By James J. Gormley, Gormley NPI Consulting03.16.23
Today, 46% of the budget of the U.S. Food and Drug Administration (FDA) comes from user fees that pharmaceutical and biotech companies pay when they apply for approval of a drug or medical device.
Unfortunately, according to attorney Jonathan Emord: “As FDA medical reviewers have repeatedly stated in congressional testimony, FDA views the drug industry as its ‘client’ and does its client’s bidding.”
So it is, perhaps, not completely surprising that the FDA has in superficie demonstrated, particularly in the years since the enactment of the Dietary Supplement Health and Education Act of 1994 (DSHEA), that it will do almost anything in its powers, and often outside of those powers, to favor pharmaceutical products, often at the expense of safe dietary supplement ingredients.
In recent years, the FDA has made liberal use of the exclusion clause, which states 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.
Cholestin, pyridoxamine, vinpocetine, CBD, NAC, and NMN are examples of this provision (and other safety provisions) being invoked, or misused, with the latter four ingredients today in various levels of regulatory limbo.
Red yeast rice—a rice fermented with the mold Monascus purpureus—is considered a traditional Asian food that has a long history of use in Chinese medicine to support digestion and healthy circulation. The FDA claimed that Pharmanex was intentionally manufacturing its product to contain high levels of the statin compound and was marketing it for its cholesterol-lowering benefits.
Cholestin was excluded from the dietary supplement definition under the exclusion clause because the approval of Mevacor as a new drug preceded Pharmanex’s marketing of lovastatin as a dietary supplement.
In 2009, FDA removed pyridoxamine (a form of vitamin B6) from the market when it invoked the exclusion provision and claimed there was no evidence the article was marketed as a supplement prior to the initiation of clinical trials for the ingredient as a drug.
CBD has been in a regulatory twilight zone ever since. In fact, in January 2023, the FDA threw up its hands, saying a new regulatory pathway for CBD is needed, which might be great, say some, if it is a carve out, but could also set a dangerous precedent.
“When you read between the lines of today’s FDA statement, the agency appears to be saying that it would prefer to defy and attack DSHEA and develop different regulatory paths for ingredients at its own discretion,” said Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA).
“That could include requiring premarket approval, unnecessary testing, or who knows what. That is an especially dangerous precedent not only for CBD but for the entire natural products industry and ingredients like hemp that clearly fall under the agency’s jurisdiction.”
On Jun. 3, 2019, FDA issued a safety warning for women of childbearing age about vinpocetine, a compound that is derived from vincamine, an alkaloid found in the Vinca minor L. plant.
To date, vinpocetine is supported by 26 years of lawful historical safe use in the U.S. alone as a food and 45 years of safe use in Europe as a functional food.
According to NPA, the FDA and the European Union consider 25 years of widespread use to be the minimum to establish a history of safe use, according to their definition. “As NPA is unaware of any chemical changes to vinpocetine over the past [45] years, this dietary ingredient has demonstrated sufficient historical safe use worldwide and domestically as a lawfully marketed dietary ingredient for use in dietary supplements,” NPA noted in 2016.
In the summer of 2020, the FDA claimed that because N-acetyl cysteine (or NAC) was approved in 1963 as an inhaled drug (Mucomyst) for obstructive lung disease, and again in 1985 as an oral drug (Acetadote) to treat acetaminophen toxicity, it cannot be legally allowed in supplements. That’s despite the fact that NAC supplements have been safely marketed and consumed for more than 30 years.
In making the case for excluding NAC as a supplement, the agency referenced a 60-year-old drug approval for an inhaled form of the compound that was discontinued many years ago.
After leading the battle in securing final guidance for NAC through a citizen petition and lawsuit, NPA dismissed its lawsuit against the agency, which still “preserves legal rights and standing should additional action be necessary,” NPA said in a November 2022 press release. “The guidance also initiates the process for export certificates for NAC, which was a primary objective of the trade association’s strategy.”
The FDA will, for now, exercise enforcement discretion for the ingredient, essentially agreeing to ignore the sale of NAC-containing supplements provided that those products are not making non-compliant claims.
