FDA's Guidance on Quality Considerations for Clinical Research with Cannabis

Following the draft guideline published in 2020, the FDA now released the final version of the document. The guidance provides the agency´s current thinking on several topics relevant to clinical research with cannabis containing human drugs (i.e., any cannabis product marketed with a claim of therapeutic benefit, or with any other disease-related claim). The document also explains key FDA regulatory concepts to stakeholders who may be less familiar with FDA regulations than other drug developers.

Cannabis and cannabis-derived compounds that may be used in manufacturing human drugs include

• botanical raw materials,
• extracts,
• highly purified substances of botanical origin.

The guidance does not address development of fully synthetic substances, sometimes known as cannabis-related compounds, which are regulated like other fully synthetic drugs.

If a device is to be used in combination with a drug (e.g., a vaporizer), the product is considered to be a combination product and must comply with the cGMP requirements in 21 CFR part 4, including requirements for Design Controls. The evaluation of extractables & leachables, including identification of qualification thresholds, should be consistent with the relevant USP chapters.

How to calculate the delta-9 THC content

According to the documents, calculating the delta-9 THC content may provide sponsors and investigators with information about the control status of a raw material, intermediate, drug substance, or drug product. However, they should not rely on the 0.3 percent delta-9 THC by dry weight threshold when evaluating THC as impurity for the purposes of quality control and application submission. In general, the percentage of delta-9 THC in botanical raw materials is calculated as the total amount of delta-9 THC (i.e., THCA + THC) naturally present in the material relative to the dry weight prior to extraction or other manufacturing steps. However, this type of dry weight calculation has limited utility for intermediates such as solutions and for finished products of various dosage forms. Therefore, the FDA recommends to base the calculation of total delta-9 THC percentage on the composition of the formulation with the amount of water removed (including any water that excipients may contain).

More information is available in FDA´s final guidance Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research.