Cannabis Therapeutic Research Program, State of California, 1989

NOTE: The following appendices are not being distributed with this report. The U.S. Food and Drug Administration, The California State Library in Sacramento, and the Medical Library at University of California, San Francisco have been provided with copies of the complete report with all appendices. Also, a copy has been filed at the Research Advisory Panel, 350 McAllister Street, 6000 State Building, San Francisco, CA 94102.

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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.

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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 associates¹ 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.

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 Cannabis

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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 same twentyfour 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 .hat 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.

Summary of Legislation

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 aid to investigate several still unanswered questions about THC.

At the end of 1933, 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 consultant-oncology 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 form 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 a arranged with NCI and NIDA to ship drug supplies directly to designated pharmacies a procedure that cut costs to the State by eliminating ware housing and distribution. The U.S. Drug Enforcement Administration (DEA) retained its authority for accountability ability and to inspect storage facilities ties.

Investigational THC a 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:

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.

The Cannabis Therapeutic 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 part-time 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:

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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.

Physician Enrollment

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 care 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 an 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.

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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.

Research Subjects

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.

Research Subject Protection

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 seq 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 point-by-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.

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/m²body 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 patients? 3) What is the general acceptance of THC and marijuana by practicing oncologists and by cancer patients? 4) Once an effective dose has been established, does tolerance develop to THC's antiemetic effect?

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/m²to 5mg THC/m²in Protocols I, 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<

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effectiveness of THC used 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 Ciba-Geigy 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 Mario 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

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TABLE A

HISTORY OF CANNABIS THERAPEUTIC PROGRAM

1980

I. PROTOCOLS

Protocol I: Oral THC In Adults Receiving Cyclic Chemotherapy (7.5 mg/m²q 4 h)

Protocol II: Oral THC In Adults Receiving Daily Chemotherapy or Radiation Therapy

Protocol III: Oral THC in Pediatric Patients (ages 5-14) (5.0 mg/m²q 4 h)

Protocol IV: Smoked Marijuana for Patients Receiving Cis-Platin, Dacarbazine, 5-Azacytadine (7.5 mg/m²q 3 h)

II. DATA COLLECTION
Three Data Forms:

1) Medical history completed by oncologist

2) Oncologist-evaluation of treatment episodes

3) Patient evaluation of treatment episodes

II. OTHER

1. Data analysis contract with Dept. Of Biostatistics, University of California, Berkeley

1981

I. PROTOCOL MODIFICATIONS:

A. Protocols I, II, and III Combined: Oral THC in
Patients Receiving Chemotherapy and Radiation Therapy

B. Oral THC starting dose for adult patients decreased from 7.5mg/m²to 5.0mg/m²

C. Radiation treatment restrictions eliminated.

I. DATA COLLECTION
Data collection forms reconstructed and color coded.

III. OTHER

1. Patient Package Inserts prepared.

1982

I. PROTOCOL MODIFICATIONS:

1. Starting dose for patients receiving oral THC lowered from 5.0mg/m²to 2.5mg/m²in an effort to reduce bothersome side effects while maintaining efficacy.

2. Oral THC treatment begun the day before chemotherapy rather than 6 hours.

3. Smoked marijuana protocol modified to permit out-patients and marijuana "naive" patients to participate.

II. DATA COLLECTION

Three data forms condensed into one data collection form.

III. OTHER

1. Alternative smoking method described in revised patient package insert.

2. Data analysis contract with Dept of Health Services.

1983

I. PROTOCOL MODIFICATIONS:

1. All patients who could benefit from THC treatment admitted, regardless of history of non-response to conventional antiemetics.

2. Other standard antiemetics permitted for use in combination with THC.

II. NEW PROTOCOLS

1. Controlled double-blind antiemetic study using THC in combination with Transderm V.

2. Controlled double-blind antiemetic study using THC in combination with dexamethasone.

3. Delta-8-THC pilot antiemetic study initiated.

4. Glaucoma protocol submitted to FDA.

to investigators to assure data collection and reporting was not available for this program. Generally, data forms submitted by investigators were complete and timely. Occasionally, forms returned to the Panel office were incomplete, late or were not submitted at all. Investigators were reminded that complete and usable data were needed for research purposes, that they had agreed to cooperate and submit proper forms on time; that failure to do so constituted a serious protocol violation and that the protocol had the "force of law" equal to any duly adopted regulation. Further, the oncologists were provided with specific instructions on how to improve their data collection procedures. Fewer than a dozen investigators were terminated from the study because of failure, after several notices, to respond adequately to the Panel's requests for data. Other investigators left the study because of other reasons, such as moving out of the State.

The careful arrangements made to control access and distribution of THC and smoked marijuana resulted in a program free of any diversion, abuse, or even of discrepancies in inventory. No complaints were received from enforcement agencies or other sources. Violations would have come to the attention of the Panel because of the continued interest and cooperation of the United States Drug Enforcement Administration (DEA).

