From Seed to Study Subject: New Draft Guidance From the FDA and Four Takeaways for Using Cannabis in Clinical Trials

By Helen Goldstein, Angela L. Perez, William F. Mulholland, II and Joshua Schneiderman

Earlier this week, the U.S. Food and Drug Administration (FDA) released draft guidance on the use of cannabis and cannabis-derived compounds in clinical research. This guidance represents an important step towards normalizing the cannabis industry among its traditional pharma rivals. It also provides helpful direction to those who are already conducting research involving cannabidiol, otherwise known as CBD.

The guidance provides a number of helpful and practical considerations for those looking to advance clinical research and drug development in this field, several of which are highlighted below. 

1. Make an Early Determination as to Whether the Candidate Is or Will Be a Controlled Substance

As a result of the 2018 Farm Bill, there are two federally recognized types of cannabis – hemp and marijuana. Cannabis is classified as hemp, which is not a controlled substance, if it contains no more than 0.3 percent by dry weight of the compound delta-9 tetrahydrocannabinol (THC). Exceed that threshold and the cannabis is considered marijuana, a Schedule I controlled substance under the Controlled Substances Act.

In the new guidance, the FDA clearly states that “[c]annabis under the 0.3 percent delta-9 THC limit may be used for clinical research,” but also warns that “intermediates or drug products that contain greater than 0.3 percent delta-9 THC by dry weight, even if the starting materials meet the definition of hemp, may no longer meet the definition of hemp and may be considered a Schedule I controlled substance.”

The FDA, therefore, suggests that sponsors and investigators “calculate the level of delta-9 THC in their proposed investigational drug product early in the development process to gain insight into the potential control status of their product.”  The guidance even goes so far as to suggest the method by which researchers measure the level of delta-9 THC in intermediates, by-products and finished products. 

Adhering to this guidance may save time and money and reduce risk. Where the investigational drug product remains, at all times, below the THC threshold, the stricter DEA requirements do not apply. However, if the investigational drug product exceeds, at any point, the THC threshold, timely compliance efforts can help avoid expensive and potentially criminal consequences in the form of violations of the Controlled Substances Act.

2. Recognize the Challenge of Botanicals and Identify Suitable Vendors to Assist in Manufacture and Testing

Cannabis is a botanical and, in general, clinical research and development of botanicals poses many challenges. To date, there are only a handful of botanicals that have successfully navigated the FDA approval process resulting in an approved drug. One reason is that there can be substantial natural variation in the concentrations of active constituents in botanical raw material. With respect to the cannabis plant, the levels of cannabinoids, terpenes and flavonoids can be greatly affected by location of cultivation, types of soil, methods of farming and climate. The FDA has specific guidance on botanical drug development, which provides substantial detail on the Agency’s expectations.

In the new guidance, the FDA provides additional cannabis-specific recommendations aimed at addressing challenges such as the variability of the starting material.  For example, the guidance emphasizes the importance of “adequate characterization of cannabis and cannabis-derived compounds, for example via a chemical fingerprint,” to ensure batch-to-batch consistency.  The guidance also stresses the FDA’s general view that, due to the inherent variability of botanicals, data contained in published studies regarding the chemical composition of test materials is insufficient for bridging to a proposed botanical drug product and the FDA therefore recommends that sponsors establish a full toxicology program to support development of a cannabis or cannabis-derived compound for phase 3 trials and beyond.

In keeping with the foregoing recommendations, it is crucial for those engaged in drug development involving cannabis to identify and engage skilled vendors, initiate process development work and begin addressing manufacturing and quality control challenges early in the drug development cycle.

3. Secure Cultivation Sites and Farmers with Sufficient Experience and Expertise

With respect to botanicals generally, the FDA suggests that “[t]he sponsor should establish large growing regions with three or more cultivation sites or farms whose locations are purposefully selected to be representative of the regions for each of the botanical raw materials following the principles of Good Agricultural and Collection Practices.” 

These suggestions technically apply to cannabis; however, the federal THC threshold makes selection of cultivation sites particularly challenging.  In particular, there is only one source of cannabis over the 0.3 percent delta-9 THC limit that is considered legal under federal law, the National Institute on Drug Abuse Drug Supply Program.  Accordingly, those desiring to engage in clinical research involving cannabis must source the material from the NIDA DSP or rely on producers who aim to remain below the 0.3 percent threshold. 

The U.S. Drug Enforcement Administration (DEA) is currently in the process of allowing additional growers to register with the DEA to produce and distribute cannabis for research purposes. Despite all its encouragement of cannabis research, however, there is no suggestion in the guidance that the FDA will allow clinical trials using drug product exceeding the THC threshold that is sourced from non-DEA registered cultivations, even if the cultivation is permitted under state law.

Cultivating hemp under the 0.3 percent delta-9 THC limit also comes with its own unique challenges. The new guidance directs attention to the U.S. Department of Agriculture’s (USDA) interim final rule, “Establishment of a Domestic Hemp Production Program” that provides sampling and testing methods for evaluating the level of delta-9 THC in a cannabis botanical raw material. Some states have enacted local regulation that, if approved by the USDA, must match or exceed these testing requirements. Hemp cultivation is complicated by the fact that the genetics of any given cannabis seed is not the sole determinate of whether the resultant crop can be successfully tested and harvested before exceeding the 0.3 percent threshold (known in the hemp industry as “going hot”); the timing of harvest and other botanical variables such as soil profile and climate all are crucial factors. A farmer’s knowledge of and experience with this USDA testing regime, which occurs before harvest, can help when attempting to produce biomass that meets regulatory requirements.

Counsel can assist in conducting due diligence of hemp and marijuana cultivators to assess their sophistication and qualifications. Once the cultivators have been selected, counsel can assist in establishing the contractual relations and securing ancillary services.

4. Identify and Work Effectively with All Interested Agencies

While the FDA is involved in any clinical research, research with cannabis will necessarily involve the DEA if it is over the THC threshold. Additionally, the DEA may approve, on a federal level, marijuana cultivation sites in states and localities where such activity is already permitted.  In this case, state and local regulation may also control.  In California, for example, regulations promulgated by both the California Department of Food and Agriculture and the local authority control marijuana cultivation.

If under the THC threshold, those involved in cultivation of hemp biomass will be subject to regulation by state departments of agriculture or, in the absence of a state hemp program, the USDA.

Regulatory compliance in the cannabis field starts from seed and runs through to study subject. Depending on the needs of the client, counsel can assist in managing these agency relationships and support efforts to secure all necessary licenses, permits and approvals. 

Snell & Wilmer’s cannabis and life sciences groups welcome this new guidance. With attorneys whose work spans both of these industries, Snell & Wilmer would be happy to consult with pharma and biotech companies, as well as other medical researchers, looking to engage in research in this emerging area.

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