August 22, 1996
Abrams, Donald I, MD
Community Consort ium
3180 18th Street, Suite 201
San Francisco, Ca 94110
Our Reference: 1R01AI40866-01 ARRB
The scientific merit review of your application, referenced above, is complete. As part of this initial review, reviewers were asked to provide written evaluations of each application and to identify those with the highest scientific merit, generally the top half of applications they customarily review, for discussion at the meeting and assignment of a priority score. Your application did not receive a score. Unscored applications are neither routinely reviewed at a second level by a national advisory council or board nor considered for funding.
Enclosed is your summary statement containing the reviewers' comments. You should call the program official listed below to discuss your options and obtain advice.
Lawrence R. Deyton, M.d. Niaid Extramural Activities (301) 496-0700 firstname.lastname@example.org
If you choose to resubmit, it is important to respond specifically to comments in the summary statement, as outlined in the instructions in the application kit (PHS 398, Rev. 5/95).
cc: Business or institutional official of applicant organization
LAWRENCE R. DEYTON, M.D. SUMMARY STATEMENT (301) 496-0700 (Privileged Communication) ld4i@nih. gov Application Number: 1 R01 AI40866-01 DUAL PROGRAM CLASS CODE: CA/JHK DUAL: DA ARRB Review Group: AIDS & RELATED RESEARCH STUDY SECTION 2 AIDS - EXP Meeting Dates: IRG: JUNE 1996 COUNCIL: SEPT/OCT 1996 17 VA Requested Start Date: 12/01/96 ABRAMS, DONALD I, MD COMMUNITY CONSORTIUM 3180 18TH STREET, SUITE 201 SAN FRANCISCO, CA 94110 Project Title : SMOKED MARIJUANA FOR HIV-ASSOCIATED ANOREXIA AND WASTING IRG Action: ** Human Subjects : 30-HS INV-CERTIFIED NO IRG CONCERNS/COMMENTS Animal Subjects: 10-NO LIVE VERTEBRATE ANIMALS INVOLVED GENDER, MINORITY, & CLINICAL TRIAL CODES NOT ASSIGNED PROJECT DIRECT COSTS YEAR REQUESTED O1 244,762 TOTAL 244,762
NOTICE: The NIH has modified its policy regarding the receipt of amended applications. Detailed information can be found by accessing the following URL address. http://www.nih.gov/grants/policy/policy.htm
**NOTE TO APPLICANT: As part of the initial scientific merit review process, reviewers were asked to identify those applications with the highest scientific merit, generally the top half of applications that they customarily review. At the study section meeting, those applications were discussed and assigned a priority score. All other applications, including this application, did not receive a score. Provided below is a compilation of reviewers' comments prepared prior to the meeting, without significant modification or editing by NIH staff.
CRITIQUE #1: Specific Aims. The primary objectives are noted as "to evaluate the safety and efficacy" of smoked marijuana. Though relatively reliable evidence of toxic reactions to marijuana exists, emphasis is placed on increased calorie consumption as the primary dependent variable. The arguably more important outcomes concerning toxic reactions are not emphasized, even though noted as specific aims. The rational basis, in light of costs, for the many secondary aims, such as endocrine function and changes in HIV RNA, seem weak. Changes in body composition, though closely related to the primary specific aims, are listed as secondary outcomes. Overall, the basis for each aim in relation to likely incr. eased knowledge and costs is poorly presented.
Background. The literature review is reasonable. It provides a somewhat more complete overview of possible toxic reactions from smoking marijuana. It does not provide a convincing argument for or against the use of marijuana as a treatment for HIV. Given the political and medical concerns for such treatment, a more complete description of the direction of the planned trial is important.
