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In comments responding to FDA’s revised NDI draft guidance, industry trade associations challenge the agency’s stance on nature-identical botanical ingredients.
Now that the public comments on FDA’s revised new dietary ingredient (NDI) draft guidance are in, it’s clear that the agency’s position on synthetic botanicals (or “synbots”) remains one of the guidance’s most problematic provisions for the dietary supplements industry. As in the previous version of FDA’s NDI draft guidance, published in 2011, the revised draft guidance largely bars synthetic botanicals from fitting the definition of dietary ingredients. But industry trade associations say FDA’s stance on synthetics is not supported by law and does not reflect research on the safety of synthetic botanicals.
According to FDA’s revised draft guidance, “Under a plain reading of the [Federal Food, Drug, and Cosmetic Act (FDCA)], a synthetic copy of an herb or other botanical does not qualify as a dietary ingredient under section 201(ff)(1)(C) of the [FDCA]. As defined in the glossary, an herb or botanical includes only plants, algae, fungi, their exudates (secretions, such as sap or resin), and their physical parts. A substance that has been synthesized in a laboratory or factory has never been part of an herb or other botanical and, therefore, is not a dietary ingredient under section 201(ff)(1)(C) of the [FDCA].”
The new draft guidance does include an exception that if a synthetic botanical has “been used as a lawfully marketed ingredient in the conventional food supply,” it may qualify as a dietary ingredient, with FDA pointing to vanillin and cinnamic acid as two synbots that fit that definition. But other synthetic botanicals, such as variations of widespread ingredients like resveratrol, 5-HTP, L-theanine, and astaxanthin, would be excluded from the definition of a dietary ingredient. Industry leaders, however, say FDA has no legal or scientific basis on which to draw that conclusion.
Equivalent to Natural Botanicals
One of industry’s main objections to FDA’s stance on synbots is that it doesn’t appear to be based in science about the safety concerns of synthetic ingredients. For instance, the American Botanical Council (ABC; Austin, TX) wrote in its comments to FDA that the agency has not provided data that speaks to any safety concern regarding the use of synthetic or semi-synthetic copies of herbal or botanical constituents.
“ABC continues to emphasize that the safety of an ingredients is the primary consideration and if a synthetic of semi-synthetic compound is chemically identical to the natural compound and has the same level of safety as the natural compound, then ABC supports the availability of the synthetic or semi-synthetic version as a legitimate dietary ingredient,” ABC said in its comments submitted to FDA.
Similarly, the Council for Responsible Nutrition (CRN; Washington, DC) said the source of a synthetic botanical should not be the criteria used to establish whether it can be accepted as a dietary ingredient. Instead, the synthetic copy’s “chemical equivalence” to the natural version of the botanical should be the deciding factor.
“There are no scientifically justifiable grounds for treating synthetic copies of botanical constituents differently when they are chemically equivalent to their plant-derived, naturally occurring counterparts,” CRN wrote to FDA. “If there are safety concerns, then the NDI notification process provides a way for FDA to evaluate and directly respond to potential issues prior to the marketing of these ingredients.”
No Basis in Law
Aside from the scientific argument, there’s also the legal argument that FDA’s take on synthetic botanicals is not supported in the Dietary Supplement Health and Education Act of 1994 (DSHEA), nor is it true to the intent of Congress when it drafted that legislation.
Specifically, industry associations like CRN and the Natural Products Association (NPA; Washington, DC) note that no regulations in Section 201(ff)(1) of the FDCA bar synthetic botanicals. In fact, the same section includes a “catch-all” provision (E) that offers a regulatory avenue for ingredients like synthetic botanicals, CRN noted. The provision says that “a dietary substance for use by man to supplement the diet by increasing the total dietary intake” can be classified as a dietary ingredient-a description synthetic botanicals ostensibly meet.
“Congress did not include limitations on synthetic ingredients, or any requirement for historical use of a substance to supplement the diet under Section 201(ff)(1)(E), and FDA therefore should not exceed its authority by imposing its own limitations through guidance,” CRN said. The association added that “neither the language of DSHEA nor the legislative history reveals any congressional intent to exclude from the definition of ‘dietary ingredient’ synthetic versions of food or botanical components and other nutritional substances that have not previously been used to supplement the diet.”
Along those lines, NPA argued that FDA’s stance on synbots “imposes unreasonable and unnecessary constraints to marketing and is plainly contrary to the law.” What’s more, FDA does make allowances for synthetic ingredients such as vitamins and minerals. NPA and others challenged the agency’s position that synthetic botanicals should be treated differently from these other synthetic ingredients for which the agency gives a pass.
“Allowing synthesized ingredients among the ingredient categories of vitamins, minerals, and amino acids but calling out synthetic copies of botanical constituents as not fitting under section 201(ff)(1) has no basis,” NPA wrote, adding that, “the guidance sets up unreasonable barriers to innovation with new ingredients.”
Yet, despite the protestations from industry, FDA already appears to be operating with this stance on synbots in mind. In its recent action against vinpocetine, a synthetically-derived ingredient FDA has “tentatively” concluded does not qualify as a dietary ingredient, the agency noted that its synthetic origin is one reason why vinpocetine not a dietary ingredient. The vinpocetine case also revolves around an investigational new drug (IND) application that allegedly nullifies vinpocetine’s status as a dietary ingredient, but the fact that FDA also called out its synbot status as a disqualifying factor suggests the language of the revised NDI draft guidance may already be part of the agency’s philosophy.
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