Industry stakeholders have mixed feelings on FDA supplement directory

Eighty.

That’s the number of dietary supplement ingredients and other substances the Food and Drug Administration has identified in a directory of FDA actions and communications that could be used by distributors, manufacturers and retailers of supplements.

The directory was launched over a year ago and revised on Feb. 21, 2024, incorporating a column to describe the FDA actions or communications associated with an ingredient and adding dozens of substances to the list, including what are known as SARMs (selective androgen receptor modulators) that FDA said have targeted teenagers and young adults in social media and mimic the effects of anabolic steroids and testosterone.

The name of the directory also has changed from “Dietary Supplement Ingredient Directory” to “Information on Select Dietary Supplement Ingredients and Other Substances.”

For about 30 years, FDA has principally regulated dietary supplement products under the Dietary Supplement Health and Education Act of 1994 (DSHEA). For consumers, industry groups and other stakeholders not familiar with all of FDA’s actions on various ingredients marketed in supplements, the directory could prove useful.

“We have any number of ingredients that are found in dietary supplements,” and it can be challenging to find information about an ingredient that FDA may have communicated about 10 years back or decades ago, said Cara Welch, Ph.D., who oversees FDA’s Office of Dietary Supplement Programs (ODSP).

Changes were made to the directory after FDA received feedback from consumer advocacy and industry trade groups, she said in an interview. Some changes appear to have been incorporated in response to a letter from four industry associations: American Herbal Products Association (AHPA), Council for Responsible Nutrition (CRN), Consumer Healthcare Products Association (CHPA) and United Natural Products Alliance (UNPA).

While the previous name of the directory was a “concise term,” Welch acknowledged not all the ingredients listed are appropriate for use in dietary supplement products. Ingredients in the directory are associated with one or more of the following seven categories.

1. Ingredient is the subject of an authorized health claim or qualified health claim.

2. Ingredient is the subject of a safety communication.

3. Ingredient is not a “dietary ingredient” under section 201(ff)(1) of the Federal Food, Drug and Cosmetic Act (FD&C Act).

4. Ingredient is excluded from the dietary supplement definition under section 201(ff)(3) of the FD&C Act.

5. Dietary ingredient has not met the safety standard in section 402(f)(1)(A) of the FD&C Act.

6. New dietary ingredient has not met the safety standard in section 402(f)(1)(B) of the FD&C Act.

7. New dietary ingredient requiring a premarket safety notification under section 413(a)(2) of the FD&C Act but for which no notification has been submitted.

Welch said she hopes distributors and manufacturers will use the directory as they are preparing to develop a new supplement, and retailers will tap the resource in determining products they intend to sell. FDA uses the directory internally, such as when communicating with the Office of Regulatory Affairs about an inspection, or when an outside party requests information on the use of an ingredient in supplements, she added.

Arguably, most of the ingredients in the directory are associated with a negative connotation, but FDA also has included ingredients that are the subject of qualified health claims.

According to FDA, "Qualified health claims are supported by scientific evidence, but do not meet the more rigorous ‘significant scientific agreement’ standard required for an authorized health claim. To ensure that these claims are not misleading, they must be accompanied by a disclaimer or other qualifying language to accurately communicate to consumers the level of scientific evidence supporting the claim.”

In the interview, Welch addressed why FDA included qualified health claims in the directory.

FDA doesn’t approve dietary supplements or frequently “make blanket statements about the safety of a [supplement] product or an ingredient in a positive sense,” she said. “Sometimes, we leave stakeholders with the impression the only time FDA’s communicating about an ingredient is a negative.”

The agency wanted the directory to include an “objective list of all the statements FDA makes about dietary supplements — not just negative, but also in the sense of ingredients that are the subject of an authorized health claim, a positive aspect,” Welch explained.

She left open the possibility that FDA will add other actions or communications in the directory that discuss the benefits of supplements. Though she said she’s not aware of such future changes, Welch added, “We are always willing to receive that feedback and as appropriate incorporate it.”

