With Chevron deference gone, will NAC rulemaking cause problems for FDA?

Could FDA’s plans to publish a first-of-its-kind regulation for N-acetyl-L-cysteine (NAC) marketed in dietary supplements backfire, resulting in something the agency seemingly abhors — litigation — following a landmark U.S. Supreme Court ruling that upends judicial deference given to the executive branch?

Or will an FDA regulation that will likely take years to complete set a precedent for the agency to invoke the same authority for other ingredients that otherwise are excluded from supplements due to their status as FDA-approved or investigated new drugs?

And why is the U.S. Food and Drug Administration planning to issue a notice of proposed rulemaking (NPRM) by December 2024 when the dust settled over NAC a few years ago, with industry and government getting along dandy?

These are some of the questions that I and others raised after it came to light that FDA is looking into exercising notice-and-comment rulemaking authority in DSHEA (Dietary Supplement Health and Education Act of 1994) for the first time in the law’s 30-year history.

Adding to the intrigue, United Natural Products Alliance (UNPA) President Loren Israelsen wonders if FDA would have committed to this resource-intensive project if it had known the nation’s highest court would gut so-called Chevron deference.

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Bear with me for a few paragraphs. Under a doctrine rooted in a 1984 Supreme Court decision, Chevron U.S.A. Inc. v. Natural Resources Defense Council Inc., American courts have sometimes deferred to “permissible” or reasonable agency interpretations of the statutes that the likes of FDA are charged with administering, such as the Federal Food, Drug & Cosmetic Act (FDCA).

“Our Chevron doctrine requires courts to use a two-step framework to interpret statutes administered by federal agencies. After determining that a case satisfies the various preconditions we have set for Chevron to apply, a reviewing court must first assess ‘whether Congress has directly spoken to the precise question at issue,’” Supreme Court Chief Justice John Roberts explained in a landmark decision this summer that overruled Chevron. “If, and only if, congressional intent is ‘clear,’ that is the end of the inquiry. But if the court determines that ‘the statute is silent or ambiguous with respect to the specific issue’ at hand, the court must, at Chevron’s second step, defer to the agency’s interpretation if it ‘is based on a permissible construction of the statute.’”

In eviscerating Chevron deference, Justice Roberts wrote in part, “Courts must exercise their independent judgment in deciding whether an agency has acted within its statutory authority, as the APA [Administrative Procedure Act] requires. Careful attention to the judgment of the Executive Branch may help inform that inquiry. And when a particular statute delegates authority to an agency consistent with constitutional limits, courts must respect the delegation, while ensuring that the agency acts within it. But courts need not and under the APA may not defer to an agency interpretation of the law simply because a statute is ambiguous.”

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One could argue section 201(ff)(3)(B) of the FDCA is ambiguous. This is the section in the FDCA that says an “article” is excluded from the definition of a dietary supplement if it’s been approved as a new drug or 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.”

The exclusion applies unless the article was first marketed as a dietary supplement or food.

FDA and the supplement industry have argued over the meaning of specific words in section 201(ff)(3)(B), which leads me to the conclusion that the statutory language is not unambiguous. But before I lose you, FDA’s interpretation of the drug preclusion clause or provision — should it find itself in court — isn’t likely to get immense deference at any rate. That’s thanks to the Supreme Court’s recent ruling in Loper Bright Enterprises v. Raimondo, gutting Chevron.

“Experience has shown that Chevron is unworkable,” Justice Roberts wrote. “The defining feature of its framework is the identification of statutory ambiguity, which requires deference at the doctrine’s second step. But the concept of ambiguity has always evaded meaningful definition. As Justice Scalia put the dilemma just five years after Chevron was decided, ‘How clear is clear?’”

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Amid this sea change in U.S. law, we must ask ourselves a simple question: Why is FDA pursuing an NAC rulemaking in the first place? As you may recall, FDA and industry essentially made peace over NAC in the summer of 2022 after the agency issued a final guidance announcing its intent to exercise “enforcement discretion” regarding the distribution and sale of NAC-containing supplements.

This guidance was not issued out of the blue. FDA — and by extension the U.S. Department of Justice — had been dealing with a lawsuit filed by the Natural Products Association (NPA), following FDA warning letters in 2020 that asserted NAC could not be marketed in supplements since the article was approved as a new drug in 1963.

Before going to U.S. District Court, NPA had filed a citizen petition in 2021, requesting the commissioner of FDA either determine NAC is not excluded from the definition of a dietary supplement or recommend to the secretary of the U.S. Department of Health and Human Services (HHS) that it issue a regulation finding the ingredient is lawful.

FDA denied the petition the next year, but in its announcement of its response to the petitions filed by NPA and Council for Responsible Nutrition (CRN), disclosed it was considering exercising enforcement discretion and hadn’t yet reached a decision on NPA’s alternative request for a rulemaking.

UNPA’s Israelsen is scratching his head regarding FDA’s motivation for pursuing a rulemaking. Consider that FDA’s exercise of enforcement discretion has allowed the ingredient to continue to be marketed in dietary supplements, notwithstanding FDA’s view that the ingredient is excluded from the definition of a dietary supplement due to the 1963 drug approval.

