By Todd Harrison, Venable LLP06.25.24
My last article was critical of FDA’s handling of new dietary ingredients (NDI) and the filing of NDI notifications (NDINs). Not every problem related to NDIs and NDINs is FDA’s fault. However, developing a guidance document that is not consistent with the law increases distrust of the agency within industry.
That said, the dietary supplement industry must also shoulder some of the blame. Reliance on spurious self-affirmed generally recognized as safe (GRAS) dossiers to avoid filing NDINs simply adds to the distrust between the FDA and industry.
More damaging is the willingness of some companies to ignore NDI and NDIN issues altogether by going to market without attempting to determine the actual safety of a new ingredient.
I don’t intend to paint the FDA or industry with a broad brush. Rather, it is the collective fault of agency and industry that we don’t have a workable NDIN process that can benefit consumers. However, there are possible solutions if both FDA and industry would be willing to sit down and think through these issues more deliberately.
Here I present some scenarios along with potential solutions. The purpose is to start a conversation, understanding there is no perfect solution, while also recognizing the existing situation is not tenable.
The first part should be relatively straightforward as the Food, Drug, and Cosmetic Act (FDCA) defines a dietary supplement. However, definitions are open to interpretation. For instance, FDA takes the position that an isolated constituent of a pre-Dietary Supplement Health and Education Act (DSHEA) botanical is an NDI. However, this ignores the definition of a dietary supplement, which includes a concentrate, metabolite, constituent, extract, or combination of any dietary ingredient.
Thus, if a botanical was marketed prior to Oct. 15, 1994 and it contains a particular constituent at more than de minimis levels, that constituent should not necessarily be considered an NDI, as it was indeed marketed in a dietary supplement prior to Oct. 15, 1994.
While at one level I appreciate FDA’s concern, a long history of use of a primary constituent should be sufficient to avoid the NDI designation, as its safety is generally well-characterized by now.
With that said, we must also consider when the presence of a particular constituent is significantly increased, such that it may raise safety concerns.
A possible legislative solution would be to require the filing of a notification if the constituent is present at significantly greater levels than had historically been used in dietary supplements. This would have two main benefits: 1) it would allow for innovation and increase standardization of botanicals and their historically used constituents, while 2) recognizing if standardization significantly increases exposure well above what was historically consumed, there could be safety issues and the manufacturer should have evidence that this new level is safe.
I appreciate this may raise concerns about what is a significant increase. I believe that should be left to the manufacturer; but the manufacturer must maintain sufficient safety data that the increase in exposure does not pose a safety concern. Alternatively, we could simply state that anything over a 20% increase, for example, is considered “significant.”
Neither would be a perfect solution, but could offer a starting point for an honest conversation, and perhaps a sensible compromise.
An alternative approach that would allow for more innovation would be to view synthetic botanicals as dietary substances that are bioidentical to natural botanicals. Of course, this begs the question whether the synthetic version should be considered an NDI subject to an NDIN. Arguably, if it is bioidentical, there is no practical reason to treat synthetic botanicals differently from the actual botanical, thus eliminating the need to file an NDIN.
On the other hand, if such evidence does not exist, the ingredient should be considered an NDI subject to the NDIN provisions of the act. Making that determination may be difficult. To state it differently, if the synthetic version is bioidentical and is no more bioavailable than its natural cousin, there is no reason to treat one as a grandfathered ingredient and the other as an NDIN. Admittedly, this may be difficult to prove.
An interesting regulatory solution would be for FDA to request the company file a limited NDIN that shows there is a reasonable basis for its conclusion. If there is not, FDA could request additional safety information, understanding it is still FDA’s burden to establish they are not bioidentical and the synthetic version poses a safety concern.
A reasonable legislative solution would be to amend the FDCA to expressly permit bioequivalent synthetics and only require notification if the synthetic version would act differently from the natural version.
There are numerous potential pathways here, and my approach may be overly simplistic, but it is a conversation worth having.
This environment becomes a breeding ground for plaintiff class action cases against supplement companies that cannot sue FDA over the issue. Oftentimes, preclusion is not cut and dry. NAC is a perfect example. It has long been marketed as a dietary supplement before FDA decided it should be precluded, only to later decide it would exercise enforcement discretion facing pressure from industry.
