Request for Applications - Archive

Summary

Since 1999, Health Canada, in collaboration with CIHR, has solicited applications for clinical trials aimed at increasing the knowledge base on the safety and efficacy of marijuana and cannabinoids through the Medical Marijuana Research Program. A description of this Program is available on this website. Health Canada and CIHR have now initiated the Marijuana Open Label Safety Initiative that will focus on the conduct of clinical studies designed similarly to those often termed "Phase IV" in the drug development process.

Table of Contents

Introduction
Background
Who is Eligible to Apply?
Mechanism of Support
Funds Available
Allowable Costs
How to Apply and Evaluation Process
General CIHR Guidelines and Conditions of Funding
Contact Information

Introduction

The purpose of this Initiative is to conduct open label clinical studies with both smoked and non-smoked marijuana.

Background

Open label clinical study is used in this Initiative to indicate a clinical study where all subjects receive the drug. Studies that involve the administration of pre-determined doses or patient-specific doses of marijuana to all subjects will be considered under this Initiative.

Health Canada's Medical Marijuana Research Program (MMRP) solicits research applications on the safety and efficacy of marijuana. Both randomized controlled clinical trials (RCT) and trials focusing only on safety are considered relevant under that Program. The application and review procedures for trials submitted under that Program have been integrated with the normal CIHR procedures for RCT and operating grants. This Program will continue.

Health Canada has evaluated the MMRP and has identified some barriers to the conduct of the studies needed by Health Canada to establish an adequate knowledge base for making policy decisions on the use of marijuana for medical purposes. In the absence of a commercial sponsor, potential researchers have been required to assume all of the responsibility for the development of the necessary regulatory documentation to support the conduct of clinical studies. Health Canada recognizes this is an onerous burden to place on researchers and is therefore taking this into consideration for the new Marijuana Open Label Safety Initiative (MOLSI). This Initiative will provide more assistance to researchers by making available some essential elements needed for the conduct of clinical studies. The application and evaluation procedures have been designed specifically for this Initiative. See How to Apply and Evaluation Process below.

The MOLSI is soliciting proposals to conduct studies with both smoked and non-smoked marijuana with the following objectives:

Primary Objective

• To collect standardized safety data on the use of marijuana for medical purposes.

Secondary Objectives

• To assess dosage use.
• To collect data on the satisfaction with the Health Canada product and for subjects who have used marijuana from other sources for symptom control, to compare it with their past experience.
• To determine the incidence of adverse events attributed to the use of marijuana and to determine if there are any predisposing factors.

Health Canada, in collaboration with the Canadian Consortium for the Investigation of Cannabinoids in Human Therapeutics (CCIC) and other Canadian researchers, has prepared a template that outlines issues that need to be considered by applicants in submitting applications under this Initiative. Researchers may use this template for the design of protocols. Health Canada is also preparing draft clinical study protocols based on this template that will be made available soon to researchers on this website under this Initiative description. These draft protocols will describe open label clinical studies with marijuana in patients with selected specific diseases and conditions.

Applicants are not limited to using these protocols for studies. Protocols aimed at the evaluation of marijuana for the treatment of the symptoms of other diseases are also eligible. Researchers may modify the above protocols for other studies. The design of protocols according to the template or based on the draft protocols that will be made available does not ensure approval of the proposed research. Other factors, such as the qualifications and research experience of applicants and the availability of resources and facilities to perform the research, will also be assessed.

As the primary objective of this Initiative is the collection of safety data on the use of marijuana, Health Canada expects that studies under this Initiative will involve, in total, more than 500 subjects. It is recognized that this may involve the conduct of several disease specific studies. In order to ensure that the safety data from these studies is as compatible as possible to permit analysis of the results from all studies, some elements described in the template are compulsory.

Studies must comply with Canadian requirements applicable to the conduct of clinical trials with controlled substances and with Guidelines related to Good Clinical Practice. This includes the need to submit a Clinical Trial Application (CTA) in accordance with Division 5 of the Food and Drug Regulations, Drugs For Clinical Trials Involving Human Subjects. Requirements related to the Controlled Drugs and Substances Act pertaining to the use of a controlled substance in a clinical study may be obtained from the Health Canada contact indicated below.

Ethics approval must be obtained from a recognized research ethics committee prior to study commencement. Each participating site will obtain approval to conduct this study from an appropriate Research Ethics Board (REB). The investigator must be familiar with the principles elaborated in the Declaration of Helsinki (Hong Kong 1989 revision) and must adhere to these principles.

