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Leading CBD companies Charlotte’s Web and Irwin Naturals submitted NDI notifications for full-spectrum hemp extracts. FDA objected to the notifications on the grounds of the drug-exclusion clause and the agency’s concern about safety substantiation.
FDA objected to two New Dietary Ingredient (NDI) notifications in July filed by industry-leading cannabidiol (CBD) companies Charlotte’s Web and Irwin Naturals. Both companies had filed NDI notifications for full-spectrum hemp extracts, not CBD isolates, yet FDA objected to both notifications citing a legal conflict with CBD isolate drug Epidiolex. The agency also expressed concern over the scientific evidence the companies submitted to substantiate their NDI filings. In its objection letters to both companies, FDA stated that both companies’ full-spectrum hemp extracts “may not be marketed as or in a dietary supplement.”
In both objection letters, the agency first cited the Food, Drug, and Cosmetic Act’s Investigational New Drug (IND) preclusion provision that states that articles first publicly studied as a pharmaceutical drug cannot be marketed as a dietary supplement. FDA’s ongoing argument has been that because GW Pharmaceuticals first studied and came to market with its Epidiolex drug, which is made from CBD isolate and not full-spectrum hemp, CBD is precluded from being sold as a dietary supplement ingredient.
FDA’s new objection letters make clear the agency is applying the preclusion clause to reject not only any CBD isolate ingredient as a supplement but also to object to full-spectrum hemp as a whole. Full-spectrum hemp not only contains CBD but also other constituents of the cannabis plant such as essential oils, terpenes, and other cannabinoids.
Supplement companies have argued that full-spectrum hemp extract is separate from CBD isolate and that the Act’s IND preclusion does not apply to full-spectrum.
Nevertheless, FDA’s objection letters to Charlotte’s Web and Irwin Naturals, both issued on July 23, 2021, state: “FDA has concluded that CBD products are excluded from the dietary supplement definition under 21 U.S.C. § 321(ff)(3)(B) (section 201(ff)(3)(B) of the Act). CBD is the active ingredient in the approved drug product, Epidiolex. Furthermore, the existence of substantial clinical investigations involving CBD has been made public. FDA has also determined that CBD was not marketed as a dietary supplement or conventional food before it was authorized for investigation as a new drug.”
In the Irwin Naturals letter, FDA additionally stated, “Based on the record, FDA has concluded that NDI 1199 is designed to ensure consistent levels of CBD; that it is produced from hemp plants that contain robust amounts of CBD; that the manufacturing process results in a product that delivers a relatively high amount of CBD per day, comparable to a drug product; and that currently marketed products indicate that you market ‘full-spectrum hemp extract’–containing products as CBD products. Looking at the totality of the record, FDA has concluded that your NDI 1199 is a CBD product and thus is subject to the exclusion from the definition of dietary supplement…”
FDA’s objection letters also cite concerns over the safety data the companies included in their NDI notifications.
To Charlotte’s Web, the agency wrote: “We also conclude that, even if your NDI 1202 was not excluded from the definition of dietary supplement, the agency has concerns about the adequate safety evidence included in your submission as a basis for concluding that a dietary supplement containing NDI 1202 will reasonably be expected to be safe under the conditions of use described in your notification. The notification included some evidence intended to show adequate history of safe use and also included reports of safety studies. These categories of evidence had deficiencies on their own and, even when all of the evidence was considered as a whole, the notification failed to show that the NDI will be reasonably expected to safe.”
The agency further stated, “For example, your submission provided two years of marketing for NDI 1202 as evidence of history of use, which is insufficient to establish the safety of your ingredient when used under the proposed conditions of use. Furthermore, FDA was unable to accept your proposed no-observed adverse effect level (NOAEL), which was based on the publication by Dziwenka et al., 2020, because the publication included inadequate information for the purposes of assessing the reliability of the conclusions in the publication. FDA requested that you provide the agency with the supporting or underlying data that formed the basis for the Dziwenka et al. 2020 study, but you did not provide FDA with this data. In addition, none of the clinical and preclinical studies that you provided adequately address certain reported toxicity endpoints of CBD such as hepatoxicity and reproductive toxicity…For these reasons, the information in your submission indicates that, even if your NDI 1202 were not excluded from the definition of a dietary supplement, your notification does not provide an adequate basis to conclude that a dietary supplement containing the ingredient, when used under the proposed conditions of use, would reasonable be expected to be safe.”
