sign in sign up
<<
Home , Dietary supplement

[Regulatory] Vol. 19 No. 6 Nov/Dec 2014

Defining ‘Dietary Supplement’

By Sandy Almendarez, Editor in Chief

Before the Dietary Supplement and Act of 1994 (DSHEA) was enacted 20 years ago, the U.S. supplement was homeless. It didn’t have legal footing in the market, and companies selling ingredients to bolster dietary intake could rarely defend itself if FDA determined their products were additives without GRAS (generally recognized as safe) designation. Pre-1994, FDA successfully argued products that would be categorized as supplements today were food additives, which needed to be GRAS to enter the market. “Over the years, FDA had used the provision to claim an ingredient in a food supplement was not GRAS,” said Anthony Young, Kleinfeld, Kaplan and Becker LLP. “The product would be seized, and FDA would assert through an affidavit from one of its scientists that the ingredient was not GRAS, and the burden of proof would then shift to the food supplement company to prove it to be GRAS. This was beyond the capacity of many companies.” The Federal Food, , and Cosmetic Act (FD&C) of 1938 established a category of for special dietary use, which required the labeling of and and other dietary properties, but it took until DSHEA to create a regulatory definition of dietary supplement. “The regulatory definition of a dietary supplement in DSHEA enabled the federal government to create and implement specific regulations to consumer safety for this unique class of goods,” said Michael McGuffin, president, American Herbal Products Association (AHPA). “These regulations would not be possible without first defining what was being regulated. The definition put supplements in a more stringently regulated category of foods to strike a balance between ensuring high-quality products and informed consumer access to a wide variety of products.” Ivan Wasserman, partner, Manatt, Phelps & Phillips LLP, added the definition of dietary supplement is more complex than the definitions of other types of FDA-regulated products, including foods and . “It includes both broad inclusionary and exclusionary criteria,” he said. “The breadth of its inclusionary criteria seems to suggest a Congressional intent to allow a broad array of ingredients to be included in supplements.” Scott Bass, partner, Sidley Austin LLP, who was the principle drafter of DSHEA for the supplement industry, said the industry had three major goals for the definition of dietary supplement: 1) Include herbs 2) Explicitly say dietary supplements were not food additives 3) Account for non- and - substances, such as CoQ10 Of the three goals, Bass said the most difficult was to define the “other stuff” that would eventually turn into Section (ff)(1)(E) of the law. “What drove the ‘other stuff’ was CoQ10 []. In 1990, I handled a case where FDA said CoQ10 was an unsafe food additive, and the industry lost. We wanted to make room for the CoQ10s of the future: things that weren’t traditionally food, herbs, vitamins or minerals, and there are hundreds of substances like that now.” www.naturalproductsinsider.com Page 1

[Regulatory] Vol. 19 No. 6 Nov/Dec 2014

CoQ10 may be safe these days, but other compounds have been questioned, such as and synthetic botanicals, as being part of the definition of dietary supplement. The two compounds were called out in FDA’s July 2011 draft guidance for new dietary ingredient (NDI) notifications, with the agency questioning their ingredient status.

