Is it time for the hemp CBD dietary supplements industry to panic? Not at All, Say Insiders. This post from Nutritional Outlook highlights the questions raised by FDA’s CBD warning letters to some players of the dietary supplements industry.
When FDA sends a group of warning letters calling out a particular dietary supplement ingredient, people tend to sit up and take notice. But when that ingredient is as new, as trending, and as controversial as hemp CBD, attention goes sky high.
On February 4, FDA issued warning letters to eight makers of products being illegally sold as dietary supplements while making disease-benefit claims. Some worry the agency is seeking to exclude cannabidiol (CBD) from the definition of a legitimate dietary supplement ingredient.
In a letter to one of the companies, CBDy, FDA stated:
You should be aware that, based on available evidence, FDA has concluded that CBD products are excluded from the dietary supplement definition under section 201(ff)(3)(B)(ii) of the Act [21 U.S.C. § 321(ff)(3)(B)(ii)]. Under that provision, if a substance (such as CBD) has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, then products containing that substance are outside the definition of a dietary supplement. There is an exception if the substance was “marketed as” a dietary supplement or a conventional food before the new drug investigations were authorized; however, based on available evidence, FDA has concluded that this is not the case for CBD.
This is the same language FDA used in a Q&A publication the agency first published on its website back in May 2015, titled “FDA and Marijuana: Questions and Answers.” Buried within the document’s information on marijuana was a short nod to questions about CBD’s allowance as a dietary supplement ingredient.
FDA’s Issues with CBD Supplements
By stating it “has concluded that CBD products are excluded from the dietary supplement definition,” FDA appears to clearly spell out that, at this time, the agency does not consider CBD a legitimate supplement ingredient. CBD holds neither Generally Recognized as Safe (GRAS) status for use in food and beverages, nor has anyone filed a notification with FDA for CBD as a new dietary ingredient (NDI) for supplements.
For now, the crux of the agency’s CBD issue, based on FDA’s statements, centers on two Investigational New Drug (IND) applications that were filed by drug firm GW Pharmaceuticals for its Sativex and Epidiolex CBD drug products. Per the Federal Food Drug & Cosmetic Act (Section 201(ff)(3)(B)(ii)), if a drug company, via an IND application, has said it is investigating an ingredient as a drug, and if supplement marketers cannot prove that the ingredient was sold as a dietary supplement prior to the IND filing, then the ingredient is prohibited from being a dietary supplement ingredient. FDA has said “the law is intended to maintain incentives for companies to establish the clinical safety and efficacy of drug products.” (The agency made this statement following the 1997 case involving a red yeast rice supplement, Cholestin, and a Merck drug, Mevicor, containing the same active ingredient—a case that ultimately saw the Cholestin supplement removed from the market.)
Supplement Ingredient Prior to IND?
The easy question to ask off the bat is whether there was ever a CBD dietary supplement on the market before GW Pharmaceuticals filed—and FDA accepted—its IND applications for Sativex and Epidiolex. (The company was founded in 1998.) If proof exists, it would seem simple enough for the supplement company selling the product to step forward with the evidence. In its warning letter to CBDy, FDA invited the company to “present the agency with any evidence that has bearing on this issue” to show that CBD supplements were on the market prior to the IND filing.
In a February 19 statement responding to FDA’s recent CBD warning letters, the Hemp Industries Association (HIA) said, “It is the position of the HIA that legal hemp products containing CBD were marketed as foods and dietary supplements long before cannabidiol formulations were submitted to FDA for testing as a ‘new drug.’”
Speaking to Nutritional Outlook, HIA’s executive director, Eric Steenstra, says, “The FDA has not yet presented any evidence regarding their claim [that CBD was not sold as a dietary supplement or conventional food prior to GW Pharmaceuticals’ IND applications]. We do believe that products containing CBD were marketed and sold prior to any IND, and we intend to work with industry members at the appropriate time to share the evidence.”