The agency took a similar stance on Irwin Naturals’ scientific substantiation, writing that what was submitted was not enough to show the agency that the ingredient was reasonably expected to safe. The agency stated: “For example, your evidence for history of use was vague and did not provide an adequate description of the cannabis preparations (e.g., composition), serving levels, or frequency and durations of use, which makes it difficult to compare this history of use to the proposed conditions of use for your ingredient and establish the safety of your product. Furthermore, you provided preclinical and clinical studies on different phytocannabinoid mixtures that, in some cases, were not completely characterized and could not be compared to your ingredient; therefore, you did not adequately establish how these study results inform the expectation of safety of your ingredient.”
“The Door Is Closed”
Industry representatives Nutritional Outlook spoke to expressed disappointment and frustration at FDA’s statements in these letters. Those representatives say that now that FDA has made clear in these NDI objection letters that it is fully applying the IND preclusion clause to hemp extracts, the only pathway forward for legalizing CBD for dietary supplements falls to congressional legislation that would expressly make CBD legal in supplements.
There are already bills circulating in Congress—notably, “The Hemp and Hemp-Derived CBD Consumer Protection and Market Stabilization Act of 2021” (H.R. 841) and the “Hemp Access and Consumer Safety Act” (S. 1698). In July, it was announced that Senate Majority Leader Chuck Schumer (D-NY) is leading the draft of another bill.
On the news of the Charlotte’s Web and Irwin Naturals NDI objections, Steve Mister, president and CEO of dietary supplement industry association the Council for Responsible Nutrition (CRN; Washington, DC), told Nutritional Outlook,“I think we were disappointed more than anything, because of the fact that both of these submitters were asking for a non-objection letter on full-spectrum hemp products. FDA could have addressed this by recognizing that full-spectrum hemp is not the same as CBD isolate, and they could have avoided the whole drug-preclusion language and that whole situation. They could have acknowledged that full-spectrum is different; therefore, the drug-exclusion language does not apply. And then they could have moved ahead to considering the substance of the NDI, but instead, they rejected both of these notifications based on the fact that they say it’s the same article as Epidiolex. And that’s what was really disappointing to us.”
On the science front, John Endres, ND, chief science officer for AIBMR Life Sciences (Seattle, WA), a leading scientific and regulatory consulting firm specializing in Generally Recognize as Safe (GRAS) and NDI filings, says that FDA’s request for more scientific data seems consistent with its ongoing stance that the agency needs more data on CBD to assess its safety—yet, he says, at the same time, the information the agency is requesting “is above and beyond what the FDA typically requires for an NDI, in my experience.”
“What they’re basically saying is, ‘We see what you put into the publication, but that’s not enough raw data that would have been provided with the study report.’ And you don’t normally put all of that into a manuscript,” he says. He continued: “I guess I would say I can understand them asking for it, just due to the controversial nature of it all, but it is probably more than what they typically ask for…”
The biggest concern to industry stemming from these two NDI objections is that even if FDA were to be satisfied on the safety data front, the agency still appears it will throw up a roadblock to CBD in supplements based on the drug-preclusion provision—meaning that with FDA alone there really is no legal avenue ahead for CBD.
“I think FDA made that very clear,” says Endres. “Sure, [FDA] would be willing to receive additional [scientific] information, and they even asked for it. So, Charlotte’s Web could submit additional information. But let’s pretend that FDA said, ‘That’s great. Okay, now we have no questions with regards to safety.’ They’re still going to say, ‘But it’s still a drug.’ So, they’re pushing this over to Congress, in my opinion.”
Mister says the same. “I think these letters are a very clear signal to the industry that if we want someone to solve the CBD situation, it’s going to have to be Congress.” Furthermore, he points out, with CBD in the waiting zone, and with CBD already available on the market to consumers, establishing a legal framework for CBD is urgent.
“I think the biggest message for CRN coming out of today’s announcements is that Congress needs to act on this quickly,” Mister says. “We need to assure consumers that the CBD marketplace has a strong regulatory framework around it and that consumers are not going to be left alone to figure out which products they should be using or not—and it appears now that the only way that’s going to happen is if Congress steps in and addresses this issue.”
