By Mike Montemarano, Associate Editor 05.10.23
The U.S. Food and Drug Administration (FDA) has come to interpret the “drug preclusion” clause of the Dietary Supplement Health and Education Act (DSHEA) in a way that is inconsistent, unpredictable, and oppositional to Congressional intent, according to the Council for Responsible Nutrition (CRN), which filed a Citizen Petition that calls on FDA to reconsider its positions.
Rather than focus on a single ingredient, CRN’s petition aims to address broad changes to the precedent FDA has set in several recent decisions, including CBD, NAC, NMN, and others.
“We’ve outlined a few examples of some of the more egregious and public examples of where FDA has taken an overly broad, inconsistent, and often unfair interpretation which pulls the rug out from under companies who’ve been selling a certain ingredient for years or even decades,” Megan Olsen, senior vice president and general counsel at CRN, told NW. “We don’t believe this is about any one ingredient. The way FDA is reaching inconsistent and surprising decisions leaves us unable to know what could even be vulnerable right now. We believe that this is harming consumers, because it’s being used to remove ingredients from the marketplace which consumers have come to rely on, even if those ingredients are safe and may have health benefits.”
A ‘Race to Market’ ... While Blindfolded
Since DSHEA was enacted in 1994, dietary supplements are prohibited from including “an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted 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 Act” (21 U.S.C. § 321(ff)(3)(B)(ii)).
An Investigational New Drug (IND) application is considered confidential and FDA will not disclose its existence unless it has previously been publicly disclosed or acknowledged. Therefore, as has happened recently, dietary supplement companies might end up investing in research and development, or even issue a New Dietary Ingredient Notification (NDIN) without knowing the article was first authorized for investigation as a new drug.
CRN’s petition requests that FDA “determine that the preclusion date referenced in the statute (i.e., the date on which the ‘race to market’ between a drug and a supplement is adjudicated) is the date the existence of substantial clinical trials are made public, not the non-public date on which an investigational new drug (IND) application goes into effect.”
In the recent case of NMN, FDA even acknowledged an NDIN from Inner Mongolia Kingdomway Pharmaceutical Limited without objection, only to later rescind that position and state in a letter to Kingdomway on Oct. 11, 2022 that NMN is excluded from the dietary supplement definition.
Without clarity or consistency, other ingredients may suddenly get barred from the marketplace unexpectedly, similarly to NAC and NMN, dietary supplement stakeholders have argued. According to CRN, these removals took place “without offering legally sound reasoning, consistent with DSHEA and prior FDA interpretations of drug preclusion, to support its decision making.”
“We are deeply distressed by FDA’s decision to revoke the status of these ingredients as dietary supplements, which threatens future innovation, because by doing so, they’ve flipped the script on how drug preclusion is supposed to work, leaving all parties—manufacturers, retailers, and consumers—in a sort of regulatory limbo going forward,” said Steve Mister, CRN president and CEO.
“Without a reexamination of FDA’s position, and guidance that lends clarity and predictability to the process, manufacturers are discouraged from continued innovation of new ingredients, and retailers are not sure whether they should, or are able to, continue to make these products available to the public for fear of selling ‘illegal’ supplements.”
“It’s akin to conducting a title search on a house, determining there are no liens, only to be told after you’ve bought the house that there were actually secret liens on the property, and you’ll have to forfeit your investment,” Mister continued. “Yet that is exactly what is happening to supplement companies, which are acting in good faith and in accordance with publicly available information, in what could be perceived as an effort by the agency to unfairly protect the financial interests of pharmaceutical companies over those of supplement manufacturers.”
Substantial Research Requirement
The drug preclusion provision of DSHEA implies that “substantial research,” beyond phase I drug trials, needs to occur and be made public before an ingredient would be excluded from use in dietary supplements, according to Olsen. CRN argues that FDA is misinterpreting this section of the legislation.
Olsen argued that “substantial research” should apply to studies that would result in the approval of a drug if a positive outcome occurs, based on how other FDA regulations define the phrase. Further, that research needs to be made public prior to drug preclusion taking effect, according to the statute.
“IND authorization isn’t enough on its own,” Olsen said. “But the way FDA interprets (the statute) makes things seem otherwise, as they’ve cited phase I clinical studies as examples of substantial clinical investigation, which is the very first step after IND authorization.... We don’t believe that this is what Congress intended.”
“The date in which an IND is set isn’t public information,” Olsen continued. “Dietary supplement companies have no idea, even if they find public clinical trials, when an IND was authorized, so there’s no way to know for sure if preclusion applies. Neither drug nor supplement companies have any assurances as to when drug preclusion protections actually attach to a given ingredient.”
Marketing as a Stronger Precedent
CRN’s petition also requests that FDAdetermine that “marketing” as used in section 201(ff)(3)(B) not be limited to marketing in the U.S., “nor does it require “legal” marketing of the ingredient.” Evidence of marketing as a food or dietary supplement “should be dispositive,” the petition adds, “unless FDA has met its statutory burden of demonstrating that the marketing was unlawful.”
