Originally published by our sister publication Pain Medicine News


By Landon Gray

The FDA announced its final guidance on clinical research with cannabis that includes clarifying sources of cannabis for clinical research (including Schedule I sources), additional resources detailing expectations for Investigational New Drug (IND) applications in different stages of drug development and guidance on quality considerations for INDs, as well as considerations of control status under the Controlled Substances Act (CSA).

Often referred to as the 2018 Farm Bill, the Agriculture Improvement Act of 2018 (Public Law 115-334) altered the treatment of cannabis under the CSA. Hemp, as defined by the Department of Agriculture, includes cannabis, derivatives or extracts of cannabis with no more than 0.3% by dry weight of the compound delta-9 tetrahydrocannabinol (THC). The FDA’s authority to regulate products that contain cannabis or cannabis-derived compounds also were preserved by the 2018 Farm Bill.

New Sources

Now that the National Institute on Drug Abuse (NIDA) Drug Supply Program (DSP) is no longer the only federally legal source of cannabis, the FDA clarified its current position on sourcing cannabis for clinical research.

It is now the agency’s position that sources of cannabis with less or more than 0.3% delta-9 THC on a dry weight basis may be used for clinical research if it is found to be of adequate quality after review by the FDA as part of an IND. The FDA also stated that sponsors or investigators may use the NIDA DSP for cannabis of the 0.3% THC threshold, or they can utilize other sources authorized by the Drug Enforcement Administration (DEA). A list of DEA-authorized cannabis sources is available online.

“I believe that this is a significant announcement,” Charles E. Argoff, MD, said the director of the Comprehensive Pain Center and director of the pain management fellowship at Albany Medical Center, in New York. “With the actions taken by numerous states with respect to medical and recreational use of cannabis, as well as the scientific advances that have been made regarding this, the tension that this may cause between FDA and DEA may lead to benefits for those in the scientific and patient care communities. Perhaps such tension will lead to better studies better understanding of how to use this class of compounds in a safe and effective way for specific medical conditions.”

Quality Considerations

The FDA said as part of an IND for any drug, even those containing cannabis or cannabis-derived compounds, there is the expectation that sponsors are able to show that they can consistently manufacture a quality product. Sponsors must submit ample information that demonstrates the identity, quality, purity and potency or strength of any investigational drug during each phase of clinical investigation.

Currently, “quality control is sorely lacking,” noted Dr. Argoff.

With each successive stage of drug development, this information needed to meet the FDA’s expectation increases. Sponsors have to provide the agency with a description of the investigational drug substance that includes quantitative data concerning phytochemicals that are in the drug being proposed, including but not limited to cannabinoids, terpenes and flavonoids. More information and the pharmaceutical quality guidance document are available on the FDA’s website.

The guidance for industry, Botanical Drug Development, contains the general considerations and recommendations for botanical drugs. They provide the core principles for performing clinical research on botanical drugs, including those containing cannabis and cannabis-derived compounds. The FDA also recommended that the following principles and documents be considered by those pursuing the development of drugs containing cannabis or cannabis-derived compounds:

  • Adequate characterization of cannabis and cannabis-derived compounds, for example, via a chemical fingerprint, is critical to ensuring batch-to-batch consistency.
  • USP General Chapter <61>: Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests.
  • USP General Chapter <62>: Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms.
  • USP General Chapter <71>: Sterility Tests.
  • USP General Chapter <232>: Elemental Impurities—Limits.
  • Tests for residual pesticides should include pesticides routinely used in the botanical raw materials’ countries of origin. See USP General Chapter <561>: Articles of Botanical Origin for further information.
  • USP General Chapter <563>: Identification of Articles of Botanical Origin.
  • USP General Chapter <1111>: Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use.
  • USP General Chapter <1225>: Validation of Compendial Procedures.

CSA Considerations

The change to the control status of hemp under the 2018 Farm Bill significantly reduced the DEA’s regulatory requirements for cannabis and cannabis-derived compounds covered by the definition of hemp. However, according to the FDA, if cannabis does not meet the definition—exceeding the dry weight threshold of 0.3% delta-THC—growing- and manufacturing-related activities for use in investigational drug research must comply with applicable requirements from the CSA and DEA.

Typically, the delta-9 THC percentage present in botanical raw materials is determined by the total amount of delta-9 THC and tetrahydrocannabinolic acid (THCA) that naturally appear in a sample relative to the dry weight of the sample before extraction or other manufacturing steps. However, this type of dry weight calculation has limited utility for intermediates, such as solutions or extracts in solution (whether aqueous or nonaqueous) and for finished products of various dosage forms, the FDA said.

The FDA recommended sponsors, investigators or applicants base the calculation of the total percentage of delta-9 THC, including THCA, on the formulation’s composition with the amount of water removed, including any water contained by excipients.

The FDA also commended consultation with the DEA regarding the control status of cannabis or cannabis-derived materials in manufacturing and investigational drug products that are under development.

The agency also noted that these types of products may raise drug abuse liability concerns; therefore, the FDA may evaluate such a product during the NDA review process for potential scheduling or rescheduling under the CSA.

“This guidance allows for a path going forward to improve the quality of studies done and to gain valuable and needed information about how to use cannabis for the management of various acute and chronic pain disorders through high-quality clinical research,” Dr. Argoff said. 


What About CBD?

Recently, the FDA denied three citizen petitions requesting that the agency conduct rule-making to allow for CBD products to be marketed as dietary supplements.

Under current law, for any substance, including those containing CBD, to be legally marketed as a dietary supplement or food additive, specific safety standards must be met.

The FDA concluded existing regulatory frameworks are not suitable for cannabidiol (CBD) food and supplements and stated the agency is prepared to work together with Congress to determine the best way to proceed. The new pathway must balance public demand for CBD products with the appropriate regulatory oversight to manage risk, the agency noted.

With the available data at hand, there is no apparent determination of how much CDB can be consumed by an individual before causing harm, or the time it takes to cause harm.

“Scientific studies that the FDA reviewed show the potential for harm to the liver, interactions with certain medications, and possible harm to the male reproductive system,” the agency reported. “CBD exposure is also concerning when it comes to certain vulnerable populations such as children and those who are pregnant.”

The FDA stated it will continue monitor the marketplace and take action against CBD and other cannabis-derived products, as needed, in the best interest of public health.


Dr. Argoff reported no relevant financial disclosures. From FDA materials.