Hemp industry advocate U.S. Hemp Roundtable (Washington) also released a statement in response to the NDI news. The group stated: "The U.S. Hemp Roundtable is deeply disappointed to witness FDA’s rejection of two dietary ingredient notifications (NDINs) recently submitted for full-spectrum hemp extracts. FDA’s actions send a discouraging message to the entire hemp and CBD industry, especially in light of the fact that these firms provided more than ample safety data and cooperated with FDA’s requests throughout the process. When held to the same regulatory standards as other dietary supplements and food ingredients, hemp-derived CBD products have a strong safety profile; the dangers to consumers are only posed by the unregulated marketplace that FDA continues to propagate."
It concluded: "This should be a clarion call to Congress that it is time to step in and pass legislation to ensure that CBD products are held to the same standard as all dietary supplements and food ingredients, and to reject an NDIN-only path. It’s been more than two and a half years since hemp was legalized by the 2018 Farm Bill, and without congressional intervention, the hemp farming industry will continue to struggle, and consumers stand to lose as well."
Given the roadblock shown to the CBD industry in the NDI objection letters, how should companies proceed on CBD? For instance, is it still worth their time to invest in scientific studies on CBD? Should they continue preparing NDI notifications for if and when CBD does become legal in supplements—but refrain from submitting any notifications to FDA at this time? (Editor’s note: Nutritional Outlook recently interviewed attorney Ashish Talati, partner at Amin Talati Wasserman LLP (Chicago), on this topic on its new The Nutritional Outlook Podcast. You can listen to that episode here.)
When asked how companies should proceed, Mister says, “Every company has to make its own business decisions based on their reading of the law, their willingness to take exposure, the business risk that they’re willing to assume. All of those things go into a company’s decision, so it’s not CRN’s place to recommend to the company what an individual company should do, but we are certainly laying out all of these factors to make sure that our companies are aware of the current situation, and there certainly does not appear to be much incentive right now to file an NDI notification for a full-spectrum hemp product, because FDA seems pretty dug in that they’re not even going to get into the safety issue; they’re going to reject it right off the bat on the basis of it being the same article. So, I don’t think there’s a lot of incentive for companies, but again, each company will have to make its own business decision.”
Endres says companies still have the option of going through the independent GRAS conclusion process, which some believe to be alternate pathway to market for CBD instead of an NDI notification. Short of that, he said, “If you feel the need to get the blessing of the FDA on a dietary supplement that contains CBD, I would probably prepare the NDI notification. I would probably have serious discussions with the FDA. I would probably ask them, ‘Are you just going to issue a letter like you issued to Charlotte’s Web and Irwin, just saying, “Hey, it’s a drug, and…you don’t have adequate data to support reasonable expectation of safety”? Now I would ask them that—because the companies were probably told something different and based on that submitted to FDA and might have been surprised to get these letters that they weren’t expecting.”
He continues: “The other thing is to consider other cannabinoids besides CBD that might have good activity for efficacy for various things because I believe they don’t have the same problem with the drug exclusionary clause.”
Or, he says, “The other thing I would say is wait for Congress and see what happens with this bill, and if it goes through, you’re going to need to do something—either do an independent conclusion of GRAS or you do an NDI notification. You’re going to have to do something, so if you’re interest is in selling a dietary supplement, then start working on the NDI, betting on Congress saying it’s going to be okay and making that exemption to the drug exclusionary clause for hemp and hemp-derived ingredients, and be ready to submit the NDI when the door is back open…”
Meanwhile, will these objection letters hurt Charlotte’s Web and Irwin Naturals down the road now that FDA has filed the notifications and noted its objection on record? Endres doesn’t think so. “No, I think they could resubmit, and it’s really going to be a matter of them satisfying the toxicology team at the Office of Dietary Supplement Programs. I think it’s doable as long as there’s the provision to get rid of the drug exclusion. Then it’s just inadequate safety data. So maybe the FDA wants to see more safety studies—and they probably do.”
Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA; Washington, DC), said in a press release that his association continues to stress the need for FDA to establish a safe-usage level for CBD in the U.S. He noted that the draft legislation in progress from Senator Schumer includes a provision to set such a safety level. Moreover, on the latest NDI news, he said, "Future NDI guidance without real clarity on cannabinoids, including CBD, doesn’t help the millions of Americans who already believe FDA regulates the space. The response to this NDI indicates that there is confusion and misunderstanding on all sides of the issue, and it must be addressed by the forthcoming guidance. There have to be clear safety rules and thinking on these matters."
Updated August 16, 2021, 11:00 AM PST, with comments from Natural Products Association and U.S. Hemp Roundtable.