This is the second installment in our series on the Food and Drug Administration (“FDA”) and hemp-derived CBD (“Hemp-CBD”). Our last post focused on the Drug Exclusion Rule, which essentially states that an article cannot be marketed as a dietary supplement if it was investigated or approved as a drug before the article was marketed as a dietary supplement (or food). Today, we’ll take a look at what that use of “before” really means.
Prior Market Clause
A key component of the Drug Exclusion Rule is that the article at issue was not previously marketed before the article was evaluated or approved by the FDA (the “Prior Market Clause”). So what does it mean to “market” a product? Helpfully, the FDA FAQs link to Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues (“NDI Guidance”) to provide an explanation of the phrase “marketed as.”
The NDI Guidance, which like the FDA FAQs is nonbinding, elaborates on the idea of “marketing”:
“FDA considers ‘marketing’ a dietary ingredient to mean selling or offering the dietary ingredient for sale (1) as or in a dietary supplement, (2) in bulk as a dietary ingredient for use in dietary supplements, or (3) as an ingredient in a blend or formulation of dietary ingredients for use in dietary supplements. A dietary ingredient may be “marketed” by offering the article for sale online or at a retail establishment, listing it for sale in a catalog or price list, or through advertising or other promotion, if the promotion makes clear that the article is available for purchase. ‘Coming soon’ advertisements would not qualify.”
The NDI Guidance goes on to state “[i]n considering whether a substance has been ‘marketed as a dietary supplement or as a food,’ FDA looks for evidence of one of the following:
“1. Evidence that the substance itself was sold or offered for sale in the U.S. as a dietary supplement, dietary ingredient for use in dietary supplements, or conventional food. For example, a catalog listing a product identified as a ‘Substance A supplement’ would establish the marketing of Substance A as a dietary supplement. Similarly, business records documenting that a substance was sold or offered for wholesale or retail sale for use as an ingredient in a conventional food would establish the marketing of the substance as a food.
2. Evidence that the substance was a component of a food or dietary supplement that was sold or offered for sale in the U.S., and that a manufacturer or distributor of the food or dietary supplement marketed it for the content of the substance by, for example, making claims about the substance or otherwise highlighting its presence in the product. For example, in Pharmanex v. Shalala, the firm marketed lovastatin, a component of its red yeast rice product Cholestin, by promoting the lovastatin content of Cholestin. Merely showing that the substance was present as a component in a marketed food would not be enough to show that the substance was ‘marketed,’ however.”
Red Yeast Rice
The NDI Guidance’s reference to Pharmanex v. Shalala is of note as that case may have a major bearing on Hemp-CBD. Back in April 1997, the FDA issued a warning letter to Pharmanex, stating that it was selling a drug as a dietary supplement. Pharmanex manufactured Cholestin, a dietary supplement derived from red yeast rice intended to promote healthy cholesterol levels. Cholestin contained the substance mevinolin. Mevinolin was chemically identical to lovastatin, the active ingredient in the prescription drug Mevacor. The FDA approved Mevacor back in 1987. The FDA advised Pharmanex that it considered Cholestin to be a drug which could not be marketed without FDA approval. Pharmanex argued that red yeast rice had been used a food ingredient for thousands of years. The FDA was not convinced, ultimately holding that Cholestin containing lovastatin did not meet the definition of a “dietary supplement” because lovastatin was an “article” that had already been approved as a drug. The FDA determined that Cholestin did not satisfy the Prior Marketing Clause because it did not contain red yeast rice as that product had traditionally been manufactured and marketed. The FDA ran tests on samples of red yeast rice and found small amounts of lovastatin. In the FDA’s view, Pharmanex had manipulated red yeast rice to increase the lovastatin content and therefore the Drug Exclusion Rule applied.
Pharmanex challenged the FDA’s ruling in district court. The district court set aside the FDA’s decision, agreeing with Pharmanex that the term “article” as used in the FDCA did not refer to a single ingredient in a drug. The Court of Appeals for the Tenth Circuit reversed, holding that “article” could include the active ingredients of approved new drugs, such as lovastatin, which would exclude them from the dietary supplement definition. On remand, the district court affirmed the FDA’s original conclusion that lovastatin was not marketed as a dietary supplement or food before the FDA approved Mevacor as a prescription drug.
Cholestin containing lovastatin is no longer on the market in the US. There are still red yeast rice supplements available but the FDA monitors whether those supplements contain more than the naturally occurring amount of lovastatin.
The Future of Hemp-CBD
The Pharmanex case could dictate how the FDA treats Hemp-CBD. Hemp contains many active compounds, including cannabinoids like CBD and terpenes. Hemp can be processed in a number of ways, some of which will isolate these active compounds. Chemical extraction methods can isolate these active compounds while removing water, fiber, and other unwanted material. Alternatively, hemp can be processed without the use of chemicals (e.g., dried flowers; chopped up plant material placed in pellets, etc.).
“Full spectrum” extracts are the extracts that contain a wide array of compounds found in the hemp plant, including cannabinoids and terpenes. Processors can also isolate specific compounds by repeatedly extracting and refining the compound. Epidiolex is an example of a CBD isolate. A CBD isolate generally contains almost no other compounds. In turn, full spectrum extracts contain trace amounts of CBD and their compounds.
Following the reasoning in Pharmanex, CBD isolate may be subject to the Drug Exclusion Rule, but processed hemp, including full spectrum extracts may not due to the Prior Marketing Clause. This is because like Red Yeast Rice, hemp has been consumed as food and medicine for thousands of years. Hemp is not the same as the CBD isolate. The Pharmanex case turned on the an interpretation of the term “article.” CBD isolate is the article that was approved as a drug. Full spectrum extracts and other processed hemp products that contain naturally occurring CBD also may be outside of the scope of the Drug Exclusion Rule by way of Epidiolex. In turn, CBD isolate or processed hemp that had isolated and increased CBD could only legally be sold as drugs.
Though the parallel between Hemp-CBD and red yeast rice are impossible to ignore, there is no gaurantee that the FDA will take the same exact approach. For one, perhaps it can be established that CBD, in its isolated form was marketed prior to the Epidiolex studies being made public. CBD was first discovered by Dr. Roger Adams at the University of Illinois in 1940. However, any marketing of CBD isolate prior to the first Epidiolex investigations in 2014, would have likely violated federal law because the 2014 Farm Bill was not yet in effect, making it illegal under federal law.
However the FDA’s statement following the 2018 Farm Bill included some very interesting language:
”[P]athways remain available for the FDA to consider whether there are circumstances in which certain cannabis-derived compounds might be permitted in a food or dietary supplement. Although such products are generally prohibited to be introduced in interstate commerce, the FDA has authority to issue a regulation allowing the use of a pharmaceutical ingredient in a food or dietary supplement. We are taking new steps to evaluate whether we should pursue such a process.”
The FDA Secretary can override the Drug Exclusion Rule by issuing “a regulation, after notice and comment, finding that the article would be lawful under [the FDCA].” The statement also went onto ask for input on the future of Hemp-CBD:
“Given the substantial public interest in this topic and the clear interest of Congress in fostering the development of appropriate hemp products, we intend to hold a public meeting in the near future for stakeholders to share their experiences and challenges with these products, including information and views related to the safety of such products.”
We will continue to monitor the FDA for additional updates on Hemp-CBD.
2. 有证据表明，这种物质是在美国出售或出售的食品或膳食补充剂的成分，以及食品或膳食补充剂的生产商或分销商就该物质的含量进行营销，例如，对该物质作出声明或以其他方式强调其在产品中的存在。例如，在Pharmanex v. Shalala一案中，该公司通过提高洛伐他汀的胆石含量来推销其红曲米产品胆石的成分洛伐他汀。然而，仅仅表明这种物质作为一种成分存在于已上市的食品中，并不足以表明这种物质已上市。
值得注意的是，NDI指南中提到的Pharmanex v. Shalala一案可能对大麻cbd产生重大影响。早在1997年4月，FDA就向Pharmanex发出了一封警告信，声明其正在销售一种作为膳食补充剂的药物。Pharmanex公司生产胆石，一种从红曲米中提取的膳食补充剂，旨在促进健康的胆固醇水平。胆石中含有mevinolin物质。Mevinolin的化学成分与处方药Mevacor中的活性成分洛伐他汀相同。FDA早在1987年就批准了Mevacor。FDA建议Pharmanex认为胆石是一种未经FDA批准不能上市的药物。Pharmanex公司认为红曲米作为一种食品原料已经有几千年的历史了。FDA并不相信，最终认为含有洛伐他汀的胆石不符合膳食补充剂的定义因为洛伐他汀是一种已经被批准为药物的药物。FDA认定胆石不符合先前的销售条款，因为它不包含传统上生产和销售的红曲米。FDA对红曲米样品进行了检测，发现了少量洛伐他汀。FDA认为，Pharmanex公司操纵红曲米，以增加洛伐他汀的含量，因此适用药物排除规则。