With the U.S. Food and Drug Administration otherwise engaged for the time being with the coronavirus pandemic, any near-term movement on hemp CBD is probably being put on the agency’s back burner.
In the absence of any acute safety issue with people dying, or at the very least reporting liver toxicity adverse events to hospitals, it seems the most the FDA is doing is monitoring the market for illegal drug disease claims, which are illegal for supplements.
Supplements are governed under the Dietary Supplements Health and Education Act (DSHEA), which permit so-called “structure/function claims” that tell of a nutrient’s influence on the body’s structure or function.
So vitamin C, for example, can be said to “help maintain a body’s immune function,” but it cannot be marketed to “cure the common cold.”
On April 23, the FDA sent warning letters to two CBD companies that were marketing their products as treatments for opioid addiction.
Last November 25, the FDA sent warning letters to 15 CBD companies for violating the Federal Food, Drug, and Cosmetic Act’s prohibition against supplement companies making drug-disease claims, ranging from cures for autism and hepatitis to brain cancer and multiple sclerosis.
But many supplement industry watchers believe that after the FDA completes its safety assessment of CBD—a process that could still take another two or three years—it may conclude that the path to market may include fairly rigorous, and certainly expensive, safety and toxicity work.
It could have the effect of potentially wiping out the lion’s share of companies—and suppliers—that cannot meet the threshold.
It’s a threshold, it must be stated, that the FDA as well as the supplements industry and ingredient suppliers have routinely ignored in the 25 years since DSHEA mandated it as the way to market.
But with the FDA intent on enforcing the letter of the laws, it may decide that companies must file dossiers that subscribe to either NDIs or GRAS.
“The FDA said GRAS is not happening, and NDIs are not happening until liver toxicity is understood,” said Patrick McCarthy, CEO of ValidCare, which conducts market intelligence and research solutions for the hemp industry. “This is a time for the industry to band together and figure out how we get through this level of safety. Once we get that passed, they will go down the path of NDI, GRAS, this could be a food, a drug, a supplement, an additive, it could be all of them, but until we get the safety, we don’t know.”
That means forward-looking companies looking to dominate the future had better start investing in the work required so that if/and/or/when the FDA comes down with its edict, to the well-prepared will go the spoils.
“Manufacturers are going to want to be in process of legalizing their products through a process,” said Kimnera Hall, regulatory attorney with the Frost Brown Todd law firm. “To prepare for that, the ultimate pathway will likely contain NDI notifications and/or GRAS determinations. Knowing about them now will give you a heads-up for these processes.”
Here’s what that might look like.
The trouble with New Dietary Ingredient Notifications (NDINs) is that, though required under DSHEA, the FDA has never really come out with the details of what that might look like. The agency put out two drafts, in 2011 and 2016, both of which were met with a wave of criticism from the industry, the second draft of which involved Sen. Orrin Hatch (R-UT), co-author of DSHEA, to alert the agency that its proposed rule was not at all what the authors of the legislation had in mind, that the FDA should ditch its latest attempt and start over.
Be that as it may, and without an official final rule in place, the FDA is still more or less operating under its own guidance, like it or not. It generally includes the following:
- Companies must submit an NDIN at least 75 days before introducing a product into interstate commerce.
- Said ingredient is “reasonably expected to be safe.”
- The information in the NDIN will be held by the FDA and not disclosed for 90 days, and then it becomes a public record except for confidential information.
“You can expect the FDA to respond in one of three ways,” said Jonathan Miller, another attorney at Frost Brown Sullivan. “The FDA could acknowledge the NDI without objection. It could object to the NDI notification stating safety concerns or identifying gaps in use. Or it’s also possible you get no response from the FDA. That doesn’t constitute a rejection, but neither a finding the ingredient is unsafe or adulterated.”
NDIs are regarded as being quite expensive—maybe half a million bucks, perhaps a million. One thought is that large-scale growers can do that work, and then sell the hemp to all comers.
“The real game is whoever is first to get an NDI wins,” said Loren Israelsen, president of the United Natural Products Association. “Then the raw material supplier will have lots of other brands that fall in and can sell that specific CBD—Walmart, Walgreens, hungry big players. But there are only a few companies that can handle that rigor."
That certainly sounds like a recipe for Big Ag and would wipe out all of the thousands of small-scale boutique growers in the country.