Progress reports/preliminary studies. This very experienced team of clinical and basic science researchers has conducted previous studies of wasting in HIV patients. Host of the in-hospital procedures have been employed previously. These preliminary studies attest to the researchers' ability to conduct such studies. However, few preliminary data regarding the effects of marijuana on the outcomes planned for this study are presented. No explicit information is provided regarding possible volunteer rate, ability to recruit patients, or the types of patients likely to be recruited. Explicit pilot studies of similar illicit drug treatment would have strengthened the research plan.
As an incidental concern, the descriptions of the researchers' credentials might be better placed in the budget Justification, leaving more space in the research plan for preliminary study information.
Design and methods. This project relies on the precision of measures, large effects, and assessment of short-term outcomes. Using a random assignment placebo-controlled double-blind cross-over design, the Investigator proposes to assess a number of possible outcomes. This design entails some methodological problems due to the very nature of the design and others due to its use with this population and the drug studied.
Although the Investigator asserts that order effects due to the cross-over design are expected to be unimportant, this assertion is not supported empirically. If are order effects are shown, the second treatment condition is not comparable to the first for the two groups.
Perhaps most questionable is the assertion of use of a placebo design. The Investigator assures the reader that the placebo is not distinguishable by taste or appearance. This is a strength and is face valid. However, the effects of marijuana are known to most who would be interested in such a study. all patients will be recruited from an experienced population. This means that within the first few hours of exposure to the active medication or the placebo, expected psychological effects will be discriminable. Unless other interventions (e.g. bogus socializations) are evident that convince patients that they are taking the active medication, effects on diet and physiology may not follow the normal pattern. This said, this may not be a fatal flaw.
The biggest difficulty with the design is the small sample size, in light of weak support for effect sizes or power. The study is to detect toxic effects and to determine safety. To do so requires assessment of only very seriously large- and short-term toxic reactions, reactions not likely to be detected with so small a sample. (The Investigator has not limited the objectives of the study to large toxic effects.)
The present design is likely to miss detection of moderate-to-small toxic effects and, hence, small effects may be judged safe, when they are not.
Calorie consumption is listed as the primary dependent variable for which effect sizes and sample sizes are computed, but not reported. The details of effect size and computations of samples size are critical.
The overall objective of the study is to reverse wasting. Although detection of increased calorie consumption is related to-this goal, it is not synonymous. The study would be stronger if body weight and composition were included among primary dependent variable outcomes and used for purposes of computing sample size. This would reduce the possibility of increasing consumption but without discovering no effects on weight/wasting.
The use of a washout period, where patients are sent home, raises the possibility of individuals acquiring marijuana while in the community. This could change their outcome measures prior to the replication phase of the study. Asking patients not to do so, for persons who may be very uncomfortable and dying, seems a weak protection for contamination.
Perhaps a larger sample without a cross-over design and washout period would be stronger.
Sample and recruitment. Beyond reporting that patients will be recruited through the Community Consortium--a group of primary care physicians who refer AIDS patients for clinical studies--little information is provided about recruitment, patient selection, and consent procedures. The text notes that AIDS patients with 5-15% weight loss will be recruited. Apparently, men and women and patients with very different types of risk histories and with varying degrees of illness will be recruited. This leaves open the possibility of high levels of heterogeneity, from which error variance can be expected to be increased. The study would be stronger if a more homogeneous target sample were recruited. This might be limited to males and might exclude persons with IDU or other serious drug abuse histories.
The use of persons with as much as 15% weight loss is questionable in that this may reflect more serious illness than patients who have lost only 5%. The Investigator might consider the rate of weight loss as a more critical indicator of immediate disease status.
Apparently, patients' names will be given to researchers to be contacted, . screened, and invited to join the study. This raises questions about informed consent. At what point do patients sign releases that enable practitioners to release names, phone numbers, and implicitly disease 'status?
Cohort retention. The Investigator promises to pay each patient $500 for completing the study. This may be effective, but little information is provided regarding the success of this incentive for past studies. No mention of how dropouts will be addressed in analyses is provided.