But finding the evidence is not as simple as it seems. For one thing, FDA does not post publicly the date on which an IND application was accepted. (A January 4, 2006, press release on GW Pharmaceuticals’ own website announced that FDA had accepted the IND application for Sativex.) This makes determining an official cut-off date to answer the “Which came first?” question difficult.
Another controversy is whether GW Pharmaceuticals’ Sativex drug can be considered comparable to any of the pure CBD oils sold by the supplements industry because Sativex is a blend of both CBD and another hemp cannabinoid, delta-9-tetrahydrocannabinol (THC). CBD supplement companies selling purely CBD oils argue that these products cannot be compared “apples to apples” with Sativex because Sativex also contains THC. (GW Pharmaceuticals’ other drug, Epidiolex, however, contains only CBD.)
“There are legitimate questions that can be raised,” says Michael McGuffin, president of the American Herbal Products Association (AHPA).
McGuffin acknowledges that GW Pharmaceuticals met the three criteria it needed for an IND “that are described in the specific provisions of the law: they had an IND, they had initiated substantial clinical research, and they had said so publicly.” But, he adds, “‘What was the article?’ has to be one question.” (The Federal Food Drug & Cosmetic Act refers to an ingredient as an “article.”)
“The provision of the law says that when [a drug company meets all three criteria for the IND], then the drug industry, the drug marketer, has exclusivity for that article,” McGuffin says. But “what was Sativex? Sativex is a cannabis derivative that contains a certain amount of THC and a certain amount of CBD.”
So, while supplement companies would not be able to sell this combination of THC and CBD if the GW Pharmaceuticals IND holds true, that doesn’t necessarily mean that supplement companies wouldn’t be able to sell other cannabinoid products.
“What was the article that was protected by that provision? What’s clear is supplement companies can’t sell that [Sativex] article,” McGuffin says. But, he questions, “Is it also just as clear that supplement companies can’t sell any of the constituents contained in that article? If that is the case, or if that’s FDA’s interpretation, then how well substantiated is that interpretation?”
“I don’t think we can ignore it,” he says, continuing, “I don’t have a contrary opinion as much as I think it’s a legitimate question to ask whether FDA is correct in saying that because Sativex and Epidiolex met the three IND criteria, that means that [the dietary supplements industry] can’t market any of the constituents in any of those drug products.”
One company raising these types of questions publicly is CBD oil company CV Sciences Inc. (San Diego, CA), formerly known as CannaVest Corp. The company has written a position paper responding to the statements FDA made in the agency’s May 2015 marijuana Q&A posting. CV Sciences has been disseminating its position response to its own contacts within the dietary supplements industry. (The company says it has not, and does not plan to, however, send the document directly to FDA.)
According to CV Sciences’ paper, “all requirements to consider CBD under the IND preclusion regulations have not been adequately conducted, thus furthering our opinion that CBD is not precluded from the definition of a ‘dietary supplement.’” It continues, “it is our opinion, which is broadly shared by the marketplace, that CBD has been marketed as a dietary supplement prior to commencement and public notice of any substantial clinical investigations instituted on CBD, as the investigations that were publicized were not substantial, due to being limited in number and preliminary in nature, thereby rendering the IND preclusion inapplicable.”
Speaking to Nutritional Outlook, Stuart Tomc, vice president, human nutrition, for CV Sciences, says, “We’re going to argue the idea of what is a substantial clinical investigation and when is making it public. We’re going to take on the IND issue. If someone’s going to have to lead this debate, it’s going to be us.”
At this point, it’s still worth noting that, to date, no CBD supplement company has come forth with evidence showing that its CBD supplement product was on the market prior to a CBD IND filed by the drug industry. McGuffin says, “I’m not aware of anyone having concluded that there either was or was not a CBD product on the market prior to the GW date.”
Regardless, the fairness question raised by the IND provision excluding supplements from the market troubles many.
“What the [FD&C Act] provision says, in summary, is that for any article, if the drug industry gets there first, they get an exclusivity,” McGuffin says. “And what they need to do to get there is to say that they’re really interested in getting there. They have to satisfy those three provisions. They don’t actually have to be in the marketplace [selling product]. And if they satisfy those three provisions, they get an exclusivity.”