However, there are ingredients that may be utilized to maintain overall health and wellbeing and also in the treatment and mitigation of disease. Lovaza comes to mind. Fish oil is a dual-purpose ingredient. These products coexist quite well with each other.
One might argue that the preclusion provision appears to be a concession by Congress to the pharmaceutical industry. However, was it even necessary, given that drug ingredients are generally protected by patents and, once approved, covered by third-party payors?
The other issue with the preclusion provision is for those drugs that have an IND and may be undergoing clinical trials. This makes it difficult for a supplement company to decide whether to file an NDIN, especially if it cannot verify whether an ingredient is under an IND. It’s true that clinicaltrials.gov may provide a company with a clue, but it may not.
Moreover, FDA has steadfastly refused to define what constitutes “substantial clinical trials.” As a result, it’s even more difficult for companies to decide whether to move forward on ingredients whose IND has been abandoned or if there are ongoing clinical trials.
This situation is not FDA’s fault, but it needs to be remedied. The best path forward is to amend the FDCA to establish an approval process — yes, “approval,” not “notification” — that would allow a supplement company to submit ingredients for FDA approval if these ingredients meet the definition of both a dietary supplement and a drug, possessing dual-purpose utility: at low doses, they help maintain overall health, while at high doses, they effectively treat diseases but may have major side effects.
Finally, we need to reset the grandfather date. A list of eligible dietary ingredients that meet the definition of a dietary supplement should be developed within 12 months of the law’s passage. The list should include all dosage levels and forms, while also meeting the definition of a dietary supplement. If it does not meet the definition, FDA should specifically exclude the ingredient and such exclusion shall be deemed final agency action, allowing companies to initiate a lawsuit against FDA to establish otherwise.
As I stated in the beginning, these are just my initial thoughts, and I will have more to offer over the next few months. It’s time to fix what is wrong with the FDCA. It is an outdated regulatory structure when it comes to foods and dietary supplements. As a society, we would be more healthy if we had laws that kept up with the science behind food and dietary supplements.
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, the dietary supplement industry must also shoulder some of the blame. Reliance on spurious self-affirmed generally recognized as safe (GRAS) dossiers to avoid filing NDINs simply adds to the distrust between the FDA and industry.
More damaging is the willingness of some companies to ignore NDI and NDIN issues altogether by going to market without attempting to determine the actual safety of a new ingredient.
I don’t intend to paint the FDA or industry with a broad brush. Rather, it is the collective fault of agency and industry that we don’t have a workable NDIN process that can benefit consumers. However, there are possible solutions if both FDA and industry would be willing to sit down and think through these issues more deliberately.
Here I present some scenarios along with potential solutions. The purpose is to start a conversation, understanding there is no perfect solution, while also recognizing the existing situation is not tenable.
Dietary Ingredient Definitions
We cannot get very far though if we don’t know what a dietary ingredient is and is not. Indeed, we cannot determine whether a dietary ingredient is an NDI unless we understand the definition of a dietary supplement and what is grandfathered under that definition.The first part should be relatively straightforward as the Food, Drug, and Cosmetic Act (FDCA) defines a dietary supplement. However, definitions are open to interpretation. For instance, FDA takes the position that an isolated constituent of a pre-Dietary Supplement Health and Education Act (DSHEA) botanical is an NDI. However, this ignores the definition of a dietary supplement, which includes a concentrate, metabolite, constituent, extract, or combination of any dietary ingredient.
Thus, if a botanical was marketed prior to Oct. 15, 1994 and it contains a particular constituent at more than de minimis levels, that constituent should not necessarily be considered an NDI, as it was indeed marketed in a dietary supplement prior to Oct. 15, 1994.
While at one level I appreciate FDA’s concern, a long history of use of a primary constituent should be sufficient to avoid the NDI designation, as its safety is generally well-characterized by now.
With that said, we must also consider when the presence of a particular constituent is significantly increased, such that it may raise safety concerns.
A possible legislative solution would be to require the filing of a notification if the constituent is present at significantly greater levels than had historically been used in dietary supplements. This would have two main benefits: 1) it would allow for innovation and increase standardization of botanicals and their historically used constituents, while 2) recognizing if standardization significantly increases exposure well above what was historically consumed, there could be safety issues and the manufacturer should have evidence that this new level is safe.
I appreciate this may raise concerns about what is a significant increase. I believe that should be left to the manufacturer; but the manufacturer must maintain sufficient safety data that the increase in exposure does not pose a safety concern. Alternatively, we could simply state that anything over a 20% increase, for example, is considered “significant.”