Measurement procedures. Numerous measures are proposed, many relying on clinical laboratory techniques. For most of these, very reliable laboratories are cited. However, no explicit reliability or validity check procedures are listed. Little discussion of rational basis is provided for selected measures or alternatives. For instance, blood samples will be used to assess exposure/ dose to THC: could this be assessed as well/better using metabolites and urine assays?
The degree to which measures will be taken or how they will be interpreted for men and women is not mentioned.
The degree to which specific measures can be changed in one week (e.g. HIV RNA) is not discussed.
Overall, the Investigator provides weak justification for the many measures in light of cost and limited change possible in one week. Though not mentioned in the text, the use of so many measures raises the question of chance findings.
Intervention Procedures. Based on previous in-hospital studies, strong procedures are in place for measuring clinical signs and symptoms and for administration of marijuana. This includes instructions in how to puff and hold the breath (etc.). The text does not make clear the social settings available during the use of marijuana or the degree to which these are to be standardized. Based on the Investigator's review, social context variables may interact with the drug and affect outcomes differentially.
Data processing and analyses. The description of sample size computations, data processing, and analyses is especially shallow and did not appear to have been prepared under the supervision of the collaborations statistician. The listing of a series of possible statistical tests is not satisfactory or the promising to control for confounding with questionable sample sizes in the first place is not reasonable. Specific analyses for each aim should be provided in detail.
Minorities and women. Few details regarding the likely sample are provided. With only 15 to be recruited, very possibly imbalance in gender or racial/ ethnic groups will take place. The Investigator should target a specific population and defend the omission of other specific groups.
Summary: The Investigator proposes a study to determine whether therapeutic use of marijuana is safe and reverses wasting in AIDS patients. However, his research plan raises serious design questions regarding selection of outcome measures, their reliability, the sample size and nature to the target sample that severely limits the overall reliability of his study.
CRITIQUE #2: Several concerns are raised by this study and the more general issue of appetite stimulation as a therapy for cachexia. Because therapy would presumably be chronic, why some of the Phase I/II studies do not include chronic dosing is problematic. A more general question is whether the countering of the effects of TNF, interferon, and other cytokines by calorie loading is physiologically appropriate. Will this result in hyperlipidemia and the enhanced potential for atherosclerosis? Information is available on this from animal and human studies that should augment the rationale. Another question is whether alternative therapies exist that are specifically directed to suppressing the production of these inflammatory cytokines. In particular, with the potential for improvement in antiviral therapy is this a compellingly important issue to address?
CRITIQUE #3: This application has many strengths. The Investigator has a long-standing interest in HIV and AIDS. He was involved in the early description of the epidemiology and clinical features associated with AIDS and co-authored many studies. He is well qualified and has a strong team of coworkers with experience in conducting this type of a study.
The Investigator plans to employ a Phase I/II randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of smoked marijuana as an appetite stimulant for HIV-associated anorexia and weight loss in 15 patients. A standard Phase I trial is a dose-finding trial, in which patients are treated at each dose, the dose being escalated until the side-effects become "intolerable." The maximum tolerated dose (MTD) is identified in the Phase I trial. According to this research plan the Investigator has no intent to identify the MTD for smoked marijuana. Thus, this is not a Phase I trial, by definition. A Phase II trial usually is an evaluation of the efficacy of the treatment. Usually, neither the Phase I nor the Phase II trial is randomized. A Phase III trial is a comparative study of treatments which have the potential of providing the best available therapy. Thus, the study design looks like a Phase III trial but with a very small number of patients (~N=15). How the researchers will evaluate safety and efficacy based on so many different assays or measurements proposed is difficult to assess.
