Section 201(ff) of the FD&C Act defines dietary supplements to exclude products that contain active drug ingredients (ie, ingredients that have been approved under section 505 of the FD&C Act or have been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations have been made public). There are exceptions to this exclusion if the substance was marketed as a dietary supplement or a conventional food before it was approved or the new drug investigations were authorized, or if FDA creates an exception through notice and comment rulemaking. To date, FDA has never created an exception through rulemaking.
While many have criticized the agency as unwilling to ever issue such an exception to the exclusionary provision, the agency has recently suggested its willingness to do so in the case of N-acetylcysteine (NAC).
FDA’s longstanding position has been that NAC-containing products cannot be dietary supplements because they are excluded under the exclusionary clause of 201(ff). On March 31, 2022, the agency responded to two citizen petitions requesting reexamination of this position. FDA denied these petitions and maintained that the substance was excluded under 201(ff), but it also stated it will consider initiating a rulemaking under 201(ff) to allow NAC to be used in dietary supplements as long as no safety concerns are raised. Moreover, it issued a Final Guidance implementing an enforcement discretion policy for NAC products labeled as dietary supplements as long as those products would be lawfully marketed dietary supplements if NAC were not excluded from the definition of a dietary supplement and are not otherwise in violation of the FD&C Act.
Implications for CBD
The agency’s actions are significant beyond NAC products. This “exclusion” provision has become a hot-button issue in the cannabis space. Like NAC, FDA has determined that cannabidiol (CBD) cannot be added to products marketed as dietary supplements since CBD is an active ingredient in the approved drug Epidiolex. Those that seek to market CBD supplements have been asking FDA to create an exception for CBD. While the 201(ff) does not outline any criteria for undergoing rulemaking, the agency has maintained that it will not create such an exception unless and until it has the data to demonstrate that such a supplement can meet all other applicable provisions, including those relating to the safety of the dietary ingredients.
The agency’s actions around NAC demonstrate its willingness to act to allow dietary supplements to be marketed with active ingredients should the data indicate that they meet the safety standards for dietary ingredients. This should be a signal for those that want to market dietary supplements with CBD, the principal cannabinoid in hemp.
So how should the cannabis industry proceed under the existing statutory framework if it wants to sell dietary supplements containing CBD legally under the FD&C Act? The agency has provided a roadmap, but it is not without its roadblocks.
First, research is needed to fill in the data gaps. If the industry wants the same exception sought by manufacturers of products with NAC, the industry needs to have the data and other evidence to assure FDA that CBD can be safely used as a dietary ingredient. This includes determining a safe level for CBD in dietary supplements.
While the NDIN pathway is currently unavailable for CBD since FDA does not consider CBD products to be supplements, the industry should be looking to those standards if they want an exception. The agency has detailed information on its website outlining the types of data it expects to see, including in the 2016 draft NDIN guidance.
Furthermore, the agency has articulated the types of data it needs to address safety concerns around CBD specifically. These include data and information related to:
- Liver injury
- Drug interaction
- Male reproductive toxicity
- Sedative effects
- Cumulative exposure
- Effects on special populations (eg, elderly, children, adolescents, pregnant and lactating women)
- Information on “full spectrum” and “broad spectrum” hemp extracts (eg, how they are derived, content, how they compare to CBD isolates)
Second, once this data is available, proponents of these products should meet with FDA to demonstrate the safety concerns have been addressed. The agency has indicated it is open to such meetings and can provide feedback on the studies and data, even if the NDIN pathway is not formally available.
Third, if the data can meet the safety standard for an NDI, the proponent should submit a petition to the agency to create a regulatory exception under 201(ff) that includes all the safety data that would be needed for a successful NDIN notification.
While the industry has been frustrated by the agency’s lack of movement in this area, FDA maintains that it is treating CBD as it would any other ingredient under the existing statute. The agency would say that pathways for cannabis products currently exist. Unfortunately, these pathways are challenging for the cannabis industry.
If the industry cannot meet existing regulatory standards, then a legislative change is necessary to create an alternative pathway for CBD and/or cannabis products. And that, of course, is also an option, particularly in light of the growing number of states legalizing cannabis and the Biden Administration’s October 6 Statement on Marijuana Reform, which indicates an openness to changes at the federal level.