By: Cassandra L. Taylor, public health advisor, Office of the Center Director, Center for Drug Evaluation and Research (CDER) and Schuyler Pruyn, project manager, Office of Executive Programs, CDER
FDA has a long history of reviewing clinical research for cannabis (such as marijuana and hemp) and cannabis-derived products (such as cannabidiol or CBD). Since the early 1970s, FDA has received more than 800 investigational new drug applications (INDs) for, and pre-investigational new drug applications (pre-INDs) related to cannabis and cannabis-derived products (CCDP). Over the last 10 years, there has been increased interest in studying CCDPs as medical treatment options. We have received double the number of IND and pre-IND applications during this time. We also have seen increased clinical research of new types of cannabis products and routes of administration (ROA), which is the way the drug is administered in the body.
This clinical research mostly began with the enactment of Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, commonly called the Controlled Substances Act (CSA). The CSA established policy at the federal level on the manufacturing, distributing, importing, exporting, and use of regulated substances and placed all substances that were regulated under existing federal law into one of five schedules, depending upon their abuse potential. Certain parts of the Cannabis sativa L. plant have been controlled under the CSA since 1970 under the drug class Marihuana.
In a recent article published in Open Exploration, “A U.S. FDA Perspective on Cannabis Research and Drug Development,” we present a breakdown of CCDP applications that the agency has received over the past 50 years. We also summarize our experiences and challenges in reviewing CCDP research applications and provide recommendations and resources for those interested in studying CCDPs in human clinical trials. The article allowed us to dispel misconceptions about the types of CCDP research FDA has reviewed over the years. This article aimed to provide a clear look into the clinical research involving CCDPs in the U.S. We also hope this article can assist researchers with developing their own CCDP clinical research programs. Below are some highlights from the article.
Cannabis Research & Drug Development
Pre-INDs and INDs provide a mechanism for those researching or developing a new drug to conduct studies in humans (clinical studies). When researchers submit INDs or pre-INDs for CCDPs to CDER, CDER reviews the proposed research like we do for any other product that will be regulated as a drug.
Cannabis products are complex mixtures that often have more than one active ingredient that may provide a therapeutic effect. CDER’s review teams consider the complexity of these products when assessing if an IND meets FDA’s requirements, regardless of the source of cannabis or any other botanical (plant-based) product under study in the trial(s). Currently, FDA is reviewing more than 150 active INDs that evaluate CCDPs, including related synthetics (human-made chemicals that produce similar effects as naturally occurring substances).
To date, FDA has not approved a marketing drug application for cannabis to treat a disease or condition. However, clinical investigations of cannabis-derived products have led to the isolation of a naturally occurring compound that has become an FDA-approved drug. In 2018, FDA approved Epidiolex to treat rare, severe forms of epilepsy. Epidiolex’s active ingredient is a naturally occurring cannabinoid (cannabidiol [CBD]) that has been isolated from the plant and highly purified. Also, it is important to note FDA is reviewing clinical research on CCDPs that include a complex mixture of compounds, which is different when compared to the single molecule formulation of Epidiolex (CBD).
Therapeutic Research Areas
Nearly all clinical review divisions in CDER’s Office of New Drugs have received at least one cannabis product application (IND or pre-IND). The clinical trials conducted or proposed for consideration under these applications evaluate the use of CCDPs for many different clinical indications (symptoms or medical conditions), and the CCDPs vary in formulation, potency, strength, and ROA. The clinical trials under the majority of CCDP INDs focus on four therapeutic areas:
- Addiction and pain medicine- 53%
- Neurology- 19 %
- Immunology and inflammation- 14%
- Psychiatry- 9%
Investigators have begun studying a wider variety of ROAs. In the 1970s and 1980s, much of the cannabis in clinical trials was inhaled via cigarettes, with a few oral product types. In the 1990s and 2000s, the types of oral product types increased, but inhalation via cigarette remained the primary ROA studied. However, in the 2010s the variety of product types being researched dramatically expanded to include an array of oral products, including baked goods, botanical extracts, capsules and tablets, oils, purified (or semi-purified) extracts, sweets (e.g., candies), tinctures, as well as vaporized products.
The diversity of ROAs and product types in clinical trials has continued to grow since 2020 and includes products for inhalation, oral ingestion, topical application, and injection. This is likely due to changes in cannabis users in the U.S. In recent years, individuals have transitioned from predominantly smoking dried cannabis flower to consuming other non-flower forms, such as edibles.
Guidance Documents to Support Cannabis Drug Product Research
FDA continues to support robust scientific research needed to develop new drugs from cannabis and is committed to encouraging the research and development of these new drugs through the IND and drug approval processes. To that end, we have published two guidance documents for industry:
- Botanical Drug Development. This 2016 guidance is intended to aid applicants in developing botanical drugs and provides the agency’s current thinking regarding growing conditions and manufacturing quality controls for botanical raw materials.
- Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research. This 2023 guidance reflects FDA’s current thinking on clinical research of human drugs containing CCDPs, with a focus on manufacturing high-quality drugs.
The Future of Cannabis Research and Drug Development
We predict FDA will continue to see an increase in INDs evaluating CCDPs. As we see more medical and non-medical programs at the state-level evolve, we expect there will be increased interest in clinical research to study CCDPs. With this, we also expect to see new, innovative products for evaluation under INDs. This may include the use of newly identified or less common cannabinoids, as well as other components of the cannabis plant, such as terpenes (natural occurring chemicals found in plants). Researchers may also begin to expand on their use of edible CCDP product types, as well as investigate new ROAs.
Over the course of 50 years, FDA has gained valuable experience by assessing more than 800 INDs that evaluate cannabis products. FDA recognizes the uniqueness of CCDPs, and the technical challenges associated with botanical drug development and research. The agency will continue to support sound, scientifically based research into the therapeutic uses of CCDPs and will work with companies interested in bringing safe, effective, and quality drugs to market through our drug development and approval process.