On July 21, 2020, the US Food and Drug Administration (FDA) issued a long-awaited draft guidance, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research, Draft Guidance for Industry,” which provides insight into FDA’s current thinking on clinical research related to drugs containing cannabis or cannabis-derived compounds. Among the topics addressed are sources for cannabis for clinical research, information and resources for quality considerations, and recommendations for information to include in investigational new drug (IND) applications, including delta-9 tetrahydrocannabinol (THC) calculations.
Crash Course in Cannabis
Cannabis contains more than 80 biologically active chemical compounds, such as the two commonly known compounds delta-9 THC and cannabidiol (CBD). Under the Agriculture Improvement Act of 2018 (2018 Farm Bill), the new definition of “hemp” is “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a [delta-9 THC] concentration of not more than 0.3 percent on a dry weight basis” (emphasis added). Marijuana, on the other hand, is a term used for varieties of cannabis that contain more than 0.3% delta-9 THC (by dry weight) and can induce psychoactive effects. (The Controlled Substance Act (CSA) uses the spelling “marihuana,” but “marijuana” is the more commonly used spelling and thus is used here throughout.) Therefore, the difference between hemp and marijuana with reference to delta-9 THC is that hemp can contain no more than 0.3% delta-9 THC, whereas marijuana can contain a delta-9 THC percentage of 0.3 or higher. Both hemp and marijuana can be used to produce CBD (hemp-derived CBD versus marijuana-derived CBD).
Although the 2018 Farm Bill did not change the classification of cannabis under the CSA as a Schedule I drug, it did remove “hemp” from the Drug Enforcement Administration’s (DEA’s) regulation under the CSA, such that hemp is no longer considered a controlled substance. Accordingly, CSA-exempt hemp can be distributed and used in interstate commerce as long as the distribution does not violate other federal regulations (such as FDA regulations) or state laws.
State of Cannabis Research Regulation
While providing for DEA exemptions, the 2018 Farm Bill explicitly preserves FDA’s authority to regulate products containing cannabis or cannabis-derived compounds, including human drug products. Under section 201(g) of the Food, Drug, and Cosmetic Act, a drug is a substance “intended for use in diagnosis, cure, mitigation, treatment or prevention of disease in humans or other animals or intended to affect the structure or any function of the body of man or other animals.” A company interested in researching cannabis or cannabis-derived compounds would require an approved IND application to conduct clinical research and obtain the cannabis from a DEA-registered source. For years, the National Institute on Drug Abuse (NIDA) Drug Supply Program, in contract with the University of Mississippi, has been the only DEA-registered source for cannabis. On May 31, 2019, researchers and scientists interested in cannabis research expressed frustration at the lack of available DEA-registered sources for cannabis during FDA’s public hearing, Scientific Data and Information about Products Containing Cannabis or Cannabis-Derived Compounds.
In its July 20, 2020, draft guidance, FDA clarifies the availability of new options for researchers that do not involve obtaining cannabis from NIDA. Specifically, in light of the 2018 Farm Bill, FDA states that:
For clinical research involving cannabis over the 0.3% delta-9 THC limit, to date NIDA remains the only federally legal source.
For clinical research involving cannabis under the 0.3% delta-9 THC limit, researchers may obtain cannabis from other sources to conduct research.
In the draft guidance, FDA provides suggested resources for quality considerations that a company would need to take into account when preparing an IND for a drug containing cannabis or a cannabis-derived compound. Examples of resources include:
ICH Guidance Q2 (R1) Validation of Analytical Procedures: Text and Methodology
With reference to considerations specific to drugs containing cannabis and cannabis-derived compounds, FDA recommends adequate characterization of cannabis and cannabis-derived compounds to ensure batch-to-batch consistency, quality tests for microorganisms and impurities, and applicable CSA drug scheduling considerations. FDA cautions new drug application applicants to not rely on published literature in place of a full toxicology program to support development of a botanical drug product for phase 3 trials and beyond. FDA further recommends container-closure system and combination product considerations, as needed.
FDA recommends that companies provide qualitative laboratory data and detailed testing methods, including testing methods to evaluate the level of delta-9 THC, in particular for phase 2 and 3 studies and marketing applications, which may differ depending on dosage form.
On July 22, 2020, FDA also submitted a draft guidance titled “Cannabidiol Enforcement Policy” to the White House Office of Management and Budget for review. FDA has yet to issue any official statements providing additional details regarding the draft guidance, but the cannabis industry has been eagerly anticipating this guidance on FDA’s enforcement position regarding CBD products. We will follow up with a summary of this draft guidance once available for review.