Dietary ingredients having a “history of use” in accordance with the “Dietary Supplement Health and Education Act of 1994” (DSHEA) are not new dietary ingredients (NDIs) and hence do not require the filing of a 75-day premarket notification with the Food and Drug Administration (FDA):
“…[T]the term ‘‘new dietary ingredient’’ [NDI] means a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994” [Section 413 (c) of the Federal Food, Drug and Cosmetic Act (FDC Act); 21 USC §350(b)].
In essence, DSHEA established different regulatory requirements for dietary ingredients based simply on whether an ingredient was first marketed before or after the statute’s effective date of passage. “Old” dietary ingredients (ODIs) marketed in the U.S. before October 15, 1994 are “grandfathered” in under DSHEA, are considered to be safe for continued consumer use, and can be sold without prior notification to FDA. In the case of ODIs, a presumption of safety, based on documented historical use of the ODI, remains with the manufacturer. To remove a “grandfathered” ingredient from commerce, FDA is required to demonstrate (i.e., FDA has the burden of proof) that the product holds “an unreasonable or significant risk of injury or illness”. (So far, ephedra is the most well-known example of an ODI found to hold “unreasonable or significant risk” and removed from commerce.) For ingredients entering commerce after DSHEA’s passage, no presumption of safety exists; the burden shifts to the manufacturer to submit evidence demonstrating a “reasonable expectation of safety”; however, it is up to FDA to determine if the ingredient is unsafe. Products containing NDIs that have not been notified may be subject to recall as being “adulterated.”
The above-described understanding of DSHEA guided the firms that manufacture and market dietary supplements for seventeen years – until the FDA published its controversial “Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues” in July 2011. This guidance attempted to turn the language and spirit of DSHEA on its head by requiring industry to supply exhaustive documentation of safety in what has now become of a system of pre-market approval, rather than pre-market notice. Industry stakeholders have expressed many concerns regarding the draft guidance and other related matters over the past year. These concerns have distilled into five main issues which FDA has identified as topics for review and additional consideration (Tan Sheet, June 25, 2012):
ODI list: In addition to the new draft guidance, FDA has indicated in other places on its website1 that “There is no authoritative list of dietary ingredients that were marketed in dietary supplements before October 15, 1994. Therefore, manufacturers and distributors are responsible for determining if an ingredient is a “new dietary ingredient” and, if not, for documenting that a dietary supplement that contained the dietary ingredient was marketed before October 15, 1994.” The draft guidance effectively shifts the burden of proof that an ingredient holds “grandfathered” status from FDA’s having to prove it does not have grandfather status, to the marketer’s having to prove that it does.
Supplement v. ingredient notification: The draft guidance’s reinterpretation of DSHEA requires that each supplement product (i.e., the retail product, which would include excipients) containing a NDI be notified (supplement-based notification), rather than the ingredient itself (ingredient-based notification).
Standard of science: Within the draft guidance, the level of evidence required to demonstrate a “reasonable expectation of safety” for a NDIN has effectively, although not officially, been increased to a “reasonable certainty of no harm”, the standard required for food additive petition approval. Many further assert the standard has been effectively raised to that of a drug or quasi-drug.
Nature-identical botanicals: The draft guidance rejects use of synthetic, albeit nature-identical, versions of botanical ingredients as legitimate dietary ingredients.
Solvents and current technology: The draft guidance broadens the definition of “chemically altered” to include use of solvents other than water or aqueous ethanol for extraction and the use of current technologies.
Of the five issues, the one that FDA will reportedly address first is the ODI list, with the stated goal of “establishing an agreed upon list of grandfathered ingredients” (Tan Sheet, June 25, 2012).
Under DSHEA, the type of documentation suitable to support ODI status (that a claimed ODI was indeed on the market prior to October 15, 1994) was the same broad-based evidence admissible in a court of law. Bills of sale/lading, invoices, sales receipts, product catalogs, photographs, ledger entries, product labels, advertising materials, and affidavits of manufacture were all used by individual firms as a means of documenting their companies’ ingredients. To prevent loss of institutional memory over time and assist industry as a whole, the major dietary supplement trade associations developed – with assistance of confirmed and unconfirmed recommendations from industry – a number of ODI lists: The “CRN List of Dietary Ingredients – ‘Grandfathered’ Under DSHEA”,2 compiled by the National Nutritional Foods Association (NNFA; now the Natural Products Association; NPA) with additions submitted by the Council for Responsible Nutrition (CRN); the “Old Dietary Ingredient List” from the Utah Natural Product Alliance (UNPA; renamed the United Natural Products Alliance in 2005), and the first and second editions of Herbs of Commerce3 by the American Herbal Products Association (AHPA). The UNPA then combined the association lists in in the late 1990s to create one master list.4 According to the content of FDA Docket No. 2004N-0454, this master list has been submitted to FDA on more than one occasion.
Despite the efforts cited above, FDA has repeatedly claimed that there are no authoritative lists of “grandfathered” ingredients that can be used to establish that a dietary ingredient is an ODI. This position, which dismisses the relevance of “grandfathered” lists submitted by the trade associations in 1996-1998 for establishing pre-DSHEA ingredients, was also reiterated in the new draft guidance5 in Section IV. “Determining Whether a New Dietary Ingredient (NDI) Notification is Necessary”:
Question IV.A. 10. “Is there an authoritative list of dietary ingredients that were marketed prior to October 15, 1994 (a so-called “grandfathered list” or “old dietary ingredient list”)?