“NDIs are big and expensive,” said Israelsen. “There’s a lot of work required around safety, toxicity, how you grow the plant, GMPs, that will take a lot of work. We don’t know if anyone in the industry can do that.”
There would be howls of consternation if the FDA begins to aggressively mandate NDIs to hemp when it has not exactly rigorously imposed them on the rest of the industry for the last quarter-century.
“The industry strongly disagrees,” said Hall, “but the FDA believes CBD is a New Dietary Ingredient.”
One workaround is compiling GRAS dossiers—Generally Recognized As Safe. The details are set out in the Federal Register here.
These dossiers must be both technical evidence of safety as well as common knowledge and accepted consensus by qualified experts. It is generally accomplished through the publication of pivotal safety—and unpublished data can be used to corroborate pivotal data but it need not be necessary to make the safety conclusion.
“Once it’s published and has been in the public domain, then it’s accepted as a means of showing consensus among qualified experts,” said Tom Jonaitis, a specialist at the EAS Consulting Group, which compiles GRAS notifications for companies.
Once safety studies are published, the process could be complete in as little as one to two months, said Jonaitis. Expert panels are typically comprised of between three and five members who are qualified by scientific training and experience and are familiar with U.S. food law. Experts need to address pertinent areas such as chemistry and statistics.
A subtle yet significant difference between the two is that the GRAS safety standard is a “reasonable certainty of no harm under the intended use conditions” while the NDI safety standard “does not present a significant or unreasonable risk of illness or injury.”
Can’t figure out the difference? Call EAS, or Burdock Group, or Spherix Consulting Group, or other such experts.
Some of the data requirements of GRAS notifications, Jonaitis said, include:
- Chemistry: Ingredient identity, physical-chemical properties, source, cultivation methods, a detailed characterization and defined to 100% purity with accepted/validated methods.
- Specifications: That you can consistently produce with the manufacturing process as well as data supporting the impurity profile – residues, solvents, heavy metals, microbials; and accounts for batch-to-batch variability.
- Batch analysis: Typically 3 to 5 samples.
- Stability: Tests that show that the bulk ingredient remains stable and within all specs over the shelf-life of the product. For food, that it’s stable in food matrices, showing that food processing (e.g., high heat) does not degrade the ingredient.
- Exposure. What is the purpose of the ingredient? Why are you adding it? For foods, which food are you adding it to, and what is the maximum level. For supplements, what is the recommended Daily Intake. For supplements, also the dose and duration of use. What is the target population?
“GRAS is probably quickest,” said Jonaitis. “GRAS is for the food route, which gives you access to food uses and then for use in supplements. If you go the NDI route, it’s only for supplements. There is that aspect. But you can still use unpublished studies for NDIs.”
Studies for GRAS notifications include at least one in vitro study and one or two in vivo studies, said Jonaitis. A sub-chronic dosage study in rodents include 28-day studies in rats and/or a 90-day dietary feeding study in rats, which will take about one year to complete.
“You want to find the highest level that does not show any adverse event level to get an accepted daily intake in humans,” he said.
Additional studies include a 2-year carcinogenicity study in rats, which also addresses neurotoxicity, reproductive toxicity and developmental toxicity in pregnant rats.
Human studies may be needed, depending on the safety profile of the ingredient and the availability of published data.
The FDA has raised safety concerns regarding chronic exposure in humans, potential liver injury, male reproductive toxicity, effects on the developing fetus and children, and interactions with drugs and other herbs.
“Yes, the GRAS route gives more flexibility versus NDINs regarding being able to use in both food and supplements, but it could actually require more studies since exposure could reach a broader consumer audience,” said Jonaitis. “Either route will take a substantial amount of resources to establish safety—at least for the first few companies going through either route.”
The either/or option of NDI or GRAS could be precluded with either Congressional legislation or the FDA accepting that hemp and all its phytochemicals have been in commerce since before DSHEA was passed in October 1994 and thus qualify as Old Dietary Ingredients.
It also concerns many in the boisterous hemp CBD world that an overly aggressive regulatory take on a plant that’s widely used and beloved by consumers the nation over would be imprudent, to say the least.
“If they were to actually jump the front of the line on the CBD issue with NDIs before they enforced NDIs for a supplement, this industry would crack in half,” said Kevin Bell, an attorney with the Arnall Golden Gregory law firm, which represents the Natural Products Association trade group. “A lot of people would have a problem with that.”