He continues, “If the supplement industry gets to the marketplace first, we can share the marketplace with the drug industry. So, a basic fairness question arises: ‘Is that fair that the drug industry gets exclusivity and we get a shared marketplace?’”
Consider, also, the long time it takes for a drug firm to get its drug product to market. Merck, McGuffin says, took years, possibly longer than a decade, to get to the marketplace with Mevicor after the scientific publications on lovastatin, the active ingredient in red yeast rice, appeared as far back as 1979. In the case of CBD, McGuffin points to a 1973 university-researched article on CBD for health benefits, titled “The anticonvulsant activity of cannabidiol and cannabinol.” Fast-forwarding to today, McGuffin says, “That’s 34 years of publicly available information. Can one drug company now own that? Is that okay?”
Instead, he says, “What if there was some kind of time restriction? What if, for example, an additional criteria was established that the drug industry has to establish those three [IND] criteria within X years from the first publication of the scientific research on that substance” in order to maintain its market exclusivity?
“Let’s assume that we want rules that protect the research interests of the drug industry,” he says. “But we also want rules that protect consumer access to long-used ingredients. Do we want to think about a revision to this provision in the law?”
Short of a revision to the law any time soon, CBD firms are taking steps on their own to protect their industry—namely, by ensuring they and their colleagues are marketing these products lawfully and responsibly.
CV Sciences’ Tomc says he was “thrilled” to see FDA issue warning letters to companies making illegal drug claims. “We were thrilled that the warning letters went out, because these people don’t understand the dietary supplement space [and] come from the cannabis space or are entrepreneurs,” he says. “We actually think these warning letters are great for the CBD market.”
“We implore, we beseech, all the other CBD companies to follow the regulations of the FDA. We need to make sure that people aren’t making medical claims because we’re not selling medicine,” adds Sarah Syed, director of marketing, CV Sciences. “It’s a challenge because the market is growing, but many people don’t know what they’re doing wrong. They don’t know what they don’t know, and they don’t know the regulations behind dietary supplements and the health claims that you cannot make.” Syed and Tomc point out the “variance” of companies in the market, which includes larger, established firms like CV Sciences as well as small start-ups and individuals growing their own cannabis.
Efforts are being made to bring the larger CBD market in line with the regulations, including efforts by AHPA’s own Cannabis Committee. The committee was formed five years ago when, McGuffin says, “we saw this emerging marketplace and need of a forum and community for the best companies to get together and discuss how they could establish businesses with long-term marketplace opportunity and not a short-term marketplace opportunity.”
Just last week, on February 19, the committee held a call with a wide representation of CBD companies in the market. Tomc says, “Here was the tone: Don’t make disease claims. If you are making disease claims, hang up right now, fix it, and come back.” Tomc says these types of calls “show the industry is being proactive.”
Does the CBD industry at large worry that the recent FDA warning letters threaten the future of the CBD supplements industry? Tomc says no. He says that while FDA has “insinuated” that CBD may not be a dietary supplement ingredient, he also points out that warning letters only went to many of what he calls the “smaller players” in the CBD market. “All the letters went to very small players in the CBD space,” he says. “The larger players in this space really have not received any warning letters.”
Does this mean only smaller companies have made disease claims? Or does it mean that FDA, as a whole, has chosen not to actively pursue the category unless companies are breaking the law? Has the agency decided to leave the responsible CBD supplement market alone until the case is settled as to whether or not CBD is a legitimate supplement ingredient?
In the agency’s own words in its May 2015 Q&A piece, FDA did not state that it is banning CBD. Instead, it said, “When a product is in violation of the FD&C Act, FDA considers many factors in deciding whether or not to initiate an enforcement action. Those factors include, among other things, agency resources and the threat to the public health. FDA also may consult with its federal and state partners in making decisions about whether to initiate a federal enforcement action.”