Many in industry read Section (ff)(1)(E) as a "catch-all" provision allowing virtually any ingredient to be in a supplement, Wasserman said, while FDA lately seems to reading it more narrowly. “My take is under that provision, probiotics and synthetic botanicals are dietary ingredients if they are being used to increase their total dietary intake, which they obviously are in a supplement. There are, of course, other restrictions on dietary supplements, including the NDI requirement, so a broad reading of that clause would not open the floodgates to any and all ingredients.” Daniel Fabricant, Ph.D., executive director and CEO, Natural Products Association (NPA), who was the director of FDA’s Division of Dietary Supplement Programs when the NDI draft guidance was released, prefers the term “dietary ” over “probiotics,” and asks, “Was this bacteria part of the ? Would it fit under (ff)(1)(E) part of the definition? I think the agency’s position is that those ingredients have been food additives or GRAS ingredients. If it’s a GRAS or food additive dietary bacteria like casei, it would fit. But it remains to be seen for bacteria that wasn’t in the diet prior.” Steve Mister, president and CEO, Council for Responsible (CRN), noted probiotics were a large category of products marketed pre-DSHEA, so they meet the DSHEA dietary ingredient definition. “In terms of probiotics, they were used prior to the passage of the act and are commonly found in food. Therefore, they come under the definition.” However, “For new probiotics not used in food, the route to the dietary supplement market is different, Young explained. “Such an ingredient must first be used in food so that it can meet the definition of ‘increasing the total dietary intake.’ The ordinary course is for the never-used-in-food to be GRAS self-affirmed by experts, then used in food, then available for use in supplements as an NDI for which no notification is required.” Young said the issue with synthetic botanicals appears to be whether a synthesized version of a constituent of a botanical can be a dietary ingredient. “FDA has said, ‘No, a synthetic constituent of a botanical was never in the botanical; only the natural constituent can be a dietary ingredient.’ The industry has a number of arguments as to why FDA’s analysis is flawed, including that the natural constituent is in the food supply, and this is simply a synthetic form intended to increase the total dietary intake. This issue will be resolved eventually by the courts.” Justin Prochnow, shareholder, Greenberg Traurig LLP, said the supplement industry takes the position that if a synthetic ingredient is bio-equivalent, there should be no difference between a synthetic version and a naturally occurring ingredient. “FDA has publically taken the position that synthetic components cannot be constituents because, as Dan Fabricant likes to say, ‘There is no synthetic arboretum.’” Fabricant said FDA is careful never to call any food item identical. “When you’re dealing with compounds in nature, especially compounds in botanicals, they are not identical, and they can act differently in the body.” However, he noted some cases allow for synthetic botanicals, such as synthetic . “In a lot of ways, it will be on a case-by-case basis,” he said. www.naturalproductsinsider.com Page 2

[Regulatory] Vol. 19 No. 6 Nov/Dec 2014

Per DHSEA, supplements must be digested; however, some products with alternative ingestion pathways, such as inhaling or topical applications, have marketed themselves as supplements. And FDA has warned them accordingly. At press time, Prochnow said FDA has sent 21 warning letters regarding products labeled as dietary supplements but offered for uses other than “intended for ingestion,” four of which were sent in 2014. These warnings include a wide range of uses instead of ingestion, including topical use, eye drops, nasal drops and sprays, inhalants, detoxifying bath salts, clay bath products, suppositories and patches. “The significance is that FDA looks very closely at the definition of dietary supplement when determining whether a product has been properly labeled and marketed as a dietary supplement and ‘intended for ingestion’ is a fundamental requirement,” Prochnow said. Mister said the statute is clear that dietary supplements have to be ingested. “If you are rubbing it on your skin, then that certainly is not ingested,” he said. “Anything that is topical and they are calling themselves a supplement is falling outside of the definition.” A nasal gel case set the precedent on this issue, where the court agreed with FDA that “ingestion” is not through the nose. In the early 1990s, Ener-B, a product from Nature's Bounty, was marketed as a supplement that was intended to be applied to the inside of one's nose. It bypassed digestion through the gastrointestinal (GI) tract and instead was absorbed directly into the blood stream through the nasal mucosa. FDA seized products and won the case in court, arguing that the product delivery made it a drug, not a supplement. Products that are inhaled are also not supplements. “There was a case when I was at the agency with a product called Aero Shot where the directions were a little confusing,” Fabricant said. “They talked about inhaling the product. FDA has been clear about keeping those boundaries and keeping those types of products off the market.” Sublingual products say they work faster because they are absorbed into the blood stream through the mouth using sprays or dissolvable strips, Mister said. “However, those products never enter the digestive tract. FDA has a number of warning letters out that say the method of action needs to be through the digestive track, and that if a product is being absorbed through the blood stream in your mouth, then that is not a dietary supplement because it is not being ingested.” Per DSHEA, supplements are not foods, which seems pretty clear until innovative supplement manufacturers look to meet consumer demand for new ways to ingest supplement ingredients. Sometimes, these products flirt with the properties of foods. While some products could legitimately go either way, depending on their claims and serving size, such as liquids with GRAS ingredients, some product manufacturers appear to be skirting the regulations of foods by putting a Supplement Facts Panel on their products. Ingredients that go into foods must be GRAS or food additives, which theoretically have higher safety standards than supplement ingredients. Dietary ingredients for supplements must either have a proven history of use or come with studies that show it is reasonably expected to be safe, which GRAS ingredients must be generally accepted by experts based on current research that it is safe under the labelled conditions of use, and food additives require premarket approval from FDA.

