By Todd Harrison, Venable LLP10.04.24
Recently, I have seen more questions regarding when an ingredient is precluded from being a food or dietary ingredient and how to determine whether it is indeed precluded. Generally, drugs, dietary supplements, and foods are treated as distinct regulatory categories, and have different requirements. While there is a wide range of possible ingredients that may be used in either type of product, ingredients subject to “substantial clinical evaluation” prior to their use in a dietary supplement or food generally cannot be used as, or in, a dietary supplement or a food.
That said, statutory nuances related to drugs, dietary ingredients, and food ingredients provide a basis to conclude that select drug ingredients subject to “substantial clinical evaluation” may be properly used as or in a dietary supplement, or as a medical food if use as a supplement or food predates substantial clinical evaluation.
Under the FDCA, drugs are defined as products intended for use in the diagnosis, treatment, or prevention of disease,2 and are subject to extensive premarket approval requirements.3 These requirements focus on the unique formulation of a drug and its active moiety to evaluate the drug’s safety and efficacy.
By comparison, dietary supplements are considered a subset of food4 that are ingested and intended to support or maintain health via one or more “dietary ingredients.”5 Similarly, medical foods and foods for special dietary use are also considered foods with their own unique provisions. While dietary supplements are not subject to premarket approval requirements like drugs, the FDCA provides that a product cannot be marketed as a dietary supplement if it includes an “article” that has been: 1) authorized for investigation as a new drug; 2) for which substantial clinical investigations have been instituted on the article and their existence made public; and 3) was not marketed as a food or dietary supplement prior to being authorized for investigation as a new drug.6
As a practical matter, this exclusion establishes two key questions that determine whether an ingredient can be included in a dietary supplement: 1) Whether the ingredient was first marketed as a food or dietary supplement before its inclusion in a new drug investigation; and 2) Whether the ingredient has been authorized for investigation as a new drug and has been subject to “substantial clinical investigation.”
On the first point, the statute is relatively straightforward in establishing that an ingredient can properly be considered a dietary ingredient for use as or in a dietary supplement so long as the ingredient was first marketed as a food or dietary supplement before becoming the subject of a drug investigation. The second point, while seemingly self-explanatory, involves several important nuances.
First, the FDA has not specifically defined “substantial clinical trials” in the context of dietary ingredients both under the FDCA and its associated regulations. The legislative history behind the Dietary Supplement Health and Education Act (DSHEA) is equally thin, merely noting that “substantial clinical investigations” do not include a special type of IND referred to as “compassionate use” or single-patient studies.7 The agency has never attempted to define the limits of this provision.
With that said, the FDA in 2008 did request comments to § 301(ll) which is the exclusionary language related to food ingredients that had undergone substantial clinical trials.8 Specifically, the FDA requested comments related to “substantial clinical investigations” that have been instituted, as well as its applicability to dietary ingredients as a subgroup of foods.9
However, FDA has not discussed the comments received nor attempted to define the term “substantial clinical investigations” or attempted to argue that § 301(ll) applies to dietary supplements. FDA’s reluctance to impose its own definition of “substantial clinical investigations” provides a window into its thought process, as it has only raised the issue when it believes significant Phase II and III trials have been conducted.
Accordingly, we believe limited Phase I and Phase IIA trials may not be sufficient to establish “substantial clinical investigations” if the drug pathway was abandoned shortly thereafter and was unrelated to the safety of the ingredient. This latter point is important. If early clinical trials raise safety concerns, this may be enough for FDA to conclude the trials were substantial but were only abandoned because of safety concerns and, thus, precluded.
Further Reading: Scanning the Regulatory Horizon for Dietary Supplements
Under § 201(ff), “substantial clinical investigation” is directly tied to an “authorized” investigation for a new drug. This means ingredients that are first used under an authorized IND and undergo substantial clinical trials cannot be used as or in a dietary supplement. By comparison, § 301(ll) does not feature the IND component found in § 201(ff). Instead, the statute as worded only encompasses the institution of “substantial clinical trials,” which could be interpreted to mean any phase of a clinical trial. With that said, we believe the same arguments exist for § 301(ll) as § 201(ff)(3)(B).
An ingredient that is not the subject of an IND but still subject to substantial clinical trials may nevertheless be marketed as a dietary ingredient even though it may be excluded as a
food ingredient. Further, any attempt to apply the general food exclusionary provision to dietary supplements is arguably improper under basic constructs of statutory interpretation, which dictate specific statutory language controls over language found in a more general provision.
Where an ingredient is featured in both a drug and dietary supplement, and the drug product becomes the subject of a clinical trial, that ingredient may still be used in the dietary supplement. For instance, if an ingredient is present in the food supply in chemically unaltered form at levels greater than trace amounts, the ingredient is not subject to notification under the act. The determinative factor is whether an ingredient was available in the food supply or as a dietary ingredient before the authorization of an IND and prior to substantial
clinical investigations.
The FDCA defines dietary ingredients (individually or collectively) to include any article that was marketed as a food or dietary supplement before the article was approved as a new drug (an “approved NDA”) or included as part of an IND and subject to “substantial clinical investigations.”
