To help pharmaceutical companies navigate the approval process for drugs containing cannabis or cannabis-derived compounds, on January 23, 2023, the FDA issued guidance on "Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research." The FDA intends for the guidance to provide sponsors with recommendations and approaches to help improve the efficacy and approval rates of clinical trials involving cannabis compounds. The guidance addresses only naturally derived cannabinoids, not fully synthetic versions of substances that occur in cannabis, i.e., cannabis-related compounds such as dronabinol.
The guidance first explains that the Agriculture Improvement Act of 2018, also known as the 2018 Farm Bill, changed how cannabis is treated under the Controlled Substances Act (CSA). Specifically, it removed hemp—now defined as including cannabis and derivatives or extracts of cannabis with a delta-9 THC content of less than 0.3 percent by dry weight—from the definition of marihuana under the CSA. This may make it easier for pharmaceutical companies to evaluate the use of hemp as a source of cannabis and cannabis-derived compounds for drug development.
The guidance then discusses the sources of cannabis that can be used to obtain the target compounds for clinical trials. For years, the only federally legal source of cannabis for clinical research was through the National Institute on Drug Abuse Drug Supply Program (NIDA DSP) via the University of Mississippi. The DEA recently expanded the list of authorized growers of Schedule I cannabis. Accordingly, for compounds that contain over 0.3 percent delta-9 THC, the guidance urges sponsors and investigators to either use the NIDA DSP or a supplier on the DEA's list of approved growers. For compounds with less than 0.3 percent delta-9 THC, the guidance suggests that any source may be used as long as the compound is "deemed to be of adequate quality by the FDA when reviewed as part of an investigational new drug application (IND)."
Quality and consistency of cannabis compounds are key to approval. As part of an IND, sponsors must show consistent quality, purity, and potency or strength in each phase of clinical investigation. The consistency of cannabis and cannabis-derived compounds has been a recurring issue. The guidance lists multiple resources that detail improved quality practices to help implement a more consistent product. The guidance further recommends, among other things, that those pursuing drug development using cannabis or cannabis-derived compounds consider (1) adequately characterizing cannabis and cannabis-derived compounds, for example via chemical fingerprinting, to ensure batch-to-batch consistency; (2) conducting microbial enumeration tests; (3) testing for specified microorganisms; (4) employing sterility testing; and (5) testing for residual pesticides routinely used in the plant's country of origin. The guidance also provides additional resources for consideration by drug developers in this space.
Lastly, the FDA urges caution with measuring the percent of delta-9 THC within a cannabis or cannabis-derived investigational drug product. To ensure DEA and CSA compliance, the FDA advises calculating delta-9 THC content early in the development process. When calculating the delta-9 THC content, sponsors and investigators should not rely on the 0.3 percent delta-9 THC by dry weight threshold when evaluating tetrahydrocannabinols as impurities for the purposes of quality control and application submission. A dry weight calculation has limited utility for intermediates such as solutions or extracts in solutions and for finished products of various dosage forms. The FDA recommends that a sponsor, investigator, or applicant evaluating intermediates or finished products that contain cannabis or cannabis-derived compound by basing the calculation of total delta-9 THC percentage (THCA and THC) on the composition of the formulation with the amount of water removed, including any water that excipients may contain. Documentation of this step-by-step calculation should be submitted with an IND. See the FDA's guidance for additional recommendations on how to calculate percent delta-9 THC for liquid and solid dosage forms.
Readers are encouraged to read the guidance, also available on the FDA's website.
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