This is a theoretical and frightening scenario: Children who have fallen ill after taking CBD in a supplement are rushed to hospitals with liver failure or death. The damage is traced to CBD-containing products manufactured by prominent U.S. brands. And regulators dismantle a fledgling industry built on the promise of promoting health.
As FDA ponders whether to establish a legal pathway for CBD in dietary supplements, manufacturers are investing in a number of studies to demonstrate their products are safe at specific doses, industry lawyers and company executives said.
The investments could ultimately promote consumer confidence, placate an agency that has raised unanswered questions about the safety of CBD, and contribute to avoiding a crisis like the one in the vaping industry tied to severe respiratory illnesses.
Stuart Titus, Ph.D., CEO of Medical Marijuana Inc., noted his company and its competitors are providing CBD-containing products to many young children who suffer from such conditions as autism and epilepsy.
“We don’t want parents to be afraid of giving a product to a child because of adverse or negative consequences,” he said in an interview. The vaping crisis, he added, serves as a “warning signal” that perhaps the CBD industry must be “more diligent about some of our processes and regulations just to be sure we’re providing safe products that don’t contain synthetic or artificially derived cannabinoids … untested in the human population.”
In a November 2019 email, Ashish Talati, a lawyer in Chicago who advises businesses on FDA regulatory matters, said he is representing suppliers and finished product companies with more than half a dozen ongoing or completed studies on CBD isolates and full-spectrum hemp products. Among other research, the studies include 14-day and 90-day studies in rats, added Talati, a partner with Amin Talati Wasserman LLP.
“It’s a whole battery of (toxicology) work,” he said in a phone interview.
Talati explained the safety studies could provide the foundation for the eventual submission of new dietary ingredient (NDI) or generally recognized as safe (GRAS) notifications to FDA, or a self-GRAS determination, based on his clients’ wishes. These notices to FDA and self-GRAS determinations reflect the typical regulatory pathways in which companies establish the safety of their ingredients in conventional food and supplements.
“These are responsible companies that want to do the right thing and certainly want to make sure that their products are safe,” Talati added.
A partner in Washington with Arnall Golden Gregory LLP (AGG), attorney Kevin Bell said his firm’s clients are investing in CBD safety studies for various reasons, including to prepare for NDI or GRAS submissions to FDA.
However, several industry lawyers explained companies aren’t willing to submit NDI notifications (NDINs) to FDA at this time because the agency has determined CBD cannot be marketed in a dietary supplement. Its reasoning is tied to its conclusion that CBD was first studied as a drug by GW Pharmaceuticals plc, whose CBD medicine Epidiolex was approved by FDA in 2018.
Robert Durkin is another lawyer at AGG and a former FDA official who served as deputy director in the Office of Dietary Supplement Programs (ODSP). Submitting an NDIN to FDA for a CBD-containing product, Durkin suggested, wouldn’t benefit the notifier at this time.
FDA “wouldn’t necessarily give the person who submitted it feedback on the quality of the (safety) data” due to its determination that CBD is excluded from the definition of a dietary supplement, he explained in an interview.
Some companies in the CBD market want to engage in dialogue with FDA about the safety of their products, Talati said, “but the path needs to be available.”
Companies would provide product-specific safety data to FDA if the agency authorized CBD in dietary supplements through the authority vested in the secretary of the U.S. Department of Health and Human Services (HHS), according to several industry attorneys.
“If FDA allows this ingredient … big companies will submit NDI notifications and/or GRAS notifications or anything else that they need to share with the agency to show safety,” Talati said.
But another lawyer in the nation’s capital who advises clients on FDA regulatory matters said a company that filed an NDI notification with FDA and whose submission was rejected based on the GW Pharmaceuticals issue could force the agency’s hand in court. Todd Harrison, a partner with Venable LLP, pointed to Section 413(b) of the Dietary Supplement Health and Education Act of 1994 (DSHEA).
Section 413(b) gives a person the right to file a petition with the HHS Secretary, “proposing the issuance of an order prescribing the conditions under which a new dietary ingredient under its intended conditions of use will reasonably be expected to be safe.” The statute requires a decision on the petition within 180 days of the filing.
