After a four-year review by FDA’s cannabis working group focused on whether cannabidiol could be regulated not as a drug but as a dietary supplement, the regulator today announced that it could not permit CBD to be regulated as a supplement due to significant safety concerns and uncertainties. Instead, FDA is asking Congress for help to design a fit-for-purpose regulatory pathway for CBD. It’s a decision that’s likely to raise significant questions for FDA, including about its time management, risk assessment process and whether relying on Congress will lead to a preferable outcome.
First, some background on cannabidiol and how it’s regulated.
- Cannabidiol (CBD), a biologically active chemical compound derived from the Cannabis sativa plant, significantly benefited from the passage of the 2018 Farm Bill. Prior to this, the Controlled Substances Act (CSA) considered hemp—a variety of the Cannabis sativa plant from which high concentrations of CBD can be obtained—and marijuana to be the same. This meant that prior to the passage of the 2018 Farm Bill, hemp and its derivatives were considered Schedule I substances under the CSA.
- However, the Farm Bill created a new definition for hemp and marijuana, allowing hemp to be removed from the CSA and facilitating an explosion in commercialization of CBD products. Specifically, hemp was defined as: “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol (THC) concentration of not more than 0.3 percent on a dry weight basis.”
- For the FDA, this change has created novel challenges. According to the agency, hemp products like CBD “must meet any applicable FDA requirements and standards, just like any other FDA-regulated product.” And as companies wishing to market CBD products have discovered, there are several FDA requirements that are proving especially cumbersome.
- Specifically, FDA does not recognize CBD as a legal dietary ingredient for the purpose of dietary supplements, or a legal food ingredient, since the 2019 approval of GW Pharma’s Epidiolex CBD formulation to treat some forms of childhood epilepsy. As a result, any company now marketing a CBD product without FDA’s express permission is doing so illegally.
- But the FDA has indicated that it wants to create a regulatory pathway for certain CBD products to be legally marketed. Since at least 2019 the FDA has indicated that it intends to make use of a legal provision that would permit companies to market CBD as a dietary ingredient under certain circumstances. Since that time the FDA has released guidance on cannabis quality, as well as product-specific guidance to facilitate development of CBD generics. Additionally, the agency has released a report on CBD products, funded CBD research and held a public meeting on cannabinoids, among other actions.
- In July 2020, FDA took a major step and finished work on a draft guidance document that would create a new “enforcement policy” for CBD products. That guidance, Cannabinoid Enforcement Policy, is thought to contain FDA’s position that regulators won’t consider certain CBD products to be violating federal law – but only if they meet specific conditions. However, the draft guidance was later withdrawn from development and was never released.
There’s more to the story on the dietary supplements side.
- The Dietary Supplement Health and Education Act of 1994 (DSHEA) established the framework for regulation of dietary supplements. Under DSHEA, manufacturers are responsible for ensuring their products are safe and any claims made are substantiated with evidence. Sponsors of dietary supplements may only make claims that their products affect the structure or function of the body and may not make any claim that a supplement is effective at treating or preventing a specific disease. These products do not need approval prior to being marketed – unless they contain a new dietary ingredient (provided they meet other requirements).
- Sponsors of a New Dietary Ingredient (NDI) – defined as a dietary ingredient not marketed before October 15, 1994 – or a dietary supplement containing an NDI are required to submit what is known as a Premarket Safety Notification to the FDA at least 75 days prior to marketing the product. These applications are more commonly referred to as New Dietary Ingredient Notifications, or NDINs. The application must contain information including the amount of the NDI present in a dietary supplement, the proposed conditions of use, evidence to establish the safety of the product (such as evidence regarding a product’s history of use) and proof of a product’s identity.
- In the 75 days between submitting information and marketing, the FDA’s Office of Dietary Supplement Programs (ODSP) will review the information provided in the premarket safety notification (also called new dietary ingredient notifications, or NDINs). The agency will then respond to the sponsor of the NDIN with either of two responses: An acknowledgement letter accepting the notification, or with a letter stating that the NDI cannot be used in dietary supplements at this time due to problems with the NDIN in its current form.
- Some substances are not permitted to be defined as dietary supplements under 21 USC section 321(ff)(3)(B), including substances defined as new drugs under 21 USC Section 355 or substances subject to prior clinical investigations preceding the marketing of the substance as a dietary ingredient.