The study objectives and inclusion and exclusion criteria must agree with those in the template. The frequency of and information collected during subject assessments must comply with the requirements set out in the template. Similarly, studies must conform to the direction in the template on the collection of adverse event information and outcome measures.

Only marijuana available from Health Canada's supply that is grown under contract by Prairie Plant Systems Inc. may be used in studies under this Initiative. Health Canada's marijuana may be considered to constitute a series of preparations of the plant that will contain, if required for the proposed study, varying but defined and controlled contents of tetrahydrocannabinol (THC) and other cannabinoids. These preparations will contain up to five different THC contents ranging from about 2% to 25% THC. Placebo material, a preparation containing very low levels of THC, will also be available. As all marijuana preparations will be prepared on an as-needed basis, it is essential that researchers contact Health Canada regarding the availability of marijuana preparations. Access to a Drug Master File for this marijuana will be made available to satisfy the chemistry and manufacturing requirements of the CTA. The maximum daily dosage must not exceed three grams.

Investigators must also agree to make the results of their study available to Health Canada and to transfer all collected and analyzed information to a central information management system for integration and global analysis.

Under the MOLSI, support elements currently available under the MMRP will also be made available to potential researchers. These include expert assistance, where requested, for the preparation of a CTA. Health Canada will make available an Investigator's Brochure that may be used as is or modified, as appropriate and a Monograph for marijuana that summarizes current scientific and medical knowledge about the use of marijuana for medical purposes.

Investigators are responsible for ensuring that they have appropriate professional insurance to cover activities of the study. Institutional insurers must be advised of the study and asked to give coverage of the study in writing.

Who is Eligible to Apply?

Eligibility criteria for all CIHR research funding (grant) programs apply. Please refer to Eligibility for Research Funding Programs on the CIHR website.

The business office of the institution of an eligible Principal Applicant generally administers CIHR funds. The eligibility requirements for Institutions are found on the CIHR website in the Financial Administration of Funds Guide.

Mechanism of Support

This RFA is funded as a strategic Initiative and is designed to solicit project grant applications with the duration of up to three years.

Funds Available

• The maximum amount for a single grant is $1.5 M per year.

• The funds for this Initiative will come from the same funding envelope as the MMRP.

Allowable costs

Applicants should review CIHR's guidelines on Eligible Expenditures for Research Funding Initiatives for a complete listing and description of allowable costs and activities.

How to Apply and Evaluation Process

Applicants must submit an Operating Grant Full Application using standard CIHR forms from the CIHR Operating Grants application package by February 1, 2003. The Registration package is not required. As the funding cycle for this Initiative is not synchronized with other CIHR processes, an ad hoc committee of experts with competencies relevant to applications will be selected by CIHR to review applications. Both the proposed research and the applicant will be assessed during this review. Dates for further submissions will be specified in subsequent information on this initiative.

General CIHR Guidelines and Conditions of Funding

All conditions, as specified in CIHR's Grants and Awards Guides , shall apply to those funded through this Initiative. Conditions cover areas such as Applicant and Institutional Responsibilities, Ethics, Official Language Policy, Access to Information and Privacy Acts, Acknowledgement of Health Canada and CIHR support etc. Successful recipients will be informed of any special financial conditions when they receive CIHR's Authorization for Funding Form (AFF). The principal applicant (with funding responsibilities) will be required to submit a final report to Health Canada and CIHR summarizing the results and describing how the grant funds were used.

Contact Information

Suzanne Desjardins, Ph.D.
Manager
Evaluation and Research Coordination Division
Office of Controlled Substances
Drug Strategy and Controlled Substances Program
Healthy Environments & Consumer Safety Branch
Health Canada A.L. 3503B
Ottawa ON K1A 1B9
Phone: (613) 946-4223
Fax: (613) 952-2196
e-mail: suzanne_desjardins@hc-sc.gc.ca

Template

Performance and Evaluation of this RFA

To promote and initiate the development of novel, innovative health research about the safety of marijuana for medical purposes. Generate valid and reliable data in this area. Evaluate the incidence of adverse effects associated with the use of this substance. On short term, CIHR and HC expect to support a small number of successful research projects with a view of collecting meaningful data on the medical use of marijuana.

