SUPPLEMENTARY INFORMATION:

In the Federal Register of April 3, 2019, FDA published a notice announcing a public hearing to obtain scientific data and information about the safety, manufacturing, product quality, marketing, labeling, and sale of products containing cannabis or cannabis-derived compounds. In addition, we notified the public that FDA was establishing a docket for public comment on this hearing. The information from the hearing and comments provided to the docket were solicited to help inform our regulatory oversight of these products and as an important step in our continued evaluation of cannabis and cannabis-derived compounds in FDA-regulated products. We asked that comments be submitted by July 2, 2019.

In response to requests for an extension of the comment period to provide additional time to develop meaningful and thoughtful responses to questions, on June 20, 2019, we published a notice that appeared in the Federal Register that extended the comment period for 14 days, until July 16, 2019.

In light of the continued interest and increased research activity in this space, as well as the need for additional scientific data on this topic, we have decided to reopen the comment period and extend it indefinitely to allow interested parties to continue to comment and to provide relevant data to the Agency on this subject. If, in the future, we decide to close the comment period, we will publish a Federal Register notice to that effect. This extension will allow stakeholders to continue to provide new and emerging information, in as close to real time as possible, as research in this area evolves.

We are particularly interested in data that may help to address uncertainties and data gaps related to the CBD. Studies that may help to address such uncertainties and data gaps may include, but are not limited to:

• The risk of liver injury from CBD,e.g., clinical studies to evaluate potential liver injury following long-term exposure of CBD in healthy populations and in people who may be more susceptible to CBD-induced liver injury ( e.g., due to preexisting liver disease), long-term (chronic), repeated dose studies in an appropriate animal model to determine the most sensitive liver toxicity endpoint, and to establish a no observed effect level (NOAEL), as well as studies to investigate the mechanism of liver injury;
• Toxicities of some of the active metabolites of CBD,e.g., animal toxicology studies of the major human metabolites such as 7-COOH-CBD, as well as pharmacology studies to fully characterize the binding profile and activity of major metabolites of CBD ( e.g., 7-OH-CBD, 7-COOH-CBD);
• Impact of CBD on the male reproductive system,e.g., long-term (chronic), repeated dose studies in an appropriate animal model to determine the most sensitive male reproductive toxicity endpoint and to establish a NOAEL, and studies to characterize the mechanism mediating CBD effects on the male reproductive system for the purpose of assessing human relevance;
• Effect of CBD co-administration with other medicines, alcohol, dietary supplements, tobacco products, and herbal products;
• Impact on neurological development,e.g., neurodevelopmental toxicology studies of CBD and 7-COOH-CBD to characterize the long-term functional impact of these compounds on the developing brain; addition of long-term neurodevelopment adverse outcomes in ongoing or future clinical trials of CBD to assess learning, cognition, and behavior;
• Sedative effects of CBD,e.g., studies to characterize the effect on driving performance and ability to operate heavy machinery due to CBD's sedative effects;
• Transdermal penetration and pharmacokinetics of CBD,e.g., methods development for the evaluation and assessment of dermal penetration of CBD;
• Clinical studies (including real world data/evidence) to address safety questions related to long-term sustained or cumulative exposure to CBD, including in vulnerable populations such as children, the elderly, and women who are pregnant or breastfeeding;
• Long-term (chronic) repeated dose toxicity studies in appropriate animal models, evaluating the most relevant toxicological end points (e.g., male reproductive toxicity and liver toxicity), to better characterize the potential long-term effects of CBD, with systematic reporting of relevant parameters including, but not limited to, histopathology, hematology and clinical chemistry analyses, testosterone and other hormone levels, and urinalysis;
• Clinical studies on the effect of different routes of CBD administration (e.g., oral, topical, inhaled) on its safety profile;
• Effect of CBD on pets and food-producing animals,e.g., animal studies that demonstrate the effect of CBD exposure in different target animal species, breeds, or classes, including information on the formation of residues in edible tissues of food-producing animals and safety of chronic exposure;
• Studies to characterize the potential for bioaccumulation of CBD over long-term exposure,e.g., appropriately designed absorption, distribution, metabolism, and elimination studies in appropriate animal models; and
• Effect of CBD on the eye,e.g., studies to determine if CBD is distributed into the eye following various routes of exposure, studies to characterize CBD's potential effect on intraocular pressure, and assessment of potential impacts in potentially sensitive populations such as patients with glaucoma.

85 FR 14206