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California Research Advisory Program
Cannabis Therapeutic Program
EXECUTIVE SUMMARY
The nausea and vomiting caused by chemotherapy for cancer is often so severe as to limit treatment. Drugs currently used to combat that nausea and vomiting have very limited effectiveness and unpleasant side effects. In 1979, the Legislature became concerned that the status of marijuana as a stringently regulated drug might be inhibiting research into its possible therapeutic effects and that many cancer patients were being deprived of a possibly effective treatment for nausea and vomiting. The Legislature therefore directed the Research Advisory Panel, created by the Legislature in 1969, to provide compassionate access to marijuana, or its active component delta-9-tetrahydrocannabinol (THC), by establishing a clinical trial conforming to federal and ethical standards for research using human subjects and a new drug.
The Panel recruited 486 oncologists from throughout the State and 321 of these provided oral THC for 2,356 patients and marijuana cigarettes for 119. The limited efficacy of THC was in the meantime being established by double-blind studies carried out elsewhere. The Panel study was a "Phase III" study providing experience under conditions of actual practice. Throughout the program over 1,716,000 dosage units of investigational drug were provided without charge by the National Cancer Institute (NCI) and the National Institute on Drug Abuse (NIDA) to 114 approved pharmacies. The cost of the Cannabis Therapeutic Program for the eight years was $400,000.
Oral THC has been shown to be clearly efficacious for relief of nausea and vomiting in some patients, but not a total answer to the terrible emetogenic effect of current anticancer chemotherapy. Side effects were frequent but not serious, but were a factor in limiting patient acceptance. The Panel established a cumulative dose schedule for THC, not previously studied, that provided the same efficacy with fewer troublesome side effects.
In addition to the major study of smoked marijuana or oral THC alone, the Panel sponsored research into an analogue of THC, delta-8-tetrahydrocannabinol, combinations of THC with other antiemetics and the use of THC for nausea and vomiting from causes other than cancer.
In 1984, the Legislature added to its mandate a study of the same drugs in the treatment of glaucoma. Only 9 patients from the entire State received THC under the new program. The drug given chronically is safe, but not demonstrably effective.
The program was effectively ended in October, 1986, when THC was marketed as dronabinol (Marinol). The California experience was a factor in the decisions of the U. S. Food and Drug Administration (FDA) to permit its marketing.
The Research Advisory Panel does not recommend an extension of Article 6 of Chapter 5 of Division 21 of the California Health and Safety Code. California investigators can still carry out research using human subjects and THC, but the Panel can no longer provide the drug free.
The Research Advisory Panel wishes to express its appreciation to the Legislature for directing the establishment of a program which resulted in meeting the needs of that time for compassionate access, as well as satisfying a continuing need for research on the medicinal effects of such a controversial drug.
January 24, 1989
With the development of effective cancer chemotherapeutic agents and multi-drug regimens, the prognosis for many patients with even advanced cancer has improved. However, the widely used chemotherapeutic regimens induce nausea and vomiting with regularity. as does radiation therapy to the abdominal area. In some cases, the treatment for cancer may cause more immediate discomfort than the disease itself, often leaving patients with nausea and vomiting so severe as to impede their leading even a semblance of normal life. For many patients, the mere anticipation of chemotherapy induces vomiting and causes depression, occasionally leading to the refusal to receive further potentially life saving treatment. This nausea, vomiting and loss of appetite may have not only a profound psychological impact on the patient, but also produce significant weight loss. Cancer itself may also produce significant anorexia and weight loss and the problems are compounded by chemotherapy.
Drugs to control the side effects of nausea and vomiting from anticancer treatment have
proved to be inadequate. When administered with chemotherapy, phenothiazine derivatives
such as prochlorperazine (Compazine) and thiethylperazine (Torecan) have been only
partially successful in controlling the nausea and vomiting caused by many anticancer
drugs and their side effects, especially a subjectively unpleasant sedation, are severe.
