The US Food and Drug Administration (FDA) recently issued a final guidance, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research.” The guidance finalizes a 2020 draft guidance outlining how sponsors and investigators can legally conduct clinical trials for certain drugs containing cannabis or cannabis-derived compounds such as cannabidiol (CBD).

As we have previously written, following the passage of the Agriculture Improvement Act of 2018 (Farm Bill), hemp, including cannabis and derivatives or extracts of cannabis with a delta-9 tetrahydrocannabinol (THC) concentration of no more than 0.3% on a dry weight basis, is no longer a controlled substance under the Controlled Substances Act (CSA). This change prompted the FDA to issue a 2020 draft guidance outlining its recommendations to help ensure that sponsors of drug products that use cannabis in human drug clinical research meet clinical research regulatory requirements and standards.

The final guidance minimally updates the FDA’s 2020 draft guidance. Changes from the draft to the final guidance include “clarifying sources of cannabis for clinical research (including Schedule I sources), adding resources explaining expectations for investigational new drug (IND) applications in various stages of drug development, and providing guidance on quality considerations for INDs.”

SOURCES OF CANNABIS AND QUALITY CONSIDERATIONS

Drug sponsors and clinical trial investigators may use hemp, including cannabis and derivatives, in human drug clinical research if the FDA deems the cannabis to be of “adequate quality” when reviewed as part of an investigational new drug (IND) application. Noting that cannabis and cannabis-derived compounds are held to the same regulatory standards as botanical raw materials, drug substances, or drug products, the FDA encourages sponsors to consider the recommendations in its final guidance, “Botanical Drug Development” (December 2016). The FDA also lists additional resources, including the applicable United States Pharmacopeia (USP) chapters on quality testing, and guidance on the assessment of leachables from packaging and delivery systems.

The FDA further advises researchers to create tests and measurements to determine the quantities of specific cannabinoids and their effects on the body of humans and animals, noting that relying on published literature is not adequate for bridging to a proposed botanical drug product because the particular botanical drug product under review may differ from that of the published study. The FDA also recommends the development of assays to characterize the metabolic profile of major cannabinoids in humans and toxicology species to avoid delays in development.

CONTROLLED STATUS UNDER THE CSA

Prior to the passage of the Farm Bill, the National Institute on Drug Abuse (NIDA) Drug Supply Program (DSP) was the only domestic federally legal source of cannabis for clinical research. While the NIDA DSP remains the only federal legal source of cannabis over the 0.3% THC threshold for clinical research, sponsors and investigators of clinical studies now have new sourcing options for hemp. However, the FDA cautions that hemp with THC concentration higher than 0.3% that is used in medical research must continue to comply with the CSA and implementing Drug Enforcement Administration (DEA) regulations.

The guidance details recommendations on the calculation of THC concentration to determine whether cannabis and cannabis-derived substances are controlled under the CSA. The FDA recommends that “[s]ponsors and investigators proposing drug development activities involving controlled substances should consult DEA about the applicable requirements,” adding that they “may find it useful to calculate the delta-9 THC content in their proposed cannabis or cannabis-derived investigational drug product early in the development process to gain insight into their product’s potential abuse liability and control status.”

KEY TAKEAWAYS

• This FDA final guidance provides key clarifications on quality requirements for cannabis and cannabis-derived compounds used in clinical research.
• The final guidance follows the passage of the Medical Marijuana and Cannabidiol Research Expansion Act in December, which creates a mechanism for FDA approval of cannabis-derived drug products and requires the DEA to register researchers and suppliers of cannabis for medical research.

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