CRN President and CEO Steve Mister expressed concern that the FDA directory “is trying to be too many things to too many people” by including, for instance, qualified health claims, which could confuse people reading a list that also features ingredients like DMAA. FDA has determined 1,3-dimethyamylamine — the subject of extensive civil litigation over a period of several years — does not qualify as a dietary ingredient.

“If something is the subject of a health claim, that’s a pretty good thing,” he said. “That means FDA has recognized it actually does have a benefit for reducing the risk of a disease. But the other stuff [in the directory] is all negative.”

On the other hand, Mister perceived value in a list of ingredients that FDA determined are illegal. For instance, he suggested a retailer being pitched an ingredient to sell could reference the directory. Mister also believed that adding a column to the directory explaining the reason(s) an ingredient was added could help to reduce confusion.

Mister credited AHPA’s President Michael McGuffin for leading the effort by industry trade groups to request substantive changes to the directory.

"AHPA is pleased to see FDA implement some of the changes that we, along with CHPA, CRN, and UNPA, directly requested in our letter to Dr. Cara Welch following the initial publication of the directory last year," McGuffin said in an email. "While the changes made are encouraging and reflect a willingness by the agency to implement 'constructive stakeholder feedback' in at least some cases, the purpose of the directory remains questionable, and the website remains potentially misleading to consumers. In the interest of seeing the agency provide more balanced information about the product category, we will continue to push FDA to discontinue its longstanding practice of overemphasizing risks and ignoring benefits in its communications about dietary supplements."

Dan Fabricant, Ph.D., is president and CEO of the Natural Products Association (NPA). Fabricant, who essentially had Welch’s job about a decade ago, characterized the directory as “an attempt to swipe at the industry.”

“There’s no point to it,” he argued. “What’s the public health benefit having acetaminophen there next to NAC (N-acetyl-L-cysteine)?”

FDA has concluded both substances are excluded from the definition of a dietary supplement product, though the analysis is more complicated when digging into the particulars.

In the case of acetaminophen, also known as Tylenol, FDA’s directory links to a 2009 warning letter to Procter and Gamble. In the letter, FDA asserted “the presence of acetaminophen and dextromethorphan HBr, along with phenylephrine HCl (‘VICKS DayQuil Plus Vitamin C’) or doxylamine succinate (‘VICKS NyQuil Plus Vitamin C’), with the intended uses of these ingredients as, respectively, pain reliever/fever reducer, cough suppressant, nasal decongestant, and antihistamine, render the entire product a drug in both cases.”

NPA sued FDA over NAC after FDA concluded in 2020 warning letters that NAC was excluded from the definition of a dietary supplement because it was approved as a new drug in 1963. FDA published an enforcement discretion guidance in 2022 that essentially gave manufactures and retailers the green light to resume sales of NAC-containing supplements.

In the directory, FDA links to its August 2022 guidance on NAC and its responses in March 2022 to citizen petitions regarding NAC filed by CRN and NPA.

Fabricant also was critical of FDA’s decision in February to add galantamine to the directory. FDA linked to a 22-year-old warning letter to a company that still sells galantamine supplements.

FDA has concluded galantamine is excluded from the definition of a dietary supplement and was authorized for investigation as a new drug before being marketed in supplements. According to researchers who recently tested both “supplements” and drugs containing galantamine, the ingredient has been approved as a prescription medication for the treatment of mild to moderate dementia from Alzheimer’s disease.

Fabricant pointed to galantamine to support his concerns about the directory, questioning how the recipient of the 2002 warning letter responded to FDA and whether FDA moved to act against galantamine supplements based on its determination.

Galantamine, he concluded, is another instance of FDA “mucking this up: 22 years past the fact.”

Some consumer advocates with an interest in dietary supplement issues contacted for this story had no immediate comment on FDA's revised directory.