FDA Draft Guidelines for Cannabis and Cannabis-Derived Compounds
On July 21, 2020, the FDA issued draft guidance, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research, Draft Guidance for Industry,” which provides insight into the FDA’s current thinking on clinical research related to drugs containing cannabis or cannabis-derived compounds. The guidance addresses the following topics described in more detail below: 1) sources for cannabis for clinical research, 2) information and resources for quality considerations, and 3) recommendations for information to include in investigational new drug (IND) applications, including THC calculations.
In short, this FDA guidance assures the research community that cannabis-products containing less than 0.3% delta-9 THC sourced outside of the NIDA Drug Supply Program (DSP) may be used in clinical research, however how to calculate and differentiate between products containing less than 0.3% delta-9 THC and those containing more remain a challenge.
- Sources of Cannabis for Clinical Research
In light of the changes made by the 2018 Farm Bill, the FDA states that for clinical research involving cannabis under the 0.3% delta-9 THC limit, researchers may obtain cannabis from sources outside of the NIDA DSP to conduct research. The NIDA DSP remains the only domestic federally legal source of cannabis over the 0.3% delta-9 THC limit.
- Quality Considerations
In the guidance, the FDA provides suggested resources for quality considerations that a company would need to take into account when preparing an IND for a drug containing cannabis or a cannabis-derived compound. Examples of resources include:
- Current Good Manufacturing Practices
- For Phase 1 Investigations: Current Good Manufacturing Practice for Phase 1 Investigational Drugs
- For Phase 2 and 3 Investigations and Marketed Products: 21 CFR Part 210 and 21 CFR Part 211
- Quantitative Data Regarding Phytochemicals Including Cannabinoids, Terpenes and Flavonoids
With reference to considerations specific to drugs containing cannabis and cannabis-derived compounds, the FDA recommends adequate characterization of cannabis and cannabis-derived compounds to ensure batch-to-batch consistency, quality tests for microorganisms and impurities, and applicable CSA drug scheduling considerations. The FDA cautions new drug application applicants to not rely on published literature in place of a full toxicology program to support development of a botanical drug product for phase 3 trials and beyond. The FDA further recommends container-closure system and combination product considerations, as needed.
- IND Application
The FDA recommends that companies provide qualitative laboratory data and detailed testing methods, including testing methods to evaluate the level of delta-9 THC, in particular for phase 2 and 3 studies and marketing applications, which may differ depending on dosage form.
FDA Approves Epidiolex for New Condition That Causes Benign Tumors, Seizures
On July 31, 2020, the FDA approved Epidiolex oral solution for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients one year of age and older. Epidiolex was previously approved for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. Note that Epidiolex, which had previously been scheduled as Schedule V, is no longer a controlled substance.
Other FDA News
On July 22, 2020, the FDA submitted a draft guidance titled “Cannabidiol Enforcement Policy” to the White House Office of Management and Budget for review. The FDA has yet to issue any official statements providing additional details regarding the draft guidance.
- Scientific Conference on November 19, 2020: CBD and Other Cannabinoids: Sex and Gender Differences in Use and Responses
- Product-Specific Guidance for Generic Drug Development: Draft Guidance on Cannabidiol Oral Solution
DEA’s Interim Final Rule
On August 20, 2020, the Drug Enforcement Administration (DEA) published an Interim Final Rule on industrial hemp and hemp derivatives, which immediately went into effect, to conform DEA regulations with the Agriculture Improvement Act of 2018 (the 2018 Farm Bill). The most significant change in this Interim Final Rule is that it modifies 21 CFR 1308.11(d)(58) by stating that the definition of “Marihuana Extract” is limited to extracts “containing greater than 0.3 percent delta-9-tetrahydrocannabinol on a dry weight basis.” This means that researchers working with cannabis and cannabis-derived products that contain less than 0.3% delta-9 THC do not need to obtain a Schedule I registration. In this regard, there is no longer the need to complete the analysis of whether a product was derived from the hemp plant or marijuana plant, but rather now the delineation for a product derived from a cannabis plant is if the product itself contains less than or greater than 0.3% delta-9 THC. Conversely, if a product is derived from the hemp plant (a plant that contains less than 0.3% delta-9 THC) but through processing and extraction contains more than 0.3% delta-9 THC, it will be considered a Schedule I substance and thereby require a Schedule I registration.