Patient compliance is therefore limited. Other drugs, e.g.. metoclopramide, loperamide,
and high dose corticosteroids have had brief vogues of extensive use.
Anecdotal reports from cancer patients suggested that smoking marijuana provided a significant antiemetic effect. In 1975, Sallan and associates initiated a small controlled study to evaluate the efficacy of delta-9-tetrahydrocannabinol (THC), a principal active component of marijuana, as an antiemetic agent. Additional small controlled trials2' including some carried out in California and approved by the Research Advisory Panel, showed that THC given by mouth provided some benefit to some patients suffering from nausea and vomiting of chemotherapy. Although this preliminary research partially confirmed the anecdotal findings, the reported degree of effectiveness, as well as reported adverse effects varied considerably among research studies.
The promising research studies furthered a widespread interest in marijuana by patients undergoing chemotherapy. However, marijuana was and is a Schedule I controlled substance (i.e., a drug with a high abuse potential that lacks an approved medical use under federal law) and only a very limited number of people were eligible to legally use it and only at the few locations of the ongoing research studies. Some very sick people resorted to illegal use of this Schedule I controlled substance.
1. Sallan SE. Zinberg RE. Frei NE 111. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. M Engl J Ned 1975: 293: 795-7.
2. Card S. Beers AL Jr. Bogard M. McMahan RT, Nangalik A. Ashman AC. Levine S. Two-pronged study of tetrahydrocannabinol (THC) prevention of vomiting from cancer chemotherapy. IRCS Ned Sci 1980; 8: 203-4.
Orr LE. MKeran JF. Sloome S. Antiemetic affect or tetrahydrocannabinal compared with placebo and prochlorperazine in chemotherapy associated nausea and emesia. Arch Intern Ned 1980: 140: 1431-3.
Sallan SE. Cronin C. Zolen 14. Zinberg NE. Antiemetica in patients receiving chemotherapy for cancer. New Engl J Ned 1980; 302: 135-8.
The California Legislature found that the potential medicinal value of Cannabis sativa
had received Insufficient -study due to a lack of financial incentives for the undertaking
of appropriate research by private drug manufacturing concerns. Individual physicians
could not utilize cannabis in their clinical practice and it was not feasible for them to
conduct research because of governmental controls which include time consuming
applications with rigorous approval and monitoring procedures and reports. The Legislature
decided that 'compassionate access' to this controversial drug should be provided for
cancer patients. At the same time, the Legislature recognized that treatment should be
provided under the general controls that apply to all new drug research. To accomplish the
two aims: 1) compassionate access 2) achieved by research meeting the U.S. Food and Drug
Administration and ethical standards and without contributing to the drug's availability
through illicit channels, the Legislature turned to the Research Advisory Panel, an agency
established and utilized by the Legislature since 1969.
The Legislature established the Panel as an autonomous multidisciplinary committee of experts with diverse backgrounds who serve without pay and without vested interests in the matters discussed.
Panel members are appointed, not by a single elected official or State office, but by various public and private agencies: the Attorney General, the University of California, the Department of Health Services, the State Board of Pharmacy, a private University designated by the Governor, the California Medical Association, and the Governor. For the purposes of this assignment, the Panel was authorized to appoint two additional members with expertise in oncology or glaucoma. Appendix I contains the sections of the California Health and Safety Code pertaining to the Research Advisory Panel.
The Research Advisory Panel has existed since 1969 when it was created by the Legislature to encourage research into the nature and effects of abused drugs, to review and approve research involving Schedules I and II controlled substances and to function as a human subjects' protection committee in research involving scheduled substances. The Panel established, approved and monitored methadone maintenance programs, providing treatment under the guise of research, until such programs became legal as treatment. Because of its legislated mandate and the composition of its membership, the Panel is in a unique position to provide a level of control over research beyond that required of an industrial sponsor or a University. Prior to the new assignment which is the subject of this report, the Panel had sponsored a symposium on marijuana research in California And provided seed funds for twelve California investigators, two of whom have subsequently developed comprehensive and influential programs with federal funds. In 1978, the Panel was monitoring some twenty four research projects involving marijuana or THC.
In 1979, when Senator Presley and the Legislature began consideration of the need to provide compassionate access to marijuana, the Research Advisory Panel had approved five research projects employing marijuana or THC and involving as many as five hundred cancer patients suffering severe nausea and vomiting caused by their cancer treatment.
The Panel counseled that State sponsored trials would be required because the patent
protection necessary to attract industrial sponsorship was lacking. It was also pointed
out that standardized THC and marijuana cigarettes from the National Institute on Drug
Abuse (NIDA) be used rather than confiscated marijuana that would be of variable and
unknown potency and generally unsuitable for oral use; that initial trials be limited to
patients receiving cancer chemotherapy; and that the treatment of glaucoma, then seen as
unpromising by available experience and literature, be added later.
The goals of the Legislature and of the Panel, to provide compassionate access through a multicenter research-project that complied with FDA regulation were incorporated into Senate Bill 184 (Appendix II) that became law on January 1, 1980, as Chapter 300, Statutes of 1979 (Therapeutic Marijuana Project. Article 6, Chapter 5, Section 11260 et seq. of the Health and Safety Code). The law mandated that the Research Advisory Panel establish a 4-year pilot research program into the medical use of cannabis and its derivatives, particularly in treating patients suffering from cancer. The law stated that making marijuana available to individual physicians in a State-sponsored program for the investigational use of cannabis and its derivatives would enable qualified physicians and surgeons in the State to study the benefits of the drug in a controlled clinical setting and to gain additional knowledge with respect to dosage and effects.
In addition, the law required the Panel to develop guidelines and protocols for the program and to approve physicians for participation in the program. It authorized the Panel to contract for pharmaceutical formulation, distribution and testing of cannabis and cannabinoids, to obtain such substances from designated sources, and to charge participating physicians for the cost of obtaining the materials supplied. The Panel was required to report ,annually to the Legislature on the status and results of the program.
The legislation, with its mention of qualified physicians in diverse geographic areas, was clearly intended to provide patients with 'compassionate access, to these controlled, investigational drugs. The intent was not to foster undisciplined use of marijuana but rather to increase knowledge about the use of this drug. Thus, both the legislation and the investigational status of the drug enforced the Panel's obligation to conduct useful clinical research and to investigate several still unanswered questions about THC.
At the end of 1983, with the Cannabis Therapeutic Program underway, the Panel made an appraisal of the need for extending the Program. At that time, because of the expressed need of patients to continue having compassionate access to marijuana, and because of the ongoing research into the use of THC with other antiemetics, the Panel requested an extension of the program. Noting that over 1700 patients had enrolled in the study over the past four years, Legislation was introduced by Senator Presley to extend the original statute. On July 11, 1984, Governor Deukmejian signed SB 1765 (Chapter 417, Statutes of 1984 -Appendix III) into law. This legislation extended the Cannabis Therapeutic Program four years beyond its previously scheduled ending with a termination date of June 30, 1989.
This legislation also directed the Panel to establish another statewide program to make marijuana and THC available to patients undergoing treatment for glaucoma.
The Panel immediately began to prepare an application for Investigational New Drug Exemption (IND) to the FDA for approval to study cannabis in humans. The Panel drafted a protocol for the pilot project, appointed consultantoncology members, and scheduled public meetings for comments from practicing oncologists, pharmacists and nurses before finalizing the protocols and submitting an IND to FDA. The Panel, through negotiations with the National Cancer Institute (NCI) and the National Institute on Drug Abuse (NIDA) arranged a supply of THC capsules and marijuana cigarettes to approved pharmacies without charge.
Before the Program was fully implemented, a number of additional steps were taken: an
Investigator's Brochure was developed; an informed consent document was written and
reviewed by an outside human subjects' committee to assure patient protection; a data
processing unit was contracted to analyze results of investigators' reports; and a uniform
investigator review and approval process was developed to assure that access to ordering
the drug was controlled.
Marijuana is available as a raw plant, dried and minimally processed for smoking or cooking. Its most active ingredient; delta-9-tetrahydrocannabinol (THC) was available as a synthetically derived chemical and formulated as a solution in oil in a soft gelatin capsule. Although the California legislation provided that seized illegal marijuana could be used, the Panel decided that the only reliable source of standardized marijuana would be NIDA and that NCI was the only economical source of the encapsulated THC.
The investigational drugs would be made available by NCI and NIDA at no cost to California participants. To further conserve the limited State funds, the Panel arranged with NCI and NIDA to ship drug supplies directly to designated pharmacies, a procedure that cut costs to the State by eliminating warehousing and distribution. The U.S. Drug Enforcement Administration (DEA) retained its authority for accountability and to inspect storage facilities.
Investigational THC and/or marijuana cigarettes were shipped to 114 of the 132 approved California pharmacies during the life of the Cannabis Therapeutic Program. The total quantities shipped were as follows:
Marijuana cigarettes 27,650
Tetrahydrocannabinol l0mg capsules 5,640
Tetrahydrocannabinol 5mg capsules 1,033,300
Tetrahydrocannabinol 2.5mg capsules 649,900
Due to limitations of shelf life, the above quantities are greater than the quantities actually administered to patients.
The Panel is pleased to report its investigators and pharmacies maintained effective control of this large inventory of controlled substances. The Panel received no reports of any diversion, or even inventory discrepancies, of investigational marijuana or THC capsules.
Program was funded with an initial appropriation of $100,000 for the start-up costs and the first year of program operation. Funding for subsequent years of this research project was through the standard budgeting process of the State. Overall, the total cost of the Cannabis Therapeutic Program from 1979 through 1988 was $400,000. The Principal items over those years were salaries for one research project coordinator (Research Assistant II), a parttime student research assistant, data analysis services and consultation at critical junctures. Panel members or their employing agencies volunteered their time.
Investigator status was granted to physicians who were board eligible or board certified medical oncologists. radiation oncologists, hematologists, or otherwise qualified physicians (e.g., pediatric oncologists) and who:
a. completed an Investigator Application,
b. held a current license to practice medicine in California,
c were otherwise qualified by their training and/or experience,
d. completed the Federal FDA Investigator's Form (FD Form 1573), and
e. agreed and certified in writing that they would follow all provisions of the protocol.
Participating investigators were required to assume full responsibility for determining that their patients conformed to the admission requirements. Continued participation was conditioned upon the investigator's compliance with the protocol including adequate record keeping on treatment outcome and timely submission of data forms to the Panel. The Panel assured all participants that it would carefully monitor this program, and a number of site visits were made.
The legislation directed that access be provided over geographically wide areas of the State. The Panel made extensive efforts to publicize the Cannabis Therapeutic Program throughout the State to encourage qualified oncologists in diverse geographical locations to apply. The Panel's program was announced in the newsletter of the Board of Medical Quality Assurance which is mailed to all California licensed physicians. All acute are hospitals were provided with a notice announcing the program and explaining the enrollment procedures. Recipient hospitals were asked to circulate the notice to oncology departments and to post a copy. At the meeting of the American Society of Clinical Oncology in San Diego in May 1980, the Panel announced the Cannabis Therapeutic Program to California oncologists, provided application forms to them and answered their questions; thus, the application review and approval process continued through the spring and summer.
In July and September 1980, investigator training meetings were held in San Francisco, Los Angeles, Sacramento, and San Diego and two more held in April 1981, one in Los Angeles and one in San Francisco. Ample time was allowed for questions and answers. In addition to oncologists, these meetings were attended by nurses, pharmacists, and data managers.
The agenda of these meetings included presentations on problems on the clinical pharmacology of marijuana of potential concern to the seriously ill, the elderly and the very young; a review of the research procedures; information on drug ordering, storage and dispensing; and a review of data collection and reporting requirements. These meetings were considered crucial to obtaining standardized protocol implementation, statewide, in this large scale clinical study with only a small staff for monitoring. Investigators, new to the State or new to practice, who had no opportunity to attend the training meetings were instructed individually by project staff. Although newspaper and television interviews were used to inform the general public, the Panel relied primarily on oncologists to inform patients of the program's existence.
