DSHEA Spotlight: Experts Call for Clarity on Drug Preclusion and NMN

The prospect of modernizing the Dietary Supplement Health and Education Act (DSHEA), the landmark 1994 law that laid the regulatory framework for today’s roughly $70 billion supplement market in the U.S., has been a hot topic of conversation in recent years.

A panel discussion hosted by the Orrin G. Hatch Foundation on July 21 included stakeholders from the dietary supplement and pharmaceutical industries to discuss DSHEA’s future, with a particular focus on the drug preclusion provision of the law. This provision prohibits a substance from being marketed as a dietary supplement if it was the subject of a publicly-known clinical study as an investigational new drug (IND) first, with a few notable exceptions.

The panel included Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN); Scott Bass, partner at Sidley Austin LLP, who helped draft DSHEA; and Kyle Sampson, partner at King and Spalding.

Clarity and Consistency in Drug Preclusion

The conversation was especially timely, given that the U.S. Food and Drug Administration (FDA) is due to respond to citizen petitions filed by the Natural Products Association (NPA) and CRN, which both request clarity on drug preclusion. NPA’s citizen petition was specific to preclusion of nicotinamide mononucleotide (NMN), while CRN requested more clarity and consistency in drug preclusion enforcement on a broader level.

Panelists agreed with the premise of drug preclusion, but questions about how the policy is implemented, raised by FDA’s decisions on ingredients like NMN, NAC, and CBD, remain divisive.

In the case of NMN, supplement industry stakeholders have argued that the IND trials on NMN weren’t known to the industry prior to the ingredient being marketed as a supplement. This case has called into question how publicly-known an IND study must be to trigger drug preclusion, and raised the question as to whether FDA can retroactively apply drug preclusion to an ingredient that has been marketed for several years.

“The purpose of this law is very simple,” said Bass. “I believe FDA is following the intent of the law, but there are four or five things wrong with how DSHEA was drafted. There are things we could’ve done a much better job on, but essentially, it’s being applied in a fair but very unclear way … I don’t think FDA is intentionally doing anything wrong here, it’s an imperfectly drafted statute where we all want the right result.”

There’s more than meets the eye to the NMN case, said Sampson, suggesting a precedent that disincentivizes drug research could be set depending on FDA’s response to NPA’s Citizen Petition.

“I think FDA is interpreting things correctly [in the case of NMN] but I’m concerned about what will come out in the response to the petition,” he said. “FDA can initiate rulemaking to simply allow a precluded ingredient to be marketed as a dietary supplement. It’s never been done before … What standards would FDA use to say NMN, which was authorized for investigation as a new drug, and underwent substantial, publicly-known research, should be a supplement? It could really undermine FDA’s drug approval process, and significantly impact the incentive firms have to investigate new drugs.”

Sampson said that in the case of NMN, supplement manufacturers “violat[ed] the law” by marketing NMN products prior to receiving a response to a New Dietary Ingredient Notification (NDIN). FDA’s approval of NMN as a supplement ingredient “would jeopardize consumer safety because clinical studies haven’t yet determined its safety or effectiveness … It would reward illegal activity.”

However, in the case of NAC, Sampson said that FDA siding with NAC manufacturers would be favorable, and would set a precedent for how the agency should handle long-abandoned IND research. “I think that would be fine; that would be better.”

Despite the implications of the NMN case, it’s important to consider the bigger picture, noted Mister. Preclusion “is being applied to a number of ingredients … where it’s not initially a conversation about safety, but about keeping things out of the market,” and it’s only being implemented in rare instances.

“There should be a line between what is a drug and what is a supplement, without exceptions,” said Mister. “If drug companies get to something first and publish clinical trials, they get a perpetual monopoly over that substance … We’re not trying to undermine drug preclusion, and if drug companies get there first, they should have it.”

Mister noted that while FDA has never done it before, the law grants the agency the authority to allow something to be marketed as a supplement, even if it is precluded by drug research, as long as the substance is “otherwise lawful.” But it’s not yet clear what criteria FDA would use to reach such a decision.

In cases like NAC, NMN, and CBD, there was no public notice of IND studies prior to FDA determining that the ingredients were precluded; FDA isn’t permitted to disclose the existence of an IND study, enabling those pharmaceutical researchers to “work in secret,” said Mister. “Then, the supplement industry spends tons of money bringing a product to market, only to find out later down the road that the rug will be pulled out from under them. Any equitable reading of the law requires notice for both parties.”

Bass concurred that clarity is needed on whether drug preclusion is triggered on the date of the publication of an IND trial, or on the date the trial itself was conducted. “In my opinion, it should be the date of publication; I think the intent was pretty clear there … you shouldn’t be able to take advantage of drug preclusion without publication … Until the study is publicly available in the truest sense, it shouldn’t count … It simply has to be notice that a study exists, not the actual study parameters.”  

The NAC case highlights other areas of drug preclusion where clarity is needed, as NAC was determined to be precluded due to long-abandoned investigations dating back to the 1960s for its use as a pharmaceutical inhalant. Aside from the fact that research was long-abandoned, Mister noted, the IND study investigated an inhalant form of NAC at a substantially higher dose, begging the question of whether dosage form matters in drug preclusion.

Not surprisingly, the pharmaceutical industry has opposed the prospect of IND studies being forced to go public at the moment they’re filed. However, rulemaking to shorten the window of time between study completion and required publication likely wouldn’t meet much resistance, Sampson noted.  

Overlooked Areas

Mister said there is a misconception that DSHEA has been frozen in time, when, in fact, major updates to supplement regulation have already happened, such as in 2006 when adverse events reporting requirements were added, and in 2011 when the Food Safety Modernization Act (FSMA) substantially changed compliance requirements for dietary supplement manufacturing facilities.  

There’s been much discussion, including from Health and Human Services Secretary Robert F. Kennedy Jr., about closing what’s dubbed as the “GRAS loophole.”

Short of direct amendments to DSHEA, it doesn’t seem likely to happen, said Bass, as FDA is hesitant to use the enforcement authority it has. Most new ingredients on the market have gone through a self-affirmed GRAS process instead of the NDIN pathway. “FDA has made a million excuses about not enforcing [NDIN requirements], so we need to clean up the wording to make sure FDA does its job.”