|Proposed guidelines called “game changing;” concern that new guidance may stifle innovation |
by Mark Blumenthal
On July 1, 2011 the US Food and Drug Administration (FDA) issued its long-awaited draft guidance document on New Dietary Ingredient Notifications. The 35-page document*, is titled “Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues.” The document was published in the Federal Register on Tuesday, July 5, 2011.1
This document represents the last major area of FDA’s attempts to ensure full enforcement of the Dietary Supplement Health and Education Act of 1994 (DSHEA), specifically Section 8 dealing with the safety of so-called New Dietary Ingredients (NDIs), a termed created within DSHEA’s text. (More about NDIs and the NDI notification process is presented below under “NDI Background”.)
Interested parties have 90 days (until October 3, 2011) to file public comments to FDA on the draft guidance for consideration in its formulation of a final guidance document.
Concerns from Industry
The Natural Products Association (NPA) President John Gay called the issuance of the FDA’s draft NDI guidance a “game changing” development (NPA, e-mail, July 1, 2011) insofar as the far-reaching effect it may have on many ingredients, products, and companies in the United States.
Dietary supplement industry trade associations announced numerous workshops and webinars dealing with the new draft guidelines (most of these seminars and webinars were already planned in anticipation of FDA’s announcement; information on each organization’s seminar is provided below). Some veteran industry food and drug attorneys expressed concerns over the impact of the guidance, i.e., if it were to be finalized in its more or less present state.
Food and drug law attorneys Justin and Jim Prochnow of the Denver offices of Greenberg Traurig LLP stated in an e-mail to the American Botanical Council (ABC):
While this Draft Guidance for Industry on NDIs has been long-awaited by those in the supplement industry and does provide some good insights into the FDA's thought process, it is important to remember, fundamentally, that the guidance does not represent any change in the law or regulations [emphasis added] governing new dietary ingredients. This guidance was prepared by the FDA to hopefully clarify the FDA's position with respect to many questions regarding the topic of NDIs (e-mail, July 5, 2011).
Jim Prochnow, also of Greenberg Traurig, and attorney Todd Harrison of Venable LLP have since suggested that FDA’s position may in fact represent a legal position that goes beyond its current authority under DSHEA, as noted below.
The Guidance for Industry is divided into 8 sections:
III. Scope of the Guidance
IV. Determining Whether a NDI Notification is Necessary
V. NDI Notification Procedures and Timeframes
VI. What to Include in a NDI Notification
The Appendices include flow charts on “Determining When to Submit an NDI Notification” (Appendix A), and a “New NDI Notification Form,” which can be used but is not required (Appendix B).
Justin Prochnow noted 2 sections that mandate particular attention: (1) Section IV: “Determining Whether a NDI Notification is Necessary,” and (2) Section VI: “What to Include in a NDI Notification.” He wrote that there are a total of 31 questions and answers under Section IV and 72 questions and answers under Section VI, which includes 19 questions addressing what information should be included in a NDI Notification, as well as 43 questions and answers about the history of use or other evidence of safety.
In a follow-up e-mail to ABC, Jim Prochnow wrote,
In my judgment, the combination of (A) the FDA's increased exercise of its enforcement authority, (B) its very narrow interpretation of Section 201 (ff)(1)(E) [of the Food, Drug and Cosmetics Act], and (C) this new Guidance, will clearly have a major stifling effect on the introduction of innovative products and on the creative talent of this industry” [emphasis added] (J Prochnow, e-mail to M. Blumenthal, July 5, 2011). (More commentary from Jim Prochnow is stated below in Sidebar 2.)
Loren Israelsen, a respected industry veteran and director of the United Natural Products Alliance (UNPA), an industry trade group, communicated the importance of the FDA’s draft guidance to UNPA members and stakeholders in an email on July 1, 2011.
The following are some of Israelsen’s comments and areas of concern on what he called the “BIG issues” arising out of what he termed “this watershed document:”2
1. Many common manufacturing changes to existing NDIs or ODIs trigger a new NDI status.
2. Changing solvents will usually trigger NDI status.
3. When can existing GRAS [Generally Recognized As Safe] affirmation status create an NDI status?
4. Synthetic dietary ingredients are not dietary supplements at all. They have been kicked out of the DS category.
5. Changing agricultural or fermentation conditions may trigger NDI status.
6. The manufacturer or marketer must describe how the combination of all the ingredients in a DS formula relates to the history of safe use of the DS.
7. The bioavailability of the ingredients must be addressed as formulated.
8. Manufacturers must be able to explain how potential adulterants, e.g., non-food solvents, pesticides, heavy metals, and filth are excluded.
9. A manufacturer who provides an expiration date on its label should submit appropriate supporting stability data to FDA.
10. If fermentation is a part of the manufacturing process, the manufacturer must be prepared to explain precisely and in detail the fermentation process.
11. Many marketing companies will now need to file NDIs for their finished products—something they have never had to do before.
