Dr. Abrams waited for almost nine months for NIDA to review his application. On April 26, 1995, Dr. Abrams received a letter from Dr. Alan Leshner, the Director of NIDA, rejecting his request for marijuana for his study. Leshner justified his rejection of Dr. Abrams' request by claiming that Dr. Abrams' study was scientifically flawed and therefore was not worthy of any of NIDA's limited supply of marijuana. Rather than suggest how to resolve these flaws, Dr. Leshner closed his letter by telling Dr. Abrams that he "shares your hope that new treatments will be found swiftly to improve the quality and prolong the lives of patients suffering from this terrible disease."
None of the supposed scientific deficiencies in Dr. Abrams' protocol cited by Dr. Leshner were raised by the FDA or any of the other regulatory bodies that approved Dr. Abrams' study. These deficiencies are of two types. The first is based on NIDA's misunderstanding of the kind of study that Dr. Abrams is conducting. The second set of deficiencies stem from NIDA's request for procedures and data that the FDA did not require in studies used to approve the oral THC capsule for prescription use for the wasting syndrome. NIDA is not the government agency charged with determining if drugs are safe and effective for prescription availability, yet NIDA is seeking to require data that the FDA determined were not necessary.
Nevertheless, it should be possible to resolve all of NIDA's stated concerns about the study design. Given that the AIDS wasting syndrome is life-threatening and that Dr. Leshner says he supports the swift development of new treatments, NIDA should rapidly move forward to work with Dr. Abrams to resolve these 'deficiences'. NIDA should help implement a study that will generate useful results. The concerns expressed by Dr. Leshner, and my response, are as follows:
ISSUE #1 - SAMPLE SIZE TOO SMALL
Dr. Leshner's most sweeping criticism of Dr. Abrams' study design is that the sample size is too small to generate any reliable inferences regarding the dose-effect relationship.
RESPONSE #1 - THIS IS A PILOT STUDY
Dr. Leshner's concern about too small a sample size would be pertinent if this study was intended to generate reliable inferences regarding dose-effect relationship. It is not. This study is a preliminary pilot study, a fact that should have been noted during the eight months that NIDA spent carefully reviewing Dr. Abrams' request for marijuana. The fact that this is a pilot study appears on the title page of Dr. Abrams' protocol. Futhermore, FDA required the preparation and filing of a Clinical Plan that outlined the entire sequence of studies that would be conducted with marijuana. This Clinical Plan, which I personally forwarded to NIDA, begins with Dr. Abrams' pilot study.
The use of a pilot study in clinical research is a well-established scientific procedure. In fact, only through the use of a pilot study can statisticians determine what the appropriate sample size should be for a full-scale clinical trial. It thus seems wisest to keep the sample size as is.
ISSUE #2 - DIET NOT CONTROLLED
Dr. Leshner asserts that the study is confounded because neither "the total daily caloric intake of the patients nor the percentages of the composition of the foodstuffs is assessed."
RESPONSE #2- WE WILL CONTROL FOR DIET
The data on dietary intake was not required by the FDA in any of the studies that were used to argue successfully for the approval of the prescription use of Marinol, the oral THC capsule, for treatment of the wasting syndrome. Nevertheless, this data can be gathered if it would enable NIDA to let this study proceed.
ISSUE #3 - LACK OF DOSING CONTROL
Dr Leshner claims that the study is confounded because "there is no requirement and way to ensure that subjects smoke all available materials on any fixed schedule."
RESPONSE #3 - RECOMMENDED DOSAGES AND SCHEDULES
Subjects in the Marinol trials were given recommended dosages but were not required to use the exact same dose of Marinol every day. Data was evaluated from subjects in the Marinol trials if they used any amount greater than 75% of their allotted medicines. In addition, subjects were permitted to increase or decrease their dosage upon consultation with the study staff.
Dr. Abrams' pilot study was designed to take advantage of the fact that patients can self- titrate smoked marijuana more precisely than THC in standardized oral capsules. Patients were not required to smoke all the available materials each day because that may not be the most effective method of administering marijuana. There was a fixed dosing schedule to the extent that patients were told to smoke 1/2 to 1 1/2 hours before lunch and dinner, and more frequently if needed. Furthermore, patients were instructed to use a maximum of two grams of marijuana per day.
To gather the necessary data within the context of a self-titration study, patients were required to provide a daily record of how much marijuana was used and when it was used. Thus, it will still be possible to correlate dosage with weight gain with the current study design and also provide patients with a clinically-beneficial flexibility. Part of the reason that this study is designed as a pilot study is to examine how patient self-titration actually works in practice. Given that this is a pilot study, it is not necessary to generate data sufficient to determine a dose-effect relationship.
ISSUE #4 - TWO-WEEK SUPPLY ON A TAKE-HOME BASIS
Dr. Leshner expresses the concern that the study is confounded because patients will be given a two-week supply of the study drug each time they go to the clinic for evaluation.
RESPONSE #4 - ELECTRONIC DOSAGE MONITORING
The Marinol studies provided patients with bulk supplies of Marinol on a take-home basis and the FDA had no trouble evaluating the data that was generated. For example, the single large double-blind multicenter study of Marinol provided subjects with a 16-day supply. The open label trial that followed the double-blind study provided subjects with a 30-day supply. When patients came in for evaluation, they brought their bottles along with any unused pills and exchanged them for new supplies. Most clinical trials give patients sufficient medication to last at least several weeks. Requiring patients to obtain their medicine on a daily basis would impose too great a burden on both the research team and the patients and would serve no overriding useful purpose.
Since giving patients a two-week supply of medication is of special concern to NIDA regarding marijuana, it is possible to utilize microelectronic monitoring methods to determine exactly when each daily allotment of marijuana was taken out of a container that permanently records the date and time of each removal. This technology is already commercially available and can be used in this study if NIDA insists. In this way, the research team will be able to monitor drug use patterns in a very precise manner.
DEA Administrator Robert Bonner stated, "Those who insist that marijuana has medical uses would serve society better by promoting or sponsoring more legitimate scientific research, rather than throwing their time, money and rhetoric into lobbying, public relations campaigns and perennial litigation." - Federal Register Vol. 57, No. 59 / Thursday March 26, 1992, p. 10503
All we are asking for now is simply permission to conduct that research.
email: firstname.lastname@example.org (Sylvia Thyssen, Network Coordinator)