Oral arguments with Marc Ullman: DSHEA exclusionary clauseOral arguments with Marc Ullman: DSHEA exclusionary clause
In his "oral arguments" quarterly column, attorney Marc Ullman dissects FDA’s interpretation of the exclusionary clause in the Dietary Supplement Health and Education Act of 1994. The issue, he writes, has the potential to negatively impact innovation and new ingredients for the entire trade for years to come.
January 5, 2023
Editor’s note: This article reflects the views of the author and is a quarterly column.
A series of FDA actions has created an aura of uncertainty over whether it is possible to rely on the agency’s acceptance of premarket new dietary ingredient notifications (NDINs) without comment, or objection, as a sign that any ingredient is actually lawful.
This conundrum has been created by FDA’s reading of the definition of a dietary supplement, which is set forth in 21 U.S.C. § 321(ff) (section 201(ff) of the Federal Food, Drug and Cosmetic Act [FDCA]). It states in relevant part:
(ff) The term 'dietary supplement' ... (3) does ... (B) not include - (i) an article that is approved as a new drug under section 355 of this title ... or (ii) an article authorized for investigation as a new drug ... 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 ... 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 (emphasis added).
This seemingly straightforward provision—known as the exclusionary clause in the Dietary Supplement Health and Education Act of 1994 (DSHEA)—has created a series of issues that should raise alarm bells in the dietary supplement industry.
On Sept. 6, 2016, FDA published a Federal Register notice seeking public comment on its tentative conclusion that vinpocetine (1) does not meet the definition of a dietary ingredient, and (2) is excluded from the definition of a dietary supplement under the FDCA because vinpocetine was authorized for investigation as a new drug before it was marketed as a dietary supplement or as a food. According to FDA, it concluded vinpocetine was authorized as an investigational new drug in 1981, which would prohibit its use as a dietary ingredient in dietary supplements. This notice was published two decades after FDA responded to NDINs for vinpocetine without objection and the ingredient was first offered for sale in dietary supplements. The agency never took further action after the Federal Register notice was published, and to date, vinpocetine remains on the market as a supplement.
In July 2020, FDA sent warning letters to marketers of NAC (N-acetyl-L-cysteine) dietary supplements, some of which were offered as hangover remedies. While such claims have long been subject to warning letters, FDA said NAC was approved as a new drug in 1963, and there were no records showing marketing in supplements prior to that date, consequently precluding its use as a dietary ingredient. Following significant protests from the supplement industry, including a lawsuit brought by the Natural Products Association (NPA) challenging the retroactive application of the DSHEA exclusionary clause, FDA issued a statement of enforcement discretion in a final guidance published in August, stating it would allow NAC to continue to be marketed for use in supplements.
Then on Oct. 11, 2022, FDA responded to a new dietary ingredient notification for nicotinamide mononucleotide (“NMN”) submitted on behalf of Inner Mongolia Kingdomway Pharmaceutical Ltd. FDA rejected the notification for use in dietary supplements, citing a previously undisclosed authorization to study the ingredient as an investigational new drug (IND). FDA took this action despite having previously responded to several similar ingredient notifications without raising the IND issue, including a May 16, 2022 acknowledgment letter to SyncoZymes (Shanghai) Co. Ltd. On Nov. 4, 2022, FDA confirmed to Kingdomway that its NMN could not, in fact, be lawfully sold as a dietary ingredient. In a separate letter of the same date, it advised SyncoZymes it would have to cease marketing the same NMN that had been cleared less than six months earlier.
We have a problem
While FDA appears to be content with allowing vinpocetine and NAC to remain on the market, NMN may be a much stickier wicket. FDA’s November 4 letter to SyncoZymes notes that after its initial failure to object to the company’s NDIN, “Based on new information that came to light when we were reviewing another notification, FDA initiated a review of past notification responses for NMN and concluded that NMN is excluded from the definition of a dietary supplement. This means that NMN may not be marketed as or in a dietary supplement.”
This new information appears to be a Dec. 1, 2021 letter to FDA by Metro International Biotech, requesting FDA “protect the rights” of IND holders under Section 201(ff). In a detailed response to Kingdomway, FDA advised the company that “NMN was not marketed as a dietary supplement, except unlawfully without an NDI notification, or as a food before FDA authorized it for investigation as a new drug.”
Remarkably, FDA’s position ignores that the DSHEA exclusionary clause lists three factors that appear to be required to disqualify an ingredient from use in dietary supplements due to prior investigation as a drug:
Authorization as an IND;
The existence of substantial clinical investigations; and
Public notification of the existence of such investigations.