“I felt like we had reached after considerable effort a sensible and reasonable position,” Israelsen said. “There [were] no safety issues with NAC that anybody was aware of.”

FDA “never said it publicly, but I think their sense was, ‘You know there’s a common-sense aspect to this [resolution], which is you have this old drug that was used in a different delivery system. It’s not an important product in the market today. There is really no competitive issue. There is no race to market going on here' …. Everybody was getting along OK, so who started the fight?”

FDA’s plans for an NPRM were likely in the works before the Supreme Court’s Loper Bright decision, Israelsen reckoned, “and I really wonder if the agency would have done this had they any sense that Chevron would fail.”

FDA will find itself in a “much weaker judicial” position should industry disagree with the agency, he observed.

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NPA President and CEO Dan Fabricant, Ph.D., said FDA’s planned rulemaking is a direct response to his citizen petition and he believes it would be good for the industry and FDA.

From FDA’s standpoint, “It’s better to have a reg than to try to do things through guidance or enforcement discretion,” said Fabricant, who about a decade ago oversaw FDA’s Division of Dietary Supplement Programs.

A rule would provide final clarity for NAC “but also for the future,” he said. “It sets a precedent that I think is important for the industry. The notion that this [notice-and-comment rulemaking] can’t be done in the future is completely erased from this. We’re 30 years after DSHEA where like on CBD parts of the agency threw their hands up and [said], ‘Well we don’t know what to do?’ And we’ve been like, ‘Well, you can write a reg. You have that ability in law.’”

“I think the next question is what are the factors that are determinative” when FDA writes a regulation, he added.

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It’s hard for me to fathom that supplement manufacturers would rant and rave over a notice-and-comment rulemaking for NAC, solidifying its place as a lawful ingredient in supplements, but what if Big Pharma had a problem with it and sued FDA?

A review of ClinicalTrials.gov shows NAC has been the subject of many studies, including completed research sponsored by Cambridge Health Alliance that examined the efficacy of NAC in preventing Covid-19 from progressing to a severe disease.

Is there an investigational new drug application (IND) in effect for NAC at FDA? I asked FDA’s Center for Drug Evaluation and Research that question and was advised, “FDA is generally unable to discuss existing or potential applications. That is confidential commercial information.”

(FDA’s answer didn’t sit well with me, but we’ll leave that diatribe for another day.)

Israelsen said he hasn’t talked to anyone who has a clear idea of why FDA is proposing a rule.

“I heard a lot of, ‘Boy, I’m not sure FDA really would have done this had they known Chevron was going down,’ or ‘What motivated this? [FDA officials have] enough work to do. Now, they’re putting themselves in a substantial rulemaking effort that’s going to go on for some years.’”

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Duffy MacKay, senior vice president of dietary supplements with the Consumer Healthcare Products Association (CHPA), said an enforcement discretion policy for NAC still leaves the ingredient in a “gray area.” A rulemaking could offer clarity, he suggested, and is good news for the ingredient.

“But we can’t do this every single time we run into an ingredient like this,” MacKay cautioned, highlighting the need for modernization of DSHEA.

“One of the priorities of the industry is, let’s fix this IND preclusion snag,” he continued. “Let’s get it clarified for both the supplement industry and people who want to invest in ingredients like NMN [nicotinamide mononucleotide], but also for the drug industry.”

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Should FDA end up in court over NAC — or another ingredient it maintains is excluded, such as NMN — industry lawyers will be watching closely.

“In the absence of Chevron, it becomes really interesting … because there’s no longer deference,” observed Rivkin Radler attorney Marc Ullman, who has advised the industry for decades. “It goes into a court. It’s a toss-up.”

In determining if an ingredient like NMN is excluded from supplements, among the issues a court is likely to decide is the date of the so-called race to market between the pharma and supplement sectors. FDA traces the date of drug preclusion to when an article has been authorized for investigation as a new drug, which FDA has determined is the date the first investigational new drug application for the article takes effect. That date is virtually a secret since FDA doesn’t disclose it to the public.

“FDA’s regulations prohibit us from disclosing the existence of an IND unless it has previously been publicly disclosed or acknowledged,” an FDA official, R. Philip Yeager, wrote in a 2022 letter to a representative of Inner Mongolia Kingdomway Pharmaceutical Limited. “Accordingly, although we can state our conclusions as to when NMN was first marketed as a dietary supplement or as a food and whether that date was before or after the date NMN was authorized for investigation as a new drug, we cannot specify the date of authorization or identify its source.”

Based on the language of DSHEA, Ullman has concluded the race-to-market date isn’t when an article has been authorized for investigation as a new drug but rather when “all three boxes are checked.” Again, for drug preclusion to become an issue under section 201(ff)(3)(B), the article or ingredient like NAC or NMN must have been approved as a new drug or been: (1) authorized for investigation as a new drug (2) the subject of substantial clinical investigations that have been instituted (3) and the investigations have been made public.

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Some of this may be academic if FDA changes its mind — or drags its feet — in drafting a proposed rule for NAC.

Asked about the possibility of FDA withdrawing its notice to issue an NPRM, Israelsen responded, “It wouldn’t surprise me.”