As discussed, products that are sold as a dietary supplement, food, and drug may be limited based on 1) whether the product was first marketed as a food or dietary supplement, and 2) whether the product was subject to “substantial clinical evaluation.”10
On the first point, FDA allows drug ingredients to be included in a dietary supplement so long as that ingredient was first marketed as either a food or dietary supplement. If a product (or ingredient) is first marketed as a food or dietary supplement prior to its inclusion in a clinical trial, there is no issue from an FDA perspective related to that product (or ingredient) continuing to be marketed as a food or supplement.
On the second point, a product that first underwent “substantial clinical investigation” generally may not be used in a dietary supplement or food product. If a product (or ingredient) was first marketed as a component of a food or a dietary supplement, its development as a drug product (or ingredient) would not affect the “original” use of the product as a food component. The drug ingredient exclusions for dietary supplements and food products would not bar the continued use of the product (or ingredient) in a dietary supplement or a food. Accordingly, the product (or ingredient) would be allowed for sale as both a component of a food or dietary supplement and as a drug.
While the FDCA permits a drug company to request exclusions for products, it is unlikely to be successful. Indeed, we are not aware of such a request ever being made or granted. Similarly, FDA has the ability to permit a precluded drug ingredient to also be marketed as a food or dietary ingredient. However, FDA has to date not attempted to provide any guidance on this issue, but one hopes the agency will address the issue in the near future.
2. 21 U.S.C. § 201(g)(1).
3. See, e.g., 21 U.S.C. § 355 et seq.
4. 21 U.S.C. § 201(ff).
5. Id. § 201(ff)(1).
6.Id. § 201(ff)(3)(B)(ii). For purposes of this exclusion, FDA has interpreted “authorized for investigation as a new drug” to mean that an investigational new drug application (“IND”) has been submitted and taken effect. See FDA, Draft Guidance for Industry: New Dietary Ingredient Notifications and Related Issues (Oct. 2016), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-new-dietary-ingredient-notifications-and-related-issues.
7. Dietary Supplement Health & Education Act, Pub. L. No. 103–417, 108 Stat. 4325 (1994).
8.73 Fed. Reg. 43937, 43939 (July 29, 2008).
9. Id.
10. 21 U.S.C. § 201(ff).
About the Author: Todd Harrison is Partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004, Tel: 202-344-4724; E-mail: taharrison@venable.com.
That said, statutory nuances related to drugs, dietary ingredients, and food ingredients provide a basis to conclude that select drug ingredients subject to “substantial clinical evaluation” may be properly used as or in a dietary supplement, or as a medical food if use as a supplement or food predates substantial clinical evaluation.
Key Questions and Determinations
It is important to note that foods for special dietary use and medical foods are subject to the food provisions of the Federal Food, Drug and Cosmetic Act (FDCA), including § 301(ll), which prohibits the use of an ingredient in food if the ingredient was subject to substantial clinical investigation as a drug prior to its use in food. With that said, unlike dietary supplements, the food ingredient exclusion applies regardless of whether an IND was filed for the drug.1Under the FDCA, drugs are defined as products intended for use in the diagnosis, treatment, or prevention of disease,2 and are subject to extensive premarket approval requirements.3 These requirements focus on the unique formulation of a drug and its active moiety to evaluate the drug’s safety and efficacy.
By comparison, dietary supplements are considered a subset of food4 that are ingested and intended to support or maintain health via one or more “dietary ingredients.”5 Similarly, medical foods and foods for special dietary use are also considered foods with their own unique provisions. While dietary supplements are not subject to premarket approval requirements like drugs, the FDCA provides that a product cannot be marketed as a dietary supplement if it includes an “article” that has been: 1) authorized for investigation as a new drug; 2) for which substantial clinical investigations have been instituted on the article and their existence made public; and 3) was not marketed as a food or dietary supplement prior to being authorized for investigation as a new drug.6
As a practical matter, this exclusion establishes two key questions that determine whether an ingredient can be included in a dietary supplement: 1) Whether the ingredient was first marketed as a food or dietary supplement before its inclusion in a new drug investigation; and 2) Whether the ingredient has been authorized for investigation as a new drug and has been subject to “substantial clinical investigation.”
On the first point, the statute is relatively straightforward in establishing that an ingredient can properly be considered a dietary ingredient for use as or in a dietary supplement so long as the ingredient was first marketed as a food or dietary supplement before becoming the subject of a drug investigation. The second point, while seemingly self-explanatory, involves several important nuances.
First, the FDA has not specifically defined “substantial clinical trials” in the context of dietary ingredients both under the FDCA and its associated regulations. The legislative history behind the Dietary Supplement Health and Education Act (DSHEA) is equally thin, merely noting that “substantial clinical investigations” do not include a special type of IND referred to as “compassionate use” or single-patient studies.7 The agency has never attempted to define the limits of this provision.