Over forty site visits were conducted during the course of the Cannabis Therapeutic Program. Panel members and staff made periodic visits to pharmacies and reviewed prescription records to monitor compliance with drug security and control requirements. Investigators and protocol nurses were also visited and interviewed about their study procedures. Site visit findings including Panel recommendations for improving protocol compliance, were communicated to the clinical investigators, nurses and their designated pharmacies.

The site visits resulted in increased quantity and improved quality of the data collected. Another equally important benefit was the mutual participation in shaping and improving the Cannabis Therapeutic Program fostered through these personal meetings. Site visits presented invaluable opportunities for dialogue between investigators and Panel members and staff. Panel site visitors were able to clear up misunderstandings regarding the California Cannabis Therapeutic Program, the most serious of which were those that perpetuated incomplete data collection, or improper drug storage. Conversely, investigators and staff offered suggestions and recommendations of their own, many of which were incorporated into the revised protocols.

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.

Interpretations of efficacy of THC are limited by the fact that in this study no control group could be established for comparison with the treatment group. Thus, some of the findings are more anecdotal than quantitative. However, the following results are clear, reasonable and documented.

A total of 2,475 patients were treated with THC or smoked marijuana under one or more of the following protocols:

Because of the protocol revisions previously described, data had to be tabulated separately for each of the several compassionate access THC protocols (subjects who received THC for nausea and vomiting associated with cancer chemotherapy⁴:

s Summary . These first results reflect data from an open multisite cooperative study conducted to evaluate delta-9-tetrahydrocannabinol (THC) in patients receiving anticancer therapy who previously had been treated with other antiemetics.

Oral THC was found to be effective in reducing nausea, vomiting and anorexia. Effectiveness was related to chemotherapeutic regimen, generally being most effective with the less emetogenic agents.

Side effects were common. Serious adverse reactions were reported by physicians for nine patients, but none of these were life threatening. There was no

significant difference between the effectiveness of the 5mg/m²and 7.5mg/m²doses, but 5mg/m²was associated with fewer side effects, a lower dropout rate due to side effects and a greater number of patients continuing THC treatment. Thus, 5mg/m²is the preferred dose. The incidence of clinically serious adverse reactions to oral THC was less than one percent.

Patient and Investigator Demographics. Of about 300 board certified and eligible oncologists, one hundred seventy-nine enrolled 856 patients, of which 706 were evaluable. Patients were enrolled between November 1980 and April 1982, and were followed until October 1982, at which time a final disposition was obtained on each patient. A total of 150 patients were excluded from analysis due to incomplete report forms, enrollment at doses other than 5mg/m²or 7.5mg/m²and enrollment by 26 investigators who did not adhere to the protocol.

To avoid bias caused by selective dropping-out, only results from the first treatment episode are analyzed in this report, although over half the patients received THC in two or more discrete episodes for a total of 1,622 treatments in this initial trial. Results of second and subsequent episodes are statistically more favorable since patients with disturbing side effects and those with good results self-select for continuation or termination.

Sixty percent entered the study at a THC dose of 7.5mg/m²; 40% entered at the 5mg/m²dose level. Sixty-two percent of the patients were female. The median age for women was 49, and for men was 38. Sixty-four percent of the patients had breast, lung, ovarian, or hematopoietic neoplasms. Seventy-seven percent of the patients were able to carry on normal activities despite their disease (Karnofsky performance status of 80 or more).

Ninety-nine percent of patients had failed to benefit significantly from other antiemetics, which were phenothiazines (87%), butyrophenones (6%), metoclopramide (6%), and others (3%). A wide variety of chemotherapeutic agents were used, usually in combinations. The number of patients per participating physician varied widely: 69 physicians or 41% of them had one or two patients while 25 physicians (15%) had 10 or more patients in the program (Table B).

Proportionately, among men there were more young persons than among women: 30% of the men compared with only 13% of the women were below 30 years. 44% of the men and 61% of the women were in the age group 30-59 years. The age groups above 60 years were equally represented among men and women (26%) (Table C).

The tumor sites most commonly represented among the patients in the THC program were, for women, carcinoma of the breast (38%) and cancer of the ovary or uterus (21%). The most common primary tumor sites among the men were Hodgkin's lymphoma, (18%) and lung carcinoma (18%) (Table D). It should be emphasized, however, that the distribution of primary organ locations is not representative of the prevalence by site in the general population.

Table B

Frequency Distribution of 167 Physicians by Number of Patients Treated with THC Capsules

Number
of
Patients Frequency
of
Physicians Number
of
Patients Frequency
of
Physicians

1 33 13 2

2 36 14 3

3 18 15 2

4 18 / /

5 12 18 1

6 5 / /

7 8 21 1

8 5 / /

9 5 28 1

10 6 / /

11 3 29 1

12 5 / /

167 physicians treated 809 patients with THC capsules.

