Dr. Weber: Welcome to the CDER Small Business and Industry Assistance (SBIA) Chronicles Podcast Series.
Today’s topic: FDA Regulation and Quality Considerations for Cannabis and Cannabis-Derived Compounds. There is increasing interest in the potential utility of cannabis for a variety of medical conditions. 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.
My name is Dr. Ellicia Weber, and today we are joined by Dr. Cassandra Taylor, Chemist and FDA Cannabis Subject Matter Expert from the Botanical Review Team within FDA’s Center for Drug Evaluation and Research (or CDER) Office of Pharmaceutical Quality.
Hi Dr. Taylor, thanks for joining us today to discuss the recently finalized Guidance for Industry, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research”.
Dr. Taylor: Glad to be here!
Dr. Weber: Dr. Taylor, it may be helpful to begin by clarifying the various cannabis related terms.
Dr. Taylor: Sure! There’s quite a few of them. Cannabis sativa L. is a plant that contains over 500 different naturally occurring compounds. 100 of those 500 compounds are called “cannabinoids,” and we kind of categorize them in 3 main buckets:
- The first one is Cannabis-derived compounds, so (or call them CDPs), and those occur naturally. They are extracted directly from the plant, and some examples are cannabidiol (or CBD), delta-9-tetrahydrocannabinol (or delta-9 THC). And these CDPs, they can be used to manufacture drug products and drug substances, and they include botanical raw materials; they include extracts, highly purified substances of botanical origin.
- The second bucket is something called Cannabis-related compounds. These are synthetic compounds that are made in a laboratory. Sometimes they are also found in nature in small quantities, but they can also be used to manufacture drug products.
- And the third bucket is Hemp. Hemp, which is a legal term defined by the 2018 Agricultural Improvement Act (also known as the 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% delta-9 THC on a dry weight basis.
Dr. Weber: CDPs are held to the same regulatory standards as any other botanical raw materials, botanical drug substance or botanical drug product, correct?
Dr. Taylor: Yes, that’s right. When a researcher intends to study botanical products - that includes products that contains cannabis, CDPs, or those cannabis-related synthetic compounds we just talked about - in order to determine effects of either the diagnosis, cure, mitigation, treatment, or prevention of a disease, then those products are drugs under the Federal Food, Drug, and Cosmetic Act. Researchers must meet all FDA requirements to conduct human clinical trials, regardless of their source of cannabis or any other botanical product under study in the trial. FDA has a guidance that’s available, it’s called the “Botanical Drug Development Guidance for Industry.” It’s a very helpful resource that provides FDA’s current thinking on the appropriate development plans for botanical drugs.
Dr. Weber: FDA recently finalized a guidance, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research” to provide recommendations for researchers interested in developing cannabis and CDPs for use in human drugs for clinical research. Can you describe how this final guidance differs from the previous draft guidance?
Dr. Taylor: Sure. There’s quite a few differences, but a few of the highlights include clarifying sources of cannabis for clinical research (that does include using Schedule I sources for clinical research), adding resources explaining expectations for investigational new drug applications (or INDs as we call them) throughout the various stages of drug development, and providing guidance on quality considerations for INDs. It’s important that listeners understand the guidance does not address development of cannabis-related compounds, or those synthetic ones – those are regulated just like any other synthetic drugs at FDA.
Dr. Weber: Are these products all controlled substances?
Dr. Taylor: No, they are not. The Farm Bill, which we just talked about, removed hemp from the Federal Controlled Substances Act (or the CSA). And botanical raw materials, extracts, and derivatives that contain CDPs with delta-9 THC content that’s above that 0.3 percent by dry weight - those remain Schedule I controlled substances. So that means that activities related to, you know, the growing and manufacturing these products for use as investigational drugs for research must comply with the Controlled Substances Act and the Drug Enforcement Agency (or the DEA) requirements.
DEA should be consulted regarding the control status of cannabis or cannabis-derived materials in manufacturing or investigational drugs that are under development. And even if the starting materials meet that legal definition of hemp, intermediates or drug products could be created that contain greater than 0.3 percent delta-9 THC by dry weight, and they may no longer meet that definition of hemp, and they might be considered controlled substances.
