Drug preclusion and public health: The case for a narrow interpretation of ‘article’

The definition of “dietary supplement” in the Food, Drug, and Cosmetic (FD&C) Act includes several provisions limiting what can be a legal dietary supplement based on the ingredients used and delivery form, as well as whether a substance has a history of drug use. This article explores the US Food and Drug Administration’s (FDA’s) use of this last provision, often called “drug preclusion.” The authors examine the history of the provision, Congress’s purported purpose for inclusion in the definition of “dietary supplement,” how it has been interpreted over the years, and concerns that an overly broad interpretation harms both businesses and consumers.

 

Keywords – drug article, drug exclusion, drug preclusion, grandfathered ingredients, n-acetyl-l-cysteine

 

Introduction

In 1994, the US Congress passed the landmark Dietary Supplement Health and Education Act (DSHEA)¹ that amended the FD&C Act² and created dietary supplements as a unique category of regulated product. This positioned supplements as a food subcategory governed under the food regulatory framework and a new set of requirements specific to dietary supplements. Preserving consumer access to safe, beneficial health products was a key driver for Congress in enacting this legislation. Access to these products was deemed important to consumer health and regulating them in a manner that preserves that access fits squarely within the FDA’s mission to protect public health. Over the years, however, the agency seems to have interpreted provisions of DSHEA in an overly broad manner that unnecessarily limits consumer access and unevenly favors public health for drug development.

When enacting DSHEA, Congress recognized the need to balance drug interests with this new regulatory category where ingredients from both categories could overlap. To ensure supplements would not limit drug research and development incentives and to prevent unscrupulous companies from using the supplement category to bypass the drug approval process, Congress enacted a “race-to-market” provision to prevent loopholes and protect incentives for drug research and development. This provision is often referred to as “drug preclusion.” This language was included in Section 201(ff)(3)(B) of the FD&C Act and excludes from the definition of dietary supplement:

 

An article that is approved as a new drug under Section 355 of this title, certified as an antibiotic under Section 357 of this title, or licensed as a biologic under Section 262 of title 42; or

An article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food 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 chapter.³

 

In other words, a substance that was first approved as a drug or was the subject of substantial public clinical drug studies before being marketed as a dietary supplement or food cannot be used in dietary supplements unless the FDA issues a regulation allowing its use.

The purpose of drug preclusion was twofold: To protect the commercial interests necessary to incentivize drug development and to prevent bad actors from using the supplement product category to bypass drug approval. However, the language in the drug preclusion provision recognizes that ingredients found in supplements and drugs would coexist. For example, supplements marketed before drug use may remain on the market even after drug approval or substantial drug research has been conducted. Congress also provided the FDA the discretion to issue regulations allowing an article to be used in a dietary supplement despite determining the substance was first used as a drug. The agency has never used this rulemaking authority since it was granted more than 25 years ago.

 

Since the enactment of drug preclusion in 1994, FDA statements defining the scope of the term “article” have been broad and general, failing to adequately provide the dietary supplement industry with clarity about which substances will be blocked from use in dietary supplements under this provision. The most recent FDA statements interpreting this provision set a dangerous precedent; limit access to safe, beneficial supplement products; and give drug companies an almost absolute monopoly over substances that should otherwise be available to consumers as supplements.

 

Within the dietary supplement framework, however, narrowly defining the precluded article is unlikely to disincentivize drug research and development or encourage nefarious behavior for a number of reasons. In fact, properly balancing supplement and drug interest could stimulate research, which in turn would continue to improve public health. For example, the dose discrepancy between dietary supplements and drugs would help preserve the research space aimed at exploring ingredients’ effects as drugs. In addition, the clear legal distinction between the intended use of a dietary supplement and a drug also helps preserve the incentive to invest in medical research for comparable substances and would prevent bad actors from marketing supplements as alternatives to approved drugs. For example, in the case of fish oils, one of the most popular and rapidly growing dietary supplement product categories, the coexistence of the ingredient in dietary supplement form and drug form did not discourage investment in medical research. On the contrary, it is likely that success in the dietary supplement space was a factor in stimulating the investment in drug development, leading to the development of a fish oil-based prescription drug. The FDA’s failure to abide by Congress’ intentions and balance drug and supplement interests in a manner that ensures consumer access and protects overall public health has resulted in a one-way monopoly for the use of ingredients in favor of the drug industry over dietary supplements.

