Ingredient innovation has been central to the development of the modern dietary supplement industry. But what constitutes a dietary ingredient under the law remains an open question.

This was a principal topic that FDA sought to clarify at its March 27 public meeting. Specifically, how should regulators interpret the scope of a key phrase in the Dietary Supplement Health and Education Act (DSHEA): Sec 201(ff)(1)(E)?

Sec 201(ff)(1) of the FD&C Act states the term “dietary supplement” means “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:”

• A) a vitamin;
• B) a mineral;
• C) an herb or other botanical;
• D) an amino acid;
• E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or
• F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E);

FDA is focused specifically on Clause E. Cara Welch, director of the Office of Dietary Supplement Programs, Human Foods Program, FDA, led the March 27 meeting, stating that most of what’s listed in the statute consists of “fairly well-established terms.”

Picking apart Clause E, however, can lead to differing opinions. Ingredients like probiotics, proteins, peptides, and enzymes are a sizable part of today’s $60-$70 billion supplement market. But they don’t fit neatly into the categories outlined in DSHEA.

Read More: FDA Weighs Updates to Supplement Ingredient Framework as Innovation Accelerates

Ultimately, the goal of the meeting and public comment, Welch said, is “to provide clarity and transparency around how we interpret what we consider to be the scope of ‘dietary substance’.” 

Key questions that Welch presented at the top of the meeting included:

• Does the source of a dietary substance matter?
• Does this provision depend on the production method?
• Can any ingredient be a dietary supplement? Are there limits to what the category encompasses?
• Does “dietary substance” include substances that have never been part of the human diet?
• What happens when you produce existing dietary ingredients in a new environment?
• Does it matter if a substance is both naturally present in foods and also present as environmental contaminants?

With limited legislative history available, regulators have relied on dictionary definitions and statutory context to interpret “dietary substances” as components commonly consumed as food or drink that add to overall dietary intake, Welch said.

This interpretation has worked well historically, particularly when ingredients in conventional foods transitioned into supplement form.

However, that framework is under pressure as technological advances and production methods like precision fermentation and cell culture yield novel ingredients that may not have previously been present in the food supply.

This isn’t the first time FDA has had this conversation with industry. At a 2019 FDA meeting, stakeholders discussed the scope of dietary ingredients under DSHEA, along with the New Dietary Ingredient Notification (NDIN) process.

“Every time I have these conversations I come out with a more refined vision,” about the topic, Welch said.

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Innovation Baked into DSHEA

According to many supplement stakeholders, while DSHEA couldn’t predict the types of technologies available today, it did envision a path for innovation through the NDIN process.

Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA), argued that the statutory language in DSHEA provides a flexible framework for defining dietary substances if interpreted as Congress intended.

DSHEA remains effective and does not require a structural overhaul, he added, saying the law “works incredibly well” and has “achieved the goal of promoting wide access while giving the FDA the tools to safely police the marketplace.”

Fabricant said he used many of these tools himself when he led the FDA Division of Dietary Supplement Programs during the Obama administration.

Supplements remain “one of the safest, if not the safest, commodity regulated at FDA,” he said, suggesting modernization should focus on implementation and clarity rather than rewriting the statute.

“It’s time to focus on how FDA can more effectively leverage its authorities and how industry can support the agency in regulating and policing the market. This form of dietary supplement modernization requires no act of Congress and aligns with the 2026 priorities of the FDA Human Foods Program,” Fabricant said.

Duffy MacKay, senior vice president of dietary supplements for the Consumer Healthcare Products Association (CHPA), said that Congress anticipated future innovation and purposely built regulatory flexibility into the statute.

He said that Clause E is a “catch-all” for novel ingredients not contemplated in 1994, and was not intended as a barrier to innovation. The focus should be on function (supplement the diet) and purpose (raise total dietary intake), not source (part of the usual diet) or manufacturing method.

Graham Rigby, president and CEO of the American Herbal Products Association (AHPA), said dietary ingredients are “the foundation of our industry, and dietary ingredient innovation enhances consumer choice and addresses the evolving health needs of American consumers.”

In crafting DSHEA, Congress used broad language, he said. “It asks what the substance is for — to supplement the diet and increase intake — not whether the substance was traditionally eaten in foods. In other words, the diet can and does evolve.”

If Congress wanted to accept only ingredients from the food supply, it could have said so explicitly, as it did elsewhere, in the Food, Drug, and Cosmetic Act. “Instead, DSHEA separately created the new dietary ingredient framework, which assumes that some dietary ingredients will, in fact, be new.”

Ivan Wasserman, managing partner of Amin Wasserman Gurnani, cited Supreme Court precedent, Gustafson v. Alloyd Co., Inc., 513 U.S. 561 (1995), in which Justice Anthony Kennedy noted that courts presume consistent wording has consistent meaning, while different wording implies different intent.

In DSHEA, Congress used the phrase “dietary substance” in Section 201(ff)(1)(E), but explicitly used “present in the food supply” in Section 413, Wasserman said. Because lawmakers clearly knew how to reference the food supply and chose not to do so in Clause (E), “dietary substance” should not be interpreted as limited to ingredients already present in the food supply; it must have a broader meaning.