In terms of FDA pulling CBD supplements off shelves, Tomc says, “We’re not there yet.” He adds, “There would have to be a trend toward public harm. There is no trend toward public harm. The amount of effort, the case that would have to be built—FDA is not going into health food stores and telling people you cannot carry these products. That’s not going to happen.”
He adds, “FDA did not say you can no longer sell this. There has been no enforcement action. It’s all been Q&A posturing. Nothing has happened yet. I think that’s important to remind everybody about, because we still have the process of making the argument to society in general and to regulators as to where this ingredient is going to end up.”
In the meantime, Tomc says, CV Sciences’ goal is to continue strengthening the science behind its ingredient. He says the company has completed its own toxicological study that would be the foundation of a GRAS self-affirmation. The data is now under review.
Notably, Tomc says, it would be the first toxicological study done “in the history of cannabis.” He says, “No one’s ever done it for hemp, hemp protein, hemp meal, hemp seeds, hemp oil—nothing cannabis-related has ever been tested to be safe.”
John Endres, ND, chief science officer for AIBMR Life Sciences Inc. (Puyallup, WA), which specializes in GRAS services, says, “As far as I know, there has been no GRAS self-determination completed for any CBD-rich hemp oil.”
This would make CV Sciences’ data a landmark in the CBD industry—and, indeed, the larger cannabis industry. Whether Tomc thinks such data could cause FDA to see CBD in a new, positive light, he says instead, “It could set a precedent that FDA may adopt in deciding which suppliers they’ll allow on the market.”
“What we’re doing now is demonstrating that the ingredient we’re bringing to market is safe and effective. And that’s our primary responsibility,” he continues. “The indefensible position is the lack of formal toxicological evidence of safety. I don’t blame anybody for having questions about safety until you see the data. That’s good, skeptical thinking.”
“Ingredients that are sold either for the addition to foods or as dietary supplements need to demonstrate that they are safe for consumption,” Endres says. “The CBD products that are on the market are different in that some are much higher in CBD than what is naturally occurring and therefore should be the subject of rigorous toxicological assessments to determine what the safe cumulative daily exposure is. The conclusions of such toxicological studies are then used to support regulatory status for the intended use of these products—GRAS for food ingredients and NDI notifications for dietary ingredients/dietary supplements.”
He concludes, “The completion and publication of safety studies on a CBD-rich hemp oil product in a peer-reviewed academic journal specializing in toxicology will be, to the best of my knowledge, the first in recent times and a monumental step forward in putting real science behind a product. I would have to conclude that the public and the FDA should applaud this effort as well as the time and expense it requires.”
CBD: Just the Beginning
In many ways, the challenges CBD faces are the growing pains that any ingredient relatively new to the supplements market would face, including carving out a place in the regulatory domain. The demand for this ingredient is very high, according to CV Sciences, with Tomc adding that many of the more than 500 stores carring CV Sciences’ CBD oil products complain they can’t keep up with the demand. As marijuana is increasingly legalized across the country, the CBD industry is additionally challenged by individuals and small companies wanting to participate in the supplements market but not familiar with the regulations.
But, say individuals we spoke to, the bottom line is that there are CBD companies looking to market products responsibly.
“Yes, I do believe there is a responsible center of the cannabis/CBD/medical marijuana industry developing, and we’re certainly working to keep them organized and informed,” AHPA’s McGuffin says.
HIA’s Steenstra says, “HIA member companies are marketing CBD responsibly, and none were sent letters. We believe that the vast majority are in compliance with [the Dietary Supplement Health and Education Act].”
As for CV Sciences, the company believes that one day, CBD supplements and drugs will be able to live in harmony. In its position letter, the company states, “Based on global demand for hemp-derived CBD, a compromise will eventually be reached, with artisanal hemp extracts sold in coexistence with pharmaceuticals, as is the case with prescription omega-3 fish oils and commercially available omega-3 offerings.”
“This isn’t the end of the CBD market,” Tomc says. “It’s just getting started.”