“This life-extending substance should be widely available, but the FDA is creating a situation in which only those who can afford to pay exorbitant drug prices will be able to enjoy NMN’s many benefits.”
Industry representatives broadly criticized FDA’s decision, noting the agency’s failure to raise the drug exclusion issue in its previous review of NMN ingredient notifications that are required under DSHEA.
“FDA’s sudden and contradictory announcement relative to the regulatory status of NMN as a dietary ingredient that is excluded from the definition of a dietary supplement, along with the arbitrary, erroneous, unreasonable and inequitable interpretation of the Act it relied on, adversely affects the entire dietary supplement stakeholder community,” stated NPA and the Alliance for Natural Health in a joint citizen petition dated Mar. 7, 2023.
“The current situation with NMN is yet another example of the inconsistent and mercurial way in which FDA chooses to both interpret DSHEA and use its limited resources to supposedly protect the public health. FDA has not articulated any risk to the safety of the public posed by NMN when marketed as a dietary ingredient or dietary supplement.”
“NMN is found in foods like broccoli, avocado, and cucumbers,” said Gretchen DuBeau, executive and legal director of the Alliance for Natural Health USA, upon the filing of the joint citizen petition with NPA over NMN. “This life-extending substance should be widely available, but the FDA is creating a situation in which only those who can afford to pay exorbitant drug prices will be able to enjoy NMN’s many benefits.”
If “the article” was first marketed as a supplement after 1994, under a new dietary ingredient (NDI) notification, is it enough to show the ingredient is reasonably expected to be safe? Or that it is marketed for a different indication than its pharmaceutical analogue?
Clearly, the exclusionary rule of DSHEA is increasingly being used to prevent or remove safe and legitimate dietary ingredients from the market, in some cases retroactively applied decades after a dietary ingredient was introduced and safely used by consumers.
Will Woodlee, general counsel to the American Herbal Products Association (AHPA), said during the association’s Regulatory Congress last fall that the easiest fix would be to have Congress “clearly codify the concept that prior drug exclusion doesn’t apply to ingredients that were on the market before DSHEA was enacted. For now, the industry needs to constantly look over its shoulder at all of the information from every drug company so that they know what opportunities FDA will have to pull the rug out from under them again.”
“Our system is broken,” added DuBeau. “The FDA is allowing pharmaceutical companies to ransack nature by monopolizing nutrients that can and should be dietary supplements.”
So the FDA has an opportunity to resolve these conflicts when they arise with rulemaking that grants an exception to the statutory race to market. So even if the “article” is the same for the drug and supplement—and there are many ways why they are not—FDA could fix the problem.
Unfortunately, FDA has never exercised this authority and does not seem willing to do so now for either NAC or CBD. It would seem, say some, that the FDA would rather go on a fishing expedition through its archives to find some dusty clinical use application that has been long since abandoned.
All this emphasizes the need for a reexamination of the exclusionary rule. FDA could issue guidance on this topic, but failing that, Congress needs to revise this section of the statute.
This race to market should not support pharmaceutical interests at the cost of denying consumers access to effective supplements that can, and do, significantly enhance health.
About the Author: James Gormley has been an award-winning natural products industry writer, editor and thought leader since 1995. The head of Gormley NPI Consulting, James can be reached via his website, JamesGormley.com or via email at jamesgormley01@gmail.com.
Unfortunately, according to attorney Jonathan Emord: “As FDA medical reviewers have repeatedly stated in congressional testimony, FDA views the drug industry as its ‘client’ and does its client’s bidding.”
So it is, perhaps, not completely surprising that the FDA has in superficie demonstrated, particularly in the years since the enactment of the Dietary Supplement Health and Education Act of 1994 (DSHEA), that it will do almost anything in its powers, and often outside of those powers, to favor pharmaceutical products, often at the expense of safe dietary supplement ingredients.
In recent years, the FDA has made liberal use of the exclusion clause, which states 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.