Preface

This document provides a framework outlining the key information required for developing protocols to conduct clinical studies under the Marijuana Open Label Safety Initiative. The template requirements include the use of Health Canada product, compliance with Division 5 of the Food and Drug Regulations, Drugs for Clinical Trials Involving Human Subjects and with Good Clinical Practices (see Appendix 2), generic study primary and secondary objectives, generic inclusion and exclusion criteria, maximum daily dosage, frequency and key information collected including adverse event reports, and key outcome measures. Investigators must agree to transfer all information collected and analyzed through their study to a central information system for integration and global analysis.

Investigators are responsible for developing their own specific protocol, including specific inclusion/exclusion criteria, specific outcomes and methodological approaches. It should be noted that the use of this template does not guarantee a successful application. Successful applicants are strongly encouraged to share with other successful applicants, under this initiative, the additional outcomes that were identified in addition to the compulsory outcomes included in this template.

This template was prepared with the collaboration of the Canadian Consortium for the Investigation of Cannabinoids (CCIC) for Human Therapeutics. (the list of consultees is provided in Appendix 1).

I. Study Justification

Despite the claims concerning the potential benefits of marijuana for the treatment of symptoms of several conditions, the safety of marijuana has not yet been systematically evaluated through standardized clinical studies. At the present time, safety information comes mainly from epidemiological studies of recreational marijuana use. There is limited information on the long term safety of marijuana in any population, let alone a population which is severely ill and on numerous concomitant treatments.

Currently, it is permitted, under specified conditions, for Canadians to possess and grow marijuana for medical purposes under the Medical Marihuana Access Regulations (MMAR). However, no follow-up information is being obtained on patients using marijuana under the MMAR. The availability of a standardized product, manufactured through a contract between Health Canada and Prairie Plant Systems Inc (PPS), creates an opportunity to provide research-grade marijuana to subjects enrolled in a clinical study and to monitor a range of safety parameters, as well as to collect information on doses and on subject's satisfaction which may be useful in designing randomized controlled clinical trials.

II. Study Objectives

Primary Objective

The primary objective is the collection of standardized safety data on the use of marijuana for medical purposes.

Secondary Objectives

To assess dosage use.

To collect data on the satisfaction with the Health Canada product and for subjects who have used marijuana from other sources for symptom control, to compare it with their past experience.

To determine any predisposing factors to adverse events.

III. Dosing of Marijuana

The purpose of studies under this initiative is the assessment of the safety of marijuana under varied conditions. Therefore, studies must provide within-study flexibility in route of administration and daily dosage.

Marijuana is most frequently consumed by smoking. Smoking results in a wide inter-subject variation in the effective dose due to differences in inhalation techniques and preparation of the marijuana. Although most frequently smoked in the form of a cigarette, smoking marijuana in a pipe is also an option. Marijuana may also be administered through a device called a vaporiser which heats the marijuana to a temperature sufficient to volatilize some components without combusting the material. It can also be expected that some subjects will consume marijuana by the preparation of different types of edible products that may be prepared for oral consumption.

The maximum daily dosage must not exceed 3g per day. The introduction of subjects to Health Canada's supply of marijuana should be conducted using low initial doses of the material with increases in dose being made only after adequate subject experience with the material. It is essential that the dosage information be collected for each subject. Adjustment in dosage must be documented and clearly justified on the basis of clinical evaluation (e.g. inadequate symptom relief).

Since it is anticipated that the majority of patients accessing this safety study will be experienced users of marijuana, the marijuana for these studies will be provided in the familiar form of dried plant material. It is anticipated that the product will be distributed primarily through participating pharmacies.

To reduce the risk of diversion, it is strongly recommended that the quantity of marijuana provided to subjects at one time not exceed their requirements for one week.

IV. Methods

A. Study Design

This initiative pertains to the conduct of open label safety studies on marijuana used for medical purposes for which a phase-4-study-design is recommended. Subjects will be followed for one year or until death, should death occur before the end of the study. Investigators will develop protocols to conduct disease-specific or symptom-specific studies. Examples of potential conditions include (but are not limited to) HIV/AIDS, multiple sclerosis, chronic cancer or non-cancer pain, palliative care and end-of-life.

B. Study Centres

It is intended that studies under this initiative will be conducted at several sites across Canada. The protocol must clearly indicate how many sites will be involved in the proposed study, where the site will be located and whether the site will be associated with an hospital or clinic. All centres and research sites must have qualified investigators responsible for carrying out the study and following patients. Centres must be able to comply with the protocol and with Good Clinical Practices (GCP) (see Appendix 2). They must also be capable of quality-controlled data collection and be able to secure acceptable ethics committee review of protocols to ensure that the best quality data are collected with adequate protection of the safety of subjects and investigators. All investigators participating in the study, including patients' treating physicians who have agreed to participate in the study, must comply with the protocol and must follow the GCP.

C. Recruitment of Patients

The studies will be open to all eligible subjects across Canada. Approved centres and research sites will recruit subjects. The availability of marijuana through these studies should be publicized through the popular media and through the most popular medical periodicals and journals read by medical practitioners in Canada.

It can be expected that most studies conducted under this initiative will predominantly involve subjects already using marijuana.

All potential subjects must be informed of the following when considering participation in the study:

• Patients authorized to possess and cultivate marijuana under Health Canada regulations who participate in a clinical study will not be permitted to possess marijuana other than the study drug, for the duration of the study.
• Subjects must not operate a motor vehicle and/or heavy machinery for the duration of the study.

D. Eligibility Criteria

a. Inclusion Criteria

• Adults? 18 years old
• Experienced and naïve marijuana users may be eligible
• Conventional treatments have been considered medically inappropriate or inadequate
• Subject must be willing and able to give informed consent
• Subject must be able to comply with the requirements of the study protocol

b. Exclusion Criteria

• Pregnant (should have negative urinary _HCG pregnancy test) or breast-feeding
• History of psychosis, including mental illness that could put subject at risk during the study
• Unstable ischaemic heart disease
• Unstable broncho pulmonary disease
• Discordance between self-reported drug use and urine drug screening results at recruitment
• Subject concurrent involvement in any other clinical trial

E. Screening

The study will be explained in detail to interested subjects. Once they have understood the study requirements, all participants will be asked to give an informed consent. Only consented subjects will enter in the screening phase to determine eligibility.

Once all the criteria for entry into the study have been satisfied, subjects will commence the study. A complete log of subjects who are not eligible will be kept at center, along with the reasons for ineligibility.

F. Study Drug

Only marijuana grown under contract to Health Canada by Prairie Plant Systems Inc will be used in the studies conducted under this initiative. Marijuana from two strains of plant will be available. The THC contents of the flowering tops (buds) of these strains are approximately 13% to 18% for one strain and 20% to 25% for the other one. Marijuana consisting of only the flowering tops is preferred by many users. Marijuana with other variable and predetermined THC contents ranging from about 2% to the maximum of 18% or 25%, depending on strain, will be available in five steps. These products will be prepared by incorporating low THC plant parts, mainly twigs and some leaf, with flowering tops. The marijuana will be available in foil packets containing 30g. Protocols must clearly define the approximate quantities and types of marijuana that will be used.

G. Study Visits

A schedule of visits and data collection is attached in Appendix 3. The schedule is designed to generate the most efficient data collection while ensuring that early safety concerns are identified.

1. Baseline Assessment

• Demographics : Name, age, sex
• Medical information:
  • Primary diagnosis
  • Respiratory and cardiovascular abnormalities
  • Chest x-ray, pulmonary function test and ECG
  • Neurocognitive tests
  • Hematology profile
  • Endocrine function test
  • Chemistry profile
  • Urinary drug testing
  • Medications and drug use, including OTC and natural health products:
    • Previous and current use of conventional treatment for symptoms and outcome
    • Reasons for abandoning conventional treatment

• Previous and current use of marijuana for medical purposes:
  • Previous and current use of marijuana for symptoms and outcomes
  • Form of marijuana used, including size of dose, and frequency of use
• Quality of life questionnaire
• History of tobacco alcohol and drug use, including marijuana, for recreational purposes:
  • Duration of use of tobacco and/or drug, including marijuana, for recreational purposes
  • Frequency and quantity of drug, including marijuana, used for recreational purposes
  • Frequency and quantity of alcohol consumption

2. Follow-up Assessments

Subjects must either visit the investigator or their treating physician each week during the first month following the start of the use of marijuana under the study. This will allow to adjust dosing if necessary and to review whether the subject has had any adverse effects. The subject can arrange an earlier visit if problems ensue. When the subject is stable, monthly visits will occur through the subsequent two months and will continue every three months thereafter. All serious adverse events, changes in concomitant medications and study withdrawal must be documented and reported to the investigator.

Follow-up questionnaires are suggested, in Appendix 4, to facilitate follow-up with subjects and with participating treating physicians.