With that said, the FDA in 2008 did request comments to § 301(ll) which is the exclusionary language related to food ingredients that had undergone substantial clinical trials.8 Specifically, the FDA requested comments related to “substantial clinical investigations” that have been instituted, as well as its applicability to dietary ingredients as a subgroup of foods.9
However, FDA has not discussed the comments received nor attempted to define the term “substantial clinical investigations” or attempted to argue that § 301(ll) applies to dietary supplements. FDA’s reluctance to impose its own definition of “substantial clinical investigations” provides a window into its thought process, as it has only raised the issue when it believes significant Phase II and III trials have been conducted.
Accordingly, we believe limited Phase I and Phase IIA trials may not be sufficient to establish “substantial clinical investigations” if the drug pathway was abandoned shortly thereafter and was unrelated to the safety of the ingredient. This latter point is important. If early clinical trials raise safety concerns, this may be enough for FDA to conclude the trials were substantial but were only abandoned because of safety concerns and, thus, precluded.
Further Reading: Scanning the Regulatory Horizon for Dietary Supplements
Category Distinctions
As indicated, there is an important distinction between the exclusion language for food and food ingredients under § 301(ll) and its sister provision for dietary supplements under § 201(ff)(3).Under § 201(ff), “substantial clinical investigation” is directly tied to an “authorized” investigation for a new drug. This means ingredients that are first used under an authorized IND and undergo substantial clinical trials cannot be used as or in a dietary supplement. By comparison, § 301(ll) does not feature the IND component found in § 201(ff). Instead, the statute as worded only encompasses the institution of “substantial clinical trials,” which could be interpreted to mean any phase of a clinical trial. With that said, we believe the same arguments exist for § 301(ll) as § 201(ff)(3)(B).
An ingredient that is not the subject of an IND but still subject to substantial clinical trials may nevertheless be marketed as a dietary ingredient even though it may be excluded as a
food ingredient. Further, any attempt to apply the general food exclusionary provision to dietary supplements is arguably improper under basic constructs of statutory interpretation, which dictate specific statutory language controls over language found in a more general provision.
Where an ingredient is featured in both a drug and dietary supplement, and the drug product becomes the subject of a clinical trial, that ingredient may still be used in the dietary supplement. For instance, if an ingredient is present in the food supply in chemically unaltered form at levels greater than trace amounts, the ingredient is not subject to notification under the act. The determinative factor is whether an ingredient was available in the food supply or as a dietary ingredient before the authorization of an IND and prior to substantial
clinical investigations.
The FDCA defines dietary ingredients (individually or collectively) to include any article that was marketed as a food or dietary supplement before the article was approved as a new drug (an “approved NDA”) or included as part of an IND and subject to “substantial clinical investigations.”
As discussed, products that are sold as a dietary supplement, food, and drug may be limited based on 1) whether the product was first marketed as a food or dietary supplement, and 2) whether the product was subject to “substantial clinical evaluation.”10
On the first point, FDA allows drug ingredients to be included in a dietary supplement so long as that ingredient was first marketed as either a food or dietary supplement. If a product (or ingredient) is first marketed as a food or dietary supplement prior to its inclusion in a clinical trial, there is no issue from an FDA perspective related to that product (or ingredient) continuing to be marketed as a food or supplement.
On the second point, a product that first underwent “substantial clinical investigation” generally may not be used in a dietary supplement or food product. If a product (or ingredient) was first marketed as a component of a food or a dietary supplement, its development as a drug product (or ingredient) would not affect the “original” use of the product as a food component. The drug ingredient exclusions for dietary supplements and food products would not bar the continued use of the product (or ingredient) in a dietary supplement or a food. Accordingly, the product (or ingredient) would be allowed for sale as both a component of a food or dietary supplement and as a drug.
While the FDCA permits a drug company to request exclusions for products, it is unlikely to be successful. Indeed, we are not aware of such a request ever being made or granted. Similarly, FDA has the ability to permit a precluded drug ingredient to also be marketed as a food or dietary ingredient. However, FDA has to date not attempted to provide any guidance on this issue, but one hopes the agency will address the issue in the near future.
References
1. See FDCA §301(ll)(1) (“The introduction or delivery for introduction into of any food…a drug or a biological product for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public”) as compared to FDCA § 201(ff)(3)(B)(ii) which also requires the filing of an IND as well as substantial clinical investigations.2. 21 U.S.C. § 201(g)(1).
3. See, e.g., 21 U.S.C. § 355 et seq.
4. 21 U.S.C. § 201(ff).
5. Id. § 201(ff)(1).
6.Id. § 201(ff)(3)(B)(ii). For purposes of this exclusion, FDA has interpreted “authorized for investigation as a new drug” to mean that an investigational new drug application (“IND”) has been submitted and taken effect. See FDA, Draft Guidance for Industry: New Dietary Ingredient Notifications and Related Issues (Oct. 2016), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-new-dietary-ingredient-notifications-and-related-issues.
7. Dietary Supplement Health & Education Act, Pub. L. No. 103–417, 108 Stat. 4325 (1994).
8.73 Fed. Reg. 43937, 43939 (July 29, 2008).
9. Id.
10. 21 U.S.C. § 201(ff).
About the Author: Todd Harrison is Partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004, Tel: 202-344-4724; E-mail: taharrison@venable.com.
