By Todd Harrison, Venable04.08.21
An issue that is rarely addressed during the ingredient development stage is whether to move forward as a dietary ingredient or as a drug ingredient. The two paths, however, do not need to be mutually exclusive if ingredient development is done correctly. Specifically, an ingredient may be used in both drugs and dietary supplements where the ingredient was first marketed as a dietary ingredient.1
Alternatively, an ingredient which was not first marketed as a dietary supplement may still be used as or in a dietary supplement if the ingredient has not undergone “substantial clinical investigation.” However, FDA has not defined this phrase. Thus, while there is little doubt that Phase III clinical trials would preclude its use, there is strong argument that Phase I and limited Phase II clinical trials would not necessarily preclude an ingredient being studied under an IND from being marketed as a dietary supplement in the future.
Regardless, determining if an ingredient may be marketed as both a drug and also a dietary supplement depends on if the ingredient was studied as a drug first and if it was marketed as dietary supplement before the initiation of “substantial clinical investigation.” From a developmental standpoint, it is best to market the product as a dietary ingredient prior to obtaining an IND and the institution of substantial clinical trials.
Drugs vs Supplements: By the Book
More specifically, under the Federal Food, Drug, and Cosmetic Act (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 ingredient 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 While dietary supplements are normally 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 The key question that needs to be asked is whether the ingredient was first marketed as a food or dietary supplement before the filing of the IND and initiation of “substantial clinical investigation” have been made public.
On the first part of the question, 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 part of the question, 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 studies7 and the FDA has never formally or informally attempted to define the limits of this provision.
‘Substantial’ Distinction
The only insight available is in 2008 when the FDA requested comments to § 331(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 FDA, however, has never discussed the comments received nor attempted to define the term “substantial clinical investigations,” or attempted to argue that § 331(ll) applies to dietary supplements.
Moreover, there is an important distinction between the exclusion language for food and food ingredients under § 331(ll) and its sister provision for dietary supplements under § 321(ff). Under § 321(ff), “substantial clinical investigation” is directly tied to an “authorized” investigation for a new drug. This means that 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, § 331(ll) does not feature the IND component found in § 321(ff). Instead, the statute as worded only encompasses the institution of “substantial clinical investigations,” which could be interpreted to mean any phase of a clinical trial.
As discussed, while the FDCA features “substantial clinical evaluation” within its exclusion provisions for both foods and dietary supplements, there is no formal definition of “substantial clinical evaluation” found in either context, both under the FDCA and its relevant regulations.
Despite the lack of specific definitions in either context, we note that the agency’s recent actions against dietary supplement products suggest that “substantial” likely refers to clinical evaluation past Phase I trials, and to an extent limited Phase II trials. For example, the FDA has issued warning letters relying on the exclusion language,10 but did so against products that were ultimately approved under a new drug application or that had recently begun Phase III clinical trials.11
Thus, a product (or ingredient) that has only undergone a Phase I trial, was part of an abandoned Phase I trial, or only completed a limited Phase II trial is unlikely to be considered the subject of “substantial clinical trials.” The same outcome would result (at least in the dietary supplement context) if the IND itself is withdrawn before the trials are completed, given that the exclusion language for dietary ingredients requires that an authorized IND be in effect in addition to “substantial clinical evaluation.”12
Interpreting FDA Action & Warnings
Regardless, the 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 a few times in warning letters (e.g., vinpocetine, CBD) when it believes Phase II and III trials have been conducted. Accordingly, there is a strong argument that limited Phase I and Phase IIA trials are unlikely to be considered substantial if the drug pathway was abandoned shortly thereafter and was unrelated to the safety of the ingredient.
Indeed, an important nuance here is that the clinical trials were abandoned and did not continue. If the trials proceeded to Phase III or possibly Phase IIA, FDA would take the position that the initiation of substantial clinical investigations relates back to the initiation of Phase I clinical trials for sure and likely to the filing of the IND. Thus, if the Phase I clinical trial started in April 2016 and the dietary ingredient was launched in 2017, and Phase III clinical trials started in January 2018, FDA will likely take the position that April 2016 is the date of preclusion or the date the IND was approved.
In the end, it is possible to develop a new or novel ingredient for both the dietary supplement and drug market. However, timing is the key and it is best to introduce the ingredient as a dietary supplement prior to the IND and before the institution of Phase I clinical trials to unequivocally avoid the preclusion issue.
References & Resources
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.
Alternatively, an ingredient which was not first marketed as a dietary supplement may still be used as or in a dietary supplement if the ingredient has not undergone “substantial clinical investigation.” However, FDA has not defined this phrase. Thus, while there is little doubt that Phase III clinical trials would preclude its use, there is strong argument that Phase I and limited Phase II clinical trials would not necessarily preclude an ingredient being studied under an IND from being marketed as a dietary supplement in the future.
