When FDA’s “Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues" was released for comment in July 2011, a storm of controversy erupted. Many attended FDA/industry discussions at SupplySide West, which included animated speeches. Perhaps one of the most controversial parts of the draft guidance came from the position taken by FDA on old dietary ingredients, which under the law are, “any dietary ingredient which was marketed in the United States before Oct. 15, 1994," and the lists provided to FDA by the trade associations back in 1996:
Is there an authoritative list of dietary ingredients that were marketed prior to Oct. 15, 1994 (a so-called "grandfathered list" or "old dietary ingredient list")?
No. While some trade associations and other industry groups have published lists of "old dietary ingredients," these lists have not been verified by FDA and are not backed by evidence that the ingredients listed were actually marketed prior to Oct. 15, 1994. The lists contain ingredients FDA believes are unlikely to have been marketed as dietary ingredients, such as acetaminophen or pharmaceutical glaze, and mixtures that are only vaguely described, such as "sterol complete premix." The introduction to one trade association list states that the association did not independently verify the substances on the list were in use before Oct. 15, 1994. The cover page of the list specifically states, "This list is compiled solely for reference purposes and does not constitute verification that any specific dietary ingredient was or was not marketed as a dietary supplement before Oct. 15, 1994." Moreover, the trade association's introduction to the list also states, "There is no definitive list of ‘grandfathered' dietary ingredients. The best policy is for any company to maintain its own records confirming long-term use of an ingredient." Therefore, FDA does not accept the inclusion of an ingredient on an industry list of pre-DSHEA dietary ingredients as proof that the ingredient is not a NDI.
FDA’s finger-pointing and legalistic position in the draft guidance stands in stark contrast to FDA’s acknowledgement of these lists’ submission in December 1996. Here is what Elizabeth Yetley, former nutrition research scientist, the Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH), advised the American Herbal Products Association’s (AHPA) secretary, Lorri Rosenthal:
Thank you for your letter of Sept. 17, 1996 and the listing complied by the American Herbal Products Association of herbal dietary ingredients, which may have been marketed before Oct. 15, 1996. Since the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA), the agency has frequently been asked for information concerning what dietary ingredients were marketed before Oct. 15, 1996. As you are aware, prior to that date, the agency did not maintain a list of “approved" dietary supplement ingredients. We commend AHPA for making a responsible and comprehensive effort to compile a list of botanical dietary ingredients marketed prior to Oct. 15, 1996, and we appreciate your sharing the result of that effort to FDA.
Nowhere did Yetley suggest AHPA’s honest statement that it had not independently verified the list somehow disabled the list from having any utility. Nor did she advise AHPA that it needed backup for every botanical on the list. On the contrary, she commended AHPA for its effort. The efforts of the other trade associations were comparable.
The then-named National Nutritional Foods Association (NNFA, now the Natural Products Association [NPA]) had a TruLabel program that required dietary supplement marketer members to provide the association with labels from each product, and this information was maintained in a database by NNFA. NNFA was able to use this TruLabel database in compiling its 1996 submission to FDA—hard-source evidence. And yes, the submission did include drug ingredients, plainly and prominently described as drug ingredients—not masquerading as dietary ingredients, but named as drug ingredients. The draft guidance treatment of carefully compiled and qualified lists showed no respect to the good faith efforts of the associations.
Is FDA going to challenge the “old" status of ingredients on these lists? Not likely. With the exception of the case in 2005 with pyridoxamine, there is a principled basis (orphan new drug development) for doing so. Remember, for FDA to challenge the status of an ingredient in a dietary supplement, the FDA must go to court, bear the burden of proof and prove that the ingredient is new.
My own view is that the draft guidance is an effort to provide FDA with “cover" should there be a serious safety incident arising out of the use of a dietary ingredient. Those long in tooth will recall the association of L-tryptophan produced by Showa Denko with an epidemic of eosinophilia-myalgia syndrome (EMS), a debilitating and sometimes fatal disease. Showa Denko changed its manufacturing process, which is believed to have changed the impurity profile—the part of the ingredient known to exist, which is not evaluated. The Draft Guidance is written in such a way to make it FDA’s position that every new form of an old ingredient, including vitamins, minerals, and amino acids, would require an NDI notification to FDA. This gives FDA cover if there is ever another serious safety incident, and the ability to wash its hands of responsibility.
DSHEA does not require notification of a new dietary ingredient that has “been present in the food supply as an article used for food in a form in which the food has not been chemically altered." And for many vitamins, minerals and amino acids, these ingredients are sold both as dietary ingredients and food ingredients. If they are lawfully used in food, then their use as a dietary ingredient that has “been present in the food supply as an article used for food in a form in which the food has not been chemically altered" is lawful without an NDI notification. This is how new forms of old dietary ingredients come to the marketplace.
For more tips to help understand laws regulating the supplement and functional foods market, visit INSIDER’s Regulatory Content Library. Also, hear more on the topic during the panel discussion, "Current Issues Regarding New Dietary Ingredient (NDI) Notifications," on Thursday, Oct. 8, at 9 a.m., during SupplySide West, Las Vegas.
Anthony L. Young, Esq., partner, Kleinfeld, Kaplan and Becker LLP, has practiced food and drug law for almost 40 years. He is a seasoned observer of FDA enforcement activities and has defended dietary supplement, food, drug, medical device and cosmetic manufacturers and distributors before FDA and in federal courts. Young serves as general counsel to the American Herbal Products Association (AHPA, ahpa.org) and represents dietary supplement manufacturers and distributors and their suppliers.