Table C
Characteristics of Study Population of the Initial Trial

Age Distribution: Male Female

19 yrs or less 23 7.52 29 5.79

20 - 29 yrs 67 21.90 36 7.19

30 - 39 yrs 57 18.63 81 16.17

40 - 49 yrs 30 9.80 99 9.76

50 - 59 yrs 44 14.38 125 24.95

60 - 69 yrs 56 18.30 96 19.16

70 yrs or more 23 7.52 32 6.39

Unknown 6 1.96 3 0.60

Base: 890 patients receiving capsules.

Exclusions: 2 patients with sex unreported.

Table D

Distribution of Primary Tumor Site by Sex

Primary Tumor Site Males Females

No. Percent No. Percent

Lip, Oral Cavity & Pharynx 7 2.3 5 1.0

Digestive Organs & Peritoneum 36 12.0 21 4.2

Examples:

Stomach 6 2.0 1 0.2

Colon, Caecum 11 3.7 10 2.0

Pancreas 6 2.0 4 0.8

Respiratory & Intrathoracic Organs 68 22.6 49 9.8

Examples:

Lung-Trachea 53 17.6 40 8.0

Thymus, Heart & Mediastinum 12 4.0 6 1.2

Bone, Connective Tissue, Skin & breast 39 13.0 216 43.3

Bone & Articular Cartilage 20 6.6 10 2.0

Connective & other
Soft Tissue 10 3.3 11 2.2

Female Breast

191 38.3

Genitourinary Organs 41 13.6 124 24.8

Examples:

Uterus

6 1.2

Ovary & Other Uterine Adnexa

106 21.2

Prostate 10 3.3

Testis 24 8.0

Lymphatic & heamatopoeitic Tissue 73 24.3 46 9.2

Examples:

Hodgkin's Disease 55 18.3 30 6.0

Myeloid Leukemia 9 3.0 8 1.6

Other unspecified sites 37 12.3 38 7.6

Total 301 100.0 499 100.0

Study design. The California statute that established the cannabis program includes the objective of providing 'compassionate access' to marijuana for cancer patients receiving chemotherapy and radiotherapy. Strict experimental control measures were thereby precluded. Patients served as their own controls, however, through comparison with previous antiemetic trials.

Drug dose and schedule. The drug was supplied by the National Cancer Institute as soft gelatin capsules containing 2.5, 5 and 10mg delta-9 tetrahydrocannabinol dissolved in sesame oil. Based on dosage, two cohorts of patients participated in this initial study. Patients in the first cohort received 7.5mg THC/m²every four hours while awake starting six hours prior to anticancer therapy, and continuing for 24 to 48 hours after its completion. If severe side effects occurred, the physician had the option to either delay, omit, or reduce the next dose, or discontinue THC treatment. Preliminary results from the 7.5mg/m²dose regimen indicated that a lower starting dose of THC might be better tolerated. Thus, patients in the second cohort were those given 5mg THC/m²in the same manner.

Efficacy. In 482 patients, the identical anticancer treatment was used with the THC treatment episode and with the prior treatment episode, allowing comparison of the efficacy of THC to a standard antiemetic. As illustrated in Table E, nausea and vomiting were better controlled by THC than by previous antiemetics in 75% and 73% of patients respectively. Fifty-five percent of patients reported improved food intake. Although some nausea and vomiting occurred in most patients during the THC trial, as shown in Tables F and G, nausea was absent in 17% and mild in 38% of the patients. Vomiting was absent in 30% of the population, and in another 33% occurred an average of less than four times daily. As illustrated in Table H, 62% of patients rated THC moderately to very effective. Physicians' effectiveness ratings for THC used in conjunction with various chemotherapy agents are summarized in Table I. Depending on the anticancer agent used. THC was effective in anywhere from 38% to 66% of the patients. No statistically significant associations were found between effectiveness and age, sex or primary tumor site.

Effectiveness and Chemotherapeutic Drugs. Because of the size of this statewide cooperative study, assessment of effectiveness of THC was possible with specific chemotherapeutic regimens. As rated by physicians THC was most effective with chemotherapy regimens known as CMF⁵*, FAC**, and AC***. Physicians rated THC as moderately or very effective in 82 percent of the treatment episodes involving CMF, 76 percent of those involving FAC, and 75 percent of those involving AC. THC was least effective with DTA**** and CISCA*****, yet over 40 percent of these patients benefitted significantly.

Table E

Patient's Assessment of Symptoms:
THC Compared to Previous Antiemetic*

Severity of Symptoms Nausea Vomiting Anorexia

No. % No. % No. %

Less with THC 363 75 350 73 264 55

Same 78 16 61 13 119 25

Greater with THC 41 9 67 14 93 20

Total 482 100 478 100 476 100

*Only includes patients whose anticancer treatment was unchanged.