Cholestin, pyridoxamine, vinpocetine, CBD, NAC, and NMN are examples of this provision (and other safety provisions) being invoked, or misused, with the latter four ingredients today in various levels of regulatory limbo.
Red Yeast Rice and Pyridoxamine
Pharmanex v. Shalala was a 2001 case in which the U.S. Court of Appeals ruled that the FDA had the authority to prohibit a company, Pharmanex, from marketing its Cholestin red yeast rice as a supplement. Cholestin’s active compound—monacolin K—was identical to lovastatin which was approved as a cholesterol-lowering drug (Mevacor) in 1987.Red yeast rice—a rice fermented with the mold Monascus purpureus—is considered a traditional Asian food that has a long history of use in Chinese medicine to support digestion and healthy circulation. The FDA claimed that Pharmanex was intentionally manufacturing its product to contain high levels of the statin compound and was marketing it for its cholesterol-lowering benefits.
Cholestin was excluded from the dietary supplement definition under the exclusion clause because the approval of Mevacor as a new drug preceded Pharmanex’s marketing of lovastatin as a dietary supplement.
In 2009, FDA removed pyridoxamine (a form of vitamin B6) from the market when it invoked the exclusion provision and claimed there was no evidence the article was marketed as a supplement prior to the initiation of clinical trials for the ingredient as a drug.
CBD, Vinpocetine and NAC: A Hazy Regulatory Landscape
The 2018 Farm Bill removed hemp with no more than 0.3% THC content on a dry weight basis from the Controlled Substances Act (CSA). FDA quickly invoked 201(ff)(3)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act) to claim that CBD is precluded from being a dietary ingredient because of the prior approval of Epidiolex as a drug. This artificial hurdle has dogged mainstream retailers from selling ingestible CBD products for years now.CBD has been in a regulatory twilight zone ever since. In fact, in January 2023, the FDA threw up its hands, saying a new regulatory pathway for CBD is needed, which might be great, say some, if it is a carve out, but could also set a dangerous precedent.
“When you read between the lines of today’s FDA statement, the agency appears to be saying that it would prefer to defy and attack DSHEA and develop different regulatory paths for ingredients at its own discretion,” said Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA).
“That could include requiring premarket approval, unnecessary testing, or who knows what. That is an especially dangerous precedent not only for CBD but for the entire natural products industry and ingredients like hemp that clearly fall under the agency’s jurisdiction.”
On Jun. 3, 2019, FDA issued a safety warning for women of childbearing age about vinpocetine, a compound that is derived from vincamine, an alkaloid found in the Vinca minor L. plant.
To date, vinpocetine is supported by 26 years of lawful historical safe use in the U.S. alone as a food and 45 years of safe use in Europe as a functional food.
According to NPA, the FDA and the European Union consider 25 years of widespread use to be the minimum to establish a history of safe use, according to their definition. “As NPA is unaware of any chemical changes to vinpocetine over the past [45] years, this dietary ingredient has demonstrated sufficient historical safe use worldwide and domestically as a lawfully marketed dietary ingredient for use in dietary supplements,” NPA noted in 2016.
In the summer of 2020, the FDA claimed that because N-acetyl cysteine (or NAC) was approved in 1963 as an inhaled drug (Mucomyst) for obstructive lung disease, and again in 1985 as an oral drug (Acetadote) to treat acetaminophen toxicity, it cannot be legally allowed in supplements. That’s despite the fact that NAC supplements have been safely marketed and consumed for more than 30 years.
In making the case for excluding NAC as a supplement, the agency referenced a 60-year-old drug approval for an inhaled form of the compound that was discontinued many years ago.
After leading the battle in securing final guidance for NAC through a citizen petition and lawsuit, NPA dismissed its lawsuit against the agency, which still “preserves legal rights and standing should additional action be necessary,” NPA said in a November 2022 press release. “The guidance also initiates the process for export certificates for NAC, which was a primary objective of the trade association’s strategy.”
The FDA will, for now, exercise enforcement discretion for the ingredient, essentially agreeing to ignore the sale of NAC-containing supplements provided that those products are not making non-compliant claims.
