By Riëtte van Laack —
The dietary supplement exclusionary clause is, as its name suggests, a clause in the Federal Food, Drug, and Cosmetic Act (FDC Act) definition of dietary supplement. That clause excludes those ingredients that were first marketed as drug ingredients. Specifically, FDC Act 201(ff)(3)(B) provides that a dietary supplement does not include:
(i) an article that is approved as a new drug under section 355 of [the FDC Act], certified as an antibiotic under section 357 of [the FDC Act], or licensed as a biologic under section 262 of title 42, and
(ii) an article authorized for investigation as a new drug, antibiotic, or biologic 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 [FDA] has issued a regulation, after notice and comment, finding that the article would be lawful under [the FDC Act].
The phrase in subsection (ii) “authorized for investigation as a new drug” is generally accepted to mean that an IND is in effect. However, there is a continuing disagreement between FDA and industry about how that phrase should be read with the phrase “and for which substantial clinical investigations have been institute and for which the existence of such investigations has been made public.” FDA interprets the exclusionary clause to mean that the critical date is the date that the IND came into effect, not the date on which the existence of the substantial clinical investigations under the IND has been made public. Because the existence of an IND is not public, FDA’s interpretation puts the dietary supplement industry at a disadvantage and creates great uncertainty. Under FDA’s interpretation, it is impossible to determine whether there is a non-public IND prior to starting work on developing an ingredient as a dietary supplement.
By way of background, the exclusionary clause was added to the law to protect the pharmaceutical industry against making significant investments in drug development to then be undercut by a dietary supplement marketer who would take the identical product and introduce it as a dietary supplement. However, FDA’s interpretation creates that exact risk for a dietary supplement manufacturer who invests in development of a dietary supplement.
Dietary supplement trade associations, including the Natural Products Association (NPA) and the Center for Responsible Nutrition (CRN) have filed citizen petitions challenging FDA’s interpretation several times. On August 28 of this year, NPA sued FDA challenging FDA’s determination that NMN is excluded from the dietary supplement definition.
What led to NPA’s lawsuit? The facts are detailed in the complaint. Briefly, on October 11, 2022, FDA issued a letter in response to a new dietary ingredient notification (NDIN) by Inner Mongolia Kingdomway Pharmaceutical Ltd. (MKP) asserting that “NMN is excluded from the dietary supplement definition under [FDC Act § 201(ff)(3)(B)(ii)] and may not be marketed as or in a dietary supplement.” This letter was somewhat of a surprise because several months earlier, on May 16, 2022, FDA issued a response letter to NDIN 1247 for NMN by SyncoZymes (Shanghai) Co. Ltd. acknowledging receipt of SyncoZymes’ NDIN without any comments related to the status of NMN. Such a response letter is generally interpreted as a no objection letter.
In a supplemental letter dated November 4, 2022, FDA addressed MKP’s arguments that FDA’s determination was incorrect. FDA cited February 16, 2021, as the first date on which another manufacturer could have marketed its NMN-containing dietary supplement lawfully after submitting an NDIN to the Agency on December 3, 2020. FDA asserted that even if an NMN supplement was marketed on that date, it would still be excluded because, according to FDA, NMN was authorized for investigation as a new drug under an IND before December 3, 2020. FDA did not disclose the exact date of the IND because that information is confidential.
Subsequently, in March 2023, the National Products Association (NPA) filed a citizen petition (CP) requesting that FDA determine that NMN is not excluded or, in the alternative, that FDA decide to exercise enforcement discretion and allow the continued marketing of NMN as a dietary supplement. FDA provided an interim response to the citizen petition 180 days after the petition was filed, stating that due to competing agency priorities FDA had not reached a decision on the citizen petition.
On 28 August, 2024, almost a year after FDA’s interim response to the CP, NPA filed a complaint in US District Court for the District of Columbia seeking preliminary and permanent injunction prohibiting FDA from taking any regulatory action against firms producing or marketing NMN. As detailed in the complaint, NPA’s complaint follows FDA’s “Notice of FDA Action” letter to a member of NPA stating that FDA detained that member’s import of NMN because “it appears to be a new drug . . . without an approved New Drug Application.” (According to NPA, this action shows that FDA has made a final decision on the status of NMN and is engaging in enforcement efforts in accordance with that decision).
The complaint challenges FDA’s alleged misapplication of the exclusionary clause. In the 47-page complaint (and many exhibits), NPA makes it case providing seven reasons why FDA’s interpretation of the exclusionary clause is incorrect. Primary arguments are that the canons of statutory interpretation require that the critical date for the exclusion to apply is the date that the existence of the substantial investigations is made public rather than the date that the IND is granted, and that FDA must consider whether the clinical studies that were done are substantial, an issue that NPA claims FDA did not consider in its determination that NMN was excluded.
This is not the first time that NPA sued FDA over its interpretation of the exclusionary clause. Previously, it sued the Agency regarding the exclusion of N-acetyl cysteine (NAC). That lawsuit was withdrawn when FDA issued final guidance that, although it had determined that NAC was excluded, it would exercise enforcement discretion while considering rulemaking under FDC Act section 201(ff)(3)(B) to permit the use of NAC in or as a dietary supplement. Although that guidance resolved the immediate concerns for industry regarding marketing NAC, it left the uncertainty about interpretation of the exclusionary clause. It remains to be seen if the courts ever get an opportunity to weigh in on the meaning of the exclusionary clause. We will of course continue to follow this issue.
