It’s been more than four years since FDA adopted a second draft guidance relating to new dietary ingredient notifications (NDINs) required under the Dietary Supplement Health and Education Act of 1994 (DSHEA).
Asked during a recent conference about finalizing an NDI guidance, FDA official Steven Tave responded the agency is “trying to get that guidance, or at least parts of that guidance, as close as possible to final as we can.”
“In the interim, I think we’ve seen a lot of successful [NDI] notifications over the years,” said Tave, director of the Office of Dietary Supplement Programs (ODSP).
During an Oct. 14 virtual conference (“NOW, NEW, NEXT”) hosted by the Council for Responsible Nutrition (CRN), Tave said he and his colleagues have sought to make it known that ODSP is a resource for industry.
“My office is available for prenotification meetings” before an NDIN is submitted to FDA, he said. “We want to make sure that everybody understands how to submit a notification and has the ability to do so.”
Tave joined ODSP as its acting director in March 2016, only five months before FDA published a revised draft NDI guidance, which supplanted a document published five years earlier.
“I’m fairly certain that when asked about the final [guidance] then … my stock response was, ‘Well, it took us five years to put out the revised draft. I don’t want it to take us five years to put out a final,’” Tave reflected during the conference. “But we’re now in October 2020, and you know how guidances move.”
He added, “We have tried to make forward progress on areas that we think can be addressed and resolved administratively or through regulatory action.”
The 2016 document concerns FDA’s interpretation of certain provisions in a 26-year-old law aimed to ensure the safety of novel ingredients in supplements. Many industry executives remain in favor of the agency publishing a final guidance.
“Having a draft guidance in perpetuity contributes to a lot of confusion,” said Andrew Shao, Ph.D., senior vice president of global regulatory and scientific affairs of ChromaDex Corp., in an interview over the summer. “It makes the law, the requirements, subject to a lot of different interpretation that some companies will use in an irresponsible way to their advantage.”
ChromaDex has submitted to FDA two NDINs for its flagship ingredient, Tru Niagen; and on both occasions, the agency did not object to the safety-related notifications.
Failure to finalize a guidance “suggests the agency is waffling,” Shao added. “It’s up in the air. And it suggests that some of these issues about what’s a new dietary ingredient, what’s an old one, are subject to interpretation. And that you can take a stand depending on not what’s best for consumers, but what’s in your best financial interest.”
During the recent conference, CRN’s leader, Steve Mister, asked Tave about the NDI guidance, as well as FDA’s plans to possibly develop a list of pre-DSHEA ingredients exempt from the NDIN requirement. During a public meeting in October 2017, FDA explored the concept of a pre-DSHEA list.
“I think we heard a lot of useful views on that,” Tave said in response to Mister’s question. A pre-DSHEA list “seems like something that would be nice to have in an ideal world. It’s also going to take a lot of resources to compile, and whether that’s the best use of our resources right now, I’m not sure.”
Bill Frankos, Ph.D., retired from FDA in 2010 when he was the director of what was then known as FDA’s Division of Dietary Supplement Programs. Frankos, currently an executive with Herbalife Nutrition, is in favor of FDA implementing a system of NDI master files, completing an NDI guidance and developing a list of pre-DSHEA ingredients.
“In order to make the NDI notification process as robust as Congress had expected in 1994, FDA needs to give priority to publishing a list of grandfathered ingredients, along with a final NDI notification guidance,” Frankos said via email. “Without these two additional publications, it will be difficult to increase the number of NDI notifications FDA receives.”
Frankos also believes industry and the public would “have more confidence in the NDI notification process” if FDA provided an NDI number that confirmed submission of an NDIN.
“The holder of the NDI could provide that official number to each of its customers, and the official NDI number could be put on the label next to the NDI ingredient name,” Frankos explained. “If an NDI does not have an associated NDI number, then the public and the FDA could question the manufacturer about why they don’t have an NDI number. Many times, public pressure is stronger than government pressure in getting companies to do the right thing.”
Bob Durkin, who previously served as deputy director of ODSP under Tave, said in an interview that a list of “old” dietary ingredients would be helpful to industry and need to remain open for updates as new evidence emerged of prior marketing or history of use. Under DSHEA, dietary ingredients marketed in the U.S. before October 15, 1994 are not considered NDIs, and consequently, they are exempt from the notification requirement.
“A really good first step would be for a consensus on what’s acceptable as substantiation or evidence of prior marketing or history of use,” explained Durkin, who in late 2019 joined the law firm Arnall Golden Gregory LLP (AGG). “I think it’s more about establishing a mechanism to do a self-assessment about whether an ingredient belongs on the list or not.”
One of Durkin’s colleagues at AGG, Kevin Bell, questioned the value of a third NDI guidance.
“I don’t know that I currently believe there’s value in another version … and I especially don’t believe so if the FDA’s position is that there is some ‘regulatory gap’ in the NDI process for which they do not intend to [enforce] the existing law today,” the attorney said in a phone interview.
As profiled in a series of articles reported by Natural Products Insider, Bell has represented a supplement manufacturer, Natural Alternatives International Inc. (NAI), which requested FDA enforce against forms of beta-alanine produced in China, whose identity and safety has not been vetted by the agency. In November 2018, NAI submitted an NDIN to FDA for its ingredient CarnoSyn beta-alanine, which FDA acknowledged the following year without objection.
Durkin suggested FDA made comments inconsistent with its position in the 2016 draft guidance when the agency articulated to a reporter possible legal pathways for forms of beta-alanine that haven’t been the subject of an NDIN.
“A draft guidance is only valuable if it truly represents the agency’s current thinking, and if the agency’s so willing to go back on the draft guidance when it’s convenient, it really makes it meaningless,” Durkin proclaimed.
Responding to a reporter’s questions over the summer, FDA referenced comments by GNC, which argued in a July 15, 2019 public filing—through its outside counsel, Riëtte van Laack of Hyman Phelps & McNamara P.C.—that once an NDIN has been submitted to FDA and incorporated in a dietary supplement, multiple notifications for the same ingredient are not required.
“Some stakeholders interpret section 413 to mean that once an NDI has been the subject of one NDI notification and introduced into the market, other products containing that ingredient are excepted from the notification requirement,” FDA explained in a June 5 email through a spokesperson.
GNC’s lawyer argued an ingredient is “present in the food supply” if it shows up in a conventional food or dietary supplement, which triggers an exception to the NDIN requirement in Section 413(a)(1) of DSHEA.
“Once the first NDIN has been submitted and the NDI has entered the food supply, the exemption in Section 413(a)(1) applies and no additional notifications for that ingredient are required,” van Laack wrote in the public filing.
Despite citing GNC’s position in the email, FDA doesn’t agree with it. In the 2016 NDI guidance, the agency stated, “Interpreting ‘food supply’ to include dietary supplements for purposes of this exemption from the NDI notification requirement would expand the exception to the point that it would risk swallowing the rule.”
Asked for clarification during an interview this summer, Tave emphasized a guidance document like the one above only represents the agency’s current thinking and cannot be enforced in court.
“The guidance documents always say at the beginning, ‘This is not the only way that a firm can comply with the law.’ And if firms have other ways to comply, they are allowed to do so,” he said.
But Durkin concluded in the recent interview, “I think the agency needs to really come to grips with [its] current thinking of how things are interpreted, or a draft guidance is meaningless.”