Table F

Nausea during THC Protected Anticancer Treatment

Nausea Rating Number of Patients Percent

None 112 17

Mild 248 38

Moderate 166 25

Severe 130 20

Total 656 100

Table G

Vomiting during THC Protected Anticancer Treatment

Amount of Vomiting Number of Patients Percent

None 197 30

1-3 times 218 33

4-6 times 83 13

7 or more times 158 24

Total 656 100

Table H

Patient Overall Assessment of THC Effectiveness

Degree of Effectiveness Number of Patients Percent

None 152 24

Slight 92 14

Moderate 196 30

Very 203 32

Total 643 100

Table I

Physician's Effectiveness Rating of
THC by Chemotherapy Regimen

Chemotherapy Regimen Total Number of Patients Moderate or Very Effective Rating

No. %

5 Fluorouracil, Adriamycin
and cyclophosphamide 32 21 66

Cyclophosphamide, methotrexate and 5 fluorouracil 56 37 66

Adriamycin and cyclophosphamide 90 57 63

Cyclophosphamide, Adriamycin, vincristine and prednisone 51 28 55

Cisplatin, cyclophosphamide and Adriamycin 50 20 40

Dacarbazine and Adriamycin 34 13 38

Safety. Physicians were required to make a separate report of any clinically serious adverse reaction, defined as a reaction while taking THC that required the use of drugs or hospitalization of the patient. During the course of this trial, five clinically serious adverse reactions were reported among the first 856 patients treated with THC. There were two instances of severe psychological distress (anxiety), and one case each of myoclonic jerking, postural hypotension, and grand mal seizure. Complicating factors, for example, brain metastasis associated with the seizure, were present in three cases. All patients with serious adverse reactions had the drug immediately discontinued and recovered fully with no sequelae. Generally, no other drug treatment was needed.

Side Effects. Side effects were common: even at the lower dose, about 80% of patients had at least one side effect, and in 26% of those patients, at least one side effect was considered severe. The severe side effects with an incidence of 5% or greater were all central nervous system effects. A significant difference between the sexes was observed: nine percent of women reported severe anxiety as compared to 4% of men (p-.025).

Influence of Dose Level. The THC dose level was found to influence the frequency of side effects and drug-related reasons for dropping out of the study, but did not influence drug effectiveness.

The frequency and nature of various side effects rated as moderate and severe for both THC

dose levels are listed in Table J. Dose level influenced which side effects were reported most frequently as severe. At 7.5mg/m²the two most common severe side effects were confusion and anxiety. At 5mg/m², these were sedation and confusion. Patients receiving 5mg/m²reported an average of 3.3 moderate and severe side effects, compared with 4.4 2 per patient receiving 7.5mg/m². Side effects were almost always less severe when the lower dose of THC was used, and this difference was significant for seven of the 13 categories of side effects.

While there was no statistically significant difference between the high overall dropout rates associated with either dose level, patients receiving the higher dose were more likely to drop out because of side effects than were those on the lower dose. Fortyseven percent of the patients receiving 5mg/m²and 49% receiving 7.5mg/m²dropped out of the study before receiving a second THC treatment. Approximately 20% of patients in both groups dropped out for non-drug reasons (e.g., moved, died, completed chemotherapy). Of the patients who received 5mg/m², 68% dropped out because THC was ineffective, and 32% dropped out because THC produced side effects judged by the patient to be intolerable. In contrast, in the 7.5mg/m²group, only 521 dropped out due to drug ineffectiveness, and 48% dropped out due to intolerable side effects, a significant difference between doses (P<.05). There was no difference in the overall drop-out rate between the two dosage groups.

Table J

Comparison of the Incidence of Side
Effects with 5/mg/m²vs. 7.5mg/m²THC

Side Effect (Incidence as percentage) 7.5mg /m² 7.5mg /m² 7.5mg /m² 5mg/ m²

Dry mouth** 46.5 35.4 3.9 3.2

Tachycardia 12.0 10.9 2.0 1.1

Ataxia** 21.9 18.3 5.4 1.1

Dizziness 41.7 27.1 8.7 4.6

Orthostatic hypotension 16.8
14.1 3.0 2.5

Anxiety** 22.3 14.4 9.1 3.8

Sedation* 56.9 47.7 6.8 7.0

Depressed mood*** 24.0 13.3 7.1 3.5

Elated mood 31.1 35.4 4.1 3.9

Panic 7.0 4.0 0.4 4.2

Confusion** 34.4 27.5 10.4 5.6

Distortion of perception 26.3 22.1 6.6 3.5

Fantasizing 16.0 15.1 4.0 2.1

N (5mg) - 285-285 N (7.5mg) - 404-413

* P<.05** p<.01 *** P<.001

However, in those patients reporting two or more severe side effects isolated as separate groups, patients receiving 5mg/m²were more likely to continue on to a second THC treatment, regardless of the number of severe side effects reported. Forty three percent of the patients who had experienced two or more severe side effects continued on to a second THC treatment when started at 5mg/m². This compared with 29% of those started at 7.5mg/m².

