FDA Debuts List For Rapidly Announcing Noncompliant Ingredients In Supplements

FDA announces addition of Dietary Supplement Ingredient Advisory List page to its website to identify ingredients it has preliminary determined should be used in dietary supplements. It also publishes warning letters submitted recently to firms marketing supplements containing two ingredients agency has concluded should not be used: eight were warned about using an ingredient identified as "DMHA" and three about using phenibut.

The US Food and Drug Administration delivers on its plan for a "rapid response tool" to identify and publish ingredients the agency says could be ineligible for use in dietary supplements. The tool doesn't, however, deliver brand names or identify firms marketing products containing the ingredients.

The FDA announced the addition of the Dietary Supplement Ingredient Advisory List to its website on April 16 with four ingredients – andarine, higenamine, hordenine and 1,4-DMAA– that the agency has preliminarily determined should not be used vitamin, minerla or supplement products because they are not dietary ingredients or are new dietary ingredients that have not been notified to the agency with proof of a reasonable expectation of safety for their intended use. It will take regulatory action against firms marketing products containing any of the four ingredients if it moves its decision against an ingredient's eligibility from a preliminary finding to a conclusion.

Additionally, the FDA published warning letters submitted recently to firms marketing supplements containing two ingredients that the agency has concluded should not be used in VMS products: eight were warned about using an ingredient identified as "DMHA" in their products, and three about using phenibut (see sidebar below).

Frank Yiannas, FDA deputy commissioner for Food Policy and Response: the Advisory List "is not exhaustive; it will always be a work in progress" as "new ingredients are identified and others are removed."

While the Ingredient Advisory List debuts with four ingredients based on preliminary findings by the FDA, the agency also is separately identifying ingredients that it has concluded are not eligible for use in VMS products and on which it already has conducted regulation actions, including warning letters. In addition to DMHA and phenibut, FDA's separate listing of those ingredients comprises acacia rigidula; BMPEA; DMBA; methylsynephrine; picamilon; tianeptine and vinpocetine.

In its announcement, the agency explains that the list isn't intended to identify ingredients as unsafe but to more rapidly publish information on ingredients found in supplements that the FDA says are not eligible for use. Notifications on the most recent updates and changes to the list will be provided to users who register with the FDA for the service.

"As the dietary supplement marketplace has grown, the introduction of new ingredients often raises complex questions involving science, policy, and the law. In the time it takes the FDA to make a final determination, consumers and industry might mistakenly conclude that a lack of action by the FDA indicates that these ingredients are lawful," said Frank Yiannas, deputy commissioner for Food Policy and Response, in the FDA's announcement.

Yiannas, appointed to his post in December, said in addition to getting information to consumers and the industry more quickly, the list "provides an opportunity for stakeholders to share information with us that they think might be relevant to our determination."

Offenders And Their AKAs

The first four ingredients, and the other terms used to identify them on labels,on the Dietary Supplement Ingredient Advisory List are:

• andarine: GTx 007, GTX-007;

• propanamide: 3-(4-(acetylamino)phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-, (2S)-SARM S-4, S-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylpheanyl)propionamide
  S-4 cpd;

• Higenamine: isoquinolin-6,7-diol, 1,2,3,4-tetrahydro-1-[4-hydroxybenzyl]-
  DL-DEMETHYLCOCLAURINE, Norcoclaurine, (+-)-Norcoclaurine,
  (+-)-Demethylcoclaurine, (+-)-O-Demethylcoclaurine, (R)-Higenamine,  (R,S)-Norcoclaurine, 1-(4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol, 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol, 1-(p-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline
  1-(4-Hydroxybenzyl)-1,2,3,4-tetrahydro-6,7-isoquinolinediol
  6,7-Isoquinolinediol, 1,2,3,4-tetrahydro-1-((4-hydroxyphenyl)methyl)-, (+-)-, 6,7-dihydroxy-1-(4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline
  6,7-Dihydroxy-1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline, (+-)-1,2,3,4-Tetrahydro-1-((4-hydroxyphenyl)methyl)-6,7-isoquinolinediol;

• Hordenine: anhaline, eremursine, N,N-dimethyltyramine, peyocactine,
  p-hydroxy-N,N-dimethylphenethylamine, 4-[2-(Dimethylamino)ethyl]phenol;

• 1,4-DMAA: 1,4 dimethylamylamine, 1,4 dimethylpentylamine

The FDA's separate list identifying ingredients that it has concluded are not eligible for use in VMS products and on which it already has conducted regulation actions comprises:

• DMHA (1,5-dimethylhexylamine);

• phenibut (4-amino-3-phenylbutanoic acid);

• acacia rigidula (vachellia rigidula, chaparro prieto, blackbrush);

• BMPEA (beta-methylphenethylamine, R-beta-methylphenethylamine HCI);

• DMBA (1,3-dimethylbutylamine, 2-amino-4-methylpentane citrate);

• methylsynephrine (oxilofrine, p-hydroxyephedrine);

• picamilon (pikatropin, nicotinyl-gamma-aminobutyric acid);

• tianeptine;

• vinpocetine (ethyl apovincaminate, common periwinkle vinpocetine).

