On July 21st, 2020, the FDA released a draft guidance document for developers of cannabis and cannabis derived compounds, aptly titled “Cannabis and Cannabis Derived Compounds: Quality Considerations for Clinical Research: Guidance for Industries.” The draft is clear that it applies to botanical raw materials, extracts, and highly purified substances of botanical origin. It is equally clear that it does not address the development of fully synthetic versions of substances which naturally occur in cannabis.
Background information is provided which re-iterates the previously understood tenets that human drugs with cannabis and cannabis derived compounds are subject to the same FDA regulations as any other drug, and that new products go through the same clinical trials under INDA and subsequent NDA application prior to approval. The definition of “hemp” created in the 2018 farm bill is provided as well: “cannabis and derivatives or extracts of cannabis with no more than 0.3 percent by dry weight of the compound delta-9 tetrahydrocannabinol (THC).” This definition removed hemp from the umbrella of marijuana and the categorization as a class 1 controlled substance and is important for context throughout the draft.
Three sections of recommendations are included: Sources of Cannabis, Resources for Information on Quality Consideration, and Percent Delta-9 THC Calculation.
NIDA DSP remains the sole federally legal supplier of cannabis containing over 0.3% dry weight delta 9 THC, but for cannabis – or hemp – containing equal to or under the 0.3% dry weight delta 9 THC threshold there are no stated limitations on legal suppliers of hemp. This opens up sourcing from varied suppliers. Regardless of the source, though, the selected tests for evaluating THC levels in the raw materials should be in line with the USDA’s “Establishment of a Domestic Hemp Production Program” or the superseding guidance. Clear direction is also provided for sponsors whose process creates levels of 0.3% delta-9 THC that are above threshold – refer to the DEA for more details.
For those entering Phase 1 clinical trials, “cGMP for Phase 1 investigational drugs” is provided as a resource for recommendations on method development and laboratory controls with relation to analytical testing. The same document is referenced for assistance when submitting information in support of ensuring the identity, quality, purity, and potency of the investigational drug. Sponsors are in a unique position due to the naturally variable botanical nature of the raw material - they must be able to demonstrate that their processes consistently produce products that meet criteria for the above requirements. For those in phases 2 and 3, the draft refers to 21CFR210 and 211 for guidance on current good manufacturing processes and specifically calls out the selection of a ‘reliable laboratory’ for validated analytical tests. Finally, sponsors are instructed that the use of the 0.3% threshold for delta-9 THC is not an appropriate standard when THCs are considered impurities.
An entire section of the draft is devoted to detailing the methods to be applied when testing delta-9 THC levels in intermediaries and finished products. This addresses the differences in testing a raw material and a finished product, and there are clear differences for testing liquid versus solid dose products. By streamlining the testing process early, the FDA has ensured accurate, comparable results which accurately reflect the intended purpose and has taken the burden away from the sponsor for determining test method.
There is information on what not to do as well. Animal testing appears to be discouraged for early clinical development based on the known issue of disproportionate metabolism of some cannabinoids in humans, and the difference between animal and human metabolism of cannabidiol. NDA applicants are recommended to not solely rely on published literature in lieu of data from a full toxicology program at phase 3 and beyond, despite the allowance of such information during early clinical stages.
The new draft guidance provides extensive references for those pursuing clinical research on cannabis and cannabis derived compounds and appears to understand that many manufacturers may be facing quality regulation for the first time. However, the document will be useful to any party going through clinicals with a drug containing cannabis or cannabis derived compounds, as it provides clarity on the FDA’s position on areas from method development to cGMPS to (non)clinical and analytical testing.
Key Takeaways:
- The new draft guidance applies to botanical raw materials, extracts, and highly purified substances of botanical origin
- Clear guidance is provided on quality aspects and non-clinical testing to enter clinical studies and file an NDA
- Cannabis raw materials, products, byproducts, or intermediaries with a final value of greater than 0.3% delta-9 THC should be discussed with the DEA
ProPharma Group has extensive experience consulting clients through the regulatory approval process. Contact us to learn how we can support your product from development to commercialization.