New Ingredient Types and Production Methods

While much of the debate centers on statutory interpretation, stakeholders also emphasized how evolving ingredient technologies are testing the boundaries of Clause E.

Fabricant pointed to peptides as an example. While present in common foods like eggs, milk, and meat, advances in delivery technologies now allow peptides to remain intact and target specific physiological functions. He cautioned that technical modifications should not automatically push these ingredients into drug territory.

“It’s critical that we explore how peptides fit into the definition of a dietary supplement because we are only beginning to fully appreciate and understand their essential role in health and wellness at a molecular level,” said Fabricant. “To have a physiological effect, certain peptides will likely need technological modifications, such as coatings or the addition of functional groups to the base molecule.”

In the case of probiotics, the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) did not formally define them until 2001, noted Amy Smith, president of the International Probiotics Association (IPA) and senior director of medical affairs, North America, Kerry ProActive Health.

Probiotic species are currently recognized as appropriate for use in foods and dietary supplements by regulatory agencies around the world, Smith said, with strain-specific information needed only to justify safety when required.

Additionally, FDA’s current interpretation doesn’t account for “incidental” ingestion of microbials found, for example, in the soil from which food is grown. “Plant and soil microbes colonize the human GI tract and lead to enhanced microbial diversity,” she said.

“Modernization of the interpretation of dietary substance is needed to acknowledge the appropriate nature of probiotics as a category to supplement the diet of those lacking beneficial microbes,” she added.

Fabricant noted innovation in the microbial space has been “massive” since DSHEA, resulting in billions of dollars in food, beverage, and supplement sales. Unfortunately, the regulatory pathways to market for probiotics aren’t always clear.

Probiotics have entered the diet through a variety of sources, including yogurts, fruits and vegetables, and others from the human intestine and breast milk. “Probiotic companies attending this FDA public meeting are improving on existing genera, species, and strains based on physiological targets that we didn’t understand 30 years ago. How do we ensure these ingredients fit with the framework of DSHEA and have a lawful pathway to market?”

Drug Preclusion Problems

Another major concern for industry is the drug preclusion clause, which Fabricant described as a “race to market” dynamic between supplements and pharmaceuticals.

However, industry sometimes doesn’t even know where the starting line is given that FDA has said it can’t disclose the date of Investigational New Drug (IND) applications.

Lack of transparency around IND filings, he said, creates uncertainty and discourages companies from investing in new dietary ingredients.

“Advancing science to promote health and wellness does not make a dietary ingredient a drug,” he noted.

Rather than legislative reform, he suggested guidance, technical clarification, and collaboration to ensure emerging technologies can be evaluated clearly within the dietary substance clause.

These concerns are not hypothetical. NPA has sued FDA twice in recent years over its application of the drug preclusion clause.

“Fortunately, these cases have revealed that FDA has authorities, or the flexibility, to allow a dietary ingredient to be sold in a supplement, even if it’s determined that an IND predates the marketing of the supplement. For example, FDA can exercise enforcement discretion as it has done with NAC.”

The other option is a notice-and-comment rulemaking. “We request that FDA complete a proposed rulemaking for NAC since this would provide an important precedent and guidelines for future dietary ingredients that are subject to a previously filed IND.”

“The notion that our industry is innovating and investing in what some would consider to be ‘pharma-like’ research should not be an impediment to develop innovative ingredients used to supplement the diet and promote health,” Fabricant added.

Source vs. Function

According to Weslee Glenn, vice president of innovation at Ayana Bio, just because something was grown in a tank rather than the ground doesn’t mean the phytocomplex is novel. Additionally, cell culture production may offer benefits that include purity, consistency, and sustainability compared to wild harvesting or modern farming practices.

MacKay argued that FDA has previously accepted NDI notifications for synthetic botanical ingredients without objection, including synthetic vitamin C vs. citrus-derived ascorbic acid, synthetic beta-carotene vs. carrot-derived beta-carotene, and synthetic fibers vs. plant-derived fibers.

Ultimately, the manufacturing method should inform safety assessments but not preclude an ingredient’s evaluation as an NDI, he said.

Meanwhile, the Generally Recognized As Safe (GRAS) process shouldn’t serve as a roundabout way to establish the safety of ingredients intended for dietary supplements.

No matter how FDA handles synthetic botanicals, Rigby said consumers have a right to understand where their dietary ingredients come from.

“Ingredients not extracted from botanicals, but chemically equivalent to those found in nature must not be labeled in a manner that may mislead consumers about their source or identity,” he said. “This approach promotes technology and innovation while protecting farmers and stakeholders, industry and consumers alike, who honor the millennia-long traditions of cultivating, preparing, and consuming herbs.”

Welch said the March 27 meeting was “step 1,” noting that continued dialogue will help FDA better understand DSHEA’s intent, current market dynamics, and how innovation fits within the dietary substance framework.

FDA will accept comments on these topics and related questions through April 27.