Any common-sense reading of the plain language of the statute would suggest the important date is the one on which all three factors would be satisfied. Otherwise, why include the requirement that any substantial clinical investigation be made public? The reason would seem obvious: To ensure dietary ingredient innovators be given fair notice that their investment in research is not undertaken on an ingredient already blocked from the market.
In its November letter to Kingdomway, FDA notably focused solely on the date on which NMN was authorized for investigation as a new drug. FDA incredibly declined to state what that date might be, citing a regulation (21 CFR 312.130) prohibiting agency disclosure of the existence of an IND that has not been previously disclosed or acknowledged by the holder thereof. Instead, we are left only with information provided by Metro International Biotech that it holds an IND for NMN and the accompanying citation to studies published in March and September 2021.
We were warned but didn't realize it
While it was not apparent at the time, a post-hoc review of FDA’s 2016 revised version of its “Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry” reveals FDA told us it was prepared to undertake exactly this kind of analysis to stifle innovation in the supplement industry. In response to questions 7 and 9 in section D of this document, “Additional Issues to Consider Before Submitting an NDI Notification,” FDA stated (emphasis added):
7. When FDA reviews an NDI notification, does the agency consider whether the prohibition in section 301(ll) of the FD&C Act applies to the use of the NDI in a dietary supplement?
No. Section 301(ll) of the FD&C Act (21 U.S.C. 331(ll)) prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under 21 U.S.C. 355, a biological product licensed under 42 U.S.C. 262, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. When reviewing NDI notifications, FDA’s current practice is not to consider whether section 301(ll) or any of its exemptions apply to the NDI. Accordingly, a “no objection” response to an NDI notification should not be construed to be a statement that a dietary supplement containing the NDI, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll) of the FD&C Act.
9. May I use an ingredient in a dietary supplement if it has been clinically tested as a drug but has not been approved as a drug in the U.S.?
It depends on whether the ingredient was authorized for investigation in clinical trials under an investigational new drug application (IND), whether the date the IND went into effect was before or after the date the ingredient was first marketed as a food or as a dietary supplement, whether the clinical trials were “substantial clinical investigations,” and whether their existence was made public.
Notably, the response to question 9 focuses only on the date that the IND went into effect without reference to when the substantial clinical investigations were undertaken or the date they were publicized. In response to question 7, the agency expressly warns the supplement trade that acceptance of an NDIN without any objection from FDA cannot be taken as an assurance that the ingredient does not violate the exclusionary clause.
Thus, in 2016, FDA stated it was prepared to enforce a regulatory regime that would allow a dietary supplement company to invest significant resources into the development of new ingredients with potential public health benefits—but without any protection from a pharmaceutical company like Metro International Biotech that comes along later claiming market exclusivity based on a previously obtained IND for a constituent of a natural substance.
FDA’s analysis suggests this scenario could even occur on a substance where:
(1) The existence of an IND has not been made public;
(2) The IND holder ceased research on the “article” or ingredient many years ago; and
(3) The IND holder only decided to invoke the exclusionary clause when potential health benefits became apparent from the submission of an NDIN.
This type of outcome is not far-fetched given FDA’s focus solely on the date the IND became active rather than accounting for the satisfaction of the three factors in the exclusionary clause: Authorization as an IND, the existence of substantial clinical investigations and public notice thereof as the trigger date.
The potential is obvious for FDA’s interpretation of the exclusionary clause to become a significant disincentive for the natural products industry to research new, innovative ingredients. No search of the public record could provide any assurance that FDA had not authorized any new ingredient as an IND because public notification of its existence would be irrelevant. The mere fact that an IND had been authorized at some point in the past would be sufficient to bar the ingredient from the market as a dietary supplement.
This interpretation makes no sense given Congress’ decision to list three distinct factors, including public notice of the existence of the IND. Indeed, FDA’s policy seemingly creates an incentive for the pharmaceutical industry. FDA even seems to be incentivizing companies to adopt the business model of patent trolls and obtain INDs for moieties it may not intend to investigate unless the natural products industry identifies a commercial use in an NDI notification. The potential for the long-term stifling of innovation by the supplement industry and the attendant harm to public health appears to be very real.
Companies troubled by the potential for FDA’s latest anti-supplement initiative should reach out to their trade associations and ask for action, pressuring FDA to adopt a common-sense reading of the exclusionary clause. If litigation becomes necessary—as it did with NAC—industry should be prepared to show the appropriate support. In conclusion, this issue has the potential to negatively impact innovation and new ingredients for the entire trade for years to come.
Marc S. Ullman represents clients in matters relating to all aspects of Food and Drug Administration regulatory issues with a focus on the dietary supplement/natural products industry; Federal Trade Commission proceedings and litigation concerning consumer protection compliance and response to enforcement actions, concerning advertising practices, privacy and cyber security.
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