“This petition is bigger than any single ingredient,” Olsen said. “We’ve seen references to NMN being marketed and sold as a dietary supplement well before it appears that any drug clinical trial started. We don’t know when the IND authorization went into effect, and no trial on NMN that we’re aware of meets the ‘substantial’ threshold. We want FDA to be transparent and clear in a way that can be challenged by CRN or any other party, and the chance to hear those challenges out in court.”
CRN also requested that the agency treat prior affirmative statements recognizing the legal status of a dietary ingredient as irreversible on the grounds of drug preclusion. This became a major point of contention last fall when the agency declared that NMN was subject to drug preclusion after responding to a New Dietary Ingredient Notification (NDIN) with no objection. In 2016, FDA declared vinpocetine should be excluded from use in dietary supplements despite NDI filings dating back to 1997 that were not objected to.
Chevron Deference Called into Question
The U.S. Supreme Court has taken up Loper Bright Enterprises v. Raimondo, a case which experts have noted may lead to the overturn of a legal precedent known as Chevron deference.
This precedent, which stems from the 1984 case Chevron v. Natural Resources Defense Council, comes from the Supreme Court ruling that all courts should defer to a federal agency’s interpretation of an ambiguous statute.
Federal agencies often cite the Chevron deference in court cases and other rulemaking decisions. FDA has cited it in court and in communications about drug preclusion, among other rules.
“A new precedent around the Chevron deference, particularly how it’s used to force courts to give more weight to agency interpretations, would be very useful,” Olsen said. “We want the court to step in and treat both sides of an argument fairly and on their own. Right now, the court is constantly grappling with how much weight it is required to give to an agency’s interpretation. I think every decision we’ve questioned in our Citizen Petition is ripe for a more level playing field should there be changes in how courts are required to use Chevron deference.”
Laying out the Options
While it may take a while for a decision in Loper Bright Enterprises v. Raimondo, Olsen remains hopeful that FDA will be amenable to discussing the requested changes in the meantime.
“Our request concerns not only the effects that drug preclusion has on the supplement industry, but on consumer access at large,” Olsen said. “This petition also serves other purposes beyond seeking an answer from the agency. Legislators have taken interest in this, such as Representative Jeff Duncan (R-SC), who has called for hearings and is concerned about NMN and the matter of drug preclusion,” said Olsen.
“This could also lay the groundwork for amendments to the statute, to make it more in line with how we believe it was meant to be interpreted. Also, the petition could serve as the first step in a legal challenge if CRN’s board ever wanted to go down that path. We want to open a lot of options and explore as many ways as possible to correct course on this issue.”
Rather than focus on a single ingredient, CRN’s petition aims to address broad changes to the precedent FDA has set in several recent decisions, including CBD, NAC, NMN, and others.
“We’ve outlined a few examples of some of the more egregious and public examples of where FDA has taken an overly broad, inconsistent, and often unfair interpretation which pulls the rug out from under companies who’ve been selling a certain ingredient for years or even decades,” Megan Olsen, senior vice president and general counsel at CRN, told NW. “We don’t believe this is about any one ingredient. The way FDA is reaching inconsistent and surprising decisions leaves us unable to know what could even be vulnerable right now. We believe that this is harming consumers, because it’s being used to remove ingredients from the marketplace which consumers have come to rely on, even if those ingredients are safe and may have health benefits.”
A ‘Race to Market’ ... While Blindfolded
Since DSHEA was enacted in 1994, dietary supplements are prohibited from including “an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted 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 Act” (21 U.S.C. § 321(ff)(3)(B)(ii)).
An Investigational New Drug (IND) application is considered confidential and FDA will not disclose its existence unless it has previously been publicly disclosed or acknowledged. Therefore, as has happened recently, dietary supplement companies might end up investing in research and development, or even issue a New Dietary Ingredient Notification (NDIN) without knowing the article was first authorized for investigation as a new drug.
CRN’s petition requests that FDA “determine that the preclusion date referenced in the statute (i.e., the date on which the ‘race to market’ between a drug and a supplement is adjudicated) is the date the existence of substantial clinical trials are made public, not the non-public date on which an investigational new drug (IND) application goes into effect.”
In the recent case of NMN, FDA even acknowledged an NDIN from Inner Mongolia Kingdomway Pharmaceutical Limited without objection, only to later rescind that position and state in a letter to Kingdomway on Oct. 11, 2022 that NMN is excluded from the dietary supplement definition.
Without clarity or consistency, other ingredients may suddenly get barred from the marketplace unexpectedly, similarly to NAC and NMN, dietary supplement stakeholders have argued. According to CRN, these removals took place “without offering legally sound reasoning, consistent with DSHEA and prior FDA interpretations of drug preclusion, to support its decision making.”