At the conclusion of the initial enrollment period in September 1980, three hundred and twenty physicians applied for participant status and 218 investigators from 21 counties actually met all registration requirements by attending one of the four investigator's seminars. By the time the program ended in 1988, 486 investigators had registered and 321 had enrolled patients.
At the conclusion of the enrollment-period in September 1980, over 80 designated pharmacies were registered with DEA to dispense Schedule I controlled substances, THC and marijuana. By the end of the program, 132 pharmacies had been approved to distribute THC and/or marijuana.
Initially, eligible patients were males and non-pregnant females, five years of age and older, with histologically documented malignancies receiving chemotherapy or radiation and experiencing nausea and vomiting which was not relieved by treatment with conventional antiemetics.
Participation in the program was completely voluntary. Therefore the study population was self-selected. The limitations placed on the Panel by the conflicting aims of the program did not permit the establishment of a control group. Each patient acted as his/her own control, and previous experience with conventional antiemetics was compared with the experience with THC treatment.
The use of either THC or marijuana for therapeutic purposes was experimental; therefore. the Panel required investigators to obtain a voluntary, informed consent before enrolling any cancer patient into the program. The Panel prepared a written consent form which disclosed the potential benefits as well as the attendant risks of participation in the experiment. This document was reviewed and approved by the Human Subjects' Protection Committee of the California Department of Health Services. The consent form, written in lay language without unnecessary technical terms, ambiguous phrases or exculpatory clauses, made clear, among other conditions, that participation, both initial and continued, was entirely voluntary.
Pursuant to Section 24170 et seg of the Health and Safety Code, the Rosenthal 'Protection of Human Subjects in Medical Experimentation Act,' each subject also received a copy of the 'Research Subject's Bill of Rights.' Physicians practicing in hospitals or other institutions were also subject to review by their own research or human subjects committees. At the investigators' meetings, the Panel stressed that informed consent is not a mere formality.
English and Spanish versions of the consent form were provided. Patients who did not speak either language were enrolled only if a competent translator was available to explain the consent form pointby-point and to attest in writing to the patient's understanding of it. Patients aged 5 to 17 were required to have parental consent before enrolling in the study and must have joined with their parents in giving consent.
There were two objectives set forth in the statutes:
1. to allow qualified oncologists in diverse geographical locations to provide the drug on a compassionate basis to seriously ill persons not responding to conventional treatment, and
2. to facilitate clinical trials of Cannabis and its derivatives in cancer patients pursuant to the federal IND procedures.
Both the legislation and the investigational status of the drug under federal law obliged the Panel to conduct useful clinical research to address several unanswered questions about THC and marijuana effects. However, compassionate access made some of the basic research processes unusable, e.g., a double-blind controlled study. Therefore, to accomplish these two potentially conflicting objectives, the Panel planned a large collaborative Phase III3 trial.
At the time the Panel designed its protocols, several controlled studies of THC's effect on nausea and vomiting had been completed. Controlled studies demonstrating efficacy results were variable and optimal dosage was not established. Individual doses in most other studies were inflexible and ranged from 2.5 to 15mg THC/m2 body surface area. The time at which the first dose of THC was administered in these studies varied from 1/2 hour to 24 hours prior to the initiation of chemotherapy. The frequency of THC administration varied from every 2 .hours to every 8 hours. Therefore, a major research objective was to determine the optimal THC dose and dosing schedule.
