CRN’s new citizen petition to FDA requests that agency modify, clarify its stance on drug preclusion clause of FD&C Act

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The Council for Responsible Nutrition (CRN; Washington, DC) sent FDA a citizen petition on May 9, 2023, asking the agency to “reconsider” how it has been invoking the drug preclusion clause of the Food, Drug, and Cosmetic Act (FD&C Act) to claim that certain ingredients cannot legally be dietary supplement ingredients. In its petition, CRN asks FDA to acknowledge that the agency cannot retroactively use the drug preclusion clause to ban supplement ingredients that the agency previously indicated it considered legal. It also asks FDA to issue guidance clarifying what the agency believes renders an ingredient a legal supplement ingredient versus an illegal supplement ingredient in the presence of the drug preclusion clause.

Section 201(ff)(3)(B) of the FD&C Act is often referred to as the “drug preclusion clause” because it states that an ingredient that was first investigated as a drug before coming to market as a supplement cannot be sold as a supplement. Congress’s intent in including this provision in the law was, CRN’s petition says, to prevent drug companies from taking a less costly path to market by selling their drug product under the guise of a dietary supplement instead of going through the rigors of drug approval.

As CRN and other supplement industry stakeholders have stated, in recent years, FDA has often sought to ban certain supplement ingredients, by citing the drug exclusion clause. These are ingredients that the agency formerly acknowledged as legitimate supplement ingredients. These ingredients include vinpocetine and n-acetyl-L-cysteine (NAC). Most recently, the agency said last year that beta-nicotinamide mononucleotide (NMN) is not a dietary ingredient, citing the drug preclusion clause.

Previous agency actions did not indicate that FDA considered these ingredients illegal dietary ingredients. For instance, as CRN’s petition points out, before FDA surprised the industry in November 2022 by stating, in a response to a company’s new dietary ingredient (NDI) notification, that NMN is actually not a legal supplement ingredient “based on new information that came to light when we were reviewing another notification,” the agency previously had expressed no objections to a different NDI notification for NMN submitted earlier in May 2022.

As the petition points out, FDA’s “reversal” on NMN’s legal stance was similar to its actions regarding NAC and vinpocetine, which are both also ingredients that FDA previously expressed no objections to but which the agency later, citing the drug preclusion clause, then declared illegal in supplements.

Supplement companies have invested in bringing these products to market, believing FDA considers them legal, putting the companies at a significant disadvantage when FDA changes its position and gives the market to drug companies only. The petition states: “Based on FDA’s interpretation, however, and the exact situation we saw unfold with NMN, a dietary supplement company can unknowingly invest significant resources researching and developing a dietary ingredient, only to have it removed from the marketplace.” Not only that, the petition points out, consumers who have come to rely on these dietary supplement ingredients lose access to them once FDA changes course and, as a result, retailers begin removing the supplements from the market.

In conclusion, the petition says, “…FDA has increasingly interpreted section 201(ff)(3)(B) over nearly three decades in a manner that overly advantages drugs at the expense of dietary supplements.”

CRN’s petition also lists reasons why the association believes FDA’s interpretation of the drug preclusion clause is questionable and why it should not be used to restrict these supplements from the market. The petition requests that FDA take several actions.

It asks FDA to only apply the drug exclusion clause if an ingredient was the subject of “substantial clinical investigations” that were made public. First off, it says, the drug preclusion clause should not be applied to ingredients that are only the subject of Phase I or early clinical trials. The petition states: “Congress’s use of the word ‘substantial’ in ‘substantial clinical investigations’ conveys that it intended for this phrase to encompass more than mere ‘clinical investigations’—otherwise, Congress would have simply used the term ‘clinical investigations’ without qualifying that these investigations need to be ‘substantial.’”

Secondly, the petition asks FDA to determine that the preclusion date be considered as the date on which the existence of the substantial clinical trial is made public, “not the non-public date on which an investigational new drug (IND) application goes into effect.” Often, such information is lacking in the public or even the regulatory sphere. For instance, the petition points out that sometimes FDA itself is not aware of whether or not an ingredient has been studied as a drug. This is evidenced by the fact that FDA staff previously acknowledged NDI notifications for ingredients like NMN without objection. The petition says that “it appears that FDA staff was not even aware of the purported IND for NMN…”

Drug investigations, and details about the exact article being studied, are not always made public by drug companies. In addition, communications between a drug company and FDA regarding a drug company’s IND application are confidential, meaning there’s no way for supplement companies to accurately ascertain whether or not an ingredient is currently being, or has been, studied as a drug. The petition states that “because IND effective dates are not public, this interpretation creates a nonsensical scenario where supplement companies will have no way to know if a substance was marketed as a food or a dietary supplements before the IND trigger date.”

In conclusion, the petition states, “It strains credibility to suggest that Congress would have intended to create a scenario in which innovative supplement manufacturers could discover a novel health-related use for an ingredient, scour the publicly available literature and find no indication that it was being used in substantial clinical investigations as a drug, then develop their own safety and efficacy research, and invest in marketing the ingredient in a supplement, to then have the ingredient precluded from supplement use based on limited clinical study of an ingredient and non-public, undiscoverable information that is only available to certain FDA offices. Yet that scenario is precisely what the collection of FDA interpretations of this section have effectively created. As we have demonstrated in this petition, FDA’s approach to drug preclusion language interpretation has served one purpose—to favor drug interests over supplements in a manner that is inconsistent, ignores important statutory construction principles, and negates the purpose of DSHEA," referring to the Dietary Supplement Health and Education Act of 1994.

The petition makes additional requests. It asks that regarding the preclusion’s “which came first requirement” that essentially states that if an ingredient was first marketed as a dietary supplement before being investigated as a drug it can remain on the market, that any supplement marketing should be considered globally and not just be restricted to marketing in the United States.

The petition also asks FDA to acknowledge that it cannot retroactively pull dietary ingredients off the market that it previously indicated as being legal. The petition asks FDA “to determine that the agency’s prior affirmative statements recognizing the legal status of a particular article as a legal dietary ingredient prevents FDA from subsequently reversing that decision on the grounds of drug preclusion.”

Finally, the petition requests that FDA issue public guidance clarifying how the agency intends to implement the drug exclusion clause moving forward. Currently, the petition points out, “most of FDA’s drug preclusion interpretations remain difficult if not impossible to challenge because FDA makes these interpretations in warning letters and through other mechanisms that are not considered final agency action.” If a company tried to challenge FDA’s interpretation in court, the petition points out, “it’s likely that FDA will argue that these determinations are not final agency actions.”

CRN also drew a line between its petition and others that have been submitted—notably, a citizen petition filed this March by the Natural Products Association (Washington, DC) and the Alliance for Natural Health (Edinburg, VA), which asked FDA to reevaluate its position on NMN. CRN says that its petition is different because it is not limited just to NMN but rather extends to any ingredient. “Any actions requested in other citizen petitions that specifically reference an outcome for NMN should be considered separately by FDA, and CRN requests that a response to this petition not be delayed by a response to other petitions," the petition states.