 

This article will discuss FDA and court interpretations of the drug preclusion provision and a possible solution to uphold the intent of the drafters of DSHEA, which was to “protect the right of access of consumers to safe dietary supplements … in order to promote wellness.”⁴

 

Interpretation of drug preclusion language

A narrow interpretation of drug preclusion is merited to achieve both the DSHEA goals and the drafters’ intent when including the drug provision language in this landmark act. As already discussed, the two main purposes of drug preclusion were to protect drug investments and prevent companies from circumventing the drug approval process. A narrow interpretation achieves these purposes – preventing companies from marketing dietary supplements that are substantially similar to drug products – but still preserves consumer access to other forms, doses, and intended uses of a substance as a dietary supplement. Drug preclusion should not confer monopoly status for all forms, amounts, and intended uses on dietary ingredients first used as a drug.

 

In interpreting the drug preclusion clause, the FDA, industry, courts, and other stakeholders have focused closely on what the drafters meant by the term “article” in the statute. The article is what is precluded from being used as a dietary ingredient if the drug preclusion clause applies. The legislative history related to this provision and post-DSHEA enactment interpretations by the FDA and courts are limited. The most notable case interpreting the scope of drug preclusion, Congress’s intent, and the definition of “article” is a federal appellate court case from 2000, Pharmanex Inc. v. Shalala.⁵

 

The case involved the presence of red yeast rice in a product marketed as a dietary supplement under the name Cholestin. Red yeast rice naturally contains a substance called monacolin K, or lovastatin, that is identical to the active ingredient in the prescription drug Mevacor, which was approved by the FDA in 1987 for treating high cholesterol levels. The agency recognizes red yeast rice as an appropriate dietary ingredient under Section 201(ff) of the FD&C Act, and traditional red yeast rice has been sold for decades in the US. In the case of Cholestin and its red yeast rice content, however, the agency alleged that the red yeast rice used in the product had been purposefully cultivated to contain high levels of lovastatin that, according to the FDA, were higher than the levels found in traditional red yeast rice. Pharmanex, the manufacturer of Cholestin, also marketed the product for its lovastatin content and, in some marketing material, compared Cholestin with the prescription drug Mevacor by pointing out that lovastatin found in Cholestin is the same as the active ingredient used in Mevacor.

 

In an FDA administrative decision, the agency found that the lovastatin used in Cholestin was an “article approved as a new drug” under the drug preclusion clause because it contained the active ingredient in Mevacor; therefore, lovastatin could not be marketed as a dietary supplement because Mevacor was approved as a drug before Pharmanex marketed its lovastatin containing supplement.⁶ Pharmanex challenged this FDA determination in the US District Court for the District of Utah.⁷ The district court ruled in favor of Pharmanex, finding that only finished drug products, not individual active ingredients like lovastatin, can be considered “articles approved as new drugs.”⁸

 

The US Court of Appeals for the Tenth Circuit reversed the decision, upholding the agency’s interpretation of the term “article” to include active ingredients as well as the finished drug products.⁹ According to the Tenth Circuit, the term “article” is used throughout the FD&C Act to refer both to finished drug products and the drug products’ components. The drug preclusion clause does not distinguish which definition the DSHEA drafters intended to be used here, making the use of this term ambiguous. The Tenth Circuit, therefore, determined that they must give deference to the FDA’s interpretation under US legal precedent that favors an agency’s interpretation of an ambiguous law.¹⁰

 

However, the Tenth Circuit determination was limited to a narrow question about the scope of the term “article,” as that term is used in other sections of the FD&C Act. This decision is only the opinion of one federal circuit. It is not binding on other courts outside of the Tenth Circuit and still leaves important open questions about drug preclusion, such as:

• What scientific and other parameters should be used to determine when substances are the same “article;”
• Whether dose, form, and intended use should be taken into consideration;
• Whether the provision applies to substances that coexisted as supplements and drugs before DSHEA passage; and
• Other critical questions about the timing of drug versus supplement use for the “race-to-market” provisions.