Other research questions to be addressed were: 1) Does the antiemetic effectiveness of THC (and marijuana) vary with the anticancer agent? 2) What are the nature and incidence of the side effects of THC ',,and marijuana) in typical oncological patients7 3) What is the general acceptance of THC and marijuana by practicing oncologists and by cancer patients7 4) Once an effective dose has been established, does tolerance develop to THC's antiemetic effect7
3. Among the safeguards for developing an investigational new drug in a step-wise testing process: the drug is tested in animals before humans. in normal volunteers before patients. and in small groups of people before large groups. Preclinical refers to non-human experiments. e.g.. toxicity and pharmacology experiments in animals. Phase I is conducted in small numbers of normal human volunteers to determine dosage levels and other pharmacologic parameters. Phase 11 clinical trials typically involve small numbers of patients and comparisons to other treatment and must be controlled and almost always double blind. Phase III is to confirm effectiveness and to assess adverse effects in a large and diverse patient population. Usually these studies are uncontrolled. represent the conditions of actual practice, and evaluate toxicity rather than efficacy. Phase IV is to report on drug safety and effectiveness after marketing.
With all of the above considered. protocols were prepared and a comprehensive investigational new drug application (IND) was submitted to the Federal Food and Drug Administration (FDA) March 28, 1980. The initial application included four protocols for THC and marijuana administration. See Appendix IV.
Protocol I was the study of oral THC capsules as an antiemetic in adult cancer patients receiving cyclic chemotherapeutic agents known to produce nausea and vomiting. (Cyclic chemotherapy was defined as single or multiple doses of chemotherapeutic drugs given within a two-day period, with each treatment cycle separated by one week or more.) To be eligible, patients must have failed to benefit from conventional antiemetic drugs such as Compazine or Tigan during at least one previous treatment episode.
Protocol II was similar to Protocol I except that adult patients would be receiving daily anticancer therapy which could either be chemotherapy or radiation therapy.
Protocol III (Pediatric Protocol) was similar to Protocol I except that it was designed for pediatric patients aged 5 through 14 years. Also, patients receiving up to five consecutive days of chemotherapy could be enrolled provided that treatment episodes were separated by three weeks or more. Special safeguards such as the minimum age of 5 years, consent by both parents and by the child. lower starting dosage of THC, and special mental health evaluation, were incorporated into this protocol.
Protocol IV (Smoked Marijuana Protocol) was an evaluation of smoked marijuana in adult cancer inpatients receiving one or more of three extremely emetogenic chemotherapeutic agents, e.g., Cisplatin, dacarbazine or 5-azacytidine alone or in combination with other agents. This protocol was initially limited to patients 15 years of age or older who were marijuana experienced.
The goal of these first four protocols was to obtain patient data rapidly and as safely as possible on the critical issue of THC dose and side effects. The plan was to quickly define a practical safe dose and then modify, eliminate or add to the protocols as necessary.
The above research protocols were modified several times during the course of the Cannabis Therapeutic Program, to ensure the broadest compassionate access and as much useful data as possible. At the outset of the program, pediatric consultants suggested that the usual treatment lasted for 48 hours or less with treatment separated by one week or more. The duration of chemotherapy allowed by Protocol III was limited accordingly. However, the Panel soon learned that a regimen of 5 days of chemotherapy repeated every 3 weeks was frequently used in pediatric practice. Therefore, the Panel modified the criteria for Protocol III to include those chemotherapy regimens lasting for five consecutive days, provided that treatments are separated by three weeks or more.
After the first 150 patients were treated with cannabis under Protocols I and II, the data were scrutinized by Panel members, staff and consultants. Two-thirds of patients reported benefit, but the Panel noted that a large number of patients complained of troubling, although not dangerous, side effects from THC. It also appeared that these side effects influenced a patient's continuation in the program with an initial dropout rate of 48 percent. Therefore, in August 1981, the Panel lowered the starting dose of THC capsules from 7.5mg THC/m2 to 5mg THC/m2 in Protocols II and III. The rationale for this change was a continuation of the attempt to achieve an optimum dose of THC, balancing antiemetic efficacy with troublesome side effects.