Discussion. This first study included patients with a wide variety of cancer types, covering a broad age range, and receiving treatment from oncologists in community as well as university settings. It thus served as a test of the antiemetic effect of THC under conditions similar to those which would exist in clinical practice were the drug generally available.

Oral THC was found to be a safe and effective antiemetic for most cancer chemotherapy patients. This study shows that a single THC dose of 5mg/m²causes fewer side effects than 7.5mg/m²while maintaining equal effectiveness. The larger dose, 7.5mg/m², should be considered for patients not deriving sufficient protection from 5mg/m².

1) The large number of patients studied strengthens conclusions reached regarding the effectiveness.

and safety of THC. As of Cocchetto's 1981 review of the literature, the largest sample size of the studies reported was only 116 patients. Ungerleider, et al., reported on 214 patients in 798-2. This Research Advisory Panel study, on the other hand, collected detailed treatment reports and patient histories from 706 patients.

2) Most of the patients enrolled in this initial program had not responded to conventional antiemetics, thus posing a more difficult therapeutic test than if THC had been the first antiemetic drug used.

The high drop-out rate and observations of individual patients suggested that the rapid appearance of side effects in patients with limited experience with disinhibiting drugs led to anxiety and even panic. THC has an appreciable latent period, and. if the drug is given immediately before chemotherapy a relatively large single dose must be given to get a rapid effect. Such doses may be effective but, when the effect is fully developed, will cause more pronounced side effects. THC is known to have a long half-life. Giving THC in a cumulative manner, that is, giving repeated smaller doses at a longer time period prior to chemotherapy, should allow more time for behavioral tolerance to develop and achieve better patient acceptance but maintain efficacy. To test that hypothesis a second trial was designed.

Summary. The Cumulative Dose Protocol was designed to test the above hypothesis, that the patient acceptance of oral THC could be improved by using a cumulative dose schedule without the loss of efficacy. The data below support that hypothesis.

Patient and Investigator Demographics. Patient demographics are similar to those of the first study and are summarized for both protocols in Table K. Patients had a wide variety of tumor types and received an assortment of chemotherapeutic agents. In age, sex distribution, tumor types, and anticancer treatment, the two cohorts did not differ significantly. All patients had failed to achieve satisfactory benefit from standard antiemetic before starting the study. The most common antiemetic drug used prior to THC was prochlorperazine.

Study design. Patients enrolled in the Cumulative Dose Protocol received 2.5mg THC/m²orally q4h, starting 4 doses prior to anticancer treatment. These patients were compared to a previous group of patients who were treated under the standard protocol, in which they received 5.0mg THC/m²orally q4h, starting only 2 doses prior to anticancer treatment.

Results. The following is an analysis of the results reported by California oncologists of their patients enrolled in the Cumulative Dose Protocol. In this report, only the first THC treatment was used in the comparative analysis of the effectiveness and side effects to avoid bias due to over representation of results from repeated trials on patients with good response.

Efficacy. Physician ratings of nausea, vomiting and overall effectiveness were similar in the initial and the cumulative protocols. Table L compares the two cohorts as regards oncologists or nurses ratings of nausea, vomiting and overall THC effectiveness. Although there is a slight trend toward less nausea and less vomiting with higher dose, with 95% confidence it is found that the distribution of nausea and vomiting ratings are similar for both protocols. Similarly, 57% of patients rated THC as "moderately" or "very" effective, exactly the same for the two dosage schedules, indicating that side effects influence the overall evaluation.

Side Effects. Table H summarizes the reports of moderate and severe THC side effects and their severity as recorded by oncologists or nurses on a standardized list. In no case was the percentage for a moderate or severe side effect increased by the cumulative dosing regimen; and the incidence of twelve of the thirteen side effects listed was significantly reduced when compared to patients using the initial THC protocol.

THC Related Dropouts. After the first treatment episode 27.5% of patients receiving the cumulative dosing regimen and 22.9% of those receiving the standard THC dosage dropped out of the trial. There is no statistically significant difference in these dropout rates.

Conclusion. Based on the preceding findings, it appears that prolonged exposure to low dose THC is superior to standard THC therapy as an antiemetic regimen for cancer chemotherapy patients. The cumulative dose method decreases the number of moderate and severe side effects. The cumulative dose method had no affect on the drug's reported efficacy and had no affect on dropout rate.

