FDA took two important steps last week to clarify the regulatory landscape for cannabis products, including CBD products. First, FDA issued a draft guidance on Quality Considerations for Clinical Research Involving Cannabis and Cannabis Derived Compounds. This guidance builds off of earlier guidance FDA has issued about the quality and regulatory considerations that govern the development and FDA approval of cannabis and/or cannabinoid drug products. See e.g., here and here. The draft guidance iterates a federal standard for calculating delta-9 THC content in cannabis finished products, which addresses a significant gap in federal policy regarding those products. While the testing standard is neither final nor binding on FDA or DEA, when finalized it would iterate what FDA considers to be a scientifically valid method for making the determination of whether a cannabis product is a Schedule I controlled substance. Therefore, it may be useful in many contexts, including federal and state cannabis enforcement actions. We encourage affected parties to file comments on FDA’s Guidance, which they may do until September 21, 2020.
Second, FDA sent to the Office of Management and Budget for review a proposal on how FDA intends to exercise enforcement discretion over CBD consumer products. See here. While the contents of this guidance have not yet been made public, we forecast that it likely will align with FDA’s past enforcement actions and memorialize the agency’s intent to pursue enforcement actions against CBD consumer product companies that make egregious claims about their products treating or preventing serious diseases or conditions.
Guidance on Considerations for Cannabis Clinical Research
FDA’s guidance recognizes that Congress’s enactment of the Agricultural Improvement Act of 2018 (“2018 Farm Bill”) improved domestic access to pre-clinical and clinical cannabis research material that may be used in the research and development of novel therapies. However, currently marijuana only may be obtained domestically from the University of Mississippi under contract with the National Institute on Drug Abuse. While DEA issued a policy in 2016 to allow for the additional registration of marijuana cultivators for legitimate research and licit commercial purposes, the Office of Legal Counsel in June 2018 issued an opinion finding that such policy violates the United States’ obligations under applicable treaties. However, in March of this year, DEA issued a proposed rule to allow for the registration of additional cultivators of cannabis for these licit purposes. See here.
There is an alternative pathway to the procurement of Schedule I research material which FDA’s guidance does not mention: importation. Researchers may obtain certain Schedule I material pursuant to a federal DEA Schedule I importer registration, and DEA has in the past issued such registrations. See 21 CFR 1301.13(e)(1)(viii).
As FDA recognizes, primary authority for the regulation of controlled substances, including marijuana, lies with DEA. Therefore, throughout its guidance, FDA encourages sponsors to engage with DEA at various points in the drug development process, including at the pre-clinical stage, to assess the scheduling status of their investigational products, to the extent that is unknown.
FDA’s guidance also touches upon myriad clinical and quality considerations that product sponsors should make when developing botanically-derived cannabis drug products. FDA’s guidance does not address the development of synthetic drug products containing cannabinoids, as those products are governed by FDA’s existing guidance and principles regarding those products. A few critical components of FDA’s guidance include the following:
- Sponsors should ensure that, as with any IND, the application demonstrates that the drug product can be manufactured consistently with the same quality, and sufficient related data to support this must be provided. Demonstration of “batch-to-batch consistency” will be an important characteristic for drug products containing cannabis or cannabis-derived compounds.
- FDA will pay particular attention to the types of phytochemicals present in the drug product, such as cannabinoids, terpenes, and flavonoids; marketing applications should include a description of analytical methods used. In addition, FDA will consider tests for residual pesticides to be part of the drug development process.
- FDA identifies the known issue of disproportionate metabolism when it comes to a human’s ability to metabolize cannabidiol (“CBD”) compared to animals. FDA also reminds sponsors that devices (g., inhalers) used in combination with a drug are considered combination products and must meet specific cGMP requirements.
Another important component of the draft guidance is FDA’s recommendation for calculating percent delta-9 THC by dry weight, which was not addressed by the 2018 Farm Bill and has not since been publicly clarified by FDA, DEA, or the US Department of Agriculture. FDA’s guidance proposes that calculation be made as follows:
For a solution-based material (intermediate, in-process material, or final drug product):
- Determine the density of the liquid formulation and convert 1 mL of the formulation to mass units (mg).
- Calculate water content (in mg) of each active and excipient component present in 1 mL of the formulation.
- Sum the water content (in mg) for all components present in 1 mL of the liquid formulation and subtract this amount from the total mass of 1 mL (from step 1). This is the water-adjusted total mass of 1 mL of the formulation.
- Calculate the mass, or mg amount, of delta-9 THC present in 1 mL of the liquid formulation.
- Calculate the percentage delta-9 THC by dividing the mass of delta-9 THC from step 4 by the total water-adjusted mass in step 3 and multiplying by 100.
For a solid oral dosage form (e.g., tablet or capsule):
This percentage is similarly calculated and would be the weight of delta-9 THC in the dosage unit divided by the total water-adjusted formulation weight multiplied by 100. For oral capsules, the mass of the capsule itself should not be included in the denominator weight. Include only the capsule fill. The water-adjusted formulation weight used in the calculation should reflect the removal (in mass units such as mg) of all water content present for each of the components, whether active or inactive, in the formulation.
While FDA recommends sponsors submit documentation regarding the steps of this calculation when they submit an IND, it clarifies that this recommended calculation should not be used for other purposes such as chemistry, manufacturing, or controls. However, FDA’s articulation is a significant step in closing the gap on having a federally established, scientifically valid method for determining whether a product will be a Schedule I controlled substance. Therefore, the cannabis industry should review this standard closely and critically, and consider offering comment to the agency.
Guidance on FDA’s Exercise of Enforcement Discretion Regarding CBD Consumer Products
This guidance likely will have a more immediate and direct impact on the cannabis industry, in particular the CBD consumer product industry. We believe it will highlight how and whether FDA intends to exercise enforcement discretion over the panapoly of CBD products in the marketplace. Historically, FDA has chosen not to pursue enforcement actions, e.g., the issuance of Warning Letters, seizures, or injunctions, against companies who marketed CBD consumer products that do not make therapeutic claims about treating or preventing serious diseases and conditions. While we can’t say with certainty, we expect FDA’s guidance to align with this historic approach. We will continue to monitor FDA’s issuance of this guidance and provide an update as soon as it clears OMB review.
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