The Court of Appeals for the First Circuit held in the Grinspoon decision that it is not necessary to show FDA approval of a drug for marketing in interstate commerce in order to show that there is a “currently accepted medical use in treatment,” which is one of the criteria for moving the drug out of Schedule I. This opinion rejected the DEA’s test.
In response the DEA created a new five-factor test that included, as relevant here, a requirement that there be “adequate and well-controlled studies proving efficacy.” What does that term mean? We can see from the DEA Ruling denying Americans for Safe Access’s petition to hold an evidentiary hearing as to whether cannabis should be moved out of Schedule I that the DEA interprets it to mean Phase III clinical trials, i.e. the type of hugely expensive clinical trials involving thousand of patients that are necessary…. to obtain FDA approval of a drug for marketing in interstate commerce.
Coincidence? I think not.
Examination of the FDA report and recommendations and the DEA’s own reasoning in the DEA Ruling show beyond doubt that the DEA is treating its own five-factor test as a requirement of the full scope of clinical trials that are required to be included in a New Drug Application to the FDA for permission to market a drug.
Let us start with the DEA’s analysis.
At page 40579 of the DEA Ruling, the DEA discusses in full its reasoning as to why the petitioner has not shown the existence of a “currently accepted medical use in treatment for cannabis,” reviewing the elements of the five-factor test. It states as follows with regard to the third element of the five-factor test: “adequate and well-controlled studies proving efficacy”:
DHHS states that no studies have been conducted with marijuana showing efficacy for any indication in controlled, large scale, clinical trials.
To establish accepted medical use, the effectiveness of a drug must be established in well-controlled, well-designed, well-conducted, and well-documented scientific studies, including studies performed in a large number of patients (57 FR 10499, 1992). To date, such studies have not been performed. The small clinical trial studies with limited patients and short duration are not sufficient to establish medical utility. Studies of longer duration are needed to fully characterize the drug’s efficacy and safety profile. Scientific reliability must be established in multiple clinical studies. Furthermore, anecdotal reports and isolated case reports are not adequate evidence to support an accepted medical use of marijuana (57 FR 10499, 1992). The evidence from clinical research and reviews of earlier clinical research does not meet this standard.
As noted, DHHS states that a limited number of Phase I investigations have been conducted as approved by the FDA. Clinical trials, however, generally proceed in three phases. See 21 C.F.R. 312.21 (2010). Phase I trials encompass initial testing in human subjects, generally involving 20 to 80 patients. Id. They are designed primarily to assess initial safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary studies of potential therapeutic benefit. (62 FR 66113, 1997). Phase II and Phase III studies involve successively larger groups of patients: usually no more than several hundred subjects in Phase II and usually from several hundred to several thousand in Phase III. 21 C.F.R. 312.21. These studies are designed primarily to explore (Phase II) and to demonstrate or confirm (Phase III) therapeutic efficacy and benefit in patients. (62 FR 66113, 1997). No Phase II or Phase III studies of marijuana have been conducted. Even in 2001, DHHS acknowledged that there is “suggestive evidence that marijuana may have beneficial therapeutic effects in relieving spasticity associated with multiple sclerosis, as an analgesic, as an antiemetic, as an appetite stimulant and as a bronchodilator.” (66 FR 20038, 2001). But there is still no data from adequate and well-controlled clinical trials that meets the requisite standard to warrant rescheduling.
In the concluding section, the DEA Ruling again states:
To establish accepted medical use, among other criteria, the effectiveness of a drug must be established in well-controlled scientific studies performed in a large number of patients. To date, such studies have not been performed for cannabis. Small clinical studies with limited patients and short duration such as those cited by the petitioner are not sufficient to establish medical utility. Larger studies of longer duration are needed to fully characterize the drug’s efficacy and safety profile. Anecdotal reports, patients’ self-reported effects, and isolated case reports are not adequate evidence to support an accepted medical use of cannabis.
The section of the DEA Ruling containing the FDA’s report and recommendation states in relevant part:
In addition to demonstrating efficacy, adequate safety studies must be performed to show that the drug is safe for treating the targeted disease. DHHS stated that safety studies for acute or subchronic administration of cannabis have been carried out through a limited number of Phase I clinical investigations approved by the FDA, but there have been no NDA-quality studies that have scientifically assessed the efficacy and full safety profile of cannabis for any medical condition.
It is beyond doubt that the DEA is requiring the completion of Phase III clinical trials, including from “several hundred to several thousand” subjects, as evidence that there are “adequate and well-controlled studies proving efficacy.” In citing to Title 21, Section 312.21 of the Code of Federal Regulations, the DEA quite clearly is demanding clinical trials, the results of which are sufficiently thorough that they could be submitted to the FDA as part of a New Drug Application. We can assume so because that section appears in the part of the Code of Federal Regulations governing the FDA drug approval process and sets forth the elements of those clinical trials. I do not claim to be an expert on FDA clinical trials, but I understand that the clinical trials must be randomized, double-blind trials in which there are patients receiving the active substance being tested and a placebo and that neither the investigators nor the subjects know who is in the “control” (placebo) group.
This standard is entirely unreasonable since as shown above, there is absolutely no requirement in the CSA that there be any showing of efficacy before the DEA begins rulemaking about the correct classification of a Schedule I drug.