This is the first in a series of articles on FDA’s attempts to increase its visibility into the safety of novel dietary supplement ingredients in the U.S. market.
An FDA plan to give manufacturers of dietary supplements a chance to rectify their failure prior to going to market to notify the agency of new dietary ingredients (NDIs) in their products represents “a great opportunity to … correct that wrong,” an FDA official said in an interview.
In draft guidance published in May, FDA disclosed plans to exercise enforcement discretion for 180 days regarding the requirement to timely file an NDI notification (NDIN) with the agency. This amnesty period would start following publication of a notice in the Federal Register announcing the availability of a final guidance.
The NDIN requirement is aimed to ensure novel ingredients are “reasonably” expected to be safe, and represents a critical piece of FDA’s oversight of the market because it’s the agency’s only chance to review the safety of NDIs in supplements before they’re available to consumers.
The safety standard for NDIs is not as high as the GRAS (generally recognized as safe) standard for a conventional food ingredient: “a reasonable certainty of no harm under the conditions of its intended use." However, FDA has received far fewer NDINs than it has expected over the 28-year history of the Dietary Supplement Health and Education Act of 1994 (DSHEA).
Cara Welch, who directs FDA’s Office of Dietary Supplement Programs (ODSP), said she is hoping “a number of notifications” are submitted to FDA during the 180-day period “because that provides the safety data that we’re looking for.”
“The goal really, though, is the safety data, so we can have a better picture of the safety of those products that are currently on the market,” she told Natural Products Insider in an interview.
She said FDA is not looking for a specific type of ingredient or product, but rather NDINs that should have been submitted to the agency but were not.
Welch’s predecessor, Steve Tave, estimated in 2019 that FDA should have received at least 4,600 notifications since passage of DSHEA, but had only received just over 1,100.
His estimate was based, in part, on an assumption that the U.S. contained 50,000 dietary supplement products—the low end of the number of products (50,000 to 80,000 or more) FDA has reckoned are in the market.
Asked why FDA is issuing the guidance now, Welch responded, “I don’t know that there’s a particular reason ‘why now’ other than this is … one of the many steps that we’re taking to … move forward and modernize how we’re regulating the dietary supplement industry.”
The more notifications FDA receives “shrinks the pool of those who have not complied with the NDI notification requirement,” she said. “That will help FDA identify those that continue to be in violation, and moving to the next step, facilitating enforcement to uphold the NDI notification requirement.”
Welch added, “We want to see who’s willing to submit in order to figure out how small that pool of notifications that have not been submitted will be. And then we can focus our enforcement action.”
FDA stakeholders for many years have criticized the agency for not vigorously enforcing the NDIN requirement, including in response to a batch of warning letters recently issued. The guidance could be interpreted as a signal that FDA intends to step up its enforcement on NDIs—and Welch did not disagree with such a hypothesis.
“The purpose of this policy is to provide an opportunity for supplement manufacturers and distributors to correct the past failure,” she said. “Those that … choose not to correct that failure and continue to be in violation would be an area where we are hoping to have more enforcement actions.”
She did not elaborate on specific enforcement strategies likely to be used, such as whether FDA would move beyond warning letters to court actions that require collaboration with the U.S. Department of Justice.
Welch suggested FDA is seeking to foster “active participation” in the NDIN process to not only rectify past behavior but change future behavior as well.
“At first, we … allow this temporary time to submit your late notification, and that will encourage people to submit them on time in the future and identify for FDA which firms are just choosing not to comply, even when we sort of take away the fear of retribution for the late notification,” she said.
Reaction from stakeholders
Pieter Cohen is a physician and associate professor of medicine at Harvard Medical School, who has studied novel and potentially harmful ingredients marketed in dietary supplements, including higenamine. He doubted the grace period would open up the floodgates for ingredient submissions to FDA. He and other FDA critics maintain FDA has a history of lax enforcement against non-compliant firms.
FDA officials “haven’t gone after companies for the last 28 years, so the notion of “a grace period honestly doesn’t make much sense to me,” Cohen said in an interview. “All of this is performance art.”
He added, “What we need to see is whether or not the FDA is actually going to move to remove from the market the thousands—maybe tens of thousands of products—that contain … a new dietary ingredient which has not gone through the proper channels.”
American Herbal Products Association (AHPA) President Michael McGuffin isn’t surprised by Welch’s remarks concerning FDA enforcement.
“It’s exactly what she should be saying, isn’t it,” he said in an interview. “There’s no reason to issue a statement of a temporary enforcement discretion unless the day after or shortly thereafter you’re going to cease enforcement discretion and instead enforce.”
If FDA does step up its enforcement, McGuffin questioned which ingredients it would target. For example, would FDA step up its enforcement against kratom, which is already the subject of an import alert, or ingredients the agency has flagged on a list published online, some of which are NDIs including Acacia rigidula, cesium chloride and DMBA?
McGuffin supports active FDA enforcement of various requirements applicable to dietary supplements, including, for example, cGMPs (current Good Manufacturing Practices), reporting requirements for serious adverse events and NDINs.
“We think this is a really well-regulated, safe class of goods,” McGuffin said, “but it’s only as well regulated as the enforcement.”
Marc Ullman isn’t holding his breath that FDA’s hope to elevate its enforcement actions against non-compliant NDIs will bear fruit. He’s an attorney with Rivkin Radler LLP, whose lawyers including Ullman counsel dietary supplement firms on FDA regulations, including the NDIN requirement.
“When I discussed with FDA the residual formaldehyde in knockoffs of my clients’ astaxanthin, I had hope for enforcement. Nothing happened,” he said in an interview. “When I went in and I met with FDA to discuss the presence of a variety of unknown peaks, and knockoffs of my client’s PQQ, I had hopes that there would be some enforcement. Nothing happened.”
Ullman added, “Why would we think they’ll do anything other than complain they need more authority?”
FDA’s goal “shouldn’t be just to rack up NDIN numbers,” according to Bob Durkin, a former ODSP official who practices law in the nation’s capital with Arnall Golden Gregory LLP (AGG).
Rather, its objective should be to “identify violative” products that pose “a public health risk” and remove them from the market, he said in an interview.
Durkin’s colleague, AGG Partner Kevin Bell, expressed doubt that FDA’s enforcement discretion policy would move the needle on compliance in a meaningful way.
Last year, Bell’s request to FDA to enforce against generic forms of beta-alanine manufactured in China was denied in a letter signed by Welch. Like Ullman, Bell had expressed concerns to FDA about so-called knockoff or copycat ingredients that haven’t been reviewed by FDA but resemble NDIs that have invested in safety and obtained "acknowledgement" letters from FDA after notifying the agency.
“I don’t think there’s any teeth in this [draft guidance] because then what,” Bell said. “If this artificially inflates some numbers for a period of time, it doesn’t mean anything. It’s like saying I’m going to put more speed limit signs up on the interstate. ‘Don’t worry because no one’s ever going to get a ticket. We’re just going to put more signs up.’”