At the end of September, the FDA responded to two citizen’s petitions on the topic of drug preclusion. The FDA confirmed that NMN is lawful to be marketed as a dietary supplement in the United States, reversing its 2022 position. While NMN is permitted to return to the market, FDA rejected most of the other requests. In particular, petitioners said they were hoping for more balance in the drug preclusion doctrine, which prevents supplement companies from using an ingredient that has been previously marketed or studied as a drug.
Drug preclusion
CRN’s General Counsel Megan Olsen broke down the history of the drug preclusion provision, pointing out that the “last-minute” clause added to the Dietary Supplement Health and Education Act (DSHEA) has created significant problems for the supplement industry. While the provision’s intent was to protect the investment in drug research by ensuring a company can develop an ingredient as a drug without being immediately undercut by supplement companies, the clause has left supplement manufacturers in a state of uncertainty about an ingredient’s marketability.
“The way that the statute has been interpreted by FDA over the last 30 years–especially in the last six to seven years–has been very problematic for the dietary supplement industry in a manner that is very stifling to innovation and really leaves supplement companies in a position where they don’t know what is precluded–it is very murky,” Olsen said.
CRN and other trade associations have challenged FDA’s interpretations through the courts and citizen petitions, but Olsen said the FDA has maintained broad, case-by-case definitions that provide little clarity for companies. She also highlighted FDA’s recent shift on requiring “lawful marketing” without providing burden of proof standards, leaving the industry uncertain about which ingredients might be restricted.
The elimination of ‘lawful marketing’ requirements
The FDA changed its position on whether a dietary supplement must have been lawfully marketed before a new drug’s approval, stating it will no longer require proof of lawful marketing for the “race to market” framework. However, the agency now insists that the marketing of the ingredient as a dietary supplement must have taken place in the United States—regardless of whether it was legal or not.
Carlos Lopez, senior vice president, general counsel at Niagen Bioscience, which markets the Niagen-branded nicotinamide riboside (NR), said he was surprised that FDA removed regulatory impediments to NMN, but was particularly alarmed by the agency’s decision to eliminate the “lawful marketing” requirement.
Lopez argued this undermines drug development incentives and consumer safety by encouraging bad actors to bypass pre-market verification processes.
“For FDA to hang its decision on the removal of the concept of lawful marketing was even more shocking,” Lopez said.
“It undermines a lot of the critical policy reasons for DSHEA to begin with. FDA is very clear in its response that the purpose of drug preclusion was to incentivize new drug development. Another purpose of DSHEA is to protect consumer safety, and I think removing this lawfulness requirement that FDA has long believed in undermines both of those things because it creates even more incentive for bad actors to do an end run around the pre-market verification process and just set up a website and start selling whatever hot ingredient they want.”
Bob Durkin, partner and co-chair of the regulatory group at Amin Wasserman Gurnani LLP, was critical of the agency’s inconsistent interpretational approach, noting how they contorted their reasoning throughout the petition response by selectively applying different analytical methods.
“When you look at the way they’ve answered particular questions, they’ll rely heavily on textualism or grammar or plain reading, and then they’ll use it a different way when they answer a different portion of the questions,” Durkin said. “They sort of had their cake and ate it too. I thought it was really interesting when they relied on their own guidance document as support for their answer to the citizen’s petition.”
“Like the other panelists, I was surprised and a little confused at the way this decision came out,” said Miriam Guggenheim, partner at Covington & Burling LLP.
Despite expecting the current administration to favor supplements over pharmaceuticals and believing statutory changes were not necessary, Guggenheim said she was particularly shocked that the FDA focused on unlawful marketing rather than marketing outside the United States, which she said seemed like an obvious solution.
“This was the issue where I thought we had great opportunity, I thought, gosh, we’re going to solve drug preclusion in this administration where we have leadership that has expressed the view that prior administrations and prior FDA leadership had erred too far in favor of pharmaceutical industry to the detriment of the dietary supplement and even food industry,” Guggenheim said. “I thought drug preclusion is the perfect place to rectify that. The marketing outside of the U.S….seemed like a slam dunk to me, so the real surprise to me was that FDA turned the decision on allowing marketing that was not necessarily lawful.”
What’s next? Weighing the risk
The panelists agreed that significant uncertainties persist, underscoring the complex dilemma that requires attorneys to consider whether to advise clients to enter the market without knowing if they have complete regulatory clearance to establish market presence.
In order to avoid wasting resources, Guggenheim said she is advising clients to thoroughly search ClinicalTrials.gov for any studies involving their ingredients, as clinical trials could create preclusion issues. She also recommends requesting pre-file meetings with FDA to gauge approval likelihood.
“The response is anything but clear, and there’s plenty of potential for someone to challenge FDA’s interpretation, so that’s one consideration that you need to keep in the back of your mind,” Lopez said. “As we look at an issue like this from an in-house perspective, it’s a lot broader than just one particular issue of drug preclusion. You need to consider everything and then determine what the risk is of going to market.”