Oral THC Protocol. During site visits the Panel learned that investigators perceived the Cannabis Therapeutic Program to be much more complex than it actually was. Therefore, to encourage the participation of cancer specialists and to provide greater compassionate access of cancer patients to THC, the Panel revised its protocols in July 1981. The three protocols for oral THC were combined into one streamlined protocol to simplify the program and to avoid investigator confusion. Also, the new unified protocol, referred to subsequently as the Oral THC Protocol, was modified to enable radiation patients who experienced nausea or vomiting to receive THC.
Cumulative Dose Protocol. In September 1981, the Panel hypothesized that small oral doses (e.g. 2.5mg/m2) of THC would be more useful than larger doses (e.g. 5.0mg/m2) if the repeated small doses were started sufficiently long enough before chemotherapy (e.g. 4 doses prior to chemotherapy). THC is a long acting drug with an appreciable latent period before its effect develops. The development of side effects that caused patients to discontinue THC could be predicted by the size of the single dose of THC that was used. Given cumulatively, that is, in smaller doses begun at a longer interval before chemotherapy, an effective level should be achieved with fewer side effects than if a single large dose is used in effort to achieve a rapid effect. See Appendix VI.
Cumulative Protocol for Oral THC Adopted. in 1982, the cumulative, low-dose regimen was adopted, for the Oral THC Protocol to reduce the number of patients who stopped THC therapy because of side effects that were discomforting rather than life threatening. The lower initial dose (2.5mg/m2) beginning approximately 24 hours prior to anticancer therapy allowed patients to accommodate better to THC as an antiemetic. See Appendix VII.
Combination Antiemetic Protocol. By 1983, it became apparent that oncologists were prescribing several antiemetics in combination in an effort to maximize the benefit. This approach to treatment led investigators in the cannabis study to suggest using THC in combination with other antiemetics. Only two studies involving THC used in combination with another drug had been conducted and in both cases, the other drug was a phenothiazine. The effectiveness of THC tied in combination with a variety of other antiemetics was not established and further clinical trials were needed. Additive effects, particularly if the drugs had different mechanisms of action, were expected to enhance the effectiveness of THC. Appendix VIII includes the Combination Antiemetic Protocol, consent form, patient package insert, investigator brochure. and the combination protocol for pediatric patients.
Smoked Marijuana Protocol. In March 1982, the Panel also revised the protocol for smoked marijuana to broaden access. Based on suggestions from oncologists and the absence of associated problems, the protocol was expanded to include outpatients and marijuana-naive patients who were taught a standardized smoking technique.
In late 1982, the Panel further revised the Smoked Marijuana Protocol. This protocol made any cancer patient receiving radiation therapy or any chemotherapy drugs known to cause nausea and vomiting eligible to participate, and permitted an alternative smoking technique to humidify the smoke and reduce the smoke's harshness by water filtration. Appendix IX contains the initial versions of the Smoked Marijuana Protocol which finally was also included in the Combination Protocol above.
Controlled Studies. In addition to the statewide open studies described above, the Panel sponsored two double-blind, cross-over controlled studies conducted by a small group of investigators.
THC in Combination with Scopolamine. One protocol was intended to test the efficacy of THC use in combination with Transderm V, a patch which is applied to the skin behind the ear and releases an antinausea drug, scopolamine, through the skin continuously over a period of two to three days (Appendix X). Transderm V was supplied by CibaGeigy with double-blind labeling and was to be randomly substituted with an identical placebo patch.
THC in Combination with Dexamethasone. The second protocol, also a double blind cross over study, was intended to test the efficacy of THC used in combination with dexamethasone, an antiinflammatory steroid which has been used as an antiemetic (Appendix XI). Dexamethasone was supplied by Merck Sharp & Dohme Research Laboratories with double-blind labeling and was to be randomly substituted with an identical placebo tablet. These protocols began in late 1983 and continued to be available until December 1987.
Delta-8-THC. Some reports in the medical literature claim that delta-8-tetrahydrocannabinol (delta-8-THC), a synthetic cannabinoid not present in natural marijuana, possesses actions similar to those of delta-9-THC, but possibly caused fewer central nervous system side effects. The Panel, with the assistance of Marie Perez-Reyes, M.D., developed a pilot research project to study the effects of delta-8-THC as an antiemetic.
In October 1983, the Panel submitted IND 124,094 to the U.S. Food and Drug Administration (Appendix XII). Patients were first enrolled in October 1983. The Pilot Protocol (protocol exceptions) and the Glaucoma Protocol (Appendix XIV) are discussed in detail later in the sections on findings.
Each protocol change was duly reported to FDA and discussed as necessary with that agency's representatives. No revision request was denied.
Table A provides a summary of the history of protocol changes for the Cannabis Therapeutic Program.
Initially, data on patient history and the physician's evaluation of treatment were collected at the time of treatment using three standardized forms. The "Chemotherapy and Medical History Prior to THC" form requested information regarding patient characteristics and past chemotherapy and antiemetic experience. The 'Physician's Treatment Episode Report' included information on THC dosage, chemotherapy, performance status of patient, overall THC effectiveness rating on a 4-point scale, and ratings of the incidence and severity of 13 designated THC side effects. Every day that patients received THC, they completed a "THC Evaluation Form,' rating nausea, vomiting, food intake and overall effectiveness using 4- and 5-point scales. If a patient dropped out of the study, the specific reason was noted. Details of serious adverse reactions were reported separately.
Much of the pilot testing and design of data collection forms was conducted in collaboration with investigators and their staff. The Cannabis Therapeutic Program paperwork, including the Patient Package Insert and the Treatment Report forms were thoroughly reviewed by many of these persons.
As protocols were changed, data forms were also revised in an effort to increase enrollment by reducing the burden of paperwork for investigators and patients. Revisions were color-coded for easy identification. All data forms are attached to the protocols included in the appendices.
The latest revision of the protocol (2/11/83) required completion of only one data form for each treatment episode and requested only that information which was considered essential. -
For the purposes of evaluation and analysis, data from the earlier forms were transcribed by Panel staff to the newer form for consistency in coding. Independent contractors were utilized for data entry and analysis for the first phases of the study. Thereafter, Panel staff conducted the analysis for the concluding phases.
In general, there were few problems with protocol compliance. Physician cooperation was exemplary despite protocol details, controlled substances prescription forms, and reports to be completed. This is particularly noteworthy in view of the fact that the funding usually provided by drug companies.
An important result from the site visits was the initiation of Cannabis Therapeutic Program Newsletters designed to keep investigators, nurses, and pharmacists abreast of program developments and research findings.
The Panel kept the Legislature, the medical community, and the public informed about the program and its findings through the Panel's Annual Reports to the Governor and Legislature, newsletters and announcements to investigators, presentations at professional meetings and publication in professional journals. The FDA received quarterly reports as required.
By invitation of the Illinois Dangerous Drug Commission, the preliminary results of the California Program were presented at the National Conference on Marijuana and Cannabinoid Therapeutics in Chicago in March 1982. The legal, administrative and operational aspects of the California program were shared with the professionals attending the meeting.
The Panel also published in scientific publications several reports on research findings and program development:
Gordon J. Dow and Frederick H. Meyers, The California Program for the Investigational Use of THC and Marijuana in Heterogeneous Populations Experiencing Nausea and Vomiting from Anticancer Therapy, Journal of Clinical Pharmacology, 21:128S-132S, 1981.
Dow, G.J. and others. Serious reactions to oral delta-9-THC in cancer chemotherapy patients. Clinical Pharmacy 3:14, 1981.
Meyers, F. and others. Reduced adverse effects with optimal anti-emetics dosage schedule of delta-9-THC. Proceedings of Am. Soc. Clin. Oncology, p94, 1984.
Devine, M. and others. Adverse reactions to delta-9-THC given as an antiemetic in a multi-center study. Clinical Pharmacy 6:319-22, 1987.
Flach, A. and others.
Experience on Treatment of Glaucoma with delta-9-THC, presentation for meeting of
American Academy of Ophthalmology, in preparation.
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