[NIH review panel response to 1998 "Cannabis in Acute Migraine" application submitted for July 1, 1998 deadline by Ethan Russo, M.D. posted March 1999 on MAPS website]
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NOTIFICATION OF SCIENTIFIC REVIEW ACTION January 7, 1999
Russo, Ethan B, MD Our Reference: 1R01NS37550-01A1 ZRG1 BDCN-6 (1) 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 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 never 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.
If you choose to resubmit, it is important to repond specifically to the comments in the summary statement, as outlined in the instructions in the application kit (PHS 398, Rev. 5/95). Enclosure cc: Business or institutional official of applicant organization
CHERYL KITT, PH.D. SUMMARY STATEMENT
Application Number: 1 R01 NS37550-01A1
Meeting Dates: IRG: OCT/NOV 1998
COUNCIL: JAN/FEB 1999 CI
Project Title:
CANNABIS IN ACUTE MIGRAINE TREATMENT PROJECT GENDER, MINORITY, & CLINICAL TRIAL CODES NOT ASSIGNED
PROJECT DIRECT COSTS NOTE TO APPLICANT FOLLOWS SUMMARY STATEMENT DESCRIPTION (Adapted from applicant's abstract): Rationale: Cannabis, or marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was part of the Western pharmacopoeia for this indication even into the mid-twentieth century. Current anecdotal studies indicate even into the mid-twentieth century. Current anecdotal studies continue to refer to its efficacy for this malady, while biochemical studies of THC and and anandamide have provided a scientific basis for such treatment. Design: Forty adult patients meeting International Headache Society (IHS) criteria of acute migraine with or without aura, with headache frequency of three or more attacks per month, will be recruited. Exclusion criteria will include concomitant use of MAO inhibitor drugs, pregnancy, cardiac conditions, history of drug or analgesic dependency or affliction with the chronic daily headache variant. A double-blind crossover study design will be pursued. All patients will undergo a detailed screening neurological examination. After suitable informed consent, study patients will be randomized into one of two groups. Group A patients will initially receive study medications consisting of Marinol (dronabinol, synthetic THC) 10 mg. p.o. plus smoke a placebo marijuana cigarette, or alternatively receive sumatriptan 6 mg. s.c. Group B patients will initially receive an oral placebo capsule resembling Marinol plus smoke a 4% THC marijuana cigarette, or alternatively, sumatriptan 6 mg. sc. The prolysed Cannabis dose will be titrated to the patients' responses. All patients will be monitored for one hour, at which time they will complete questionnaires regarding symptom-relief employing visual analogue scales. A Folstein Mini-mental State Examination will also be performed. Blood samples for THC will be drawn at ten minutes and two hours except in those patients who received sumatriptan. Folstein tests and questionnaires will be repeated at the two, three, and four-hour marks. At the end of three hours, any patient who desires additional symptomatic relief will be offered 1000 mg. of magnesium sulfate IV as a rescue medication. After four hours, patients will be allowed to return home, with a designated driver, or via arranged transportation. All patients will subsequently complete questionnaires at the twenty-four hour mark to determine efficacy of their treatment with respect to pain levels, nausea, photophobia, and their perceived ability to engage in work or study activities. Patients will be treated for up to 10 events per three- month block. After a two-week "washout period," groups A and B will crossover regimes. Other parameters of interest in the study will pertain to any rebound headache, the observed study medication side-effect profiles, including the patient's relative ability to function normally post treatment, and subsequent frequency of attacks. Results will be subjected to standard statistical analysis. CRITIQUE 1: Significance: The significance of the proposed study is open to question. While there are clearly gaps in our knowledge regarding the potential therapeutic effects of marijuana in migraine, there is only an anecdotal evidence to suggest that marijuana may be helpful in migraine headaches. Approach: After reviewing the revised application in its entirety (including all of the appended materials that the applicant specifically requested be reviewed), this reviewer found that the revised application is improved but still flawed. perhaps the major improvement is that the revised application calls for the use of a double-blind, cross-over design with a so-called double dummy approach. Other improvements include use of direct observation after marijuana ingestion, deletion of previously proposed use of meperidine, and the use of power analysis to calculate sample size. Despite these improvements, numerous concerns regarding the application remain. Specifically, there are continuing concerns about the application's organization, its lack of preliminary data, and various aspects of study design. These concerns are detailed below. First, as noted by the previous committee, the background section is inadequate. As suggested previously, the anecdotal approach should be abandoned and replaced with a critical and scholarly assessment of the pertinent literature on migraine headaches, along with critical assessment of the pros and cons of existing therapies. Second, the absence of any preliminary data continues to be a serious problem. Anecdotal reports, although interesting, are not sufficient. Such preliminary data is important not only for establishing feasibility, but also for providing some assurance that the anecdotal reports of marijuana's efficacy in migraine merit