 
For example, the courts in the Pharmanex case did not have to determine if the lovastatin in Cholestin was scientifically the same as the active ingredient in Mevacor because that issue was not challenged in court. In answering these questions, the FDA also should remember the unique context around the case and that the company engaged in a number of actions, according to the agency record, that the drafters of the drug preclusion clause would likely believe were the reason for including the language in DSHEA — namely, that Pharmanex manufactured and marketed Cholestin for its similarities to a prescription drug. Where supplements and drugs are intended for use in distinctly different manners (e.g., dose amounts, forms, supporting health versus treating a disease), such products can easily coexist and may complement each other.
 
Important open questions that the industry has pushed the FDA to answer, with limited engagement from the agency, include:
 

• What happens when a substance undergoes substantial clinical trials, but those trials are abandoned, and a company subsequently wants to use the substance in dietary supplements?
• What does it mean to have an identical active ingredient ‒ how should dose, form, biological mechanism of action, intended use, and other parameters be used in this analysis? and
• Should substances used as dietary supplements pre-DSHEA enactment be precluded from current supplement use because of pre-DSHEA drug use?

 
Where the FDA has purported to provide answers to these questions, the response has heavily favored drugs. Three notable examples of FDA drug preclusion interpretation in recent years involve a range of ingredients, including pyridoxamine, hemp-derived cannabidiol (CBD), and n-acetyl-l-cysteine (NAC), demonstrate this position.
 
Pyridoxamine: The case of abandoned drug clinical trials
Pyridoxamine is a form of vitamin B6 and has been the subject of industry and FDA discussions over its status as a dietary supplement since the early 2000s. It has been the subject of clinical drug studies since 1999. Because of those studies, the agency contends that pyridoxamine cannot be marketed as a dietary supplement.¹¹ In 2017, the investigational new drug (IND) authorizations for pyridoxamine were withdrawn, and the company that had originally conducted the drug clinical trials sought to market pyridoxamine as a dietary supplement.¹²
 
In October 2017, ViGuard Health submitted a citizen petition requesting the FDA declare pyridoxamine as a dietary ingredient, either by determining that the substance “is no longer an article authorized for investigation as a new drug and therefore is not excluded from the definition of a dietary supplement under 21 USC §321(ff)(3)(B)(ii),” or that the agency uses its discretionary authority under that clause to issue a regulation allowing pyridoxamine’s supplement use, despite it being an article subject to drug preclusion. ViGuard argued that the drug preclusion clause should not be interpreted to mean that an article authorized for an investigation at any time permanently excludes that article from being a dietary supplement. Pointing to the drug research and development protection purpose of drug preclusion, ViGuard argued that blocking pyridoxamine’s use as a supplement after an IND had been withdrawn would be contrary to the legislative intent of DSHEA. ViGuard also pointed to specific drug preclusion statutory language that an important element of whether a substance is precluded is if it “is subject of an IND that has gone into effect.” The present tense “is” indicates that the article should presently be the subject of an IND. If an IND is withdrawn or terminated, the substance no longer meets that requirement under drug preclusion.
 
Many in the dietary supplement industry supported this citizen petition and its interpretation of the drug preclusion clause.¹³ The FDA, however, declined to substantively answer the questions raised in the petition, citing a lack of agency resources, and ViGuard withdrew the petition in 2018. In industry discussions with the agency over the citizen petition, the agency expressed reluctance to formally determine that the drug preclusion clause does not apply where an IND has been withdrawn or terminated.
 