Table K

Patient Demographics

Protocol Protocol

(2.5 mg THC/M² with 4 loading doses) (5.O mg THC with 2 loading doses)

N = 134 N = 231

Sex

Males 38% 46%

Females 62% 54%

Age

19 yrs or younger 7% 8 %

20 - 39 years 28 % 34 %

40 - 59 years 44 % 34 %

60 yrs or Older 19 % 23 %

Table L

Comparison of Nausea, Vomiting and Overall Effectiveness
Between two THC Treatment Regimens

Ratings of Nausea Cumulative Single Dose

N = 124 N = 221

None 17 % 18 %

Mild 27 % 32 %

Moderate 34 % 31 %

Severe 22 % 19 %

Vomiting N = 124 N = 221

None 32 % 33 %

3 - times 23 % 29 %

3 - 4 times 14 % 13 %

> 4 times 31 % 26 %

Overall Effectiveness N = 122 N = 221

Not Effective 25 % 20 %

Slightly 18 % 23 %

Moderately 25 % 25 %

Very 33 % 32 %

Table M

Comparison of the Incidence & Severity of Side Effects
from THC Using Two Different Dosing Methods

Side Effect (Incidence as percentage) Rated as Moderate Rated as Severe

Cumulative* Single Dose** Cumulative* Single Dose**

Dry mouth** 19 40 3 6

Tachycardia 2 5 0 1

Ataxia** 2 15 2 1

Dizziness 11 19 6 5

Orthostatic hypotension 3 8 2 5

Anxiety** 2 8 2 2

Sedation* 19 46 9 9

Elated mood 5 20 0 7

Confusion** 8 24 2 5

Distortion of perception 5 15 0 2

Fantasizing 6 13 0 0

Depressed mood 5 7 0 4

Panic or fear 2 0 0 4

Cumulative N = 134 Single Dose N = 224

Summary. To provide a systematic and structured approach to the common practice of combination antiemetic therapy, The Panel offered a protocol for the optional use of THC alone or THC in combination with prochlorperazine or other antiemetics. The Panel hoped that required reporting of combinations of antiemetics used would provide. additional information about efficacy and side effects of various combinations. Under the Combination Protocol, the majority of investigators either chose to use THC alone or THC in combination with prochlorperazine.

The results of the Combination Protocol study support prior Cannabis Therapeutic Program studies in terms of effectiveness and side effects. Only one clinically serious adverse reaction was reported during the treatment of an additional 657 patients with THC. Also, tabulation of the data demonstrates no significant differences in reports of efficacy or side effects between those cases where THC was used alone, cases where THC was used in combination with prochlorperazine or other antiemetics. Too few treatment alluded to combined use of THC with other antiemetics to draw conclusions on the individual combinations.

Patient Demographics. The Panel tabulated 2,263 reports of treatment episodes on a total of 657 patients treated after January 1, 1984, the effective date for the combination protocol. These numbers include treatment reports for 98 patients who were administered marijuana cigarettes (including all prior protocols which permitted use of smoked marijuana) and records for 70 patients who had received prior treatments with THC capsules pursuant to protocols other than the Combination Protocol. There. were 489 patients who had not been previously treated with THC under a prior protocol and who first received oral THC under the Combination Protocol. A total of 1,674 discrete treatment episodes were reported for these 489 patients. See Table N for a description of patient characteristics. Table 0 tabulates the emetogenicity ratings of the chemotherapy for the first treatment episodes and Table P presents the distribution of types of tumors treated.

Study design. The Panel had indications that some physicians were using other antiemetics in combination with oral THC but not informing the Panel or including such data on the treatment forms. Aside from THC as an antiemetic it was clear that many oncologists were now using polypharmacy antiemetic therapy with some of the cocktails ranging up to 5 or 6 antiemetic drugs. The combination protocol gave oncologists the option to start patients either on THC alone or in combination with prochlorperazine or dexamethasone. Those combinations were encouraged by the Protocol but other combinations were permitted.

Table N

Patient Demographics

THC used alone THC and other Antiemetics Combination Protocol Totals

N = 257 N = 232 N = 489

No. % No. % No. %

Sex

Males 118 45.9 104 44.8 222 45.4

Females 139 54.1 128 55.2 267 54.6

Age

19 yrs or younger 31 12.1 31 13.4 62 12.7

20 - 39 yrs 74 28.8 101 43.5 175 35.8

40 - 59 yrs 85 33.1 63 27.2 148 30.3

60 yrs or more 67 26.1 37 15.9 104 21.3

Table 0

Comparative Ratings of Emetogenicity of the Chemotherapy

THC used alone THC and other Antiemetics Combination Protocol Totals

N = 257 N = 232 N = 489

No. % No.

