The U.S. Food and Drug Administration (FDA) sends warning letters to companies marketing supplements or ingredients that the agency deems to be illegal and/or fail to meet the definition of a dietary supplement.

In order to develop an estimate of how many companies follow through with removing illegal and potentially dangerous substances from the dietary supplements market, a team of researchers led by Pieter Cohen, MD, of Cambridge Health Alliance, writing in JAMA, tracked FDA warning letters for unapproved stimulants present in products on the market.

They assessed the frequency at which these products were removed following the receipt of an FDA warning letter, specifically with warning letters which addressed amphetamine, ephedrine, and some other drugs, which are known to carry serious health risks including hemorrhagic stroke and sudden death.

“Whether FDA warning letters lead manufacturers to recall or reformulate products is unknown. We assessed the frequency of product recalls and the presence of FDA-prohibited drugs in supplements after FDA warning letters,” the authors wrote.

FDA issued warning letters for the unapproved stimulants BMPEA, the ephedrine analogue methylsynephrine, and DMHA in 2015, 2016, and 2019, respectively. Using Google, manufacturer’s websites, and the FDA’s websites, the team searched for evidence of recalls of the implicated products.

Products that remained for sale online were purchased, and powder from these products was reconstituted and analyzed for the presence and quantity of FDA-prohibited ingredients using liquid chromatography-mass spectrometry.

Of the 31 products targeted in warning letters for the presence of BMPEA, methylsynephrine, or DMHA, only one product was recalled by the manufacturer. Meanwhile, 29% of the products remained online for an average of six years after FDA issued warning letters. Four of the nine products that were still for sale online listed the presence of at least one prohibited ingredient on the label—one product listed the same prohibited ingredient mentioned in a warning letter, while three product labels declared other FDA-prohibited ingredients.

Five of the nine products still available on the market were found to contain at least one FDA-prohibited ingredient.

In total, 29% of the products targeted by FDA warning letters remained available for purchase, and most of them were adulterated with unapproved ingredients.

“This study raises questions regarding the FDA’s actions to ensure that manufacturers are compliant with the agency’s warning letters. The FDA should consider ways to ensure that prohibited drugs are removed from supplements, perhaps by testing products sold after warning letters and mandating recalls whenever products remain adulterated,” the authors concluded.

Time to Act on Authority 

Megan Olsen, senior vice president and general counsel at the Council for Responsible Nutrition (CRN), said that warning letters alone aren’t consequential enough to be perceived as sufficient threats to bad actors.

“It is unfortunately the case that the agency is not doing its job when one can find the same rogue ingredients in the same bad products six years after warning letters have been issued,” Olsen said. “This study demonstrates that warning letters alone are not viewed as sufficient threats by bad actors and outliers. FDA should stop assuming that everyone in the market wants to do the right thing.

“FDA has recently been asking for new so-called ‘prohibited acts’ authority to clean up the industry,” she added. “In other words, FDA wants clear-cut ability to address illicit substances that have never been marketed as drugs, nor even studied for their potential effects, but are nevertheless marketed as supplements.”

CRN supports this legislative priority, insofar as expanding the agency’s authority over substances that aren’t implicated by the “drug preclusion” clause of the Dietary Supplements Health and Education Act (DSHEA). While the agency can mandate recalls of dietary supplement products, it is only done in rare instances. The agency often instead requests that companies conduct voluntary recalls.

“These illicit substances may be currently caught in a legal no-man’s land—not supplements, not drugs, and without this new authority, not clearly within FDA’s enforcement,” Olsen said. “This simple change to the law, currently part of the Senate HELP committee’s user fee legislation, would give FDA capacity that much of the industry believes it already has but FDA has been requesting explicit statutory language to clarify.”

Like Olsen, Scott Melville, president and CEO of the Consumer Healthcare Products Association (CHPA) said that he also supports comprehensive reforms to offer FDA clear authority to go after products that contain dangerous prohibited ingredients.

“There can be no tolerance for illegal products masquerading as dietary supplements, especially after a manufacturer has already received an FDA warning letter. Yet, that is precisely what was found […] The troubling situation highlights the need for increased enforcement of current law by the FDA and the Department of Justice, and the need for more comprehensive reform of dietary supplement regulation.”

According to Melville, the mandatory product listing (MPL) provision of the current user fee registration bill being considered by Congress won’t go far enough. Beyond MPL, he said FDA should also be able to increase facility inspections and remote regulatory assessments, the latter of which is an informal assessment of a facility that was introduced during the height of the COVID-19 pandemic.

“As the House and Senate confer on FDA user fee reauthorizations, the need to balance consumer access to safe and beneficial dietary supplements with FDA’s ability to swiftly remove dangerous and illegal products from the marketplace should be recognized to ensure that any agree-to reforms are meaningful and not reform in name only,” Melville said.

NPA: FDA Should Do More with the Tools it Has

According to Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA), FDA appears unwilling to take steps such as product seizures and injunctions, which it already has the authority to do. In contrast to CRN, NPA does not support granting the agency more authority when it doesn’t utilize existing tools. 

Another point of contention is the fact that FDA’s facility inspections have been declining in frequency some time, irrespective of funding, Fabricant said. He noted that a report from the Office of the Inspector General concluded that even in response to significant inspection violations, follow-up from the agency to ensure corrections were made by the facility was rare.

“This study reaffirms FDA’s performance failure gaps going back to a report published by the Office of the Inspector General in 2017. Companies who receive a warning letter are required to notify FDA within 15 days of receipt of their warning letter and the specific steps they have taken to address any violations. Failure to do so is supposed to result in legal action including seizure and injunction. This should be considered low-hanging fruit for the agency but it’s obvious there’s an element of willpower that’s absent.

“These gaps in actions indicate that new authorities to the FDA clearly aren’t warranted, when current authorities, where problems have been located, aren’t followed up with,” Fabricant continued. “This study makes it clear the agency has adequate authority to pursue products masquerading as dietary supplements, the repeated absence of follow-through requires oversight and accountability.”