pursuit. Additionally, compelling preliminary data would diminish concerns about the applicant's ability to carry out high quality clinical research. Third, the application fails to make a compelling case that use of cannabis for the treatment of migraine will offer any significant or substantial benefit over existing treatment modalities. Granted, existing pharmacotherapies are not perfect, but with careful and systematic use, can be effective in a high proportion of patients with migraine. Further, if the study is going to include subjects that develop migraine headaches three to four times a month, one could question the use of repeated acute interventions, as opposed to chronic prophylactic therapies (beta blockers, calcium channel blockers, Valproate). Given the concern about possible side effects of marijuana, it seems important to develop a case that marijuana may offer unique advantages over existing anti-migraine drugs. Finally, there are a number of study design features which still require attention. These include: the plan to include both experienced marijuana users (making it difficult to effectively preserve the blind), the plan to use the inhalation (smoking) route of administration in naive subject (high drop-out rates), insufficient consideration of possible adverse long-term effects of repeated marijuana use (abuse liability), failure to integrate the serum drug level data with the clinical data, sketchy descriptions of how the diagnosis of migraine headaches will be established, and scant discussion about possible mechanisms of the purported anti-migrainous action of marijuana. The applicant seems to focus on possible effects on serotonin receptors without considering alternate mechanisms. Even when considering serotonin receptors, the discussion seems limited to receptors of the 5HT1D type, without mention of a possible role of 5H1A receptors. Innovation: Perhaps the most innovative aspects of the project involve the use of the double blinded, cross-over design with a so-called double dummy approach for the study of possible therapeutic effects of marijuana in migraine. Investigator: As noted by the previous review committee, the PI does not appear to have substantial experience in carrying out human clinical trials. Dr. Russo does, however, have relevant experience in ethnobotany, general neurology, and serotonin pharmacology. Environment: This study will be carried out at St. Patrick Hospital, a community medical center in Missoula, Montana. This study will be performed on an out-patient basis. Feasibility of recruiting the requisite number of subjects for the proposed studies has not been demonstrated. OVERALL EVALUATION: Despite improving the application in some respects, the applicant and his colleagues have failed to revise the application along the lines suggested by the previous committee. In particular, anecdotal reports remain the driving force of the project, and no compelling scientific rationale is provided as to why marijuana should be tested in the treatment of migraine. Additionally, the absence of any preliminary data makes it difficult to assess feasibility as well as the significance of the proposed studies. Finally, significant problems in the study design remain. CRITIQUE 2: Significance: Migraine headaches constitute a prevalent, disabling medical illness. Existing therapies are not uniformly effective and efforts to devise new treatments are, potentially, of great importance. A plausible case for the use of marijuana/THC for the treatment of migraine is developed in an extensive historical review. However, this literature review is somewhat selective and does not reflect the more recent literature suggesting important cognitive impairments associated with sustained marijuana use. Approach: The research plan has been developed on the basis of published recommendations. Pilot data using the proposed methods is not presented, which represents the most important limitation of the current proposal. Innovation: The proposal is creative and a well-designed, systematic assessment on the effects of THC on migraine would add to the scientific literature. Investigator: The PI is a Clinical Assistant Professor of Medicine of the University of Washington, as well as a Clinical Neurologist at the Western Montana Clinic. He has published three peer reviewed articles. Importantly, he does not appear to have experience in the design or conduct of clinical trials. Environment: The PI makes a case for the feasibility of this clinical trial based on the prevalence of migraine and the local population. It is not clear, however, that these estimates accurately reflect the difficulties associated with enrolling subjects in clinical trials, especially those which require hospital based treatment. Overall Summary: This continues to be a creative application. However, a more balanced assessment of the current literature on the effects of marijuana is warranted. Also, the PI should consult with the investigators who have more experience in running clinical trials. Based on this consultation, pilot data which clearly documents the feasibility of the protocol and which validates the study measures must be provided. CRITIQUE 3: Significance: This is a revised RO1 application requesting one year of funding for a study of acute migraine treatment with cannabis. It was previously reviewed by the Neurology A study section in 10/97 and was unscored. The revised application was only partially responsive to the detailed initial critique. The major issues raised in the prior critique were that it was overly ambitious, lacked focus and preliminary data, and that the supportive information presented was a series of personal observations and anecdotes. It was felt that a Phase-II type trial was not justified but that an open