treatment 24 but not effective for treatments 25 and 26. The protocol nurse
had not indicated any change in the patient's chemotherapy regimen or concurrent
medications during those treatment episodes. The patient elected not to take further
delta-8-THC.
Patient Z received twelve treatments over a total of 5 months (2 months
with delta-8-THC, 2 months off the drug while undergoing radiation therapy, then a return
to 3 months with delta-8-THC). Delta8-THC was rated as beneficial with a variety of
combinations of chemotherapy agents (BCKU + CYC + VCR; ADR; CYC + VCR). The patient rated
the drug very effective for 5 treatment episodes and moderately effective for 6. Several
side effects were experienced during all treatment episodes, but all were reported as
mild. However, on the patient's last treatment, he began a new chemotherapy regimen (ARA-C
+ MTX) and found delta-8-THC not effective.
Glaucoma Protocol
In 1983, the Legislature considered anecdotal reports from a few
patients with glaucoma, and other individuals, and noted the evidence that oral THC and
smoked marijuana lowered intra-ocular pressure. In response, the legislation that extended
the Cannabis Therapeutic Program also mandated exploration of the therapeutic potential of
cannabinoids in glaucoma, an assignment with complexities beyond those encountered in the
cancer chemotherapy program.
Prior to designing a clinical trial, the Panel co-opted the services of
an ophthalmologist and distributed a questionnaire that queried every ophthalmologist in
the State about the probable availability of patients and for their suggestions. The Panel
then prepared-and submitted an application for an Investigational New Drug Exemption
(IND), accepted by the Food and Drug Administration as 123,373, that included a protocol
(Appendix XIII) for the evaluation of oral-THC and smoked marijuana in the treatment of
open-angle glaucoma.
In preparing this protocol, the Panel considered the nature of the
disease and the availability of other treatment in establishing criteria for the
acceptance of patients into the program.
There are several variants of glaucoma. All are characterized by an
elevation of the pressure within the eyeball, where pressure is transmitted to the optic
nerve with, consequently, a possible loss of vision. However, the rate of progression,
threat to vision and modes of treatment differ for different types of glaucoma. Moreover,
effective treatment with drugs or, in a few situations, surgery, is available for most
patients, a contrast with the nausea and vomiting of cancer chemotherapy.
To be certain that no patient was deprived of treatment of established
efficacy by the research needs of the Panel, patients were accepted only if they had
open-angle glaucoma inadequately controlled by conventional, non-investigational
treatment. To be certain that the desire of the patient to use THC was not generated by
emotion or by proselytizing efforts directed toward 'legalized' marijuana, a "Patient
Qualification Review Board' was established to scrutinize the medical history of each
prospective patient to ensure that their enrollment was appropriate.
In 1984, the Panel conducted a vigorous program to publicize the Panel's
investigational glaucoma treatment to ophthalmologists and prospective patients. In
addition to the usual press releases, every ophthalmologist received a mailing. The Panel
arranged a program at Grand Rounds at the University of California Medical School in San
Francisco for 200 ophthalmologists in Northern California and contacted individual doctors
known for their special interest or influence.
Nevertheless, by the end of the program, only twenty ophthalmologists
were approved as investigators and, of the twelve patients who expressed interest, only
nine received treatment. All nine were Mend-stage glaucoma' for whom it was felt that no
other treatment alternatives could be offered. All nine chose oral THC rather than smoked
marijuana.
Results. The results of treatment can be quickly summarized
because all nine patients withdrew from treatment. Four withdrew because of side effects
at 3 weeks, 2 months, and five months (2); one for lack of efficacy (4 months); two
progressed to cataract extraction and did not resume treatment (5 months, 9 months); one
changed doctors (15 months) and one concluded after 7 months that the drug was no longer
needed, a conclusion not shared by the doctor.
These patients did, however, contribute information in two areas.
Side Effects. These patients provided reassurance about
chronically administered THC in that they took doses ranging from 2.5 to 17.5mg four tim
es each day for 1-9 months. The patient who took THC for 9 months used gradually
increasing amounts until she was taking 17.5mg four times each day. The most frequent side
effects were dry mouth, sedation, ataxia and dizziness. The impression was that the side
effects lessened with continued treatment. No serious or unexpected reactions were seen...
Effect on Intra-ocular
Pressure. The doctor's judgement of the patient's clinical status
did not provide any evidence of effectiveness although some initial, but not lasting,
improvement was claimed.
The measurement of intra-ocular pressure (IOP) should provide an
objective measure of drug effect, but variability was somewhat greater than expected,
possibly because the measurement was made at varying times after the application of the
standard treatment, which was continued when the THC was started. Some of the patients
showed an initial decrease in IOP from base line levels, but this lowering was sustained
in only two patients. Even in these two patients, the possibility is that THC, an anxiety
relieving drug, or the increased attention of the drug trial increased patient compliance
with their standard treatment.
