Cannabis clinical research clarified in draft guidance

Regulatory NewsRegulatory News | 22 July 2020 |  By 

A new draft guidance from the US Food and Drug Administration (FDA) provides detailed information on the conduct of clinical research using cannabis and cannabis-derived compounds, including how to calculate levels of delta-9 tetrahydrocannabinol (THC), cannabis’ main psychoactive ingredient.
The draft guidance recommendations, which pertain only to human drug development, “are intended to provide clarity” in the wake of the 2018 Farm Bill, which removed low-delta-9 THC cannabis and cannabis products from the Controlled Substances Act (CSA) definition of “marihuana.” Cannabis and cannabis products are now defined as “hemp” if they contain less than 0.3 percent by dry weight of delta-9 THC; these products are no longer controlled substances under Federal law.
Cannabis and cannabis derivatives or extracts containing more than the 0.3 percent delta-9 THC cutoff “remain Schedule I controlled substances under the CSA,” according to the guidance. The Drug Enforcement Administration, rather than FDA, enforces the CSA.  “There may be drug scheduling considerations under the CSA for applicants pursuing FDA approval of [a New Drug Application] for a drug that contains cannabis or cannabis-derived compounds,” notes FDA.
The guidance also clarifies FDA’s position that the only “domestically federally legal source of cannabis” for clinical research remains the University of Mississippi-grown cannabis supplied by the National Institute on Drug Abuse Drug Supply Program.
Sponsors developing cannabis-containing drugs should follow the same quality considerations as when developing any other botanical drug product, says the guidance. Also, sponsors should “should provide quantitative data regarding phytochemicals that are present in their proposed product, including but not limited to, cannabinoids, terpenes, and flavonoids.”
Drugmakers involved in developing cannabis-containing products should consider using a chemical fingerprint to adequately characterize cannabis and its derived compounds to ensure batch-to-batch consistency, says FDA. The draft guidance refers clinical researchers to sections 61, 232, 561, and 563 of the US Pharmacopeia for detailed information about testing for residual pesticides and elemental impurities, species identification and microbiological examination.
Sponsors should expect to engage in a full toxicology program for phase 3 and later-stage trials, rather than relying on published literature, according to the guidance, which also notes that cannabidiol’s major human metabolite is expressed disproportionately highly in humans. “FDA would like to make stakeholders aware that this is a known issue with certain cannabinoids,” says the draft guidance.
In the guidance, developers are cautioned to attend to such details as container closure systems and the potential for a product to be considered a combination product if a delivery system such as an inhaler is to be used.
The draft guidance gives detailed information about sampling and testing methods to evaluated delta-9 THC levels, referring to existing US Department of Agriculture guidelines for sampling and testing. FDA expects to see applicants providing quantitative data about delta-9 THC content in botanical raw material, along with a detailed description of the testing methods used by the sponsor to arrive at delta-9 THC content for Phase 2 and 3 studies and marketing applications.
In the draft guidance, FDA provides extensive instructions regarding calculating delta-9 THC content in solution-based material and for solid oral dosage forms in order to take water content into account when calculating dry weight. These calculations “should not be used for other purposes such as chemistry, manufacturing, or controls,” according to the guidance.
“We recommend that you consult DEA regarding the control status of cannabis or cannabis-derived materials or products that are under development,” says FDA. “We note that intermediates or drug products that contain greater than 0.3 percent delta-9 THC by dry weight, even if the starting materials meet the definition of hemp, may no longer meet the definition of hemp and may be considered a Schedule I controlled substance.”
Additionally, FDA recommends DEA be contacted ahead of time when intermediates or by-products that may exceed the 0.3 percent cutoff for delta-9 THC would need to be shipped, so that manufacturers, shippers, and sponsors do not run afoul of CSA provisions.


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Tags: cannabis, FDA, US

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