12. What documentation will be needed to definitively determine that an ODI is, in fact, old (i.e., marketed in the United States as a dietary supplement before October 15, 1994)?
13. Every dietary ingredient and dietary supplement manufacturer and marketer must now "audit" their ingredient portfolio to determine NDI/ODI status and activate an NDI compliance program.
One group of food and drug law attorneys has stated that FDA appears to be going beyond its authority with respect to the scope of NDI notifications as established by DSHEA. Todd Harrison, an attorney with the Venable law firm, told ABC:
I find the draft guidance document as potentially devastating if FDA actually decides to act on it and start enforcement actions based on it. I would estimate that at least 65% of the if not more of the herbal supplements being marketed today have ingredients that could be considered NDIs and, thus, adulterated as a matter of law rather than these products actually present any kind of safety risk. It is a very difficult situation for the industry. Moreover, FDA's position that it can actually reject a notification is without a legal basis. DSHEA simply states that a manufacturer must notify FDA prior to marketing the ingredient with its basis for establishing its safety; it does not state FDA has the right to reject the submission. Indeed, any other reading would make this provision a pre-approval provision not a notification provision. Unlike GRAS notifications, which was the creation of FDA, the notification provision for new dietary ingredients is not. Thus, FDA cannot redefine the rules as it has in this instance. (T. Harrison, e-mail to M. Blumenthal, July 5-6, 2011)
In a follow-up email Harrison provided clarifying details on the 65% estimate: “It is a very rough estimate and is based on the herbal extracts we have reviewed over the years and there are a lot of extracts that were not on the market in 1994 with the standardizations we see today.”
Harrison and fellow Venable attorney Claudia Lewis issued an 8-page memo (below in Sidebar 3) to the firm’s clients outlining and commenting on many of the important elements of the draft document.3
New Dietary Ingredients (NDIs) were defined in DSHEA as any new ingredient sold for use as an ingredient in a dietary supplement, said ingredient not having been sold in the market in the United States as a dietary ingredient prior to October 15, 1994, the date President Bill Clinton signed DSHEA into law. A dietary ingredient is defined by DSHEA as vitamin, mineral, herb or other botanical, amino acid, dietary substance for use by humans to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of any of the above. The creation of NDIs was the result of a compromise among the framers of DSEHA: dietary ingredients currently in the market in the United States would be “grandfathered” (some herbalists prefer the term “grandmothered”); i.e., they would be presumed safe unless new data suggested otherwise, and DSHEA would provide additional authority to the FDA to remove any dietary ingredient which the agency could substantiate constituted a public health hazard (as was the case in 2003-2004 with the FDA’s removal of the controversial herb ephedra or ma huang [Ephedra sinica]).
The intention of the NDI provision of DSHEA was to protect the public against any unsafe new ingredients that might be introduced after DSHEA was passed. In this process, all importers/marketers of NDIs must notify the FDA 75 days prior to the date of intended initial market introduction of the NDI. The notification must accompany safety data sufficient to convince the FDA that the ingredient is safe in the form that it will be marketed, and at proposed levels of usage. Marketers can include traditional food and other traditional uses so long as such uses relate to the form of the product that is to be marketed.
Per the terms of DSHEA, there are 2 conditions which control the market entry of new dietary ingredients: (1) evidence that supports a reasonable expectation of safety for the marketed use; and (2) submission of data that supports this expectation 75 days before marketing, otherwise known as a “75-day notice” or a “75-day premarket notification.” “In implementing this law,” wrote American Herbal Product Association (AHPA) President Michael McGuffin and AHPA General Counsel Anthony Young, “the FDA has established a process whereby it reviews the submitted data and informs the notifying company whether it considers the data to be sufficient to ensure a reasonable expectation of safety.”4
To document that an ingredient is an “Old Dietary Ingredient” (ODI, a term not found in DSHEA but used in industry regulatory parlance) a firm must be able to provide evidence of sale in the US market as a food prior to October 15, 1994, e.g., an advertisement catalog listing, an invoice or bill of sale, bill of lading to prove shipment of said material, etc. Industry trade groups published lists of herbs and other dietary ingredients that they believed to be ODIs based on input from members. These lists were aggregated into one document in 1999 by the Utah Natural Product Alliance (now the United Natural Products Alliance, UNPA). However, FDA has never officially adopted any such lists as official listing of ODIs. Thus, there has been no specific guidance on which herbs etc. are ODIs or possibly NDIs.
In an attempt to clarify the issue for its members, AHPA established a database of NDIs in 2006 in which it invited its members to submit advertisements, invoices, etc., to provide substantiation to help ensure the claimed ODI status of a botanical item. In a 2006 press release, McGuffin presciently stated, “As we approach DSHEA’s 12th anniversary, we need to preserve the records that substantiate which ingredients were already in the market. This will become even more important as more years pass, so now is the time to consolidate the records of the industry’s historical uses.”5 In June 2011, AHPA re-launched this effort in the awareness of growing need for such a resource now that FDA would be issuing its draft guidance.6
However, simply showing and confirming a pre-October 1994 date of sale of an ingredient is not the only criteria to establish the status of an ingredient as an ODI. If the FDA deems that the proposed dietary ingredient has been “chemically altered”— e.g., in a standardized extract of an herb that has a chemical profile different from a traditional hydro-ethanolic extract of the same plant and plant part—then FDA may deem the material to be an NDI, requiring an appropriate 75-day notification. Upon receiving the safety substantiation, FDA can accept (not approve in a strict sense) or object (not reject) the NDI, or it can request more information from the marketer.