label preliminary study may be appropriate. The revised proposal continued to present anecdotes and commentary rather than detailed scientific information necessary to support the proposed research. The prior reviewers requested a detailed, coherent critical analysis of the complex migraine literature to provide support for the proposal. A critical analysis of the nature of migraine and mechanisms of the various agents used to treat this disorder was still not provided. Approach: The prior critique suggested consideration of alternative study designs and instruments (questionnaires and report forms), as well as an objective evaluation of intoxicant effects and standardized neurological examination. More definitive inclusion/exclusion criteria and participant characterization were requested as was greater detail regarding subject characteristics, specific features of their migraine disorder and substance abuse and psychiatric history. More detail regarding medical, psychiatric, social and other risks to participants was also warranted. The PI stated that the revision addressed criticisms of the earlier study section review. Although the PI was responsive to the prior methodological critique in several areas, his introduction responding the numerous issues raised in the prior review was less than one page. This was disproportionate to the number of issues that needed to be addressed. Further, the experimental design and method section was only three pages in length and was only partially responsive to earlier concerns. The applicant stated that he followed recommendations of the Headache Classification Committee of the International Headache Society (1988) and the 1997 NIH workshop on the medical utility of marijuana and guidelines for the clinical trials with marijuana. Improvements were noted in several areas including the use of a double-blind crossover design. Patients will be randomized to either group A (dronabinol/placebo marijuana cigarette or sumatriptan) or group B (oral placebo/4% THC marijuana cigarette or sumatrip tan). After a two-week washout groups A and B will crossover. Thus, smoked cannabis will be compared to dronabinol and injected sumatriptan. The PI increased the proposed sample size to forty and provided additional information regarding exclusions. He will now include a neurological examination and the length of observation was increased from two to four hours. Intravenous magnesium sulfate has been added as a rescue medication. These changes do significantly improve on the prior proposal. There had been a concern that neuropsychological tests were being used without any details regarding their sensitivity for the conditions to be studies. although a neuropsychologist was appropriately included as a consultant, the proposed hourly administration of the Folstein MMSE to assess cognitive changes is inadequate. There was no consideration of methodological issues in assessing cognitive status related to the medications being studied. As before, completion of the study design within the proposed time frame seems unrealistic. There was still no preliminary data to support the study's feasibility and the likelihood of obtaining useful new information. Innovation: This study does address an area where there is a paucity of solid empirical data and is innovative in that regard. The study conceptualization, proposed design and measurement instruments are standard, or in some cases substandard, and are not innovative. Investigator: Dr. Russo, the PI, is a clinical neurologist with knowledge and experience regarding natural medicinal approaches. The previous reviewers expressed concern that the PI had not demonstrated the expertise to conduct clinical trials and this concern remains given the absence of new supportive preliminary data meeting current clinical research standards. Environment: The study is to be conducted at the Department of Neurosciences of the Western Montana Clinic in Missoula. Only several sentences were devoted to a description of the resources and environment. It remains unclear if the necessary clinical, scientific and patient resources are available. OVERALL EVALUATION: This is a revised RO1 proposal to study cannabis treatment for acute migraine. It was previously reviewed in October 1997 and was not scored due to numerous conceptual of methodological problems. A general level, treatment of acute migraine remains an important problem for clinical investigation. However the investigator was only partially responsive to the prior critique and numerous problems remain with the proposal. These include lack of a detailed mechanistic rationale for the proposed treatment, lack of critical analysis of existing literature, paucity of methodological details, and inappropriate use of cognitive assessment instruments. Also of concern was a lack of clinical trials experience by the PI. Minority and Gender: The PI states that the study is open to all participants meeting criteria. Locally represented minorities include small numbers of Native Americans and Hmong refugees. Human Subjects: Procedures for informed consent and participant protections appear inadequate. NOTICE: The NIH has modified its policy regarding receipt of amended applications. Detailed information can be found by accessing the following URL address: http://www.nih.gov/grants/policy/amendedapps.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 revi ew. 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 is a compilation of reviewers' comments prepared prior to the meeting, without significant modification or editing by the NIH staff.
CENTER FOR SCIENTIFIC REVIEW SPECIAL EMPHASIS PANEL November 02, 1998 - November 03 1998
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.
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