This lack of clarity from the agency limits access for consumers to a beneficial ingredient and harms dietary supplement companies, particularly in light of the FDA’s interpretation that the date the IND went into effect is the date of preclusion if the other elements are subsequently met. In other words, a company can market an ingredient as a dietary supplement after an IND goes into effect and before substantial public clinic trials are conducted and could lose access to that ingredient. Once substantial public clinical trials are conducted, the agency takes the view that the preclusion date is backdated to the date the IND went into effect.¹⁴
 
Hemp-derived CBD: What makes two substances the same article?
Hemp-related provisions of the 2018 Farm Bill were designed to create an unprecedented opportunity for farmers, health product manufacturers, and consumers. Making hemp legal under federal laws and regulations opened a lucrative business market, providing consumers access to hemp-derived products and their promising health benefits. The Farm Bill removed “hemp” – defined as any part or derivative of the Cannabis sativa L. plant that contains not more than 0.3{7b6cc35713332e03d34197859d8d439e4802eb556451407ffda280a51e3c41ac} delta-9 tetrahydrocannabinol on a dry-weight basis — from the Controlled Substances Act (CSA), allowing it to be regulated like any other botanical on the market.¹⁵ Congress intended to create economic opportunities for farmers, supplement and food manufacturers, and many other stakeholders. Much of the anticipated benefits of legalizing hemp were driven by strong consumer interest in hemp cannabinoids, particularly cannabidiol or CBD. To protect public health, Congress preserved the FDA’s authority over hemp-derived ingredients when used in products already regulated by the agency, such as dietary supplements.
 
However, Congress did not anticipate that the agency would continue to block CBD supplement use based a highly concentrated CBD isolate that had been approved for use in the seizure treatment medication Epidiolex in June 2018 and not offer an alternative legal pathway for CBD supplements.¹⁶ Congress, industry, and numerous stakeholders have taken issue with the FDA’s position, noting that,
 

• The form of CBD used in Epidiolex should not be treated as the same article as the form of CBD found in many hemp extract products, and
• Even if the FDA does not reverse that position, it could use its rulemaking authority to allow CBD’s use in dietary supplements as provided under the drug preclusion clause.

 
As already noted, the agency has never used this rulemaking authority, but there is a strong case that doing so would be appropriate for CBD. The race-to-market nature of the drug preclusion provision and hemp-derived CBD’s former legal status as a Schedule I controlled substance makes this situation unique – dietary supplement companies could not have even entered the race until December 2018 – well after CBD was being clinically studied as a drug ingredient.
 
However, whether the FDA should have acted years ago to start the rulemaking process should be a moot point for some forms of CBD. The CBD found in full-spectrum and broad-spectrum hemp extracts should not be treated as the same article as the CBD isolate used in Epidiolex. The agency seemed open to this reasoning¹⁷ until fall 2021 when it issued objection letters for two new dietary ingredient notifications (NDINs) involving full-spectrum hemp extracts containing CBD.^18,19 A substance is considered a new dietary ingredient (NDI) if it was not marketed in the US before the passage of DSHEA in October 1994.²⁰ Companies using an NDI must file a notification with the FDA 75 days before introducing that NDI into interstate commerce and demonstrate that the substance “will reasonably be expected to be safe” and provide “reasonably assurances of safety.”²¹
 
The CBD in hemp extracts is a very different substance from CBD isolate found in Epidiolex, and the two substances should not be treated as the same article. The CBD isolate in Epidiolex has been removed from its other plant constituents, which affects the behavior of the substance. Extracts should be considered in their entirety, including the CBD component, because the behavior of the individual components depends on the extract’s complexity and synergistic effects.
 
In FDA correspondence regarding the hemp-extract NDINs, FDA staff seem to recognize differences between CBD found in hemp extracts and CBD used in Epidiolex, specifically noting that “[y]our notification provides data derived from cited clinical trials on Epidiolex … as evidence of safety of your NDI under the proposed conditions of use … [h]owever, it is unclear how the test articles used in these clinical trials are related to your NDI.” The agency then goes on to ask the NDI submitter to “[p]lease provide a qualitative and quantitative comparison of [how] the test articles used in the clinical trials (i.e., phytocannabinoid composition, conditions of use, target population) are related to the composition and proposed condition of use of your NDI.”¹⁹ These statements suggest the FDA’s use of two different standards for when a substance is the same as a drug active ingredient – for purposes of safety determinations more scientific evidence was needed to establish that hemp extract CBD and Epidiolex CBD are the same substance, yet the agency could determine that the substances were the same article for drug preclusion purposes.
 
