Lessons from Red Yeast Rice: Factors to Consider Regarding FDA’s Position on CBD Supplements

By Celeste D. Wheeler, James William Woodlee, and Anthony L. Young

Last week, FDA posted eight warning letters issued to companies marketing products labeled as dietary supplements containing cannabidiol (CBD).  CBD is one of the more than 80 active cannabinoid chemicals derived from the Cannabis plant and is believed to have potential analgesic, anti-seizure, anti-inflammatory, anti-psychotic, anti-anxiety, antioxidant, and neuro-protective properties.[1]  These warning letters asserted that the products at issue were marketed to treat a variety of diseases including cancer, multiple sclerosis, and Alzheimer’s.  FDA therefore warned the companies that the Agency considers these products unapproved new drugs.  In six of the eight letters, FDA also reiterated the Agency’s position, first outlined in 2015 on its FDA and Marijuana: Questions and Answers webpage, that the dietary supplement definition under section 201(ff)(3)(B)(ii) of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. § 321(ff)(3)(B)(ii)) excludes CBD products because of the existence of publicized and substantial Investigational New Drug (IND) clinical investigations involving CBD.  Although this position is not new, its application to particular CBD-product-marketing companies is new and has generated controversy and uncertainty for the CBD industry.  As discussed in greater detail below, the case of Pharmanex v. Shalala (involving Cholestin and red yeast rice), and the administrative proceeding regarding pyridoxamine, other instances in which FDA invoked an exclusion to block use of an alleged new drug ingredient in dietary supplements, provide a useful lens through which to understand FDA’s position.  The Pharmanex case and pyridoxamine proceeding also provide a framework and lessons to consider in evaluating a potential CBD supplement industry approach to FDA’s recent escalation of the situation.

Background on DSHEA and CBD’s Status

The Dietary Supplement Health and Education Act of 1994 (DSHEA) created a new class of food products, dietary supplements, containing one or more “dietary ingredients,” which the law defined as a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any of these ingredients.  21 U.S.C. § 321(ff)(1).  CBD is a constituent of a botanical—in most cases, the cannabis plant—and so it meets the definition of a dietary ingredient.  However, there is an exclusion clause in the definition of “dietary supplement” that provides that any article that is an approved new drug or was authorized for research purposes as an IND before it was marketed as a food or dietary supplement cannot be marketed as a dietary supplement if the drug is approved or if substantial clinical investigations of the article have already begun and the existence of those investigations has been made public.  21 U.S.C. § 321(ff)(3)(B)(i), (ii).  This is the clause that FDA alleges applies to CBD supplement products.

While not referred to by FDA on its Question and Answer webpage or in the warning letters in question, the “new dietary ingredients” section of DSHEA provides that a dietary supplement is adulterated unless it either (1) contains only dietary ingredients that have been present in the food supply as an article used for food in a form in which the food has not been chemically altered or (2) the manufacturer or distributor notifies FDA that it intends to introduce a new dietary ingredient into the U.S. market and provides evidence of safety.  21 U.S.C. §§ 350b, 342(f).  The law defines a “new dietary ingredient” as an ingredient that was not marketed in the U.S. before October 15, 1994.

As FDA noted in the Question and Answer webpage referenced above, FDA states that at least two CBD studies have already begun and been publicized: the investigations regarding Sativex and Epidiolex sponsored by GW Pharmaceuticals.  In 2006, GW announced that FDA had accepted its IND application for Sativex, an oromucosal spray containing both tetrahydrocannabinol (THC) and CBD intended to treat pain in cancer patients.[2]  GW has also publicized FDA’s acceptance of multiple INDs for Epidiolex, a product candidate containing CBD that is designed to treat Dravet syndrome, Lennox-Gastaut, and other pediatric epilepsy syndromes.[3]  In the six warning letters and on its webpage FDA asserted that CBD was not “marketed as” a dietary supplement or as a conventional food before FDA accepted these INDs, thereby precluding its marketing as a dietary supplement.  FDA based its conclusion on its review of the “available evidence” but encouraged the recipients of the warning letters as well as stakeholders generally to provide evidence bearing on this issue.  As explained below, the webpage invitation does not represent the initiation of a formal administrative proceeding, which FDA has previously used to determine whether the definition of “dietary supplement” excludes a particular article.  Moreover, despite FDA’s publicizing of warning letters, these are specific to the recipient companies and do not initiate any formal administrative proceeding.

The Pharmanex Example

In April 1997, Pharmanex, the manufacturer of Cholestin, a red yeast rice dietary supplement, found itself in a similar position.  Cholestin contained mevinolin (also known as monocalin K), a substance that is chemically identical to the active ingredient in the approved new drug Mevacor (lovastatin).  On this basis, FDA advised Pharmanex of its position that Cholestin was a drug requiring FDA’s approval for marketing and detained Cholestin that the company had attempted to import.  Counsel for Pharmanex maintained that red yeast rice was an ingredient with a documented history of food use going back nearly a millennium.[4]  After a series of meetings regarding this issue, Pharmanex filed a petition for FDA to stay its action on Cholestin.  Although FDA determined that there was no agency action to stay, it decided to open an administrative docket to consider the issues relevant to the marketing of Cholestin supplements.[5]  FDA ultimately decided against Pharmanex with respect to Cholestin.[6]  In FDA’s view, Pharmanex’s product did not contain traditional red yeast rice as that product had historically been manufactured and sold.[7]  Instead, Pharmanex had specifically manipulated its Cholestin supplement through the production process so that it would contain higher levels of lovastatin.  The company had also promoted the product’s lovastatin content in materials directed at pharmacists.[8]  Accordingly, FDA concluded that Cholestin containing lovastatin was an “article” that had already been approved as a drug and was therefore excluded from the definition of “dietary supplement.”[9]

Following the adverse administrative decision, Pharmanex filed suit seeking a declaration that the FDA decision was arbitrary, capricious, and not in accordance with law.  The district court agreed with Pharmanex that the term “article” did not refer to a mere ingredient in a drug.[10]  However, the appellate court reversed,[11] agreeing with FDA in finding that a previously approved “article” could include a specific active ingredient or the approved drug product itself.  The court expressed concern that permitting manufacturers to market dietary supplements with identical active ingredients to approved new drugs would undermine the new drug development process.  On remand, the district court affirmed FDA’s conclusion that lovastatin was not marketed as a dietary supplement or as a food prior to 1987 (the year that FDA approved the NDA for Mevacor).[12]  A product named Cholestin is now marketed by NuSkin, but it does not contain red yeast rice.[13]  Cholestin containing red yeast rice is no longer available as a dietary supplement in the United States.[14]  However, dietary supplements that contain red yeast rice are widely marketed, and FDA tests such products from time to time to determine if they contain lovastatin at or below the levels of traditional red yeast rice products.[15]

Although the outcome of the Pharmanex case was ultimately negative for the dietary supplement manufacturer, the case history provides lessons for manufacturers and distributors of dietary supplements containing CBD regarding a formal resolution of CBD’s status as a dietary supplement ingredient.  FDA’s action to detain Cholestin began after a pharmacist filed a complaint about the product, presumably because of its similarity to a known, marketed drug.  After meeting with FDA on its own initially, Pharmanex convinced FDA to seek public input on the issues surrounding the proper regulatory status of Cholestin’s dietary supplement ingredient and to allow its import and continued marketing during the pendency of that proceeding.  In the end, FDA’s decision turned on the specific facts concerning how the product was manufactured and promoted, including that it had been engineered to have levels of lovastatin more similar to those found in an approved new drug than to the levels found in traditional red yeast rice products.  Nearly four years elapsed from the time FDA initiated the administrative proceeding to the final court decision affirming FDA’s findings.  Cholestin remained on the market during that time.

In a similar case, Biostratum filed a petition with FDA to request that it take action against manufacturers of pyridoxamine supplements because Biostratum manufactured pyridoxamine dihydrochloride, which was the subject of an IND application.[16]  FDA concluded there that products containing pyridoxamine were excluded from the definition of “a dietary supplement” because pyridoxamine was authorized for an investigation as a new drug and there was no good evidence of prior marketing of pyridoxamine in dietary supplement type products prior to the passage of DSHEA.[17]  Again, the decision turned on the inadequacy of the factual support regarding prior marketing provided by the supplement industry.  Biostratum began asking FDA to take action regarding pyridoxamine in July 2005, and the FDA finally decided the matter in January 2009.  Pyridoxamine supplements remained on the market during those three and a half years.

In the case of CBD, FDA has already informally invited public comment on whether evidence exists that CBD was marketed as a dietary supplement or as conventional food before the start of substantial clinical investigations involving CBD.  This openness to other evidence and the red yeast rice and pyridoxamine precedents suggest a potential openness to an administrative proceeding and a formal resolution.  But more likely it is the proverbial invitation by the spider to the fly, unless the CBD industry can gather substantial information to rebut FDA’s present view.  Accordingly, before the CBD industry jumps at FDA’s informal invitation and seeks a more formal resolution, the industry must gather and evaluate the factual support showing that CBD-containing supplements or foods (e.g., hemp products) have a long marketing history.  Given the uncertainty created by FDA’s pronouncements on CBD over the past year, CBD-supplement manufacturers and distributors seeking clarity on the future of these products should consider joining forces to examine the factual predicates available to challenge FDA’s preliminary determination about CBD dietary supplements.

The CBD industry has had substantial support from families who believe children with severe epilepsy not responsive to conventional therapy respond well to CBD products.  Those families have become patient advocates for state and federal laws that make or would make CBD lawful for a variety of uses.  This movement, along with the passage of state laws making the use of marijuana lawful for medical and even recreational use, would provide a strong base to seek FDA recognition of CBD as an acceptable ingredient in dietary supplements.