Dr. Weber: Per the guidance, in clinical research, sources of cannabis defined as hemp and those containing greater than 0.3% delta-9 THC on a dry weight basis may be used if deemed to be of adequate quality by FDA when reviewed as part of an IND. What can researchers use as a source of cannabis for their studies?
Dr. Taylor: You can use botanical sources that meet all the FDA requirements to conduct human clinical trials. The National Institute on Drug Abuse (or NIDA) has a Drug Supply Program, and they’re a source of cannabis over that 0.3 percent delta-9 THC threshold that we’ve been talking about, and those can be used. DEA also continues to update their list of authorized growers, and researchers may also use those as sources of Schedule I cannabis materials for researchers, or excuse me, for research. Researchers at each study site who are planning to conduct studies with controlled cannabis study drugs need to be registered with the DEA and comply with all applicable DEA regulations.
Dr. Weber: To gain insight into their product’s potential abuse liability and control status, researchers 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 – which is also addressed in the guidance. Can you explain this further?
Dr. Taylor: Of course. FDA recommends that the calculation of total delta-9 THC percentage be based on the composition of your proposed formulation with that amount of water removed. This includes any water that might be in your excipients, and so you need to make sure that that’s also removed from your calculation. Researchers should not rely on the 0.3% delta-9 THC by dry weight threshold when they’re evaluating tetrahydrocannabinols as impurities for the purposes of quality control and commercial drug application submission. The documentation regarding the steps for the delta-9 THC calculation should be submitted in the IND.
Dr. Weber: To conduct clinical research, researchers work with the FDA to submit an IND application to CDER, which must include information from three broad areas: animal pharmacology and toxicology studies, clinical protocols and investigator information, and manufacturing information. Can you generally describe the required manufacturing information for inclusion?
Dr. Taylor: Absolutely. Researchers submitting an IND must submit sufficient information to demonstrate the identity, quality, purity, and potency or strength of the investigational drug in each phase of clinical investigation. The final guidance lists applicable United States Pharmacopeia (or USP) chapters on quality and testing, and also identifies relevant International Council for Harmonisation (or ICH) guidelines, as well as 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 researchers using CDPs consider before submitting INDs to FDA for review.
Now, the manufacturing information should also include quantitative data indicating the percent delta-9 THC by dry weight in the botanical raw materials. And if the study proposes to use cannabis that contains greater than that 0.3 percent delta-9 THC on a dry weight basis, the researcher should contact NIDA or another DEA-registered source of cannabis and/or the cannabis-derived substance to obtain information on the specific cultivars that are available for research.
Dr. Weber: And regardless of the delta-9 THC content, the researcher should provide all necessary chemistry manufacturing and controls (or CMC) and botanical raw materials information in the IND, correct?
Dr. Taylor: That’s correct. Cannabis researchers are encouraged to use Drug Master Files (or DMFs) to help support their cannabis research, speed their drug development, address concerns regarding protection of proprietary information, while participating in the drug development process. If the selected hemp, or botanical raw materials, or drug substance manufacturer holds a DMF, the researcher must obtain a Letter of Authorization (often called an LOA) to reference the CMC and botanical raw material information in the DMF when they submit their IND.
Dr. Weber: Thank you again Dr. Taylor for joining us today and providing your expertise on this topic. Are there any final words you would like to share with us today?
Dr. Taylor: Thank you so much Dr. Weber. I would like to say that here at the FDA we’re really committed to supporting robust scientific research into understanding therapeutic uses and safety of cannabis and cannabis-derived products, and we offer quite a number of resources to help researchers and investigators. That includes “FDA and Cannabis: Research and Drug Approval Process” and “FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol” webpages. They’re available for everyone. The resources also provide contact information for the CDER’s Botanical Review Team (BRT), which is what I’m a part of. We serve as the expert resource on botanical issues. The agency also continues to conduct research on various cannabis quality consideration, including BRT’s recent publications on quality standards in state programs permitting cannabis for medical uses and investigation of microorganisms in cannabis after heating in a commercial vaporizer.
Dr. Weber: You can find a link to the full SBIA Chronicles article at www.fda.gov/cdersbiachronicles. Also visit www.fda.gov/cdersbia to stay connected with upcoming webinars and conferences, sign up for SBIA email updates, and follow SBIA on LinkedIn. Thanks for tuning in!