Tag: clinical research

FDA Finalizes Cannabis Guidance Focusing on Clinical Research and Quality Considerations

On January 23, 2023, the U.S. Food and Drug Administration (FDA) issued its final guidance, “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research” (the Final Guidance). The agency outlines current recommendations for drug sponsors developing cannabis and cannabis-derived compounds for use in human drug clinical research. Cannabis and cannabis-derived compounds include botanical raw materials, extracts, and highly purified substances of botanical origin.[i] FDA published the draft version of the guidance in July 2020 and received 60 public comments. Below, we outline key points from the Final Guidance.

Background

  • The Agriculture Improvement Act of 2018 (Public Law 115-334), known as the 2018 Farm Bill, removed “hemp” from the definition of “marihuana” under the Controlled Substances Act (CSA). Now, hemp is not considered a controlled substance. “Hemp” is defined in the 2018 Farm Bill as including cannabis and derivatives or extracts of cannabis with no more than 0.3% by dry weight of the compound delta-9 tetrahydrocannabinol (THC). The Drug Enforcement Administration (DEA) still regulates as Schedule I controlled substances those botanical raw materials, extracts, and derivatives that contain cannabis or cannabis-derived compounds with delta-9 THC content above 0.3% by dry weight.
  • Cannabis and cannabis-derived compounds – even those meeting the 2018 Farm Bill’s definition of “hemp” – are typically subject to the same FDA clinical research regulatory requirements and standards as human drug products containing other substances.

Cannabis Sources and Quality Considerations

  • Sponsors may use cannabis (including hemp) in human drug clinical research if FDA deems the cannabis to be of “adequate quality.” The agency will review quality issues in the context of an investigational new drug (IND) application.
  • Historically, the National Institute on Drug Abuse (NIDA) Drug Supply Program (DSP) was the only domestic, federally legal source of cannabis for clinical research. That is no longer the case. Human drug sponsors may now source cannabis regulated as a Schedule I controlled substance from other DEA-authorized growers.
  • Human drug sponsors should consider the recommendations in FDA’s final guidance, “Botanical Drug Development” (Dec. 2016). Importantly, the agency does not recommend relying on published literature as a substitute for data from a full toxicology program to support drug product development for phase 3 clinical research (and beyond). Dedicated toxicology studies are specifically recommended for 7-COOH-CBD, the major human metabolite of cannabidiol.

CSA Controlled Status

  • When a drug sponsor submits an IND to FDA as part of cannabis-related human drug clinical research, the sponsor should determine the potential controlled substance status of any botanical raw materials, drug substances, and drug products by taking into consideration the delta-9 THC content. The agency encourages sponsors to calculate the delta-9 THC content in the proposed investigational product early in the drug development process and to consult with the DEA.
  • Generally, the delta-9 THC percentage in botanical raw materials is calculated as the amount of delta-9 THC (and THCA) naturally present in a material sample relative to the sample’s dry weight prior to extraction or other manufacturing steps. For intermediates or finished products containing cannabis or a cannabis-derived compound, sponsors should calculate the total delta-9 THC percentage using the composition of the formulation with the amount of water removed (including water contained by excipients). These calculations should not be used for other purposes (e.g., Chemistry Manufacturing and Controls (CMC)).
  • FDA may have concerns with drug abuse liability. As part of the agency’s review of a new drug application (NDA), FDA may conduct an abuse potential assessment. Such an assessment could impact drug product labeling as well as DEA scheduling or rescheduling.

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FOOTNOTES

[i] Fully synthetic versions of substances occurring in cannabis (e.g., dronabinol) fall outside the Final Guidance’s scope.

Still Waiting for Guidance on Informed Consent of Decisionally-Impaired Subjects

A July 11, 2012 article by Gina Kolata in the New York Times describes a recent discovery of a rare gene mutation that protects people from Alzheimer’s disease by slowing the production of beta amyloid.  Excessive amounts of beta amyloid in the brain are believed to cause Alzheimer’s.  The discovery bolsters hope that drugs, currently in development, that reduce levels of brain amyloid will prove effective in slowing the progression of Alzheimer’s.

The lack of clear guidelines for enrolling in clinical research decisionally-impaired subjects, or those who may become impaired over the course of a study  may hinder efforts to conduct trials of Alzheimer’s drugs.  In 2010, an Institute of Medicine summary  of a workshop on the state of clinical trials in the United States noted that 27% of investigators in the U.S. failed to enroll any subjects in trials in which they agreed to participate, and 90% of all clinical trials worldwide fail to enroll the target number of subjects on time and must extend their enrollment periods.  Though the federal Office for Human Research Protections and the Secretary’s Advisory Committee on Human Research Protections have considered the issue of participation of decisionally-impaired subjects in research in recent years, no guidance has been released.  Further, few states’ laws explicitly address who has authority to consent to research participation on behalf a decisionally-impaired individual.

In the absence of clear guidance, to be in the best position to participate in Alzheimer’s research and other research involving subjects who are or may become decisionally-impaired, institutions and their IRBs should develop their own policies on enrollment of and consent for decisionally-impaired subjects and subjects whose capacity may diminish over the course of a study.  Having policies in place before opportunities to participate in such studies arise will help ensure consistent and efficient review by institutions and IRBs.  Individuals who have a strong interest in participating in Alzheimer’s research studies should complete health care power of attorney documents, record their wishes in writing, and discuss them with their designated health care agents.

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