A trade association in the nation’s capital has urged FDA to reverse its position that manufacturers are barred from marketing products containing N-acetyl-L-cysteine (NAC) as dietary supplements.

In a Dec. 4 letter addressed to Steven Tave, director of FDA’s Office of Dietary Supplement Programs (ODSP), the Council for Responsible Nutrition (CRN) described the agency’s position as “legally invalid.” CRN also sent the letter to Douglas Stearn, deputy director for regulatory affairs with FDA's Center for Food Safety and Applied Nutrition (CFSAN).

Through warning letters sent in late July to companies selling products that purportedly claimed to cure, treat, mitigate or prevent hangovers, FDA stated NAC was approved as a drug in 1963. Consequently, the agency explained, products containing the ingredient are excluded from the definition of a dietary supplement under section 201(ff)(3)(B)(i) of the Federal Food, Drug & Cosmetic Act (FDCA).

The warning letters caused concerns in the dietary supplement industry because, in part, NAC-containing supplements are widely sold in the U.S.

“CRN is firmly committed to protecting our members’ interest in this matter to sell a lawful ingredient,” Steve Mister, president and CEO of CRN, said in an email for this story. “FDA’s warning letters on NAC issued earlier this year are not final agency actions, but rather should be viewed as the opening salvo, inviting those with sound legal arguments to respond and present an opposing point of view, which we are doing. CRN is optimistic that FDA will closely consider the legal argumentation we have laid out and evaluate its initial position regarding NAC in light of these arguments.”

Related:FDA warning letters on NAC cause stir in supplement sector

FDA records

Mister and CRN’s vice president and associate general counsel, Megan Olsen, laid out several arguments in their letter to Tave. For starters, they argued FDA’s records fail to reliably show the relevant section of the FDCA applies to NAC. In searching for the NAC drug FDA reported was approved in 1963, CRN obtained a letter through a Freedom of Information Act (FOIA) request.

“The letter contains what appears to be a handwritten approval date of 1963,” CRN’s representatives wrote to Tave. “This handwritten notation raises a number of questions about the reliability of this record, not the least of which is whether the approval date was actually 1963 or sometime later, why was the approval data handwritten, when was the notation made, and who made it. This is not the type of document that should be regarded as authentic.”

Oral inhalation

The document obtained by CRN shows the 1963 approval was for an inhaled drug. But CRN’s representatives said section 201(ff)(3)(B)(i) of the FDCA only applies if the ingredient in the dietary supplement is the same “article” as the approved drug.

FDA should not treat an inhaled substance the same article as an orally consumed substance because doing so would conflict with the agency’s “own significant precedent and guidance,” Mister and Olsen asserted.

“For example, for drug approval, FDA would not consider an inhaled drug to be ‘the same’ as an orally ingested drug,” since FDA considers—among other requirements—“the route of administration and dosage form,” they added.

“Further, a dietary supplement, by definition, must be ‘a product that …. is intended for ingestion,’” Mister and Olsen wrote. “Because of this limitation, a dietary supplement would, by its very nature, differ significantly in the route of administration and dosage form from an inhaled drug. Such significant differences, which will affect a substance’s impact on the human body, must preclude an inhaled ingredient from being considered the same ‘article’ as an orally ingested ingredient.”

Records suggest FDA didn’t approve an NAC drug “for oral use only until 2016, well after dietary supplement companies had been marketing NAC as a supplement,” CRN’s letter stated. According to the “Orange Book,” which identifies drugs approved by FDA, NAC drugs were approved for inhalation and oral use as early as 1982, the trade association acknowledged.

Mister and Olsen, however, suggested it wasn’t until August 1994 that FDA approved an NAC drug for inhalation and oral use that hasn’t been discontinued. They questioned whether such “inhaled/oral drugs could even be considered the same ‘article’ as NAC used in a dietary supplement due to their dual route of exposure; and (2) whether the approval data of discontinued drugs should be used to determine the date of preclusion for dietary supplement use.”

‘Statutory retroactivity’

FDA’s interpretation of section 201(ff)(3)(B)(i) in the warning letters also conflicts with “the presumption against statutory retroactivity,” according to CRN. Mister and Olsen highlighted “a well-established canon of statutory interpretation that legislation shall not be read to have a retroactive effect on private rights unless Congress expresses a clear, unambiguous intent to the contrary.”

Section 201(ff)(3)(B)(i) was incorporated in the Dietary Supplement Health and Education Act of 1994 (DSHEA), which went into effect on Oct. 25, 1994.

According to CRN, the exclusionary provision should be not be interpreted to apply to products containing articles approved as drugs before Oct. 25, 1994 because DSHEA’s text and the provision’s legislative history suggests “Congress expressed no clear intent for this provision to have a retroactive effect.

“Further, Congress created section 201(ff)(3)(B)(i) to protect commercial interests necessary to incentivize new drug development in the wake of DSHEA’s enactment,” Mister and Olsen explained in the letter to Tave. “A retroactive application of this section does nothing to incentivize new drug development because drugs and supplements that were both on the market prior to DSHEA’s passage already co-existed and drug companies developed these products with no expectation of DSHEA’s protections.”

‘Arbitrary and capricious’

CRN argued FDA has failed to sufficiently explain its policy change, rendering it arbitrary and capricious. According to the trade association, prior to the July 2020 warning letters, “it was FDA’s longstanding policy to permit the marketing of dietary supplements containing NAC.”

For instance, the agency never raised the drug exclusion clause in its review of more than 100 notifications of structure/function claims for NAC-containing supplements; FDA also stated NAC is a dietary supplement in its response to a petition for a qualified health claim, the trade group pointed out.

“In response to the extensive history of NAC being treated by FDA as a dietary supplement, manufacturers have invested substantial resources to develop hundreds of such products, and thousands of consumers have come to rely on such products to meet their daily nutritional needs,” Mister and Olsen proclaimed. “Now, FDA has decided to not only change its decades-long policy, but to do so through the issuance of warning letters that fail to provide any reasonable explanation for this consequential policy shift.”

Laches defense

Finally, CRN maintained FDA is barred from its enforcing its NAC policy due to the “equitable defense of laches.”

“The defense requires proof of (1) lack of diligence by the party against whom the defense is asserted, and (2) prejudice to the party asserting the defense,” the U.S. Supreme Court held in a 1963 case, Costello v. United States.

According to CRN’s representatives, FDA exhibited a lack of diligence through its “decades-long delay in bringing enforcement action against manufacturers of dietary supplements containing NAC.” Such delay, they asserted, will produce “extreme economic consequences” for manufacturers that have invested in producing NAC-containing supplements.

“These expectation-backed investments have led to the development of hundreds of products that will be affected by FDA’s new policy—products that manufacturers would not have developed had FDA taken prompt enforcement action,” Mister and Olsen wrote to Tave.

FDA response

An FDA spokeswoman, Lindsay Haake, said FDA has received CRN’s letter and is reviewing it carefully.

In an interview this summer, FDA employees addressed some of the criticisms previously raised by CRN. For instance: