By Todd Harrison, Venable11.11.21
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,1 and are subject to extensive premarket approval requirements.2 These requirements focus on the unique formulation of a drug, its active moiety, and its routes of administration to evaluate the drug’s safety and efficacy.
By comparison, dietary supplements are considered a subset of food3 that are ingested and intended to support or maintain health via one or more “dietary ingredients.”4 Similarly, medical foods are also considered foods with their own unique provisions. Finally, functional foods are merely conventional foods and are regulated in a similar manner.
Neither foods—including medical foods—nor dietary supplements are subject to premarket approval requirements like drugs. The only exception to this rule are “food additives,” which are subject to their own exception for ingredients that are generally recognized as safe (GRAS) for use in human food.
There remains a misconception that the New Dietary Ingredient Notification process is an approval process, when in fact it is merely a notification process, as the title indicates. Indeed, a review of FDA’s negative courtesy letters on new dietary ingredients—yes, these are merely courtesy letters—shows the agency is very careful never to state an ingredient “is” adulterated, but rather “may be” adulterated under the Act.
Essentially FDA is saying: “we understand that this is a notification, so don’t believe this letter affords you any right to sue us if you don’t like the comments in the letter.”
Similarly, a positive response should be viewed as follows: “have a nice life, but if something goes wrong we have plausible deniability.” In the end, once the NDIN is filed then you are free to market after 75 days, at your own risk of potential regulatory action.
Two Exclusions
With that said, there are two provisions in the FDCA that do affect the ability of a company to market a particular ingredient as either a dietary ingredient or a food ingredient. As this has most often come up in the dietary supplement context, recently with CBD, NAC, and vinpocetine, I will primarily address the preclusion issue for dietary ingredients while touching on 301(ll).
Specifically, the FDCA provides that a product cannot be marketed as a dietary supplement if it includes an “article” that has been: (1) approved as a new drug; or (2) authorized for investigation as a new drug (a) for which substantial clinical investigations have been instituted on the article and their existence made public, and (b) was not marketed as a food or dietary supplement prior to being authorized for investigation as a new drug.5
As a practical matter, both exclusions hinge on whether the ingredient was first marketed as a food or dietary supplement prior to approval or investigation as a new drug. For those ingredients that are not approved but are subject only to investigation prior to use in a dietary supplement, a determination must be made 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 would seem 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. Unfortunately, it is not so straightforward.
More specifically, FDA’s interpretation of this provision is extremely restrictive to mean that as long as the active moiety was either approved or underwent substantial clinical investigation, regardless of dose or route of administration, the ingredient is precluded. This makes little sense from a scientific perspective, as it is quite possible that 10 mg of an ingredient will act very differently than 500 mg. Moreover, whether an ingredient is administered through digestion, inhalation, or injection may very well impact the safety and efficacy of the ingredient.
I would further note, Congress specifically used the term “article,” which encompasses more than just the active moiety, but the full formulation. Thus, Congress should consider amending this part of the statute to specifically state that the article means not simply the presence of the active moiety, but also dosage and route of administration. Alternatively, it could borrow from the medical device language and use the term “substantially equivalent” with the burden on the company to show its proposed use is not “substantially equivalent” to the article of the drug while requiring any decision by FDA to the contrary be subject to judicial review—thus holding feet to the fire for both the company in the first instance and FDA in the second.
What’s ‘Substantial’?
Another problematic scenario, if the ingredient is not an FDA-approved drug but has been subject to clinical trials, relates to determining whether those trials are substantial or not.
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 investigational new drug (IND) referred to as “compassionate use” or single-patient studies.6
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.7 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.8
Importantly, however, FDA has never discussed the comments received nor attempted to define the term “substantial clinical investigations,” or attempt to argue that § 301(ll) applies to dietary supplements. Thus, 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 when it believes significant Phase II and III trials have been conducted. Thus, it is unclear whether limited Phase I and Phase IIA trials are considered substantial if the drug pathway was abandoned shortly thereafter and the abandonment was unrelated to the safety of the ingredient.
I would further note 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 that ingredients which 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.
Regardless, the absence of an IND is an important aspect to determine whether an ingredient may be excluded as a dietary ingredient but not a food ingredient. To state it differently, an ingredient that is not the subject of an IND but still subject to substantial clinical trials may nevertheless be marketed as a dietary supplement even though it may be excluded as a food ingredient.
Further, any attempt to apply the general food exclusionary provision to dietary supplements would be improper under basic constructs of statutory interpretation, which dictate specific statutory controls over language found in a more general provision. Taken together, there is an added layer of interpretation when attempting to define whether an ingredient has been subject to a sufficient degree of drug evaluation to be considered “substantial.”
Because of the differences in the statutory language between 201(ff)(3) and 301(ll), I would propose amending these two provisions into one new section that applies to both food and dietary supplements while also stating that “substantial” investigation relates to initiation of clinical trials that have not been abandoned for safety reasons prior to the initiation of Phase III clinical trials.
Legislative Proposal
In the hope of fostering dialogue, I am proposing the following legislative language:
An Article that is approved as a new drug under section 355 of this title or licensed as a biologic under section 262 of title 42 and was, prior to such approval, certification, or license, marketed as a food or dietary ingredient unless the Secretary has issued a regulation, after notice and comment, finding that the article, when used as or in a dietary supplement under the conditions of use and dosages set forth in the labeling for such dietary supplement, is unlawful under section 342(f) of this title; and not include—
(i) a food or dietary ingredient that is substantially equivalent that was not marketed prior to an approved 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
(ii) a food or dietary ingredient that is substantially equivalent and was not marketed prior to the filing of an Investigational New Drug Application as a new drug, antibiotic, or biological for which Phase III clinical investigations have been authorized and Phase I or II clinical investigations have not been otherwise abandoned for safety reasons 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. For purposes of this paragraph, the applicable date is the date of enrollment into Phase I or II clinical investigations that eventually led to the initiation of Phase III clinical investigation.
For purpose of this section, substantial equivalence shall mean that the food or dietary ingredient exhibits the same pharmacological effect as the active moiety in the finished drug product, the following factors must be taken into consideration by the Secretary in making this determination must not only consider the pharmacological effect but the route of administration and dosage level.
Judicial Review — The decision of the Secretary to find that either a food or dietary ingredient is precluded is subject to immediate judicial review with the Agency having the burden to establish that the ingredient is “substantially” equivalent to an article approved as a drug.
References
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.
By comparison, dietary supplements are considered a subset of food3 that are ingested and intended to support or maintain health via one or more “dietary ingredients.”4 Similarly, medical foods are also considered foods with their own unique provisions. Finally, functional foods are merely conventional foods and are regulated in a similar manner.
Neither foods—including medical foods—nor dietary supplements are subject to premarket approval requirements like drugs. The only exception to this rule are “food additives,” which are subject to their own exception for ingredients that are generally recognized as safe (GRAS) for use in human food.
There remains a misconception that the New Dietary Ingredient Notification process is an approval process, when in fact it is merely a notification process, as the title indicates. Indeed, a review of FDA’s negative courtesy letters on new dietary ingredients—yes, these are merely courtesy letters—shows the agency is very careful never to state an ingredient “is” adulterated, but rather “may be” adulterated under the Act.
Essentially FDA is saying: “we understand that this is a notification, so don’t believe this letter affords you any right to sue us if you don’t like the comments in the letter.”
Similarly, a positive response should be viewed as follows: “have a nice life, but if something goes wrong we have plausible deniability.” In the end, once the NDIN is filed then you are free to market after 75 days, at your own risk of potential regulatory action.
Two Exclusions
With that said, there are two provisions in the FDCA that do affect the ability of a company to market a particular ingredient as either a dietary ingredient or a food ingredient. As this has most often come up in the dietary supplement context, recently with CBD, NAC, and vinpocetine, I will primarily address the preclusion issue for dietary ingredients while touching on 301(ll).
Specifically, the FDCA provides that a product cannot be marketed as a dietary supplement if it includes an “article” that has been: (1) approved as a new drug; or (2) authorized for investigation as a new drug (a) for which substantial clinical investigations have been instituted on the article and their existence made public, and (b) was not marketed as a food or dietary supplement prior to being authorized for investigation as a new drug.5
As a practical matter, both exclusions hinge on whether the ingredient was first marketed as a food or dietary supplement prior to approval or investigation as a new drug. For those ingredients that are not approved but are subject only to investigation prior to use in a dietary supplement, a determination must be made 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 would seem 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. Unfortunately, it is not so straightforward.
