FDA’s final response to supplement industry’s NAC petitions could trigger more legal action, rulemaking—and a fight to overhaul DSHEA’s drug preclusion clause

Nutritional Outlook, Volume 25, Issue 3

Industry associations discuss with Nutritional Outlook what their next steps could be.

The battle between the dietary supplements industry and FDA over the ingredient N-acetyl-L-cysteine (NAC) entered its next phase yesterday when FDA sent a final response letter to supplement industry associations the Council for Responsible Nutrition (CRN; Washington, DC) and the Natural Products Association (NPA; Washington, DC). The letter addresses previous petitions the associations sent asking the agency to confirm that NAC is a legal dietary supplement ingredient. In yesterday’s March 31 response letter, FDA rebutted, almost entirely, numerous arguments the associations made as to why they believe NAC is a legal ingredient. The associations’ leaders discussed with Nutritional Outlook what their next steps could be.

Prior to yesterday’s response letter from FDA, industry associations had sent both informal letters and formal petitions to FDA asking the agency to defend its statements about NAC. These were sent after FDA issued warning letters in July 2020 stating that NAC—an ingredient long sold in supplements—is not a legal supplement ingredient because the ingredient was first studied as a drug. Under a famous clause in the Federal Food, Drug, and Cosmetic Act (FD&C Act)—called the drug preclusion clause—ingredients that were first approved or publicly clinically studied as drugs before being sold as supplements cannot be sold as dietary supplements.

FDA’s response letter rejects arguments in the associations’ petitions.

One of the industry arguments is that NAC was first marketed as a supplement before it was researched as a drug. FDA’s response states that the agency still believes there isn’t evidence showing the supplement was on the market first.

The petitions also claimed that FDA’s negative view of NAC’s legal status is a sudden reversal, and that past reviews by FDA of NAC structure-function claims notifications did not indicate the agency felt there was a problem with NAC’s legal status. In response, FDA said, just because the agency didn’t question NAC’s legal status in those notifications, it doesn’t automatically mean FDA was positively confirming NAC’s safety or legal status. Furthermore, the agency provided evidence of instances over the past 20 years, including past health claim petitions and new dietary ingredient notifications for NAC products, in which the agency stated that NAC cannot be considered a dietary supplement.

Third, the industry petitions argued that FDA can’t use the drug preclusion clause as a reason to retroactively invalidate the legality of ingredients that were already on the market as dietary supplements before the drug preclusion clause went into action on October 15, 1994 (when the Dietary Supplement Health & Education Act was passed). They argued that the lawmakers who wrote DSHEA and the drug preclusion provision did not intend to pull products off the market that were already legally being sold, but rather intended the clause to address products that entered the market post-DSHEA.

Here, FDA argued that the drug preclusion provision as written “does not distinguish between dietary ingredients marketed before October 15, 1994, and those marketed after October 15, 1994. Nor does the exclusion clause distinguish between drugs approved before October 15, 1994, and those approved after October 15, 1994.” Rather, the agency argued, any ingredient that runs up against the drug preclusion clause would immediately be excluded from being a dietary supplement once DSHEA took effect, suggesting that any supplement ingredients on the market after October 15, 1994, should have been removed from the market if they ran up against the drug exclusion clause. Said FDA in its response, the agency’s “interpretation of the exclusion clause does not give it a retroactive effect;” rather, it is simply FDA’s interpretation of the statute as written.

Wrote FDA: “Rather, beginning on DSHEA’s effective date, the exclusion clause impacted future conduct by providing that an article that is approved as a new drug cannot be a dietary supplement unless an exception applies (e.g., the article was marketed as a dietary supplement or as a food prior to its approval as a new drug.” Since, the agency said it found no evidence that NAC was first sold as a supplement before being investigated as a drug, NAC cannot be a supplement ingredient according to the law as written.

Industry association leaders say that now that they have FDA’s response letter in hand—which the agency deemed a “final response”—establishing FDA’s firm position on NAC, they will plan their next steps.

Kevin Bell, a partner at Arnall Golden Gregory LLP, and NPA’s legal representative, says that the tenor of FDA’s response was not surprising. “I think that letter was the response we predicted we would receive.” And Daniel Fabricant, PhD, NPA’s CEO and president, says of FDA, “They’re certainly going to uphold their policy position. They’re going to uphold their interpretation of the law.”

So, what now? NPA’s lawsuit against FDA over NAC, filed last December, is still ongoing. As for CRN, association president and CEO Steve Mister said in a press statement, “CRN also acknowledges that FDA has made clear its decision on NAC is now a final agency action, ripe for judicial interpretation. We are pleased to get this finality and clarity, while we respectfully disagree with the agency’s analysis, so CRN and our members can evaluate our options going forward. We are presently in consultation with our members about next steps, but every option—including immediate legal action—remains on the table.”

FDA’s response letter pointed out two steps the agency may take—steps that these associations will watch closely.

First, FDA said, for the time being it will exercise enforcement discretion over NAC supplements already on the market—meaning the agency will not try to remove those products from shelves. FDA also clearly stated that the agency has so far not identified safety concerns over NAC but that it is still in the process of reviewing safety evidence. In the interim, the agency said in its response letter, it will not enforce against companies selling NAC supplements, as long as they don’t violate the FD&C Act. Moreover, FDA said it plans to issue “guidance on this topic.” (Association leaders say it’s not clear what that guidance will entail or address.)