“We are deeply distressed by FDA’s decision to revoke the status of these ingredients as dietary supplements, which threatens future innovation, because by doing so, they’ve flipped the script on how drug preclusion is supposed to work, leaving all parties—manufacturers, retailers, and consumers—in a sort of regulatory limbo going forward,” said Steve Mister, CRN president and CEO.
“Without a reexamination of FDA’s position, and guidance that lends clarity and predictability to the process, manufacturers are discouraged from continued innovation of new ingredients, and retailers are not sure whether they should, or are able to, continue to make these products available to the public for fear of selling ‘illegal’ supplements.”
“It’s akin to conducting a title search on a house, determining there are no liens, only to be told after you’ve bought the house that there were actually secret liens on the property, and you’ll have to forfeit your investment,” Mister continued. “Yet that is exactly what is happening to supplement companies, which are acting in good faith and in accordance with publicly available information, in what could be perceived as an effort by the agency to unfairly protect the financial interests of pharmaceutical companies over those of supplement manufacturers.”
Substantial Research Requirement
The drug preclusion provision of DSHEA implies that “substantial research,” beyond phase I drug trials, needs to occur and be made public before an ingredient would be excluded from use in dietary supplements, according to Olsen. CRN argues that FDA is misinterpreting this section of the legislation.
Olsen argued that “substantial research” should apply to studies that would result in the approval of a drug if a positive outcome occurs, based on how other FDA regulations define the phrase. Further, that research needs to be made public prior to drug preclusion taking effect, according to the statute.
“IND authorization isn’t enough on its own,” Olsen said. “But the way FDA interprets (the statute) makes things seem otherwise, as they’ve cited phase I clinical studies as examples of substantial clinical investigation, which is the very first step after IND authorization.... We don’t believe that this is what Congress intended.”
“The date in which an IND is set isn’t public information,” Olsen continued. “Dietary supplement companies have no idea, even if they find public clinical trials, when an IND was authorized, so there’s no way to know for sure if preclusion applies. Neither drug nor supplement companies have any assurances as to when drug preclusion protections actually attach to a given ingredient.”
Marketing as a Stronger Precedent
CRN’s petition also requests that FDAdetermine that “marketing” as used in section 201(ff)(3)(B) not be limited to marketing in the U.S., “nor does it require “legal” marketing of the ingredient.” Evidence of marketing as a food or dietary supplement “should be dispositive,” the petition adds, “unless FDA has met its statutory burden of demonstrating that the marketing was unlawful.”
“This petition is bigger than any single ingredient,” Olsen said. “We’ve seen references to NMN being marketed and sold as a dietary supplement well before it appears that any drug clinical trial started. We don’t know when the IND authorization went into effect, and no trial on NMN that we’re aware of meets the ‘substantial’ threshold. We want FDA to be transparent and clear in a way that can be challenged by CRN or any other party, and the chance to hear those challenges out in court.”
CRN also requested that the agency treat prior affirmative statements recognizing the legal status of a dietary ingredient as irreversible on the grounds of drug preclusion. This became a major point of contention last fall when the agency declared that NMN was subject to drug preclusion after responding to a New Dietary Ingredient Notification (NDIN) with no objection. In 2016, FDA declared vinpocetine should be excluded from use in dietary supplements despite NDI filings dating back to 1997 that were not objected to.
Chevron Deference Called into Question
The U.S. Supreme Court has taken up Loper Bright Enterprises v. Raimondo, a case which experts have noted may lead to the overturn of a legal precedent known as Chevron deference.
This precedent, which stems from the 1984 case Chevron v. Natural Resources Defense Council, comes from the Supreme Court ruling that all courts should defer to a federal agency’s interpretation of an ambiguous statute.
Federal agencies often cite the Chevron deference in court cases and other rulemaking decisions. FDA has cited it in court and in communications about drug preclusion, among other rules.
“A new precedent around the Chevron deference, particularly how it’s used to force courts to give more weight to agency interpretations, would be very useful,” Olsen said. “We want the court to step in and treat both sides of an argument fairly and on their own. Right now, the court is constantly grappling with how much weight it is required to give to an agency’s interpretation. I think every decision we’ve questioned in our Citizen Petition is ripe for a more level playing field should there be changes in how courts are required to use Chevron deference.”
Laying out the Options
While it may take a while for a decision in Loper Bright Enterprises v. Raimondo, Olsen remains hopeful that FDA will be amenable to discussing the requested changes in the meantime.
“Our request concerns not only the effects that drug preclusion has on the supplement industry, but on consumer access at large,” Olsen said. “This petition also serves other purposes beyond seeking an answer from the agency. Legislators have taken interest in this, such as Representative Jeff Duncan (R-SC), who has called for hearings and is concerned about NMN and the matter of drug preclusion,” said Olsen.
“This could also lay the groundwork for amendments to the statute, to make it more in line with how we believe it was meant to be interpreted. Also, the petition could serve as the first step in a legal challenge if CRN’s board ever wanted to go down that path. We want to open a lot of options and explore as many ways as possible to correct course on this issue.”