Harrison said the petitioner could file a lawsuit if the government responded CBD was excluded from the definition of a dietary supplement. FDA’s position, several industry lawyers and hemp executives have argued, could be proven wrong in court since, for example, many full-spectrum hemp extracts are distinguishable from the isolated CBD studied by GW Pharmaceuticals.
“The problem right now is that there’s no way of suing FDA over it,” Harrison said in an interview.
While FDA has requested CBD-related safety data from the hemp industry, Bell and Durkin mentioned another impediment to companies sharing their toxicology work with the government.
“If they share the data now, it would likely become public,” Durkin said.
Companies who shared the data now with FDA risk losing “either intellectual property protection” or risk losing preservation of the “data as their own for their own leverage,” Bell added.
The same data, Durkin said, could be kept confidential as part of an NDIN. But again, FDA isn’t likely to give comprehensive feedback related to the safety documentation due to its position that CBD is excluded from the definition of a dietary supplement, some industry attorneys said.
Several trade groups in 2019 urged Congress to pass legislation clarifying hemp-derived CBD is a lawful dietary ingredient if the supplement meets established product safety and quality criteria. And on Jan. 13 this year, a bill introduced in the U.S. House of Representatives would allow hemp-based CBD to be marketed in food and supplements.
The legislation did not address FDA’s safety concerns. “It removes one impediment but FDA’s still going to require people to show safety of their particular extract or ingredient in the end,” Harrison pointed out. “That’s not going to change. And that’s what FDA’s been saying all along.”
In the Oct. 8 letter to Congress, the trade associations noted any CBD products subject to a “limited waiver” would need to meet the definition of hemp in the 2018 Farm Bill and comply with applicable requirements of the Federal Food, Drug & Cosmetic Act (FDCA) and FDA’s regulations related to dietary supplements, including requirements for new dietary ingredients.
Some companies have sought to demonstrate the safety of their CBD-containing products through another regulatory pathway: a self-GRAS determination in which a panel of experts outside FDA reach a conclusion about a food ingredient’s safety. Marketers of an ingredient in conventional food have frequently relied on such determinations to demonstrate the safety of the same ingredient in their dietary supplements through an exemption in DSHEA to the NDIN requirement.
That strategy, however, recently drew scrutiny from Pieter Cohen, a Massachusetts physician and associate professor of medicine at Harvard Medical School, and Scott Bass, an attorney with Sidley Austin LLP who helped draft DSHEA.
In a recent article published in the New England Journal of Medicine, Bass and Cohen described the self-GRAS process as a “loophole” that “has grown into the exemption that swallowed the law.” The authors proposed requiring manufacturers submit the vast majority of new dietary ingredients to FDA for safety assessments.
“Industry developed, and the FDA accepted, an approach whereby manufacturers convene sympathetic food-safety experts to affirm that a new, nontraditional ingredient is ‘generally recognized as safe,’” Bass and Cohen wrote.
The standard for a self-GRAS determination, Harrison emphasized, is no different than if a GRAS notice was filed with FDA. Companies must always ask whether the evidence in their self-GRAS determination would be adequate if it was filed with FDA and reviewed by the agency, he advised.
“If the evidence is not sufficient to file with FDA, then the ingredient is not GRAS,” Harrison said.
Some representatives of the hemp-based CBD industry have reported investing in rigorous toxicology studies, and they have either completed a self-GRAS determination or plan to in 2020.
Enter HempFusion, a marketer and manufacturer of hemp extracts sold in thousands of retail locations.
Jason Mitchell, co-founder and president of HempFusion, said in an interview that his company is nearing completion of toxicology work and anticipated a NOAEL (no-observed-adverse-effect-level) on his raw material would be published sometime in January in a “prominent journal.”
“We are following all the required FDA guidelines to make absolutely sure that we are taking all the necessary steps with regards to toxicology work,” Mitchell said.
The investment in the safety work is “north of seven figures,” he added in response to a question about the costs of the safety work.