www.naturalproductsinsider.com Page 3

[Regulatory] Vol. 19 No. 6 Nov/Dec 2014

“Dietary supplements must be intended for ingestion in tablet, capsule, powder, softgel, gelcap or liquid form, or if not intended for ingestion in such a form, not represented as conventional food and not represented for use as a sole item of a or of the diet,” Young said. “For the dietary ingredient industry, the benefit of having products in the supplement class is that dietary supplements must list and quantify ingredients in Supplement Facts Panel, while foods can use small amounts of ingredients and still get the value of the ingredient on the label with very small amounts in the product.” In 1998 and 1999, FDA issued several courtesy letters to companies selling foods with dietary ingredients, including margarine with plant stanol esters, soup with and soup with St. John's wort, all ingredients that were not GRAS at the time. Since then, FDA has warned several manufacturers that their products are represented as foods, but mislabeled as supplements. A recent case from 2011 involved a brownie that contained the non-GRAS ingredient . “A lot of the power of regulatory activity is the ability to put things into compartments, and FDA loves to put things in the proper buckets because then they know how to regulate it,” Mister said. “Products that straddle the line between categories are hard for the agency because they do not know what bucket they fall in.” In January 2014, FDA published a final guidance on distinguishing liquid dietary supplements from conventional beverages. The agency said it looks at a range of factors to decide the regulatory status of a liquid product, including the product or brand name, packaging, serving size and total recommended daily intake (i.e., intended consumption volume), composition, recommendations and directions for use, statements or graphic representations in labeling or advertising, and other marketing practices. For example, use of the terms “beverage," “drink," “water" or “soda" in the marketing or the product name would render the product a conventional food, according to FDA’s guidance. “That document is very noteworthy because for the first time, FDA formalized its thinking on how it is interpreting the provision in the definition of ‘dietary supplement’ that a supplement cannot be ‘represented for use as a conventional food,” Wasserman said. The “race to the market” provision, as Bass puts it, requires that ingredients being studied as investigational new drugs (INDs) are not allowed to be marketed as supplements. A pharmaceutical company is required to submit an IND application with safety data to FDA 30 days before it ships a drug across state lines, presumably to conduct clinical trials. IND notifications are there to protect study subjects. DSHEA included this clause because Congress did not want the supplement industry putting new drugs on the market, according to Bass. “I think mostly it’s been a positive effect to keep unscrupulous players from marketing drugs that shouldn’t be marketed as supplements,” he said. Fabricant noted dietary supplements make structure/function claims, and INDs are researched using disease endpoints. “If you’re doing disease claims studies on supplements, you’ll probably have to do an IND,” he said. “It’s clear that if you’re making a structure/function claim you don’t need to an IND because it’s not a drug.” Young added, “Knowledgeable companies and their researchers and research organizations that are careful can design studies that are not disease studies.” www.naturalproductsinsider.com Page 4

[Regulatory] Vol. 19 No. 6 Nov/Dec 2014

It’s clear from the definition of dietary supplement that a supplement is not a drug, but it wasn’t so clear before the passage of DSHEA in 1994. Now, it’s easy to take advantage of the fact that the supplement industry has a home in the U.S. regulatory landscape. Herbs are supplements and so are other , even if they don’t carry an approved RDA.

As Fabricant said, “Definitions always mean something. Words do matter.”

www.naturalproductsinsider.com Page 5