FDA Issues Draft Guidance on Quality Considerations for Clinical Research Involving Cannabis and Cannabis-Derived Compounds

July 22, 2020, Covington Alert

Yesterday, the Food and Drug Administration (FDA) issued draft guidance describing the agency’s thinking on topics relevant to clinical research related to the development of drugs containing cannabis or cannabis-derived compounds. While the draft guidance is limited to drug development and does not address other types of products, some of FDA’s thinking may also be applicable to cannabidiol (CBD) that could be used in food, dietary supplements, and cosmetics. In particular, FDA’s discussion of the percent delta-9 tetrahydrocannabinol (THC) calculation may be of interest to all companies developing CBD products. Below we discuss takeaways that may be applicable to CBD companies generally, and summarize points more specifically applicable to companies interested in cannabis drug development.

FDA devoted a substantial portion of the draft guidance to discussing how to test for and calculate the percentage of delta-9 THC in cannabis and cannabis-derived compounds. This calculation is significant for purposes of determining how the substance is treated under the Controlled Substances Act (CSA). The 2018 Farm Bill created a new definition of “hemp”, which includes cannabis and derivatives or extracts thereof that contain no more than 0.3% delta-9 THC, and excluded hemp from the CSA’s definition of marijuana. In addressing this topic, the agency first discussed the composition of botanical raw materials. FDA directed clinical trial sponsors to the U.S. Department of Agriculture (USDA) interim final rule “Establishment of a Domestic Hemp Production Program” (84 FR 58522, October 31, 2019) for sampling and testing methods for evaluating delta-9 THC levels. FDA further explained that the composition of a botanical raw material is generally calculated as the amount of the compound(s) of interest naturally present relative to the dry weight of botanical raw material prior to extraction or other manufacturing steps. FDA acknowledged, however, that this dry weight calculation may have limited utility for solutions, extracts in solutions, and finished products. FDA thus recommended that entities evaluating such substances base the calculation on the composition of the formulation with the amount of water removed, including any water that may be contained in excipients.

The agency then provided step-by-step instructions for how to calculate the percentage delta-9 THC in solution-based materials:

1. Determine the density of the liquid formulation and convert 1 mL of the formulation to mass units (mg).
2. Calculate water content (in mg) of each active and excipient component present in 1 mL of the formulation.
3. Sum the water content (in mg) for all components present in 1 mL of the liquid formulation and subtract this amount from the total mass of 1 mL (from step 1). This is the water-adjusted total mass of 1 mL of the formulation.
4. Calculate the mass, or mg amount, of delta-9 THC present in 1 mL of the liquid formulation.
5. Calculate the percentage delta-9 THC by dividing the mass of delta-9 THC from step 4 by the total water-adjusted mass in step 3 and multiplying by 100.

The delta-9 THC percentage in solid oral dosage forms would be similarly calculated and would be the weight of delta-9 THC in the dosage unit divided by the total water-adjusted formulation weight multiplied by 100. For oral capsules, the mass of the capsule itself should not be included in the denominator weight. The water-adjusted formulation weight should reflect the removal of all water content present for each of the components, whether active or inactive, in the formulation. For either solutions or solids, use of the proposed or established specifications for the upper limit of water content for excipients that contain water, as opposed to a measured result from a sample, may be acceptable and would be a matter for review.

FDA raised a few other points that might be applicable to companies developing CBD products in general. First, the agency noted that the major metabolite of CBD in humans, 7-COOH-CBD, is expressed disproportionately in humans compared to animals, which may be of interest to companies developing CBD animal supplements or food. Second, FDA explained that sponsors should carefully consider selection of a container closure system and assess extractable and leachable compounds. Concerns about packaging and leachable compounds potentially could extend beyond the drug context and into the food, dietary supplement, and cosmetic sectors. Finally, FDA mentioned that some manufacturing processes may generate materials with greater than 0.3% delta-9 THC, even where the source material or finished product contains less than 0.3% delta-9 THC. The agency suggested that entities generating such materials that might be shipped between manufacturing sites should contact the Drug Enforcement Administration (DEA) for recommendations. This advice would likely extend to manufacturers developing non-drug CBD products as well.

Additional recommendations made in the draft guidance are likely to be of interest exclusively to drug developers. FDA first clarified the availability of potential sources of cannabis for clinical research. Currently, the National Institute on Drug Abuse (NIDA) Drug Supply Program (DSP) is the only domestic federally legal source of cannabis with greater than 0.3% delta-9 THC for clinical research. However, cannabis with less than 0.3% delta-9 THC may also be used for clinical research.

FDA then discussed quality considerations and relevant resources for drug developers. The agency explained that sponsors should provide quantitative data regarding phytochemicals that are present in proposed products, including but not limited to, cannabinoids, terpenes, and flavonoids. Additionally, FDA referred to the United States Pharmacopeia (USP), the National Formulary (NF), and several guidance documents, including Botanical Drug Development, as resources for information. FDA explained that cannabis is held to the same regulatory standards as any other botanical raw material, botanical drug substance, or botanical drug product. FDA emphasized that adequate characterization of cannabis and cannabis-derived compounds is critical to ensuring batch-to-batch consistency, and pointed to several relevant USP chapters, including those relating to pesticide testing, microbiological examination, and elemental impurities.

FDA does not recommend that applicants pursuing approval of a New Drug Application (NDA) 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 also explained that while highly purified botanical substances are considered analogous to conventional synthetic single-chemical active pharmaceutical ingredients for the purposes of drug development, a naturally occurring compound isolated from a botanical source would be expected to have a different impurity profile from the corresponding synthetically produced cannabis-related compound, and impurities for the naturally occurring compound should be controlled accordingly. FDA noted further that there may be controlled substance scheduling considerations associated with drugs containing cannabis or cannabis-derived compounds.

In discussing percent delta-9 THC calculation, FDA explained that sponsors or applicants should provide in their Investigational New Drug (IND) applications quantitative data (such as a certificate of analysis) indicating the percent delta-9 THC by dry weight in the botanical raw material and detailed descriptions of testing methods. FDA noted that the 0.3% delta-9 THC by dry weight threshold is not appropriate as a limit when considering tetrahydrocannabinols as impurities for quality control and application submission purposes.

FDA requests comments on the draft guidance by September 21, 2020.

If you have any questions concerning the material discussed in this client alert, please contact the following members of our Food, Drug, and Device practice.