V. Collection of Adverse Events and Toxicity Information

The collection of good quality data on adverse event occurrence is of central importance to the study. All serious and unexpected adverse events must be collected and reported. Adverse events must be defined and reported using the Medical Dictionary for Regulatory Activities (MedDRA). The investigator must indicate the relationship of the event to the treatment, if known. The standards for reporting serious adverse events, as defined in the ICH guideline, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, ICH Harmonized Guideline, will be strictly followed by study investigators. The death of a subject, even when expected, must be reported on a Death Report Form. Participating treating physicians will have to be trained on serious adverse event detection and reporting.

A central database of adverse events and a dedicated data monitoring committee must be established for each study conducted under this initiative. The role of the safety committee is to ensure access to an independent data monitoring committee to review the adverse event reports, provide feedback to the regulatory authority and stop the study if the safety data are of sufficient concern.

Clinical and laboratory events or toxicities will be graded as per the NIAID standardized toxicity grading system (see Appendix 5). Events of all grades may be reportable as serious adverse drug reactions.

VI. Withdrawal from the Study and Study Discontinuation

Any withdrawal of a subject from the study must be clearly documented in the case report form. Subject will be withdrawn in the following situations:

• Patient report of lack of efficacy
• Patient report of intolerable side effects
• Serious life-threatening toxicity
• Discordance between self-reported drug use and urine drug screening results
• Non-compliance to protocol
• Conviction for trafficking the study drug

VII. Outcomes

Adverse event reporting is a major source of the safety information to be collected. In addition, baseline measurements of concurrent drug use, physiological parameters, addiction risk and neurocognitive function should be included and repeated at specified intervals. Symptoms should be quantified using standardized numerical scales, using identical measures across studies where possible to allow future meta-analyses. It is recommended that general quality of life indices such as the SF36 be employed. Global satisfaction estimates should also be included (using 11-point numerical rating scales and identical anchors across studies).

Primary outcomes must include:

• Frequency of serious adverse events
• Frequency of treatment stopping due to drug intolerance or toxicity
• Most frequent reasons for withdrawal from the study
• Most frequent predisposing factor(s) to adverse events

Secondary outcomes must include:

• Average and range of dosage used
• Changes to concomitant medication used
• Overall satisfaction with Health Canada's product

VIII. Statistical Considerations

A. Sample Size

It is strongly recommended that studies conducted under this initiative enroll at least 100 subjects.

B. Analysis

The protocol must describe how the statistical analysis will be conducted.

IX. Data Management

Investigators conducting a study under the open label safety initiative, will be responsible for collecting and managing the information, in compliance with ICH GCP. All investigators must expect to make the results of their study available to Health Canada and to transfer all collected and analyzed information to a central information management system for integration of and global analysis.

Appendix 1

The following persons were consulted for the development of this framework

From the Canadian Research Community:

• Dr. Peter Fried , Professor, Psychology, Carleton University
• Dr. Angela Genge, Montréal Neurological Hospital,
• Norbert Gilmore, PhD, MD, Centre Universitaire de Santé McGill, Hopital Royal Victoria
• Joanne Goldberg M.Sc.pht., Director, Management of the GEREQ Network, Quality Management System , GEREQ
• Allan S. Gordon, MD, FRCP, Neurologist and Director, Wasser Pain Management Centre, Mount Sinai Hospital
• Kevin Gough MD, FRCPC, Infectious Diseases & HIV, Medical Director, HIV Service, St. Michael's Hospital
• Douglas Gourlay, MD, MSc, FRCPC, Medical Consultant, Pain and Chemical Dependency, Centre for Addiction and Mental Health, Toronto Ontario, and Wasser Pain Management Centre,Mount Sinai Hospital
• Robert Goyer, B.Sc.Pharm.,D.Ph., Doyen Émérite, Faculté de pharmacie, Université de Montréal
• Dr. Mary Lynch, Director of Research, Pain Management Unit, Queen Elizabeth II Health Sciences Center
• Dwight E. Moulin, MD, Department of Clinical Neuro Sciences/Oncology, London Regional Cancer Centre
• Sergio Rueda, MA, MSc, Ph.D., (cand), Research Associate, Community Research Initiative of Toronto
• Joel Singer, Professor, Department of Health Care and Epidemiology, University of British Columbia
• Dr. Mark A. Ware, BA, MBBS, MRCP, MSc, Assistant Professor in Family Medicine & Anaesthesia, McGill University Health Centre

From Canadian Institutes of Health Research:

