FDA publishes import alert for NDIs in supplements

FDA on Friday published an import alert impacting the $50 billion-a-year dietary supplement industry, news that a Washington, D.C.-based lawyer and two former regulators found encouraging.

Import Alert 54-18 relates to “detention without physical examination (DWPE) of dietary supplements and bulk dietary ingredients that are or contain new dietary ingredients” (NDIs).

Two Chinese-based firms, and an NDI known as higenamine, are identified as being subject to DWPE under the import alert.

The import alert “is not specific to a particular ingredient,” according to an email from an FDA spokesperson. “Instead, it addresses NDIs and dietary supplements containing NDIs that the FDA has determined to be adulterated under section 402(f)(1)(B) of the Federal Food, Drug, and Cosmetic Act.”

Per the above section of the law, “a food shall be deemed to be adulterated if it is a dietary supplement or contains a dietary ingredient that is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury,” FDA explained in the import alert.

Several sources with extensive knowledge of FDA’s dietary supplement operations viewed the import alert as broadly targeting NDIs, whose identity and safety has not been reviewed by FDA. Subject to an exemption in the law related to ingredients present in the food supply, a manufacturer or distributor of an NDI must provide FDA evidence of the NDI’s safety 75 days before it’s introduced in interstate commerce.

“The FDA uses the import alert tool everyday as part of its import process,” the FDA spokesperson said. “Import alert 54-18 is relatively new, but we do expect it to be utilized as we identify and deny entry of non-compliant products containing NDIs.”

Dan Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), welcomed the recent development.

He said he was "excited" to discover that FDA published an import alert, based on a firm’s failure to file an NDI notification (NDIN).

Fabricant, who previously led FDA’s Division of Dietary Supplement Programs, described the import alert as “a great first step.”

“We obviously believe there are other things that belong on this list,” he added.

Kevin Bell, outside counsel to NPA, said the import alert is something he has wanted FDA to issue for more than two years.

“It is not ingredient-specific,” commented Bell, a partner in the nation’s capital at Arnall Golden Gregory LLP (AGG) and co-chair of his firm’s dietary supplements industry team. “If it requires an NDI and you don’t have one, you should be on this list.”

Higenamine concerns

For now, only two firms are on the so-called Red List: Jingjiang Jiangyang Fine Chemicals Co. Ltd. and Suzhou Win Health International Co. Ltd. Neither firm could be immediately reached for comment.

FDA confirmed higenamine has not been the subject of an NDIN. The ingredient, which is used in weight loss and sports supplements, was the subject of an article published in 2018 in the peer-reviewed medical journal Clinical Toxicology.

In the article, Dr. Pieter Cohen of Harvard Medical School and other researchers described higenamine as “a stimulant with cardiovascular properties” that the World Anti-Doping Agency (WADA) has prohibited. Researchers analyzed 24 supplement products available for sale in the U.S. and labeled as containing higenamine or a synonym before WADA’s 2017 prohibition. Of five products that specified an amount of higenamine, none were accurately labeled—with quantities ranging from less than 0.01% to 200% of the amount declared on the label, the article divulged.

In their analysis of the products, researchers identified up to 62 milligrams per serving of higenamine.

According to the U.S. Anti-Doping Agency (USADA), higenamine is prohibited in and out of competition, based on its classification.

It’s unclear what specific safety concerns FDA has identified related to the ingredient. Higenamine, however, is identified in an FDA “Dietary Supplement Ingredient Advisory List” of substances that do not appear to be lawful ingredients in dietary supplements.

Asked whether FDA has received serious adverse event reports (AERs) linked to the ingredient and to summarize such reports, an agency spokesperson recommended filing a Freedom of Information Act request.

Higenamine exerts additional stress on the human heart when injected into a person’s veins, said Cohen, an associate professor of medicine at Harvard Medical School, in an interview. He said it’s unknown at what dose the ingredient causes such stress when consumed in oral form.

The physician said he wouldn’t be surprised if a low dose of higenamine would be well tolerated and safe, while a high dose would prove to be dangerous.

The problem: “We don’t have the human data to know what’s what,” Cohen explained.

While Cohen said higenamine has been found in plants, he suspects it’s synthetically produced.

“It would be ridiculously expensive to isolate higenamine and sell it in bulk,” he said. “That would be unaffordable.”

Based on a third-party database that tracks products imported into the U.S., Bell’s law firm could only identify one import record for higenamine from January 2019 through the present. The shipment originating from China had an estimated value of $16,514.

“Nobody’s going to complain about this one [import alert], but I don’t know how many people it’s going to protect from harm,” said Robert (“Bob”) Durkin, a former deputy director of FDA’s Office of Dietary Supplement Programs (ODSP), who now practices law with AGG.

Adding to Red List

Durkin said firms and products can be added to an import alert based on the criteria used by FDA. Import alerts are subject to daily updates if justified by analytical or inspectional results, according to the FDA spokesperson.

Bell has already requested a meeting with FDA on behalf of his client, Natural Alternatives International Inc., (NAI) to discuss additional companies that should be added to the Red List.

Beta-alanine—an NDI supplied by NAI and several other ingredient manufacturers—was the subject of a four-part series of articles published by Natural Products Insider in 2020. FDA in 2019 acknowledged an NDIN filed by NAI for its ingredient, CarnoSyn beta-alanine. And in a 2020 letter to ODSP, Bell requested an import alert for other forms of beta-alanine that FDA hasn’t analyzed.

“NAI is the only company that has submitted an NDIN for beta-alanine to FDA,” the lawyer wrote in a Feb. 24, 2020 letter to Steven Tave, then director of ODSP. [FDA officials in February announced Tave was leaving ODSP, and he was scheduled to start a new job today as director of the Office of Strategic Planning and Operational Policy in FDA’s Office of Regulatory Affairs (ORA)]. “The company spent hundreds of thousands of dollars to not only compile publicly available information about the ingredient’s identity, manufacturing process and safety, but also to conduct its own commercially confidential, preclinical studies. The agency did not object to NAI’s basis for concluding that CarnoSyn beta-alanine is reasonably expected to be safe, as manufactured, and under the conditions of use proposed in the notification.”

Bell, Durkin and Fabricant are hopeful FDA adds other companies and ingredients to the Red List, including so-called copycat ingredients from China and elsewhere. These ingredients resemble, but are not necessarily identical to, an NDI that FDA has examined to determine whether the ingredient is reasonably expected to be safe.

“Anybody who sees this import alert and knows that there’s an NDI for that ingredient should be very concerned,” Bell cautioned.