We mention this because several organizations have previously sought to have FDA permit CBD to be marketed as a dietary supplement.
- For example, the Natural Products Association (NPA) asked the FDA in February 2022 to either determine that CBD is not excluded from the definition of a dietary supplement under 21 CFR Part 190.6, or that the agency exercise enforcement discretion “in a specific and selective manner over CBD products” after it conducts a safety review of the notification of an individual dietary supplement product. NPA is submitting the petition on behalf of cbdMD, a firm that is ready to submit its NDIN dossier for a CBD product to the FDA.
- In the alternative, NPA suggested that FDA ask the Department of Health and Human Services to issue a regulation specifying that CBD is lawful under DSHEA. Issuance of such a regulation is one of two paths to an exception to 21 USC Section 201(ff)(3)(B); the other exception is made when the article in question “or any other compound containing the article as its active moiety” was already being marketed as a dietary supplement or food before its investigational new drug (IND) authorization. (More about this later.)
- The crux of NPA’s argument here is that CBD is not new. As previously noted, dietary ingredients (and supplements) marketed before the 1994 enactment of DSHEA are not subject to the law’s requirements and can continue to be marketed even if an IND has been issued for the substance. If CBD is not considered a new dietary ingredient (NDI), NPA’s argument goes, then the 2018 Epidiolex approval does not change the regulatory status of CBD dietary supplements.
- Other substances are both drugs and dietary supplements under this exception, and two of these are cited by NPA in its petition. Both caffeine and L-carnitine are currently marketed as drugs and are legally also marketed as dietary supplements.
- CBD’s US history reaches far back, according to NPA. In fact, the petition cites an entry in the U.S. Pharmacopeia (USP) from 1850, just two years after USP was established, for an alcoholic tincture made from the dried heads of Cannabis sativa var. Indica.
- This USP entry sets the mark for when CBD was first on the market, claims NPA, which said this entry “definitively meets the bar established by the Act for a company to demonstrate that an ingredient was marketed in a product prior to the passage of DSHEA because it shows that CBD was marketed as a dietary ingredient nearly 150 years before the passage of DSHEA.”
- One critical complication is that nobody really knows what an “old” dietary ingredient is, complicating the ability of supplement firms to claim DSHEA exemption under this provision. There’s no official list of dietary ingredients that were on the market before DSHEA, and “old” ingredients are not defined in the regulations. It is up to companies and regulators to determine this on a case-by-case basis.
- It’s worth noting that this argument is one that NPA has some experience with. It filed a Citizen Petition on behalf of a firm wishing to market N-acetyl L-cysteine (NAC) as a dietary supplement. NAC is approved as a drug that treats acetaminophen toxicity, but it has also long been used as a dietary supplement with antioxidant properties. NPA’s argument in that petition was that the product was in use prior to both 1994 and the use of the ingredient in investigational studies, and is therefore suitable for (continued) use as a dietary supplement. [Read AgencyIQ’s analysis of the NAC petition here.]
- The FDA ultimately took steps toward potentially agreeing with NPA, determining that it would allow NAC to be marketed under enforcement discretion while the agency considered rulemaking to permit the continued marketing of NAC. As AgencyIQ wrote at the time, this was considered a potential harbinger of FDA’s approach toward NAC.
- NPA’s petition wasn’t the only one focused on CBD as a dietary supplement. Petitions filed by the Consumer Healthcare Products Association (CHPA) and the Council for Responsible Nutrition (CRN) also argued for FDA to establish regulatory pathways to legally market CBD as a dietary supplement.
But now the FDA has said that it has no intention of doing so, and instead believes that a new regulatory approach is needed to promote adequate oversight.
- In a statement on its website, the regulator said that, “after careful review, the FDA has concluded that a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks.”
- Notably, this proposed pathway is not one it is able to create on its own. Rather, Congress would need to create the pathway. The envisioned pathway would include the use of risk management tools, such as “clear labels, prevention of contaminants, CBD content limits, and measures, such as minimum purchase age, to mitigate the risk of ingestion by children.” These tools are not currently available as a means of overseeing dietary supplements.