• Toni Gasparini, Program Coordinator, Randomized Controlled Trial, Canadian Institutes of Health Research
• Raymond Leblanc, Ph. D., Directeur, Programmes de création des connaissances, Instituts de recherche en santé du Canada
• Ante Padjen, Ph. D., Pharmacologie et thérapeuthique, Université McGill

From Health Canada:

• Dr. Nicholas Cicutti, Assessment Officer, Cardio and Respiratory Medicine, Clinical Trials and Special Access Programme, Therapeutic Products Directorate, Health Canada
• Louise Déry, Senior Policy Advisor, Strategy Policy Team, Drug Strategy and Controlled Substances Programme, Health Canada
• Suzanne Desjardins, Ph.D., Manager, Evaluation and Research Coordination Division, Drug Strategy and Controlled Substances Programme, Health Canada
• Dr. Jim Gallivan, Assessment Officer, Clinical Trials and Special Access Programme, Therapeutic Products Directorate, Health Canada
• Michael LeBelle, M.Sc., Senior Science Advisor, Evaluation and Research Coordination Division, Drug Strategy and Controlled Substances Programme, Health Canada

Appendix 2

REFERENCE MATERIAL

The following material should be used in developing and implementing study protocol under the open label safety study initiative:

• ICH Harmonized Tripartite Guideline. Good Clinical Practice (GCP): Consolidated Guideline.
  
• Guidance for Clinical Trial Sponsors. Clinical Trial Applications
  
• Division 5 of Food and Drug Regulations
  
• ICH Harmonized Tripartite Guideline. Structure and Content of Clinical Study Reports. 
  
• Food and Drug Regulations
  
• ICH Harmonized Tripartite Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
  
• Medical Marijuana Access Regulations
  

Appendix 3
Follow up visits

* The use of standardized quick test is strongly recommended. The following are recommended: to test recall memory: Verbal Paired Associate, WESCHLER Memory
Scale, 3rd Edition, 1997; to test processing speed: WESCHLER Adult Intelligence Scale (WAIS), 3rd Edition, 1997 Digit Symbol Coding; To test visual analysis: Picture Arrangement,
WESCHLER.
** Immunoassay panel including: THC, opiates, cocaine metabolite, benzodiazepines, amphetamines. Drug identification must be done by HPLC REMEDI or equivalent.

Appendix 4
Follow-up Questionnaires

A) Patient Follow-up Questionnaire

• How often did you use marijuana? Daily? Weekly?
• How much each time? A) quantity in grams. B) For smoked marijuana, indicate the number of puff(s) taken.
• Did you use other marijuana than the marijuana provided for this study?
  If yes, Why, for what purpose? What quantity? How frequently?
• Did you use prescription drugs, and/or OTC and/or herbal product?
• If yes, could list them, and indicate for what purpose they were used?
• Did you use drug(s) for recreational purposes?
• If yes, What drug(s)? What quantity? At what frequency?
• To what extent did the marijuana provided for the study affect the symptom(s) for which you took it?
  
  Symptom 1: ________
  
  Completely relieved symptom
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse

  Symptom 2: ________
  
  Completely relieved symptom
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse
  

  Symptom 3: ________
  
  Completely relieved symptom
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse

• Did the marijuana provided for the study produce any effects that bothered you?

  Yes _______ No _______

• If yes, please list the effects and for each indicate whether they where:
  
     Very bothersome    Moderately bothersome    Slightly bothersome

• If you previously used marijuana for symptom control, how would you compare the effect of the marijuana that you have used in this study to the marijuana you previouly obtained from other sources?
  
  Symptom 1: ________
  
  Marijuana in this programme:
  
  Completely relieved symptom
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse
  
  Symptom 2: ________
  
  Completely relieved symptom
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse
  
  Symptom 3: ________
  
  Completely relieved symptom
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse
  
  
• How would you compare the marijuana that you have used in this study to the marijuana you obtained from other sources in term of side effects?
  
  Marijuana in this study:
  
  Much better
  Somewhat better
  Slightly better
  No improvement
  Slightly worse
  Somewhat worse
  Much worse
  

B) Physician Follow-up Questionnaire

• Did the patient suffer any serious adverse events? Yes_____ No_____
• If yes, complete adverse event form.
• Were there any changes in the concomitant medications given to the patients? Yes____ No____
• If yes:
  
  Medications Started: __________ ______________ _______________
  
  Medications Stopped __________ ______________ _______________
• Has the patient withdrawn or has been withdrawn from the study?
  Yes____ No_____
• If yes, why?

Appendix 5
NIAID Standardized Toxicity Grading System