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                CDER Small Business & Industry Assistance (SBIA)

CDER Small Business & Industry Assistance (SBIA)

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          FDA Regulation and Quality Considerations for Cannabis and Cannabis-Derived CompoundsCDER Small Business & Industry Assistance (SBIA) FDA Regulation and Quality Considerations for Cannabis and Cannabis-Derived Compounds
  
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Cassandra Taylor photo

Dr. Cassandra Taylor - Chemist and FDA Cannabis Subject Matter Expert
Botanical Review Team; Office of Pharmaceutical Quality | CDER | FDA

There is increasing interest in the potential utility of cannabis for a variety of medical conditions, as well as research on possible adverse health effects. Studies in clinical trial settings are needed to assess the safety and effectiveness of cannabis and cannabis-derived products for the treatment of any disease or condition, and FDA has an important role to play in supporting this scientific research and providing guidance. To clarify some terminology:

*Cannabis sativa* L. is a plant that contains over 100 different naturally occurring compounds called “cannabinoids.”
	*Cannabis-derived compounds* are compounds occurring naturally in the plant, like cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), that are extracted directly from the plant. Cannabis-derived compounds that may be used in manufacturing human drugs include botanical raw materials (BRMs), extracts, and highly purified substances of botanical origin.
	*Cannabis-related compounds* are synthetic compounds created in a laboratory and can be used to manufacture drug products. Some may also occur naturally in the plant.
	*Hemp* is a legal term defined by the 2018 Agricultural Improvement Act (Farm Bill) and is generally defined as *Cannabis sativa* L. and any part of the plant with a delta-9 THC concentration of not more than 0.3% on a dry weight basis.Though the Farm Bill removed hemp from the federal Controlled Substances Act (CSA), BRMs, extracts, and derivatives that contain cannabis-derived products (CDPs) with delta-9 THC content above 0.3 percent by dry weight remain Schedule I controlled substances. Thus, activities related to growing and manufacturing these products for use as an investigational drug for research must comply with the CSA and Drug Enforcement Agency (DEA) requirements.

FDA recently issued a final guidance “*Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research*” to provide recommendations for sponsors interested in developing cannabis and CDPs for use in human drugs for clinical research. Notable changes that were made from the 2020 draft 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. Note that this guidance does not address development of cannabis-related compounds, which are regulated like other synthetic drugs.

**Sources of Cannabis**: Both sources of cannabis defined as *hemp* and those containing >0.3% delta-9 THC on a dry weight basis may be used for clinical research if deemed to be of adequate quality by FDA when reviewed as part of an IND. Researchers may use the National Institute on Drug Abuse (NIDA) Drug Supply Program (DSP) as a source of cannabis over the 0.3% delta-9 THC threshold, or they may use other sources authorized by DEA to provide Schedule I cannabis materials for research. The DEA webpage also contains a list of DEA-authorized growers of Schedule I cannabis and information on importation of controlled substances (21 CFR 1312).

**Control Status**: Sponsors and investigators 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. However, they should not rely on the 0.3% delta-9 THC by dry weight threshold when evaluating tetrahydrocannabinols as impurities for the purposes of quality control and application submission. FDA recommends that the calculation of total delta-9 THC percentage be based on the composition of the formulation with the amount of water removed, including any water that excipients may contain. The calculation of THC percentage is detailed in the final guidance document, and the documentation regarding the steps of the delta-9 THC calculation should be submitted in the IND.

The DEA should be consulted regarding the control status of cannabis or cannabis-derived materials in manufacturing or investigational drug products that are under development. Even if the starting materials meet the definition of *hemp*, intermediates or drug products that contain greater than 0.3% delta-9 THC by dry weight may no longer meet the definition of *hemp* and may be considered Schedule I controlled substances.

**Regulation of botanical drug products**: CDPs are held to the same regulatory standards as any other BRM, botanical drug substance or botanical drug product. When a researcher intends to study botanical products (including one that contains cannabis, CDPs, or cannabis-related compounds) to determine their effects in the diagnosis, cure, mitigation, treatment, or prevention of a disease, these products are considered to be drugs under the Food, Drug, and Cosmetic Act. Researchers must meet all FDA requirements to conduct human clinical trials, regardless of the source of cannabis or any other botanical product under study in the trial. FDA’s “Botanical Drug Development Guidance for Industry” is a helpful resource that provides FDA’s current thinking on appropriate development plans for botanical drugs and recommendations for researchers to consider.