“This life-extending substance should be widely available, but the FDA is creating a situation in which only those who can afford to pay exorbitant drug prices will be able to enjoy NMN’s many benefits.”
—Gretchen DuBeau, Alliance for Natural Health USA
NMN in the Crosshairs
This brings us to late 2022, when the FDA made a determination that β-NMN (beta-nicotinamide mononucleotide, or NMN) could not be sold in nutritional supplements by virtue of its investigation as a drug prior to its lawful marketing as a dietary supplement.Industry representatives broadly criticized FDA’s decision, noting the agency’s failure to raise the drug exclusion issue in its previous review of NMN ingredient notifications that are required under DSHEA.
“FDA’s sudden and contradictory announcement relative to the regulatory status of NMN as a dietary ingredient that is excluded from the definition of a dietary supplement, along with the arbitrary, erroneous, unreasonable and inequitable interpretation of the Act it relied on, adversely affects the entire dietary supplement stakeholder community,” stated NPA and the Alliance for Natural Health in a joint citizen petition dated Mar. 7, 2023.
“The current situation with NMN is yet another example of the inconsistent and mercurial way in which FDA chooses to both interpret DSHEA and use its limited resources to supposedly protect the public health. FDA has not articulated any risk to the safety of the public posed by NMN when marketed as a dietary ingredient or dietary supplement.”
“NMN is found in foods like broccoli, avocado, and cucumbers,” said Gretchen DuBeau, executive and legal director of the Alliance for Natural Health USA, upon the filing of the joint citizen petition with NPA over NMN. “This life-extending substance should be widely available, but the FDA is creating a situation in which only those who can afford to pay exorbitant drug prices will be able to enjoy NMN’s many benefits.”
It's Not About Safety
It’s important to remember that safety is not the issue in these cases; it’s an economic argument to protect the financial incentives to carry out drug research. Does the statute envision that safety should even be a consideration? Law does not instruct FDA how to determine that the article “would be lawful under this chapter.”If “the article” was first marketed as a supplement after 1994, under a new dietary ingredient (NDI) notification, is it enough to show the ingredient is reasonably expected to be safe? Or that it is marketed for a different indication than its pharmaceutical analogue?
Clearly, the exclusionary rule of DSHEA is increasingly being used to prevent or remove safe and legitimate dietary ingredients from the market, in some cases retroactively applied decades after a dietary ingredient was introduced and safely used by consumers.
Will Woodlee, general counsel to the American Herbal Products Association (AHPA), said during the association’s Regulatory Congress last fall that the easiest fix would be to have Congress “clearly codify the concept that prior drug exclusion doesn’t apply to ingredients that were on the market before DSHEA was enacted. For now, the industry needs to constantly look over its shoulder at all of the information from every drug company so that they know what opportunities FDA will have to pull the rug out from under them again.”
“Our system is broken,” added DuBeau. “The FDA is allowing pharmaceutical companies to ransack nature by monopolizing nutrients that can and should be dietary supplements.”
A Way Out … or Forward
Law does provide a way out of this quagmire, however. The drug exclusion provision states, “…unless the Secretary [of Health and Human Services], in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this chapter.”So the FDA has an opportunity to resolve these conflicts when they arise with rulemaking that grants an exception to the statutory race to market. So even if the “article” is the same for the drug and supplement—and there are many ways why they are not—FDA could fix the problem.
Unfortunately, FDA has never exercised this authority and does not seem willing to do so now for either NAC or CBD. It would seem, say some, that the FDA would rather go on a fishing expedition through its archives to find some dusty clinical use application that has been long since abandoned.
All this emphasizes the need for a reexamination of the exclusionary rule. FDA could issue guidance on this topic, but failing that, Congress needs to revise this section of the statute.
This race to market should not support pharmaceutical interests at the cost of denying consumers access to effective supplements that can, and do, significantly enhance health.
About the Author: James Gormley has been an award-winning natural products industry writer, editor and thought leader since 1995. The head of Gormley NPI Consulting, James can be reached via his website, JamesGormley.com or via email at jamesgormley01@gmail.com.