In addition, the DEA took several other steps in the interim final rule towards the deregulation of hemp:
- Adding language clarifying that hemp-derived “tetrahydrocannabinols” that contain 0.3% or less THC are not Schedule I and, in fact, are not controlled unless specifically controlled elsewhere under the Controlled Substance Act. Note, though, that the IFR explicitly stated that this exclusion applies only to naturally occurring constituents of the hemp plant – i.e., “ For synthetically derived tetrahydrocannabinols, the concentration of Delta-9 THC is not a determining factor in whether the material is a controlled substance. All synthetically derived tetrahydrocannabinols remain schedule I controlled substances.”
- Removing from Schedule V a “drug product” in an FDA-approved finished dosage formulation that contains cannabidiol (CBD) and no more than 0.1 percent (w/w) residual tetrahydrocannabinols (e.g. Epidiolex).
- Removing DEA import and export controls for hemp extract that does not exceed the statutory 0.3% THC limit.
Note that while the aspect of the interim final rule clarifying that cannabis-derived products containing no more than 0.3% THC are not controlled should be helpful to researchers who want to work with substances like plant-derived CBD, since they will no longer need to obtain a Schedule I DEA registration to simply conduct research with the product, the aspect of the rule specifying that even hemp-derived products are Schedule I if they contain greater than 0.3% THC is of concern to a number of commenters, particularly in the hemp industry, who have noted that high-THC byproducts may be produced in the course of processing hemp. That concern is noted (along with a request for clarification about the status of synthetic cannabinoids) in the comment letter submitted by COGR on behalf of the research university community. This concern is one of the bases for a lawsuit that has been filed by a hemp industry organization, which is challenging DEA’s Interim Final Rule as exceeding DEA’s authority and failing to follow proper administrative rulemaking procedures.
H.R. 8337, Continuing Appropriations Act, 2021 and Other Extensions Act
This year’s continuing appropriations bill included language extending (until September 20, 2021) the repeal date of Section 7606 of the Agricultural Improvement Act of 2014, which is the section of the 2014 Farm Bill on the “Legitimacy of Industrial Hemp Research” which authorized cultivation of hemp for research purposes by institutions of higher education and state departments of agriculture under hemp “pilot programs.” Under the 2018 Farm Bill, that authorization had been set to expire by October 2020 (after which all hemp cultivation was to have been conducted in compliance with a USDA-approved state regulatory plan or under a USDA-issued license). This means that even prior to USDA’s approval of California’s hemp production plan, institutions of higher education are still permitted to cultivate hemp for research purposes.
California Hemp Regulations
California has submitted a State Plan to the USDA for review of its hemp rules. The final approved State Plan will be available on the USDA website.
SB 864 (Wilk) Industrial Hemp: Lab Test Reports
While there are no specific concerns with SB 864, we have been working with the author’s office and the CA Department of Food and Agriculture (CDFA) to use SB 864 as a vehicle to pursue a technical fix to Food and Agricultural Code (FAC) Section 81004.5(2)(c)(ii), which was added by Senator Wilk’s industrial hemp legislation last year (SB 153). The concern is that FAC Section 81004.5(2)(c)(ii) requires testing of all cultivated industrial hemp plants rather than a sample.
SB 864, as currently drafted, allows commercial entities to test a sample rather than all plants (see 81006(e)(3)). We are requesting to align requirements of university research and commercial hemp grower activities. If the issue is not fixed, it could be problematic for the researchers who commit funding and effort to conduct work only to have to destroy all of their plants. Unfortunately, this bill failed in session but we will continue to pursue this fix any way we can.