Note that, even if the CBD industry cannot marshal sufficient evidence of prior marketing of CBD dietary supplements or foods, the law provides a potential pathway for CBD dietary supplements.  The last part of the approved drug/investigational drug exclusion from the definition of a “dietary supplement” contains the following proviso: “unless the Secretary, in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this Act.”  In FDA’s Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues IV. D. 8 (July 2011), FDA provides its interpretation of this language as follows:

The general rule is that an article that has been authorized for investigation as a new drug or as a biologic before being marketed as a food or as a dietary supplement cannot be marketed as a dietary supplement if substantial clinical investigations of the article have begun and the existence of such investigations has been made public. FDA can create an exception to this prohibition by regulation, but only if the agency finds that the use of the article in dietary supplements would be lawful. To date, no such regulations have been issued. The appropriate mechanism to request such a regulation is to file a citizen petition under 21 CFR 10.30.

From red yeast rice and Pharmanex, pyridoxamine, and, so far, CBD, the dietary supplement industry should understand that administrative processes and proceedings involving disputed ingredients take a relatively long time from beginning to end, require substantial fact finding and analysis to show that a product was a dietary supplement or food first and an approved or investigational new drug second, and, in the end, DSHEA itself provides for a citizen petition to have FDA simply declare the ingredient lawful.  Given its botanical origin and strong grass roots support, CBD could make an interesting candidate for this regulatory override option.

[1] See Drug Caucus Hearing on Barriers to Cannabidiol Research Before the S. Caucus on International Narcotics Control, 114th Cong. (2015) (statement of Nora Volkow, M.D., Director, National Institute on Drug Abuse), available at http://www.drugcaucus.senate.gov/sites/default/files/Volkow.pdf.

[2] FDA Accepts Investigational New Drug Application for Sativex, Press Release (2006), available at http://www.gwpharm.com/fda-accepts-application.aspx.

[3]GW Pharmaceuticals Provides Update on Orphan Program in Childhood Epilepsy for Epidiolex, Press Release (2013), available at http://www.gwpharm.com/GW%20Pharmaceuticals%20Provides%20Update%20on%20Orphan%20Program%20in%20Childhood%20Epilepsy%20for%20Epidiolex.aspx.

[4] See Dietary Supplement Health and Education Act: Is the FDA Trying to Change the Intent of Congress? Before the H. Committee on Government Reform, 106th Cong. 97-100 (1999) (statement of Daniel A. Kracov).

[5] See FDA Docket No. FDA-1997-P-0065, available at http://www.regulations.gov/#!docketDetail;D=FDA-1997-P-0065.

[6] See Letter from William B. Schultz to Stuart Pape (May 20, 1998), available at http://www.fda.gov/ohrms/dockets/dockets/97p0441/ans0002.pdf.

[7] Id. at 21.  As FDA’s administrative decision letter explains, traditional red yeast rice is manufactured at culturing temperatures of 33 to 42 degrees Celsius, which does not produce significant amounts of lovastatin.  In fact, of eleven products sampled by FDA, eight had no lovastatin, two had levels of 0.012%, and one had 0.066%.  These were all well below the lovastatin content FDA found in Cholestin.

[8] Id. at 10-11.

[9] See 21 U.S.C. § 321(ff)(3)(B)(i).

[10] See Pharmanex, Inc. v. Shalala, 35 F. Supp. 2d 1341 (D. Utah 1999).

[11] See Pharmanex v. Shalala, 221 F.3d 1151 (10th Cir. 2000).

[12] Pharmanex, Inc. v. Shalala, No. 2:97CV262K, 2001 U.S. Dist. LEXIS 4598 (D. Utah Mar. 30, 2001).  While the CBD warning letters focus on the exclusion under21 U.S.C. § 321(ff)(3)(B)(ii), the Cholestin case involved 21 U.S.C. § 321(ff)(3)(B)(i), which excludes from the definition of “dietary supplement” articles that have been approved for marketing as drugs, antibiotics, or biologics.

[13]Cholestin, https://www.nuskin.com/content/nuskin/en_CA/products/pharmanex/targeted_treatments/heart_health/02003611.html

[14] Mayo Clinic, Red Yeast Rice, http://www.mayoclinic.org/drugs-supplements/red-yeast-rice/background/hrb-20059910 (last updated Nov. 1, 2013).  Note, however, that FDA periodically issues warning letters to companies marketing red yeast rice products with high levels of lovastatin.

[15] See note 7 supra.

[16] Biostratum Citizen Petition, No. FDA-2005-P-0259-0005 (July 29, 2005).

[17] See FDA Response to Biostratum Citizen Petition, No. FDA-2005-P-0259-0005 (January 12, 2009).