Post Marketing Survey of Investigators
Eighteen months after dronabinol reached the market, the Panel decided
to audit its function and survey the use of THC as a marketed drug. To accomplish these
goals, a survey was mailed to 237 oncologists-investigators. A reminder postcard was
mailed one week later and a 622 (n-148) response rate was achieved.
Prescribing of Dronabinol. The survey asked to what extent
dronabinol had been prescribed over the 18 months since it became available. Of the
respondents, 103 (70%) indicated that they had continued to prescribe tetrahydrocannabinol
as dronabinol. The other 45 (302) indicated they had not ordered THC since they prescribed
it under the Cannabis Therapeutic Program.
Those investigators who reported that they had not used commercial
dronabinol were also the investigators who had treated fewer patients with investigational
THC during the program. The 45 investigators who are not using THC had treated only 304
patients during the Cannabis Therapeutic Program (average of 6.8 patients each). The 103
who now use dronabinol had treated 1163 patients during the Cannabis Therapeutic Program
(average of 11.3 patients each). The survey shows a tendency for those oncologists who
used experimental THC more extensively during the Panel's compassionate access program to
continue to prescribe dronabinol.
The survey instrument was intended to establish the factors responsible
for restricted use: efficacy, undesirable side effects, price, the triplicate prescription
form requirement, and the strict limitations of the FDA approved package insert.
Table A& summarizes the respondents' responses to this
question. Physicians who did not order THC cited side effects, ineffectiveness and
availability of other effective antiemetics (reported most often as a comment) as reasons
for not prescribing dronabinol. Those using THC for their patients included cost and
triplicate form requirement as the primary concerns and causes of limited use.
The influence of patient demand on prescribers is reported in Table AB.
Those who do not order THC are not influenced by patient demand.
Impressions of Efficacy. There was no significant difference
between those who order and those who do not in reports of the number of antiemetics that
would be tried first before prescribing dronabinol. See Table AC.
Polypharmacy is still popular. Of those using dronabinol 58.3% (n - 60)
used it in combination with other antiemetics. (Note that in our analysis of the
combination study, little or no advantage in combination antiemetic therapy was actually
found. See page 36.
The dronabinol prescribers have somewhat more favorable opinion of
dronabinol's efficacy for nausea than have the non-prescribers in this survey. See figures
I and 2.
The difference in opinion between the two groups of dronabinol's
efficacy for vomiting is somewhat less. See figures 3 and 4.
Reasons to Hesitate to Prescribe Dronabinol
-------------------------------------------
Non-prescribers Prescribers Total
n - 45 n - 103 n - 148
No. % No. % No. %
---- ----- ---- ----- ---- -----
Side effects too severe 17 37.8 38 36.9 55 37.2
Not effective 14 31.1 26 25.2 40 27.0
Indications too limited 1 2.2 8 7.8 9 6.1
Requires Triplicate 3 6.7 22 21.4 25 16.9
Cost too high 6 13.3 27 26.2 33 22.3
Other 15 33.3 16 15.5 31 20.9
No response 5 11.1 15 14.6 20 13.5
---------------------------------------------------------------------
Table AB
Main Reason for Participation in
Cannabis-Therapeutic-program
Prescribers Non-prescribers Total
n - 103 n - 45 n - 148
No. % No. % No. %
---- ----- ---- ----- ---- -----
Contribute to
research 27 26.2 12 26.7 39 26.4
Patient demand 23 22.3 4 8.9 27 18.2
Provide compassionate
access 44 42.7 23 51.1 67 45.3
Other 1 1.0 2 4.4 3 2.0
No response 6 5.8 4 8.9 10 6.8
-------------------------------------------------------------------
Table AC
Number of Antiemetics Prescribed
Before Prescribing Dronabinol
---------------------------
Prescribers Non-prescribers Total
n - 103 n - 45 n - 148
No. % No. % No. %
---- ----- ---- ----- ---- -----
None 0 0 0
1 7 6.8 0 7 4.7
2 31 30.1 7 15.6 38 25.7
3 47 45.6 15 33.3 62 41.9
4 or more 17 16.5 14 31.1 31 20.9
No response 1 1.0 9 20.0 10 6.8
Evaluation of the Cannabis Therapeutic Program.
In general, our investigators were favorably disposed toward the Panel's efforts to
carry out the objectives of the Cannabis Therapeutic Program. See figure 5.
Discussion of Results of Cannabis Therapeutic Program
A general consistency was noted in results of impression of
effectiveness of THC and smoked marijuana as an antiemetic throughout the various
protocols.
Side effects are significant, but were never observed to be life
threatening. Clinically serious adverse reactions, defined as reactions while taking THC
or marijuana that required the use of drugs or hospitalization of the patient, were
observed primarily at the beginning of the study. Nine cases were reported during the
first 1569 patients and only one throughout the balance of the study. This great reduction
in severe side effects may be due to several factors: 1) The recommended initial dosage
was first lowered from 7.5 to 5mg/m2. 2) Then, cumulative dosing technique was
recommended. 3) Patients with metastes to the brain were excluded from the study. 4)
Perhaps as the hospital staff became more familiar with the clinical use of this
disinhibiting drug, they were better able to allay a feeling of panic in the inexperienced
subjects.