More specifically, FDA’s interpretation of this provision is extremely restrictive to mean that as long as the active moiety was either approved or underwent substantial clinical investigation, regardless of dose or route of administration, the ingredient is precluded. This makes little sense from a scientific perspective, as it is quite possible that 10 mg of an ingredient will act very differently than 500 mg. Moreover, whether an ingredient is administered through digestion, inhalation, or injection may very well impact the safety and efficacy of the ingredient.
I would further note, Congress specifically used the term “article,” which encompasses more than just the active moiety, but the full formulation. Thus, Congress should consider amending this part of the statute to specifically state that the article means not simply the presence of the active moiety, but also dosage and route of administration. Alternatively, it could borrow from the medical device language and use the term “substantially equivalent” with the burden on the company to show its proposed use is not “substantially equivalent” to the article of the drug while requiring any decision by FDA to the contrary be subject to judicial review—thus holding feet to the fire for both the company in the first instance and FDA in the second.
What’s ‘Substantial’?
Another problematic scenario, if the ingredient is not an FDA-approved drug but has been subject to clinical trials, relates to determining whether those trials are substantial or not.
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 investigational new drug (IND) referred to as “compassionate use” or single-patient studies.6
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.7 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.8
Importantly, however, FDA has never discussed the comments received nor attempted to define the term “substantial clinical investigations,” or attempt to argue that § 301(ll) applies to dietary supplements. Thus, 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 when it believes significant Phase II and III trials have been conducted. Thus, it is unclear whether limited Phase I and Phase IIA trials are considered substantial if the drug pathway was abandoned shortly thereafter and the abandonment was unrelated to the safety of the ingredient.
I would further note 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 that ingredients which 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.
Regardless, the absence of an IND is an important aspect to determine whether an ingredient may be excluded as a dietary ingredient but not a food ingredient. To state it differently, an ingredient that is not the subject of an IND but still subject to substantial clinical trials may nevertheless be marketed as a dietary supplement even though it may be excluded as a food ingredient.
Further, any attempt to apply the general food exclusionary provision to dietary supplements would be improper under basic constructs of statutory interpretation, which dictate specific statutory controls over language found in a more general provision. Taken together, there is an added layer of interpretation when attempting to define whether an ingredient has been subject to a sufficient degree of drug evaluation to be considered “substantial.”
Because of the differences in the statutory language between 201(ff)(3) and 301(ll), I would propose amending these two provisions into one new section that applies to both food and dietary supplements while also stating that “substantial” investigation relates to initiation of clinical trials that have not been abandoned for safety reasons prior to the initiation of Phase III clinical trials.
Legislative Proposal
In the hope of fostering dialogue, I am proposing the following legislative language:
An Article that is approved as a new drug under section 355 of this title or licensed as a biologic under section 262 of title 42 and was, prior to such approval, certification, or license, marketed as a food or dietary ingredient unless the Secretary has issued a regulation, after notice and comment, finding that the article, when used as or in a dietary supplement under the conditions of use and dosages set forth in the labeling for such dietary supplement, is unlawful under section 342(f) of this title; and not include—
(i) a food or dietary ingredient that is substantially equivalent that was not marketed prior to an approved 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
(ii) a food or dietary ingredient that is substantially equivalent and was not marketed prior to the filing of an Investigational New Drug Application as a new drug, antibiotic, or biological for which Phase III clinical investigations have been authorized and Phase I or II clinical investigations have not been otherwise abandoned for safety reasons 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. For purposes of this paragraph, the applicable date is the date of enrollment into Phase I or II clinical investigations that eventually led to the initiation of Phase III clinical investigation.
For purpose of this section, substantial equivalence shall mean that the food or dietary ingredient exhibits the same pharmacological effect as the active moiety in the finished drug product, the following factors must be taken into consideration by the Secretary in making this determination must not only consider the pharmacological effect but the route of administration and dosage level.
Judicial Review — The decision of the Secretary to find that either a food or dietary ingredient is precluded is subject to immediate judicial review with the Agency having the burden to establish that the ingredient is “substantially” equivalent to an article approved as a drug.
References
- 21 U.S.C. § 201(g)(1)
- See, e.g., 21 U.S.C. § 355 et seq.
- 21 U.S.C. § 201(ff).
- Id. § 201(ff)(1).
- 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).
- Dietary Supplement Health & Education Act, Pub. L. No. 103–417, 108 Stat. 4325 (1994).
- 73 Fed. Reg. 43937, 43939 (July 29, 2008).
- Id.
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.