“No. Each supplement manufacturer or distributor is responsible for establishing that the dietary ingredients in its dietary supplements comply with the NDI notification requirements. While some trade associations and other industry groups have published lists of “old dietary ingredients,”7 these lists have not been verified by FDA and are not backed by evidence that the ingredients listed were actually marketed prior to October 15, 1994. The lists contain ingredients FDA believes are unlikely to have been marketed as dietary ingredients, like acetaminophen or pharmaceutical glaze, and mixtures that are only vaguely described, like “sterol complete premix.” The introduction to one trade association list8 states that the association did not independently verify that the substances on the list were in use before October 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 October 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.”8
Further explanation within the draft as to what documentation would be accepted as proof that an ingredient was pre-DSHEA was not comforting:
Question IV.A.8. “What documentation would I need to show that my dietary ingredient was marketed prior to October 15, 1994?”
“Documentation to show that a dietary ingredient is not a NDI should consist of written business records, promotional materials, or press reports with a contemporaneous date prior to October 15, 1994. Examples include sales records, manufacturing records, commercial invoices, magazine advertisements, mail order catalogues, or sales brochures. Documentation should include adequate information to establish that marketing took place in the U.S., the identity (e.g., chemical or botanical name) and form (e.g., ground herb, water extract, oil) of the marketed ingredient, and whether the ingredient was marketed as a dietary ingredient or for some other purpose.”
“Affidavits attesting to recollection of historical events which are unsupported by contemporaneously created written records are not adequate to show that an ingredient was marketed prior to October 15, 1994. Even if a person who submits an affidavit attesting to his or her recollection of when a dietary ingredient was first marketed is honestly stating his or her present beliefs, we do not regard such assertions alone, without any sort of objective, verifiable documentation from the time of marketing, as an adequate basis to establish prior marketing of a substance as a dietary supplement.”
Beyond general industry-wide outcry, specific responses to the ODI issue have included:
Dan Burton (R-IN) filing the “Dietary Supplement Protection Act of 2011”6 (H.R. 3380). The bill proposes that the cut-off date for grandfathered ingredients be changed from October 15, 1994 to January 1, 2007, the date that good manufacturing practices took effect for the supplement industry (Nutritional Outlook, December 2011); and
UNPA’s culling 273 questionable ODIs from the industry lists, including entries such as acetaminophen, calcium gluconate, zinc oxide, dextromethorphan, ephedra, blue cheese powder, and maple syrup (Health News Daily, Dec. 6, 2011; Tan Sheet, Dec. 12, 2011).
It is doubtful that the status of grandfathered ingredients will be resolved separately from the draft guidance. The most recent meeting (June 19, 2012) between FDA (Commissioner Margaret Hamburg, Deputy Commissioner for Foods Mike Taylor, and Assistant Commissioner Jeanne Ireland) and members of Congress (Sens. Orrin Hatch (R-Utah) and Tom Harkin (D-Iowa)) to discuss the new draft guidance, produced a cautiously optimistic result. As reported by CRN and NPA, FDA intends to issue a revised guidance. Although no details or time lines were provided, the decision was later confirmed in a letter by Daniel Fabricant, Ph.D., Director of FDA’s Division of Dietary Supplement Programs, to the dietary supplement industry. No one anticipates any substantive progress until well into 2013.
<http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements /ucm257563.htm#iv>; site accessed September 8, 2012.
2<http://www.fda.gov/ohrms/dockets/dockets/05p0305/05p-0305-cr00001-04-Council-For-Responsible-Nutrition-vol1.pdf >; accessed August 17, 2012; “Council for Responsible Nutrition List of Dietary Ingredients – ‘Grandfathered’ under DSHEA” Council for Responsible Nutrition: Washington, D.C., September 1998.
Awang, D., Hu, S.Y., Kartesz, J., Tucker, A., Tyler, V. (1992) Herbs of Commerce, 1st ed. American Herbal Products Association: Silver Spring, MD; McGuffin, M., Kartesz, J.T., Leung, A.Y., Tucker, A.O. (2000) Herbs of Commerce, 2nd ed. American Herbal Products Association: Silver Spring, MD.
<http://www.fda.gov/ohrms/dockets/dockets/04n0454/04n-0454-c000014-01-vol5.pdf>; site accessed August 22, 2012. FDA Docket No. 2004N-0454; UNPA Comments to FDA RE: NDIs, February 1, 2005. (“UNPA Old Dietary Ingredient List”, 1999)
<http://www.fda.gov/food/guidancecomplianceregulatoryinformation/guidancedocuments/dietarysupplements/ucm 257563.htm>; site accessed August 14, 2012. (The reader is encouraged to consult Section IV. “Determining Whether a New Dietary Ingredient (NDI) Notification is Necessary” to ascertain FDA’s current thoughts regarding this issue.)
Referred to the House Committee on Energy and Commerce: Subcommittee on Health on November 4, 2011. Current status: Still pending.
National Nutritional Foods Association, NNFA List of Dietary Supplement Ingredients In Use Before October 15, 199421 (April 26, 1996). Docket No. FDA-2005-P-0259 [Document ID: FDA-2005-P-0259-0012]
Council for Responsible Nutrition, CRN List of Dietary Ingredients “Grandfathered” Under DSHEA22 (September 1998). Docket No. FDA-2005-P-0259 [Document ID: FDA-2005-P-0259-0010].”