“No matter how much money you throw at it, it does not make it happen faster,” Mitchell noted. “It still takes no less than 15 to 18 months to complete, and in most cases, more than 24. By the time we’re done, we will have had more than 20 months invested in this process.”
Mitchell said he expects HempFusion’s self-GRAS determination will be published in March 2020.
But FDA seems skeptical there’s a consensus among experts that CBD is safe. In a Nov. 25 news release, FDA referenced toxicity data that the agency said raised “serious concerns about potential harm from CBD,” including possible liver injury, and FDA suggested “it cannot conclude that CBD is generally recognized as safe (GRAS) among qualified experts for its use in human or animal food.”
The statement caught Durkin’s attention. For FDA to determine CBD is not GRAS means the agency surveyed “all the open source available data and literature to make that conclusion,” he said. Apparently, the agency believes the publicly available data “does not support a positive GRAS determination,” Durkin added.
FDA expressed its reservations about the safety of CBD more than a year after CV Sciences Inc. announced in 2018 that its “hemp-derived CBD gold extract” had received self-affirmed GRAS status. CV Sciences’ safety work was published in the Journal of Toxicology.
Asked to comment on the remarks by FDA and Durkin, an executive for CV Sciences said qualified experts who are asked to review whether an ingredient is GRAS assess the scientific data based on the specific ingredient and labeling instructions.
“CV Sciences’ GRAS self-affirmation was based on our ingredients (PlusCBD Oil), the specific level of CBD (and other bioactive compounds) in our GRAS hemp extract, the recommended serving size on our label, and the intended user,” said Douglas (“Duffy”) MacKay, senior vice president of scientific and regulatory affairs with CV Sciences, in an email.
For instance, the company’s products recommend consumers not use them if they are breastfeeding or pregnant, he noted. “This is because more scientific data is needed to demonstrate that our hemp extract is safe for pregnancy, and until then we will play it safe,” MacKay said.
“Our research demonstrates the safety of our ingredients for the protection of our consumers, as well as to abide by the law,” he said in a separate email. “Consumer safety should be the hemp industry’s highest priority.”
MacKay, however, identified “major concerns” with other products on the market, such as those containing high amounts of CBD, and he questioned whether those companies have researched the safety of their products.
In a 2019 interview at SupplySide West in Las Vegas, Durkin said companies selling dietary supplements must have a reasonable expectation that their products are safe before they are introduced to the market.
“If folks are on the market without having a basis for concluding that their product is reasonably expected to be safe, they’re in clear violation of the (FDCA),” said Durkin, who at the time of the interview had recently left FDA to join AGG.
During the same interview, another former FDA official chimed in. Daniel Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), said companies that have failed to submit an NDIN to FDA or comply with the GRAS standard are risking exposure to private litigation.
“If people are already on the market without the NDI or without a real GRAS, they’re going to get everything they deserve from the plaintiff’s bar and everyone else eventually,” concluded Fabricant, who also has lobbied FDA to establish a safe level at which CBD can be marketed in a supplement.
To date, many companies have reported no serious safety concerns linked to their CBD-containing products. Titus, of Medical Marijuana, said about 150 patients in Brazil, including young children, have been using its CBD products since 2014.
“Not only are the children not experiencing any unwanted or negative consequences from (CBD), but it’s actually helping them with their developmental challenges,” he noted.
The kids’ parents, Titus added, are reporting various improvements related to appetite, sleep and mood, for example.
Titus said he has been using CBD for more than seven years and described likely being “in the best health and … shape” of his life at 63 years old.
“There’s … anecdotal evidence that this product is overwhelmingly safe,” he reflected.
Still, some hemp executives, including Titus, understand why FDA is proceeding cautiously: to ensure the compound doesn’t cause any adverse consequences to human health. Geoff Whaling, chairman of the National Hemp Association, said he shared the agency’s view “that we don’t know what the long-term cumulative effects are of CBD.”
“Right now, someone can get CBD in their water,” Whaling noted in an interview. “They can get it as a tincture. They can get it in a lotion. They can get it in gummy bears. (And) they can get it in gum.”