NAC: Drug preclusion’s effect on grandfathered ingredients
The most recent example of the agency’s use of drug preclusion is perhaps its most concerning and overreaching. In July 2020, it issued seven warning letters and a press release about dietary supplement products claiming they could prevent or cure hangovers.²² Within these warning letters, the agency also questioned the legality of NAC – an ingredient found in some of the products subject to the warning letters. According to the warning letters, NAC cannot be a legal dietary ingredient because it was first approved as a drug in 1963 and, thus, excluded from being an ingredient in a dietary supplement because of the drug preclusion provision.
 
NAC is a form of the amino acid L-cysteine. It is found naturally in foods such as onions and garlic and helps increase levels of glutathione (a major antioxidant) and has known respiratory benefits. It has a long history of safe use as a dietary supplement that has been well documented by the FDA, other authoritative government bodies, and industry.^23,24 NAC as a supplement and a drug had co-existed on the market for years before DSHEA’s enactment of the drug preclusion clause.²⁵ Further, the 1963 drug approval is for an inhaled form of NAC, which is significantly different form of NAC than that used in dietary supplements. A product must be “intended for ingestion” to be a legal dietary supplement.²⁶
 
When the FDA issued its 2020 warning letters, the dietary supplement industry quickly pointed out these issues to the agency and expressed significant concern about the agency’s application of drug preclusion to an ingredient that had been on the market before the enactment of DSHEA (ingredients used as dietary supplements pre-DSHEA are often called “grandfathered” ingredients).²⁷ Applying drug preclusion to grandfathered ingredients negates the drug development incentive purpose of this clause – before DSHEA, a drug company would have no expectation that drug development would be protected from supplement use.
 
In March 2022, the FDA responded to industry concerns by issuing a response to two trade association citizen petitions. The agency’s response addressed both the preclusion clause’s application to pre-DSHEA, grandfathered substances, and supplement forms in a manner that strongly favors drug interests and raises significant concerns regarding how drug preclusion could be used in the future.²⁸
 
With regard to pre-DSHEA application, the FDA determined that “[t]he [preclusion] clause does not provide an exception for drugs that were approved prior to DSHEA, drugs that were authorized for investigation prior to DSHEA, or dietary supplements or foods that were marketed as such prior to DHSEA.”¹⁰ Under this interpretation, FDA can preclude – and has done so, in the case of NAC – an ingredient from supplement use based on decades old drug approval or clinical research, unless the supplement industry can provide evidence of supplement use that predates the drug use. This puts the supplement industry at a disadvantage, as supplement companies likely have retained only limited records of supplement use from before DSHEA for the purposes of demonstrating an ingredient’s grandfathered status. A supplement could have been in use long before drug use, but a company would have had no reason to retain decades-old records predating drug approval or research before the FDA’s recent interpretation of pre-DSHEA application of drug preclusion.
 
Further, FDA determined that “[t]wo products can contain the same ‘article’ under [drug preclusion] even if they have a different route or administration.”¹⁶ FDA cited the precedent in the Pharmanex case as supporting this determination, but Pharmanex involved two products that were intended for oral ingestion. Similar to the suggestion made for hemp-derived CBD that form, dose, and biological mechanisms of action need to be examined for comparing safety data but not for determining drug preclusion, in the FDA’s NAC response letter, the agency notes that “while a drug’s route of administration is relevant for purposes of drug approval under Section 505 of the FD&C Act, this does not mean that route of administration must be considered to determine if ingredients are the same ‘article’ for purposes of the [preclusion] clause.”¹⁶
 
Again, the FDA’s interpretation of drug preclusion here does not seem to square with its intended purpose to protect drug investment and prevent an end-run around the drug approval process. Because supplements are limited to orally ingested forms, a supplement would, by its very nature, differ significantly from inhaled, topical, and injected drugs. Such significant differences will affect a substance’s impact on the human body, removing concerns that supplement use would disincentivize drug development or allow a company to bypass drug approval using the supplement product category.
 