Marijuana cigarettes		27,650
Tetrahydrocannabinol	10mg capsules	5,640
Tetrahydrocannabinol	5mg capsules	1,033,300
Tetrahydrocannabinol	2.5 mg capsules	649,900

TABLE OF CONTENTS	Page
Executive Summary	v
Cancer Chemotherapy, Nausea and Vomiting	1
The Problem	1
Inadequacy of Drugs in Current Use	1
Early Experience with Marijuana and THC	1
Cannabis Therapeutic Program	3
Legislative History	3
The Research Advisory Panel	3
Panel's Role in Development of Legislation	4
Summary of Legislation	4
Implementation of the New Law	5
Extension of Law and Provision for Glaucoma Studies	5
Protocol Development	5
Drug Supply	5
Cost	6
Investigator Eligibility	6
Physician Enrollment	7
Research Subjects	8
Research Subject Protection	8
Study Objectives	9
Protocol History	10
Data Collection	13
Data Quality Control	13
Abuse	15
Site Visits	15
Dissemination Dissemination of Findings and Results	16
Detailed Protocol Results	17
Number of Patients Treated	17
Initial Trial	17
Cumulative Dose Study	28
Combination Protocol	32
Results of Study with Smoked Marijuana	41
Protocol Exceptions (Pilot Protocols)	48
Results of the Controlled Study Protocols	49
Glaucoma Protocol	50
Post Marketing Survey of Investigators	52
Discussion of Results of Cannabis Therapeutic Program	57
Approval by FDA for Marketing of THC and Conclusion of the Cannabis Therapeutic Program	59
Approval and Rescheduling	59
Investigational THC No Longer Supplied by NCI	59
Credits	61
APPENDIX I	1
APPENDIX II	1

Smoked Marijuana Protocols	119
The compassionate access THC protocols	2400
Dexamethasone Protocol	4
Transderm-V Protocol	65
Delta-8-THC Protocol	10
Pilot Protocol (protocol exceptions)	19
Glaucoma Protocol	9

Table B Frequency Distribution of 167 Physicians by Number of Patients Treated with THC Capsules
Number of Patients	Frequency of Physicians	Number of Patients	Frequency of Physicians
1	33	13	2
2	36	14	3
3	18	15	2
4	18	/	/
5	12	18	1
6	5	/	/
7	8	21	1
8	5	/	/
9	5	28	1
10	6	/	/
11	3	29	1
12	5	/	/
167 physicians treated 809 patients with THC capsules.

Table C Characteristics of Study Population of the Initial Trial
Age Distribution:	Male		Female
19 yrs or less	23	7.52	29	5.79
20 - 29 yrs	67	21.90	36	7.19
30 - 39 yrs	57	18.63	81	16.17
40 - 49 yrs	30	9.80	99	9.76
50 - 59 yrs	44	14.38	125	24.95
60 - 69 yrs	56	18.30	96	19.16
70 yrs or more	23	7.52	32	6.39
Unknown	6	1.96	3	0.60
Base: 890 patients receiving capsules.
Exclusions: 2 patients with sex unreported.

Table D
Distribution of Primary Tumor Site by Sex
Primary Tumor Site	Males		Females
	No.	Percent	No.	Percent
Lip, Oral Cavity & Pharynx	7	2.3	5	1.0
Digestive Organs & Peritoneum	36	12.0	21	4.2
Examples:
Stomach	6	2.0	1	0.2
Colon, Caecum	11	3.7	10	2.0
Pancreas	6	2.0	4	0.8
Respiratory & Intrathoracic Organs	68	22.6	49	9.8
Examples:
Lung-Trachea	53	17.6	40	8.0
Thymus, Heart & Mediastinum	12	4.0	6	1.2
Bone, Connective Tissue, Skin & breast	39	13.0	216	43.3
Bone & Articular Cartilage	20	6.6	10	2.0
Connective & other Soft Tissue	10	3.3	11	2.2
Female Breast			191	38.3
Genitourinary Organs	41	13.6	124	24.8
Examples:
Uterus			6	1.2
Ovary & Other Uterine Adnexa			106	21.2
Prostate	10	3.3
Testis	24	8.0
Lymphatic & heamatopoeitic Tissue	73	24.3	46	9.2
Examples:
Hodgkin's Disease	55	18.3	30	6.0
Myeloid Leukemia	9	3.0	8	1.6
Other unspecified sites	37	12.3	38	7.6
Total	301	100.0	499	100.0

Table E
Patient's Assessment of Symptoms: THC Compared to Previous Antiemetic*
Severity of Symptoms	Nausea	Vomiting	Anorexia

	No.	%	No.	%	No.	%
Less with THC	363	75	350	73	264	55
Same	78	16	61	13	119	25
Greater with THC	41	9	67	14	93	20
Total	482	100	478	100	476	100

Table F
Nausea during THC Protected Anticancer Treatment
Nausea Rating	Number of Patients	Percent
None	112	17
Mild	248	38
Moderate	166	25
Severe	130	20
Total	656	100