- FDA justified this approach by arguing that the dietary supplement pathway (and the food ingredient pathway) would not be appropriate due to risks associated with CBD. “The use of CBD raises various safety concerns, especially with long-term use. Studies have shown the potential for harm to the liver, interactions with certain medications and possible harm to the male reproductive system,” FDA claimed. “CBD exposure is also concerning when it comes to certain vulnerable populations such as children and those who are pregnant.”
- FDA’s statement, attributed to Deputy Commissioner Janet Woodcock, also states that FDA intends to take action “against CBD and other cannabis-derived products to protect the public, in coordination with state regulatory partners, when appropriate.” However, it did not say that enforcement would increase, but would rather “continue.” Of note, FDA explained in a response to a petition (see below) that, “as a practical matter, FDA does not have the resources to take enforcement action against every violative product in this exploding market.”
- In the meantime, FDA sent denial letters to the Citizen Petitions filed by NPA, CHPA and CRN. While FDA’s response is extensive, it’s arguments boil down to two key points: (1) While the 2018 Farm Bill modified how CBD is regulated, it did not alter its regulatory status as a New Dietary Ingredient; and (2) While FDA was willing to consider an exemption to permit CBD to be marketed as a dietary ingredient, it would only permit that to be done if it was shown to meet a high level of safety, which it did not.
- To the latter point, FDA said it had “developed serious concerns about the safety of CBD for potential use in dietary supplements.” Among its noted concerns were ones about long-term use, its potential effects on the male reproductive system, liver injuries, and more. “The FDA has not found adequate information showing how much CBD can be consumed, and for how long, before causing harm,” it wrote. That outcome isn’t unexpected, given the safety labeling of Epidiolex (cannabidiol), which includes prominent warnings about the potential for hepatocellular injury, among other side effects.
FDA’s response here, while not unexpected, raises an extraordinary number of questions.
- For example, if FDA wants Congress’ help to create this new pathway, what approach might it solicit? The obvious front-runner is Sen. Majority Leader Chuck Schumer’s (D-NY) Cannabis Administration and Opportunity Act, which proposes to create a new Center for Cannabis Products at the FDA, which would be charged with creating a new regulatory framework for cannabis products. However, Congress’ involvement may not ultimately benefit the FDA. For example, the aforementioned legislation proposes that CBD derived from hemp would be regulated as a dietary supplement (and not a new dietary ingredient), and that FDA would be in charge of setting an upper limit (“recommended daily serving”) for CBD products, with FDA also able establish unique packaging and labeling requirements. Based on the safety concerns raised by the FDA, that option may no longer be one that it supports. There’s also significant risk to the FDA in letting Congress take the lead on this topic. Congress’ chief concern is politics and power – not scientific policymaking or legally consistent frameworks. We find it possible, and even likely, that whatever outcome that Congress chooses to legislate could be worse than the one FDA would have considered.
- With respect to risk, the horse has already left the barn. Whatever FDA’s concerns about the safety of long-term CBD use or hepatocellular injuries, the fact is that CBD products are already widely available, poorly regulated, and suffer little risk of compliance by the FDA even when they are regulated as if they are a dietary supplement. We find it curious that FDA’s reasoning largely ignores the status quo – that is, most of the risks they’re concerned with are already happening to consumers, and without any adequate oversight.
- A waste of time? The other risk is that the FDA now appears to have wasted years of time attempting to regulate, only to decide that it didn’t have the proper authority. We know better than most that it took time for FDA to collect certain scientific evidence and debate the merits of its decision, but the fact remains that this FDA working group was created in April 2019 – nearly four years ago – with the explicit purpose of exploring “potential pathways for dietary supplements and/or conventional foods containing CBD to be lawfully marketed; including a consideration of what statutory or regulatory changes might be needed and what the impact of such marketing would be on the public health.” That’s an enormous amount of time to spend debating a topic to essentially come to a null conclusion and attempt to pass the problem over to Congress. And based on the pace at which Congress typically works, it may be years before the FDA obtains any new authority, and even longer before FDA – even if it gets that authority – can then set up that new regulatory pathway. Or as CHPA described its feelings in a press statement: “FDA indecision has been the decision on CBD for far too long.” It would appear that approach is set to continue for the next few years as well.
Featuring prior analysis by Kari Oakes and Alec Gaffney
To contact the author of this analysis, please contact Alec Gaffney ( [email protected])