The Panel noted a number of problems in the conduct of such a large multi-investigator study.
It is difficult to determine the degree of uniformity among
investigators in their interpretation of 'Mild,' 'Moderate,& or 'Severe.In some cases
the reports received from investigators were incomplete. In a few cases it was apparent
that second and subsequent treatment reports were merely copies of prior reports.
Treatment reports beyond the first were not extensively utilized in the Panel's analysis
of data.
The requirements for compassionate access to THC and smoked marijuana
made the use of a true control group impossible. The publicity given compassionate access
somewhat reduced investigator compliance and reduced the strictness of Panel requirements.
Nevertheless, a few investigators were dropped from the study due to lack of cooperation.
The attempt by the Panel to conduct smaller controlled studies within
the overall Cannabis Therapeutic Program was inhibited by the lack of funds to provide
physician investigators the financial incentive usually offered by industrial sponsors of
new drug investigations.
In spite of the problems, the Panel has been able to gather valuable
information on side effects of THC therapy and dosing approaches which will minimize these
side effects. Also, even though this was not a formal, blinded, efficacy study the
tabulation of reports of impression of effectiveness is a valuable predictor of the
clinical future for this drug.
APPROVAL BY FDA FOR MARKETING OF THC
AND CONCLUSION
OF THE CANNABIS THERAPEUTIC PROGRAM
Approval and Rescheduling
The Federal Food and Drug Administration (FDA) required the same sequence of pre-marketing human trial a to demonstrate safety and effectiveness for THC as for any new drug. The Phase II, or controlled, double-blind studies, were previously reported in the literature. The Phase III studies that are represented by the Cannabis
Therapeutic Program's trials are uncontrolled, but involve a large
number of patients. In this phase, the Panel provided the largest experience simulating
conditions of actual practice, that is, the California Program was a successful Phase III
study useful to the FDA. The Research Advisory Panel, its cooperative investigators and
NCI's supply of investigational drug subsidized the marketing of dronabinol. Under the
usual circumstances the cost for the data provided in such a study would have exceeded
$1.5 million.
In 1985, the FDA concluded that the efficacy and safety of THC were well
enough established to justify approval of dronabinol for marketing under highly restricted
conditions. This action by the FDA did not immediately terminate the need for the
compassionate access protocol. Approval jointly by the FDA and DEA of the use of THC for a
single application and in a single dose form, i.e.. the oral capsule, did not override
existing California laws and regulations.
In October 1986, both Federal and State laws and regulations were changed and THC, now
classed as a Schedule II controlled substance and requiring the use of the California
Triplicate Prescription Form, became available as a prescription drug marketed as
dronabinol (Marinol). Thus, much of the need for the Cannabis Therapeutic Program ended.
During the transition period between FDA approval and the ultimate
rescheduling of dronabinol (Marinol, THC) in California, the Panel minimized confusion by
publishing pertinent information in the newsletters of various California licensing
authorities and professional societies.
Investigational THC No Longer Supplied by NCI
The National Cancer Institute stopped supplying investigational THC
after September 30, 1986; however, any investigational THC remaining in California
pharmacies was available to approved investigators. The Panel monitored the use through
August 1987, and audited the return to the DEA of unused supplies. At no time during the
program were there any discrepancies in inventory or suspicion of diversion. It was
occasionally necessary to require some investigators to file missing treatment reports
(discovered by review of pharmacy records) by considering denial of investigational
privileges.
Dronabinol finally became available as a Schedule II drug in California
on October 1, 1986. It is important to note that only synthetic THC in sesame oil and
encapsulated in a soft gelatin capsule has been rescheduled. Other forms of marijuana and
THC remain Schedule I under both California and federal Controlled Substances laws.
The U.S. Drug Enforcement Administration has stressed that dronabinol
should be prescribed only for its FDA-approved use: the treatment of nausea and
vomiting associated with cancer chemotherapy in patients who have failed to respond
adequately to conventional antiemetics. FDA labeling states that this restriction is
required because a substantial proportion of patients treated with dronabinol can be
expected to experience disturbing psychotomimetic reactions not observed with other
antiemetic agents. The FDA-approved labeling also declares that dronabinol is contraindicated
in patients whose nausea and vomiting arises from any cause other than cancer
chemotherapy. DEA warned in its regulation which rescheduled dronabinol, that it may
revoke a registrant's Schedule II license and pursue any criminal sanctions warranted
under the Controlled Substances Act if a practitioner distributes or dispenses dronabinol
in a manner that constitutes a threat to the public safety.
Investigators and pharmacies had been advised that marijuana cigarettes
would continue to be available through the Panel's Smoked Marijuana Protocol at least
through the end of 1988. In spite of this continued availability, there has been little or
no interest in continued study of marijuana cigarettes by the Panel's investigators.
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