**IND submission**: To conduct clinical research, including research in humans using materials from plants such as cannabis, researchers work with the FDA to submit an IND application to FDA’s Center for Drug Evaluation and Research (CDER). The IND must include information from three broad areas: animal pharmacology and toxicology studies, clinical protocols and investigator information, and manufacturing information. This includes protocols describing proposed studies, the qualifications of the investigators who will conduct the clinical studies, assurances of informed consent and protection of the rights, safety, and welfare of the human subjects, and quality control information for the drug(s) proposed for use.

IND sponsors must submit sufficient information to demonstrate the identity, quality, purity, and potency or strength of the investigational drug in each phase of clinical investigation and should take into account key considerations, including the impurity profile, selection of a container closure system, metabolic profile, and literature to support clinical development. The final guidance lists applicable United States Pharmacopeia (USP) chapters on quality testing, including the assessment of leachables from packaging and delivery systems, and identifies relevant International Council for Harmonisation guidelines, FDA guidances, and considerations for devices used in combination with a drug. It also contains a listing of principles, regulations, and guidance documents that FDA recommends that those pursuing research and/or drug development using CDPs consider before submitting INDs to FDA for review.

Manufacturing information should also include quantitative data indicating the percent delta-9 THC by dry weight in the BRM. If the study proposes to use cannabis that contains greater than 0.3% delta-9 THC on a dry weight basis, the sponsor should contact NIDA or another DEA-registered source of cannabis and/or cannabis-derived substances to obtain information on the specific cultivars available.

Regardless of the delta-9 THC content, the sponsor should provide all necessary chemistry manufacturing and controls (CMC) and BRM information in the IND. Cannabis researchers are encouraged to use Drug Master Files (DMFs) to support cannabis research, speed drug development, and address concerns regarding protection of proprietary information while participating in drug development. If the selected *hemp*, BRM or drug substance manufacturer holds a DMF, the sponsor must obtain a Letter of Authorization (LOA) to reference the CMC and BRM information in the DMF. To learn more, we have made available a recorded webinar, “Cannabis Clinical Research: Drug Master Files (DMFs) & Quality Considerations.”

Prior to submission of the IND, FDA offers an optional pre-IND meeting, which is very valuable in planning a drug development program. This meeting can provide researchers information that will assist them in preparing to submit complete IND applications and is a valuable opportunity to obtain FDA guidance on research plans and required content for IND submission.

Once the IND submission is ready, the researcher should send a copy of the IND and clinical protocol, including a LOA (if applicable), to FDA for review as highlighted on our website “IND Forms and Instructions.” The sponsor must wait 30 calendar days after submission before initiating any clinical trials. During this time, FDA reviewers assess if the study is safe to proceed or will be placed on clinical hold.

All investigators at each study site who are planning to conduct studies with cannabis study drugs need to be registered with the DEA and comply with all applicable DEA regulations, including the regulations for the use, manufacturing, handling, and storage of a Schedule I drug. Schedule I licenses from the DEA are needed prior to the initiation of a clinical study with cannabis study drugs with greater than 0.3% delta-9 THC on a dry weight basis. If the cannabis study drug is synthetic or semi-synthetic, the chemist who is synthesizing the drug should also be doing so under a Schedule I license. If a sponsor already possesses a Schedule I research registration with DEA for a specific cannabis study drug, all new protocols must be submitted to DEA as an amendment to that registration. Once the Schedule I license is granted by DEA, the sponsor should contact NIDA or another DEA-registered source to obtain the substances so they can then begin the study.

The agency is committed to supporting robust scientific research into understanding therapeutic uses and safety of cannabis and CDPs. In addition to the final guidance, our “FDA and Cannabis: Research and Drug Approval Process” and “FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabadiol” webpages provide sponsors and researchers with resources, including contact information for the CDER’s Botanical Review Team (BRT), which is serves as an expert resource on botanical issues.

Resources

Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research - Guidance for Industry”
	FDA and Cannabis: Research and Drug Approval Process webpage
	FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabadiol
	CDER’s Botanical Review Team
	NIDA Drug Supply Program
	Investigator-Initiated INDs
	Pruyn SA, Wang Q, Wu CG, Taylor CL (2022) Quality standards in state programs permitting cannabis for medical uses, Cannabis and Cannabinoid Research 7:6, 728–735, DOI: 10.1089/can.2021.0164.
	Sopovski DS, Han J, Stevens-Riley M, Wang Q, Erickson BD, Oktem B, Vanlandingham M, Taylor CL and Foley SL (2023) Investigation of microorganisms in cannabis after heating in a commercial vaporizer. Front. Cell. Infect. Microbiol. 12:1051272. doi: 10.3389/fcimb.2022.1051272

                                                                                  Content current as of:
      02/07/2023
              
              
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