Neither would be a perfect solution, but could offer a starting point for an honest conversation, and perhaps a sensible compromise.
Want to hear more from Todd Harrison? He'll be speaking in NYC on Sept. 12 at the Health and Longevity Conference & Showcase.
Synthetic Botanicals
FDA has attempted to limit the definition of a botanical to prohibit synthetic botanicals, arguing the definition of a dietary supplement excludes them from use.An alternative approach that would allow for more innovation would be to view synthetic botanicals as dietary substances that are bioidentical to natural botanicals. Of course, this begs the question whether the synthetic version should be considered an NDI subject to an NDIN. Arguably, if it is bioidentical, there is no practical reason to treat synthetic botanicals differently from the actual botanical, thus eliminating the need to file an NDIN.
On the other hand, if such evidence does not exist, the ingredient should be considered an NDI subject to the NDIN provisions of the act. Making that determination may be difficult. To state it differently, if the synthetic version is bioidentical and is no more bioavailable than its natural cousin, there is no reason to treat one as a grandfathered ingredient and the other as an NDIN. Admittedly, this may be difficult to prove.
An interesting regulatory solution would be for FDA to request the company file a limited NDIN that shows there is a reasonable basis for its conclusion. If there is not, FDA could request additional safety information, understanding it is still FDA’s burden to establish they are not bioidentical and the synthetic version poses a safety concern.
A reasonable legislative solution would be to amend the FDCA to expressly permit bioequivalent synthetics and only require notification if the synthetic version would act differently from the natural version.
There are numerous potential pathways here, and my approach may be overly simplistic, but it is a conversation worth having.
Preclusion Provision
Another regulatory issue that continues to disrupt the market is the preemption provision of the FDCA. Neither the supplement nor the pharmaceutical industry win when FDA takes a policy position that an ingredient is precluded from use as a dietary ingredient, but then allows the ingredient to continue to be marketed as such because there are no real safety concerns.This environment becomes a breeding ground for plaintiff class action cases against supplement companies that cannot sue FDA over the issue. Oftentimes, preclusion is not cut and dry. NAC is a perfect example. It has long been marketed as a dietary supplement before FDA decided it should be precluded, only to later decide it would exercise enforcement discretion facing pressure from industry.
However, there are ingredients that may be utilized to maintain overall health and wellbeing and also in the treatment and mitigation of disease. Lovaza comes to mind. Fish oil is a dual-purpose ingredient. These products coexist quite well with each other.
One might argue that the preclusion provision appears to be a concession by Congress to the pharmaceutical industry. However, was it even necessary, given that drug ingredients are generally protected by patents and, once approved, covered by third-party payors?
The other issue with the preclusion provision is for those drugs that have an IND and may be undergoing clinical trials. This makes it difficult for a supplement company to decide whether to file an NDIN, especially if it cannot verify whether an ingredient is under an IND. It’s true that clinicaltrials.gov may provide a company with a clue, but it may not.
Moreover, FDA has steadfastly refused to define what constitutes “substantial clinical trials.” As a result, it’s even more difficult for companies to decide whether to move forward on ingredients whose IND has been abandoned or if there are ongoing clinical trials.
This situation is not FDA’s fault, but it needs to be remedied. The best path forward is to amend the FDCA to establish an approval process — yes, “approval,” not “notification” — that would allow a supplement company to submit ingredients for FDA approval if these ingredients meet the definition of both a dietary supplement and a drug, possessing dual-purpose utility: at low doses, they help maintain overall health, while at high doses, they effectively treat diseases but may have major side effects.
Finally, we need to reset the grandfather date. A list of eligible dietary ingredients that meet the definition of a dietary supplement should be developed within 12 months of the law’s passage. The list should include all dosage levels and forms, while also meeting the definition of a dietary supplement. If it does not meet the definition, FDA should specifically exclude the ingredient and such exclusion shall be deemed final agency action, allowing companies to initiate a lawsuit against FDA to establish otherwise.
As I stated in the beginning, these are just my initial thoughts, and I will have more to offer over the next few months. It’s time to fix what is wrong with the FDCA. It is an outdated regulatory structure when it comes to foods and dietary supplements. As a society, we would be more healthy if we had laws that kept up with the science behind food and dietary supplements.
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.