Marijuana smoke contains carcinogens and more tar than tobacco smoke. Several experimental in in vitro and in vivo studies have shown the mutagenic and carcinogenic properties of tetrahydrocannabinol (THC). Sherman (1995) has been reported that marijuana smoking results in DNA damage. Marijuana smoking can lead to symptoms of airway obstruction as well as squamous metaplasia. The numbers of young patients with squamous cell carcinomas of oral, tongue, and pharynx is rapidly increasing, which is believed to be related to chronic marijuana use (Wengen, 1993). Marijuana intoxication has been implicated as a risk factor for injuries (RR=1.3, 95%CI: 1.1-1.6) and for increase risk of respiratory disease (RR=1.2, 95%CI: 1.0-1.4, p<0.05) in a large epidemiologic study (Polen, 1993). Marijuana smoking is associated with depersonalization, anxiety, tension, anger, and confusion; it is believed to produce symptoms of neurobehavioural toxicity and to be fetotoxic. We know that HIV infection or AIDS is a disease of immune suppression, that the immune suppression may lead to the development of HIV related malignancies and that the most important cause of death for HIV infection and AIDS is respiratory disease. We also know that (1) marijuana smoking/THC inhibits the function of immune system and T-cell lymphocyte counts are lower in chronic marijuana smokers compared to nonsmokers; (2) marijuana smoking can lead to DNA damage and development of cancer; and (3) it is related to increased risk of respiratory disease. Why the Investigator chooses marijuana smoking as a potential drug for the treatment of anorexia and weight loss in AIDS patients is not at all clear. What is the rationale behind his choice? What are the long-term effects of marijuana on patients with HIV infection and AIDS?
In his preliminary studies, the Investigator has conducted a similar type of trial with 12 patients but reports no pilot data on the effects of smoked marijuana on weight loss or HIV-associated anorexia.
Summary: Why the Investigator choose marijuana smoking as a potential intervention drug for HIV-related anorexia and weight loss is not at all clear, given the knowledge that marijuana smoking may result in immune suppression and respiratory disease, and that marijuana itself may be carcinogenic. What is the long-term effect of marijuana smoking on the patients with HIV infection and AIDS? The Investigator should provide detailed justifications.
CHAIRPERSON WITTES, Janet T., PhD KIVIAT, Nancy B., MD --- President Professor Statistics Collaborative Department of Pathology Washington, D.C. 20036 University of Washington Seattle, WA 98109 ALLEN, Susan Ann, MD, MPH Associate Professor LAI, Shenghan, MB, PhD Department of Epidemiology Research Associate Professor School of Public Health Department of Medicine University of Alabama University of Miami Birmingham, AL 35294 Miami, FL 33136 BRYSON, Yvonne J., MD SCHOENBAUM, Ellie E., MD Professor Associate Professor Department of Pediatrics Department of Epidemiology School of Medicine Albert Einstein College of Medicine University of California Montefiore Medical Center Los Angeles, CA 90024-1752 Bronx, NY 10467-2490 *COOLEY, Philip C., MS TANNER, Martin A., PhD Principal Scientist Professor Research Triangle Institute Department of Statistics Research Triangle Park, NC 27709 Northwestern University Evanston, IL 60208 HOVELL, Melbourne F., PhD, MPH Professor Center for Behavioral Epidemiology School of Public Health San Diego State University La Mesa, CA 91941-3301 WANG, Mei-Cheng, PhD *ZHANG, Zuofeng, MD Associate Professor Assistant Professor Department of Biostatistics Department of Epidemiology and School of Hygiene & Public Health Biostatistics Johns Hopkins University Hemorial Sloan-Kettering Baltimore, MD 21205 Cancer Center New York, NY 10021 WINCHESTER, Robert J., MD Professor SCENTIFIC REVIEW ADMINISTRATOR Division of Autoimmune and MEIER, Gilbert W., PhD Molecular Disease Division of Research Grants College of Physicians & Surgeons National Institutes of Health Columbia University Bethesda, MD Z0892 New York, NY 10032 * ad hoc reviewer
Consultants are required to absent themselves from the room during the review of any application if their presence would constitute or appear to constitute a conflict of interest.