He also noted the list "is not exhaustive; it will always be a work in progress" as "new ingredients are identified and others are removed." The agency will accept "additional feedback that may support or refute the FDA's preliminary assessment regarding" the ingredients on the list.

A rapid response tool was among the changes former Commissioner Scott Gottlieb identified in February when he announced the FDA would target strengthening its oversight of the VMS market while also allowing the industry to continue expanding the number of ingredients allowed in the products under the agency's regulatory framework created by the Dietary Supplement Health and Education Act of 1994. (Also see "Modernizing FDA's Supplement Industry Regulation Mapped Out In Five-Point Plan " - HBW Insight, 11 Feb, 2019.)

Another element of the initiative is a public meeting the agency has scheduled for May 16 to discuss adherence with the FDA's NDI notification requirement, which is the focus of the agency's Center for Food Safety and Applied Nutrition for spurring improvement in the industry's overall regulatory compliance. (Also see "NDI Notifications Take Center Stage In FDA's Evaluation Of DSHEA" - HBW Insight, 10 Apr, 2019.)

'Not Singling Out' Brands, Firms

In a statement to HBW Insight, CFSAN said brand names and product marketers linked to ingredients the FDA deems ineligible for use in VMS products could be published through other agency channels.

"At this phase, we are not singling out specific products or firms," CFSAN says. "If we ultimately determine that an ingredient is in fact unlawful, then we intend to take traditional advisory and enforcement action as appropriate," the center adds.

The FDA regularly publishes consumer alerts and other notices announcing its concerns about consumer health products it deems likely to be unsafe for their intended use. While often identifying products in recall announcements, the agency also has published alerts solely to warn consumers about certain ingredients, including several now on the Ingredient Advisory List.

Additionally, in October, the FDA published a draft guidance on recalls stating that addresses for retailers offering supplements and other food products recalled due to "a reasonable probability" using the product "will cause serious adverse health consequences or death" could be published by the agency. (Also see "Recalls With Potential For Serious Health Risks Will Identify Points Of Sale" - HBW Insight, 8 Oct, 2018.)

Utility Clear, Impact Unclear

Each of the nine ingredients on the list has been identified in warning letters that the FDA has submitted to VMS product manufacturers and marketers.

Maintaining an online list of ingredients deemed ineligible for use in VMS products might inform consumer more rapidly than the FDA previously has, but a list does little in the way of enforcement against firms using the substances, says Daniel Fabricant, president and CEO of the Naturals Products Association.

"Companies have been given prior notice because I don't know of any of these where there hasn't been a warning letter prior," Fabricant said in an interview.

Instead, the FDA appears to be indicating that it won't do anything more about companies it has warned about ingredients on its list. "It takes away from what they should be doing. Why aren't they out there taking enforcement action?" he added.

Physician and public health researcher Pieter Cohen also doubts that providing a list of violative ingredients known to be used in VMS products available in the US will have much impact on ridding the market of the products.

"It's laudable that the FDA will be operating with a bit more transparency as they share with the public and industry the ingredients they are concerned about before they make a final determination.  Unfortunately, I suspect that the FDA's new list of questionable ingredients will have little, if any, effect on what is actually on the market and therefore not create a safer environment for consumers," said Cohen, who has conducted numerous studies on the prevalence of potentially unsafe supplements in the US and has been critical of the FDA's oversight of the industry. 

In an email, he noted that one of the ingredients on the FDA's list, vinpocetine, was determined by the agency not to be a legitimate dietary ingredient, a finding it announced in September 2016. (Also see "FDA Guidance Makes Vinpocetine Compliant Despite Ban Proposal – NPA" - HBW Insight, 1 Dec, 2016.)

"Almost three years later vinpocetine is sold in dozens of brands of supplements including from mainstream retailers. If vinpocetine is not removed from store shelves after clear communication from the FDA, these other concerning ingredients newly listed … will remain available as well," Cohen said.

FDA Adjusts To Resource Levels

Other regulatory agencies, though, could see the list as an invitation for enforcement, Fabricant said. Attorneys general and other state authorities could target marketers of products containing ingredients on the FDA's list for violations of states' false advertising, consumer protection or other laws and regulations.

Additional enforcement by state agencies could be considered necessary due to the FDA's acknowledged limited resources available for its VMS industry oversight. But the agency shouldn't "dump the responsibility on states," Fabricant said. Its funding levels shouldn't determine whether the industry is sufficiently regulated, he added. "It doesn’t work that way."

The Council for Responsible Nutrition, on the other hand, sees the list potentially as help for the FDA's funding problem in the VMS space. "In addition to rapidly alerting the public, the new tool will allow FDA to exert greater regulatory enforcement in the face of limited resources," said Andrew Shao, interim senior vice president, scientific and regulatory affairs, in CRN's statement.

CRN recommends that compliant VMS firms help the FDA identify businesses marketing products with listed ingredients. "By embracing FDA’s new tool, the industry demonstrates support for the agency’s efforts to preserve the balance between access and safety for the 170 million Americans taking dietary supplements each year," Shao said.

The trade group also recommends that consumers regularly read the list to stay on top of ingredients that FDA says "appear to be unlawfully marketed" in supplements. "We are pleased that a new platform to alert consumers more rapidly than in the past has been established," Shao said.