In August 2022, the FDA finalized guidance advising supplement manufacturers, distributors, and other stakeholders that the agency will exercise enforcement discretion for NAC-containing supplement products as long the product meets all other dietary supplement requirements (e.g., GMP requirements, appropriate claims).²⁹ The guidance allows supplement companies to continue to sell NAC as a dietary ingredient, despite FDA’s determination that the ingredient is subject to drug preclusion. The agency also has indicated that it is considering using the rulemaking authority described in the first section of this article for NAC. If FDA does move forward with rulemaking, this would be the agency’s first use of this authority in the over 25 years it has been granted. While the current enforcement discretion policy (and if a subject to a rulemaking) spare NAC from a drug monopoly, the concerning precedent set by the FDA in this case still stands as a potential future limit on the use of dietary ingredients for supplement versus drug use.
 

Addressing drug preclusion concerns

Given the consistently overly broad manner in which the FDA has interpreted the drug preclusion provision since its inception, amending the drug preclusion language may be the best option to preserve consumer access to dietary supplements. A few changes to the drug preclusion clause could help align the language with what the authors of this article understand was the original intent of drug preclusion and still ensure that drug research and development are protected, and unscrupulous companies are limited in using supplements to bypass drug approval.
 
For example, amendments could include:
 

• Limiting the amount of time for which a substance would be precluded from supplement use, giving drug companies time to recoup investment, but not permanently removing a substance from supplement access;
• Clarifying that drug preclusion applies only to orally ingested drugs; and
• Making clear that public notice of substantial clinical investigations is the trigger date for preclusion for investigational new drugs.

 
As outlined in this article, a more narrowly drafted drug preclusion provision benefits businesses, drug interests, and consumers alike by fueling interest in beneficial health substances, encouraging research for a range of uses, and protecting public health.
 

Abbreviations

NAC, n-acetyl-l-cysteine; FDA, [US] Food and Drug Administration; CRN, Council for Responsible Nutrition; DSHEA, Dietary Supplement Health and Education Act; FD&C, Food, Drug, and Cosmetic [Act]; CBD, cannabidiol; IND, investigational new drug; TCH, tetrahydrocannabinol; CSA, Controlled Substances Act; NDI, new dietary ingredient; NDIN, new dietary ingredient notifications.
 

About the authors

Megan Olsen, JD, is the senior vice president and general counsel at the Council for Responsible Nutrition (CRN) in Washington, DC. She provides legal counsel and advice to CRN’s staff and members in the areas of legislation, regulatory compliance and advocacy, and international policy development. Before joining CRN, Olsen was special counsel for Wiley Rein LLP in Washington, DC. She earned a JD from the Catholic University of America Columbus School of Law in Washington, DC, and received a BA in business management from Gettysburg College in Pennsylvania. She can be contacted at [email protected]
 
Daniel Garza, BA, is the assistant to CRN’s government relations and legal departments in Washington, DC. He is responsible for providing technical and administrative support to CRN’s legal and government relations departments. Garza is a graduate of The Ohio State University with a dual degree in political science and international studies. He can be contacted at [email protected]
 

Citation Olsen M, Garza D. Drug preclusion and public health: The case for a narrow interpretation of ‘article.’ Regulatory Focus. 17 November 2022.  https://www.raps.org/news-and-articles/news-articles/2022/11/drug-preclusion-and-public-health-the-case-for-a-n

References

All references checked and/or verified on 11 November 2022.
 

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2. 21 USC § 301, et seq. https://www.govinfo.gov/app/details/USCODE-2011-title21/USCODE-2011-title21-chap9-subchapI-sec301
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