FDA Releases Guidance To Boost Cannabis Clinical Research

The FDA recently released draft guidance for industry stakeholders interested in conducting clinical research and developing drugs containing cannabis or cannabis-derived compounds.¹

“Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research, Draft Guidance for Industry” contains relevant and practical recommendations regarding cannabis sources for research, quality considerations, and calculating tetrahydrocannabinol (THC) levels in prospective drug products.

“The agency is committed to supporting the development of these new drugs through the investigational new drug, drug review and drug approval processes—and one key element of this support involves development of guidance, like this one,” Amy Abernethy, MD, PhD, FDA principal deputy commissioner, said in a statement.

The guidance featured changes to the cannabis industry through the 2018 Farm Bill, legislation that removed hemp from the definition of marihuana and effectively eliminated hemp from the federal list of controlled substances.²

The updated list of Schedule I controlled substances under the Controlled Substances Act (CSA) includes cannabis or cannabis-derived compounds with delta-9 THC levels above 0.3% by dry weight, and any cannabis product and derivatives or extracts with 0.3% or less would not be considered a controlled substance.²

Among the recommendations provided by the FDA guidance were methods for calculating THC percentage in a proposed cannabis product. For example, the following is for solution-based cannabis or cannabis-derived products:²

• Determine the density of the liquid formulation and convert 1 mL to mass units (mg)
• Calculate water content in mg of each active and excipient component present in 1 mL of the formulation
• Sum the water content for all components present in 1 mL of the liquid formulation and subtract that from the total mass of 1 mL (from step 1)
• Calculate the mass, or mg amount, or delta-9 THC present in 1 mL of the solution
• Calculate the percentage of delta-9 THC by dividing the mass of delta-9 THC from step 4 by the total water-adjusted mass in step 3; multiply by 100

Also included in the guidance were practical principles related to drug development, particularly that from cannabis or cannabis-derived compounds. The FDA included several draft implementations:

1. Adequately characterize the cannabis or cannabis-derived compounds, through a chemical fingerprint, for example
2. Ensure that product is tested for residual pesticides, including any that are routinely used in the countries of origin of botanical raw materials
3. Administer quality tests, including those specific to dosage form
4. Consider drug scheduling considerations under the CSA if applying to a new drug application (NDA), as FDA’s review may include an abuse potential assessment

Jeffrey Lombardo, BCOP, research assistant professor at the University of Buffalo Center for Integrated Global Biomedical Sciences, Buffalo, New York, told Drug Topics® in an interview that he thought the guidance document was well done.

“I thought the introduction provided a thorough understanding of key terms and current policy,” Lombardo said. “There is still a lot of confusion regarding schedule status as a Class I controlled substance and understating the Farm Bill. I think the document delineated roles and responsibilities between the FDA and DEA.”

Lombardo explained that the draft guidance focused on providing an understanding of the drug development process, including the steps needed for an investigational new drug (IND) applications, and when an investigator needs to submit an IND to the FDA for consideration.

“This process has been around for years and is a gold standard to prove safety and efficacy. The result can then be applied in a NDA for the FDA to consider approval and entry into the marketplace. Companies, sponsors, and researchers must be held to the same scrutiny if they want to be accepted by the evidence based medical community. Everyone must go through the same process as normal pharmaceuticals.”

The agency’s recommendations were largely sparked by increased interest by industry stakeholders in cannabis and cannabis-derived products, and Lombardo is encouraged by the FDA support.

"I appreciate the time and effort out regulatory bodies are putting into this guidance document. I look at it as they are putting a process in place and giving the sponsors a roadmap or protocol to follow a standard process. I've experienced patients who have benefited from these products for certain indications like pain, multiple sclerosis, and cachexia - they are real. We now need to understand if there are any long term adverse effects (AEs) with chronic use.“

Because the guidance has been released in draft form, the agency highlighted that the document is nonbinding, and that there exist alternative approaches to conducting clinical research on cannabis products for FDA approval. The FDA endorsed contacting the agency with questions and comments.²

“A range of stakeholders have expressed interest in development of drugs that contain cannabis and compounds found in cannabis,” Abernathy said. “Recent legislative changes have also opened new opportunities for cannabis clinical research. As that body of research progresses and grows, the FDA is working to support drug development in this area.”

References:

1. FDA In Brief: FDA Issues Draft Guidance to Encourage Cannabis-Related Clinical Research. News Release. FDA; July 21, 2020. Accessed July 22, 2020. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-issues-draft-guidance-encourage-cannabis-related-clinical-research.
2. Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research. FDA. 2020. https://www.fda.gov/media/140319/download.