Institute of Good Manufacturing Practices India®

USFDA furnishes new guidelines on quality considerations for clinical research with Cannabis and Cannabis-derived compounds


Cannabis is the genus of the plant belonging to the Cannabaceae family. The three main species of Cannabis are C. sativa L., C. indica, and C. ruderalis. These species are used to extract Cannabidiol for several applications. A major type of C.sativa L., hemp, is commonly referred to as marijuana. Marijuana comprises a higher concentration of the psychotropic compound (tetrahydrocannabinol or THC) and is chemically termed as cannabinoids or CBD.

Drug products comprising a synthetic form of THC (dronabinol) have been approved by the USFDA for nearly decades. Cannabis-derived CBD drug Epidiolex® is the first drug candidate to get its USFDA approval in 2018.

As per The Agriculture Improvement Act of 2018 (the 2018 farm Bill), hemp and it's corresponding products must have THC content 0.3% or less.

The USFDA has issued a new guideline on the quality considerations of cannabis for performing clinical studies that covers:-

  •  The sources of cannabis for clinical trials.
  •  Information on quality considerations, and
  •  Recommendations regarding calculating tetrahydrocannabinol (THC) levels.

The guidance also mentions the regulatory considerations for the stakeholders who are unaware about the FDA and FDA authorities. The guidelines also clarify that the same regulations should be considered for any other botanical raw material, botanical drug substance, or botanical drug product.

The Source:-

Activities such as growing and manufacturing of Cannabis to be used as an Investigational medicinal product must comply with CSA (Controlled Substance Act) and DEA (Drug Enforcement Administration) if the limit exceeds  0.3%∆-9 THC by dry weight. Currently, the NIDA DSP (National Institute on Drug Abuse/ Drug Supply Program) is the only federal legal source of cannabis to exceed over 0.3 % ∆-9 of THC limit for a clinical trial. The range below the 0.3% Δ-9 THC may be used for clinical research by others.

Quality Specifications:-

The sponsors will have to submit information regarding the identity, quality, purity and potency or strength of the Investigational medicinal plan. They also need to fulfill the essential requirements for botanical drugs provided in FDA’s guidance for industry Botanical Drug Development.

Devices and Packaging

If a combinational therapy is administered to the patient via a device such as an inhaler, it is considered as a combination product and must comply with the cGMP requirements as mentioned in 21 CFR part 4 stating requirements for design controls.

The selection of the packaging system should be done carefully including adequate characterization and safety assessment of extractables and leachables as per the FDA’s Guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics.

Percent of ∆-9 THC Calculation

The percent ∆-9 THC should be conducted at an early developmental phase to determine the potential control status of the product. The calculation of percent ∆-9 THC is based on the composition of the formulation with the amount of water removed. However, for "either solutions or solids, use of the proposed or established specifications for the upper limit of water content for excipients that contain water, as opposed to a measured result from a sample, maybe acceptable and would be a matter for review". 

Furthermore, applicants should also provide the following information:

  • quantitative data, such as a certificate of analysis (CoA) from a laboratory described in the USDA interim final rule,
  • detailed descriptions of analytical methods (for phase 2 - 3 studies and marketing applications),
  • calculations for the reporting levels of Δ-9 THC based on rounding rules provided in USP´s General Notices and Requirements.

This guidance, however, does not address the development of fully synthetic versions of substances that occur in cannabis, sometimes known as cannabis-related compounds, which are regulated like other fully synthetic drugs. This guidance is limited to the development of human drugs and does not cover other FDA-regulated products.