Regardless, determining if an ingredient may be marketed as both a drug and also a dietary supplement depends on if the ingredient was studied as a drug first and if it was marketed as dietary supplement before the initiation of “substantial clinical investigation.” From a developmental standpoint, it is best to market the product as a dietary ingredient prior to obtaining an IND and the institution of substantial clinical trials.
Drugs vs Supplements: By the Book
More specifically, under the Federal Food, Drug, and Cosmetic Act (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 ingredient 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 While dietary supplements are normally 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 The key question that needs to be asked is whether the ingredient was first marketed as a food or dietary supplement before the filing of the IND and initiation of “substantial clinical investigation” have been made public.
On the first part of the question, 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 part of the question, 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 studies7 and the FDA has never formally or informally attempted to define the limits of this provision.
‘Substantial’ Distinction
The only insight available is in 2008 when the FDA requested comments to § 331(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 FDA, however, has never discussed the comments received nor attempted to define the term “substantial clinical investigations,” or attempted to argue that § 331(ll) applies to dietary supplements.
Moreover, there is an important distinction between the exclusion language for food and food ingredients under § 331(ll) and its sister provision for dietary supplements under § 321(ff). Under § 321(ff), “substantial clinical investigation” is directly tied to an “authorized” investigation for a new drug. This means that 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, § 331(ll) does not feature the IND component found in § 321(ff). Instead, the statute as worded only encompasses the institution of “substantial clinical investigations,” which could be interpreted to mean any phase of a clinical trial.
As discussed, while the FDCA features “substantial clinical evaluation” within its exclusion provisions for both foods and dietary supplements, there is no formal definition of “substantial clinical evaluation” found in either context, both under the FDCA and its relevant regulations.
Despite the lack of specific definitions in either context, we note that the agency’s recent actions against dietary supplement products suggest that “substantial” likely refers to clinical evaluation past Phase I trials, and to an extent limited Phase II trials. For example, the FDA has issued warning letters relying on the exclusion language,10 but did so against products that were ultimately approved under a new drug application or that had recently begun Phase III clinical trials.11
Thus, a product (or ingredient) that has only undergone a Phase I trial, was part of an abandoned Phase I trial, or only completed a limited Phase II trial is unlikely to be considered the subject of “substantial clinical trials.” The same outcome would result (at least in the dietary supplement context) if the IND itself is withdrawn before the trials are completed, given that the exclusion language for dietary ingredients requires that an authorized IND be in effect in addition to “substantial clinical evaluation.”12
Interpreting FDA Action & Warnings
Regardless, the 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 a few times in warning letters (e.g., vinpocetine, CBD) when it believes Phase II and III trials have been conducted. Accordingly, there is a strong argument that limited Phase I and Phase IIA trials are unlikely to be considered substantial if the drug pathway was abandoned shortly thereafter and was unrelated to the safety of the ingredient.
Indeed, an important nuance here is that the clinical trials were abandoned and did not continue. If the trials proceeded to Phase III or possibly Phase IIA, FDA would take the position that the initiation of substantial clinical investigations relates back to the initiation of Phase I clinical trials for sure and likely to the filing of the IND. Thus, if the Phase I clinical trial started in April 2016 and the dietary ingredient was launched in 2017, and Phase III clinical trials started in January 2018, FDA will likely take the position that April 2016 is the date of preclusion or the date the IND was approved.
In the end, it is possible to develop a new or novel ingredient for both the dietary supplement and drug market. However, timing is the key and it is best to introduce the ingredient as a dietary supplement prior to the IND and before the institution of Phase I clinical trials to unequivocally avoid the preclusion issue.
References & Resources
- While FDA has not defined the term “marketed” under the Federal Food, Drug and Cosmetic Act or its implementing regulations, the agency takes this term to generally mean commercially available and held for sale in the U.S. See, e.g., FDA, FDA 101: Dietary Supplements, https://www.fda.gov/consumers/consumer-updates/fda-101-dietary-supplements (last updated July 15, 2015) (noting that FDA oversight of dietary supplements generally begins where the product “enters the marketplace.”).
- 21 U.S.C. § 321(g)(1).
- See, e.g., 21 U.S.C. § 355 et seq.
- 21 U.S.C. § 321(ff).
- Id. § 321(ff)(1).
- Id. § 321(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.
- Dietary Supplement Health & Education Act, Pub. L. No. 103-417, 108 Stat. 4325 (1994).
- 73 Fed. Reg. 43937, 43939 (July 29, 2008).
- Id
- See, e.g., FDA Warning Letter to The Dragontree Apothecary LLC (Apr. 28, 2020) (noting the exclusion as applied to a CBD product); FDA Warning Letter to X2Zero (Dec. 8, 2016) (noting the same as applied to a sibutramine product); FDA Warning Letter to Life Enhancement Products, Inc. (Nov. 22, 2002) (noting the same as applied to a galantamine product).
- See, e.g., Request for Comment on the Status of Vinpocetine, 81 Fed. Reg. 61700 (Sept. 7, 2016) (noting Phase III clinical trials).
- 21 U.S.C. § 321(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.