Table G
Vomiting during THC Protected Anticancer Treatment
Amount of Vomiting	Number of Patients	Percent
None	197	30
1-3 times	218	33
4-6 times	83	13
7 or more times	158	24
Total	656	100

Table H
Patient Overall Assessment of THC Effectiveness
Degree of Effectiveness	Number of Patients	Percent
None	152	24
Slight	92	14
Moderate	196	30
Very	203	32
Total	643	100

Table I
Physician's Effectiveness Rating of THC by Chemotherapy Regimen
Chemotherapy Regimen	Total Number of Patients	Moderate or Very Effective Rating
		No.	%
5 Fluorouracil, Adriamycin and cyclophosphamide	32	21	66
Cyclophosphamide, methotrexate and 5 fluorouracil	56	37	66
Adriamycin and cyclophosphamide	90	57	63
Cyclophosphamide, Adriamycin, vincristine and prednisone	51	28	55
Cisplatin, cyclophosphamide and Adriamycin	50	20	40
Dacarbazine and Adriamycin	34	13	38

Table J
Comparison of the Incidence of Side Effects with 5/mg/m²vs. 7.5mg/m²THC
Side Effect (Incidence as percentage)	7.5mg /m²	7.5mg /m²	7.5mg /m²	5mg/ m²
Dry mouth**	46.5	35.4	3.9	3.2
Tachycardia	12.0	10.9	2.0	1.1
Ataxia**	21.9	18.3	5.4	1.1
Dizziness	41.7	27.1	8.7	4.6
Orthostatic hypotension	16.8	14.1	3.0	2.5
Anxiety**	22.3	14.4	9.1	3.8
Sedation*	56.9	47.7	6.8	7.0
Depressed mood***	24.0	13.3	7.1	3.5
Elated mood	31.1	35.4	4.1	3.9
Panic	7.0	4.0	0.4	4.2
Confusion**	34.4	27.5	10.4	5.6
Distortion of perception	26.3	22.1	6.6	3.5
Fantasizing	16.0	15.1	4.0	2.1
N (5mg) - 285-285		N (7.5mg) - 404-413
* P<.05** p<.01		*** P<.001

Table K
Patient Demographics
	Protocol	Protocol
	(2.5 mg THC/M² with 4 loading doses)	(5.O mg THC with 2 loading doses)
	N = 134	N = 231
Sex
Males	38%	46%
Females	62%	54%
Age
19 yrs or younger	7%	8 %
20 - 39 years	28 %	34 %
40 - 59 years	44 %	34 %
60 yrs or Older	19 %	23 %

Table L
Comparison of Nausea, Vomiting and Overall Effectiveness Between two THC Treatment Regimens
Ratings of Nausea	Cumulative	Single Dose
	N = 124	N = 221
None	17 %	18 %
Mild	27 %	32 %
Moderate	34 %	31 %
Severe	22 %	19 %
Vomiting	N = 124	N = 221
None	32 %	33 %
3 - times	23 %	29 %
3 - 4 times	14 %	13 %
> 4 times	31 %	26 %
Overall Effectiveness	N = 122	N = 221
Not Effective	25 %	20 %
Slightly	18 %	23 %
Moderately	25 %	25 %
Very	33 %	32 %

Table M
Comparison of the Incidence & Severity of Side Effects from THC Using Two Different Dosing Methods
Side Effect (Incidence as percentage)	Rated as Moderate		Rated as Severe
	Cumulative*	Single Dose**	Cumulative*	Single Dose**
Dry mouth**	19	40	3	6
Tachycardia	2	5	0	1
Ataxia**	2	15	2	1
Dizziness	11	19	6	5
Orthostatic hypotension	3	8	2	5
Anxiety**	2	8	2	2
Sedation*	19	46	9	9
Elated mood	5	20	0	7
Confusion**	8	24	2	5
Distortion of perception	5	15	0	2
Fantasizing	6	13	0	0
Depressed mood	5	7	0	4
Panic or fear	2	0	0	4
	Cumulative N = 134		Single Dose N = 224

Table N
Patient Demographics
	THC used alone		THC and other Antiemetics		Combination Protocol Totals
	N = 257		N = 232		N = 489
	No.	%	No.	%	No.	%
Sex
Males	118	45.9	104	44.8	222	45.4
Females	139	54.1	128	55.2	267	54.6
Age
19 yrs or younger	31	12.1	31	13.4	62	12.7
20 - 39 yrs	74	28.8	101	43.5	175	35.8
40 - 59 yrs	85	33.1	63	27.2	148	30.3
60 yrs or more	67	26.1	37	15.9	104	21.3

Table 0
Comparative Ratings of Emetogenicity of the Chemotherapy
	THC used alone		THC and other Antiemetics	Combination Protocol Totals
	N = 257		N = 232	N = 489
	No.	%	No.