Absent the risk that FDA will seize their products, however, NAD supplement companies are likely to continue seeing retailers, such as Amazon.com, ban their supplements given the ingredient’s uncertain legal future—meaning that the legal controversy over NAC will continue to hurt supplement sales.

Secondly, in its response, FDA said it is “considering” and is “likely to propose” rulemaking that would specifically carve out an exemption for NAC so that NAC is not excluded from the definition of a dietary supplement. It’s one of the requests that NPA’s citizen petition made to FDA.

Fabricant says that while NPA doesn’t necessarily call potential rulemaking a huge victory—because the association would have preferred to see FDA outrightly recognize NAC as legal under the existing statue—“if it’s done right and if it’s done in a timely manner, I don’t think we have a problem with it.”

However, Fabricant, Bell, and Mister all caution that the rulemaking process will take a long time, meaning that retailers could continue eschewing NAC products in the meantime. Says Mister, “It takes FDA three to five years to do a rulemaking. In the meantime, that means that NAC is in limbo. Hopefully FDA will grant enforcement discretion in the meantime, but this is a very long time for this ingredient to be in limbo without clear direction from the agency that it’s legal.”

Fabricant and Bell add that they hope FDA does not issue enforcement discretion but then delay progress on rulemaking. “Are they going to use the guidance on enforcement discretion on NAC to delay a written reg?” Fabricant asks.

And while rulemaking is positive in that it would allow NAC to ultimately remain on the market, Mister says it is only a “short-term” fix that does not solve a larger problem for the industry if FDA proceeds to try to invalidate other supplement ingredients down the road based on its interpretation of the drug preclusion clause.

“On the one hand, that is good news in the short term for consumers of N-acetyl-L-cysteine because it looks like [FDA is] going to exercise enforcement discretion in the short term, so they’re not going to seize products, and they are likely to start a rulemaking which will lead to N-acetyl-L-cysteine being the exception to the rule,” he says. “But the bad news from that approach is it doesn’t solve the bigger problem. What about the next ingredient? What about the one after that? You know, this same provision is also being used to prohibit the sale of CBD…So, that’s the downside of what FDA is doing. It may provide a temporary band aid for N-acetyl-L-cysteine, but it doesn’t solve the drug preclusion problem.”

And, while CRN has not yet taken any next legal steps against FDA, Mister says that the association’s concerns over future FDA action exercising the drug preclusion clause against other ingredients in the future would be worth fighting for. “There will be other ingredients in the future where drug companies decide that they want to commercialize a drug for some therapeutic use, and they will go back and try to find some clinical trial from 20 years ago and say, ‘Well, when we did this clinical trial, we were studying it for a drug use, so therefore we got there first.’”

He says a legal fight theoretically would be worth it, “because the interpretation of this drug preclusion provision goes so much farther than just this one ingredient. That’s why it would be worth fighting about, to get clarity not only for N-acetyl-L-cysteine but for CBD and any other ingredients coming down the road in the future.”

FDA’s final response on NAC may also trigger stronger arguments over the drug preclusion clause itself. Does a statute like the drug preclusion provision, written more than 20 years ago, still make sense as written for the modern dietary supplement and drug industries? Have consumer movements such as embracing “food as medicine,” the growing intersection of natural products and healthcare, or advancing research on ingredients that can be used in both drugs and supplements changed the way the statute should be written?

It’s very possible. Says Mister: “Things have changed dramatically since 1994. We see drug companies, on the one hand, trying to disease-ify things that were not thought of as diseases 28 years ago. We have, on the other hand, more and more research on supplements that are showing the health benefits of supplements for things that we didn’t think about before, in terms of cardiovascular health and cognitive function and immune health. So, the two industries are intertwining more than they used to.”

Is there a legal world in which drugs and supplements can coexist and share ingredients—provided they stay in their own sales lane? As Mister points out, “Again, the thing that makes the difference between a drug and a supplement is what is the intended use. So, if you’ve got an article that, on the one hand, can be used to treat asthma or used to treat bronchitis, but if, on the other hand, it can also help alleviate a hangover”—which some could argue qualifies as a life stage and not a disease, he says—“then why can’t we market them in two different ways for two different uses? We market it as a drug for a drug purpose, and then we can market it as a supplement with a structure-function claim?”

These are the types of questions that the fight over NAC are raising. And, Mister says, “Maybe we need to go to Congress and revise this section of the statute.”

As for NAC in the immediate, industry leaders say they will continue to fight for its legal status.

As Fabricant stresses, “There was no safety concern here [with NAC]. There was nothing that was harming the public health. This was an ingredient that was on the market for 30-plus years, and all of a sudden the agency can come in with a pen and go, ‘Yeah, we don’t really like this anymore. We’re going to take it away.’ That should be very concerning to everybody.”

“This has never been about the safety of N-acetyl-L-cysteine,” says Mister. “This drug preclusion argument has never been about the safety of the ingredient. It’s an argument as to who got to market first, because that’s the way the statute was set up…If the drug got to market first, they get a monopoly. Period.”

FDA will continue sticking closely to its interpretation of the drug preclusion clause. “That legal technicality is the statutory interpretation of DSHEA which FDA covets and holds very closely to themselves,” says Bell. “They’re the judge, jury, and executioner on that.”

But, he concludes, “Just because they say that’s what’s right doesn’t mean that’s what’s right.”