FDA warnings that dietary supplements containing cannabis extract cannabidiol are adulterated because the substance is being studied as an investigational new drug leave open a door for firms to convince the agency that the ingredient's use in supplements pre-dates the INDs.

The warning letters published Feb. 10 to six firms making disease claims for their products are the agency's first since its April guidance that the cannabis extract cannabidiol's use in INDs renders the ingredient noncompliant for use in supplements.

"What is of note here is that, previously, the FDA had not issued any warning letters to companies taking issue with CBD oil as a dietary ingredient," said Justin Prochnow, a food and supplement law attorney with Greenberg Traurig LLP in Denver.

The latest policy statement on supplements containing cannabis-derived ingredients also comes a year after FDA submitted warnings to other firms making similar claims that stopped short of saying the ingredients are noncompliant ([A#05150309006]).

None of the six firms (see box below) is identified as a medical marijuana distributor and FDA's warnings likely will not influence distribution of those products in states that allow the sales. However, the agency makes clear through the six warnings that products marketed as dietary supplements that contain CBD are adulterated, even when no disease claims are made.

"FDA is not aware of any evidence that would call into question its current conclusion that CBD products are excluded from the dietary supplement definition" under FDA regulations due to the ingredient's use in IND studies, "but you may present the agency with any evidence that has bearing on this issue," the agency says in the warnings letters to the firms.

Cannabis INDs Are Known

"The existence of substantial clinical investigations regarding CBD has been made public," FDA says in warning letters to:

Products containing "a substance (such as CBD) … 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 … are outside the definition of a dietary supplement," according to the letters.

The letters state that the "existence of substantial clinical investigations regarding CBD has been made public," noting UK firm GW Pharmaceuticals PLC’s INDs announced in 2007 for a drug branded Sativex indicated for treatment of pain in patients with advanced cancer, and in 2014 for a drug branded Epidiolex for the treatment of Dravet syndrome, a rare form of childhood epilepsy.

The letters, submitted from the compliance directors in FDA's food safety and drug centers, rather than district offices of the Office of Regulatory Affairs – the sources of most supplement product warnings, add that an ingredient used in supplements before an IND began for the substance is exempt from the ban, but "based on available evidence, FDA has concluded that this is not the case for CBD."

FDA also warned two other firms – Green Garden Gold LLC, Dallas; and Morguetorium LLC, Thackerville, Okla. – without discussing whether their products also are adulterated due to the ingredient's use in INDs. Each of the eight warning letters explains that FDA's action followed reviews of the firms' websites, including pages on third-party online commerce or social media sites that some firms posted.

The letters do not refer to FDA officials inspecting the firms' manufacturing or processing plants and do not advise any of the firms of being noncompliant with supplement good manufacturing practices.

The disease claims are common among many products marketed as supplements but making violative claims and run the gamut from curing or preventing multiple forms of cancer to treating spinal cord injuries, and from relieving respiratory allergies and easing neurological impairments.

American Herbal Products Association President Michael McGuffin said regardless of a supplement product's formulation, making a drug claim is "clearly a magnet for the Food and Drug Administration's attention."

"It continues to be a main focus of the Food and Drug Administration to go after those companies that are making blatant drug claims," McGuffin said.

Additionally, FDA warned each firm that the adulterated products are misbranded due to the absence of adequate instructions for the intended use stated in the claims.

Door Open For Proof

The warnings on CBD-containing supplements FDA submitted in March 2015, like the recent warnings, pointed out disease claims for the products. However, the earlier warnings did not include statements on cannabis ingredients already being studied in INDs and on those ingredients not be allowed for use in supplements.

FDA added the IND information to its policy on whether supplements containing cannabis-derived ingredients are adulterated in a guidance, published in a quester-and-answer format, it posted on its website in April partly in response to the rapid growth of the market for supplement products made with cannabis- or hemp-derived ingredients in addition to an increase in states allowing sales of medical marijuana or of small amounts for personal use.

RedStrap brand products marketed by Dose of Nature are among the dietary supplements containing cannabidiol that FDA says are adulterated because the substance is being studied as an investigational new drug.

FDA's latest warning letters are not likely to slow the marketing and sales of cannabis-based ingredient supplements, but could spur firms to submit proof to the agency that CBD was available in the US in products marketed as supplements before the substance was approved for IND studies or to contest the agency's conclusions in some other way.

Prochnow said the warnings "put the ball in the court of the companies receiving the letters."

"It may take something a little more drastic than FDA warning letters" to slow the market's growth, said Will Woodlee, a partner at Kleinfeld, Kaplan & Becker LLP in Washington.

The marketplace of supplements containing CBD and other cannabis or hemp extracts is "so far advanced," McGuffin said, removing all of the products is "an unlikely regulatory requirement"

Woodlee said a firm marketing supplements containing CBD-based ingredients only for the past several years would be hard-pressed to document that supplements with those ingredients were available in the US before the CBD INDs were started.

However, FDA does not have information handy on US consumers pre-IND purchases of supplement products containing CBD.

"FDA doesn't and couldn't have access to that kind of information in any absolute sense," Woodlee said in an interview.

Evidence of those products' availability "before those INDs were in effect could potentially allow a company to turn FDA's conclusion," he said.

Alternatively, responses to the warnings that challenge FDA by, for instance, stating the INDs the agency noted are not applicable to the forms of CBD oil used in the supplement products or that the CBD oil investigations were not substantial, as required by the regulation, could prompt additional consideration by FDA officials.

"If the companies acquiesce and agree to discontinue the products or reformulate without CBD Oil (it is tough to do that when CBD is in your product name), the issue is somewhat concluded," Prochnow said in an email.

While AHPA supports FDA enforcement against products marketed as supplements but making drug claims, McGuffin noted that the six firms warned about CBD being an IND might have room to argue that their products are not subject to the ban.

"That's a question worth examining by any company that's marketing a supplement containing a cannabidiol ingredient," McGuffin said.

Meanwhile, CBD oil firms "will be watching closely to see what responses there are to the letters (those are generally not made public) and what action, if any, the FDA takes," Prochnow said.

FDA's Initial IND Warnings For CBD Supplements Could Ignite Regulatory Test

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