It is a widely held belief among many herb and dietary supplement industry leaders that many of the products currently in the market in the United States contain ingredients which in effect are NDIs and which have not been properly vetted via the required notification process.
There has been much confusion among industry members regarding the entire NDI process. Over the years, industry leaders and trade associations have requested that FDA issue guidance to clarify its policy on NDIs.
It is quite possible that some of the provisions of FDA’s draft guidance, if kept in the final document, will result in many current ingredients/products for which NDI notifications have not been filed being deemed adulterated and thus unsafe foods by FDA, thus subject to possible recall.
More information on the NDI situation, as it stood about 7 or 8 years ago, is available in 2 cogent review articles. The first was written by Patrick and Chris Noonan in HerbalGram number 63 in 20047; the other was written by AHPA’s McGuffin and Young in the Journal of the Food and Drug Law Institute.4
Industry Organizations’ Responses
While it is probable that most industry organizations will release more detailed responses as they have adequate time to review the document, on July 1, just prior to the July 4 Independence Day holiday weekend, most groups announced to their members that the Draft Guidance had been issued. In some cases the organizations expressed their gratitude that the guidance document had finally been issued, especially since the entire NDI enforcement issue has been unclear and one of the key aspects of DSHEA that has gone the longest amount of time without the ability for full enforcement, i.e., based on the need for clarification of several key issues related to NDIs. These include what constitutes an ODI.
In addition, industry has been unclear as to how FDA would interpret the “chemically altered” provision of the DSHEA in which any ODI might be considered an NDI if it were deemed to be somehow chemically changed in a way that affects the final chemical profile and thus activity and/or safety (except for certain required manufacturing steps, e.g., powdering, freeze-drying, etc.). FDA spokespersons have previously stated that the agency might classify an ODI as an NDI if such ingredient were sold in a form that utilized a novel solvent and/or extraction process that was not marketed in the United States prior to October 15, 1994.
On July 1, AHPA issued a release stating, “A preliminary review of the guidance indicates that it is a combination of reinterpretation of certain elements of the existing law and specific suggestions to assist companies in providing the information needed to avoid having FDA identify concerns or objections to an NDI notification. AHPA staff and counsel will be reviewing this guidance in greater detail over the next several days.”
According to McGuffin, "Even though the guidance is not binding, we should all be concerned about any attempt by FDA to use this forum to change the rules and practices that have been accepted and in place for 17 years. At the same time, it appears that the agency has learned from the process of reviewing submitted notifications, and has described, for the first time, at least some of its expectations for the content of NDI notifications."
AHPA’s release noted that it would hold an educational seminar for its members on this issue within the coming weeks and also reminded AHPA members that AHPA has made available several tools to assist in filing an NDI notification:
1. The AHPA NDI Database—a searchable online database of the over 575 NDI notifications that have been submitted to FDA to date. It is the only
up-to-date compilation of NDI notifications available. This subscriber-based database provides access to the actual filed documents and also gives a concise "outcome statement" for each NDI file that quickly summarizes how FDA has responded to every notification, and the problems—if any—that the agency identified for each. (More information and subscription information is available here
2. Guidance for New Dietary Ingredient Notifications for Manufacturers and Distributors of New Dietary Ingredients
, which was recently updated in June of 2011). It explains the NDI regulations, details what information to include—and exclude—in a notification, and provides 3 hands-on worksheets. This will be revised again to include any new and relevant information from the FDA guidance. (More information is available here
Council for Responsible Nutrition
Noting that industry has awaited the publication of this document for many years, the Council for Responsible Nutrition’s (CRN) President Steve Mister wrote in a release:8
As FDA has reminded us, this draft guidance document describes the agency’s interpretation of the requirements for NDIs—it is not a new regulation and does not create new rights or responsibilities for the industry. Nevertheless, this draft guidance does represent an important step for the dietary supplement industry—and for the Agency—as it demonstrates further implementation of the requirements of the Dietary Supplement Health and Education Act (DSHEA) and will give companies clearer understanding of FDA’s expectations under the law….This guidance has potential for short- and long-term implications for our industry and for our consumers’ ability to have access to in-demand products and we want to be sure the guidance is appropriate, reasonable and practical for industry and the more than 150 million consumers who use dietary supplements year after year (CRN, e-mail, July 1, 2011).
CRN also issued a release on July 5 announcing a webinar on the subject: “FDA’s NDI Guidance Document and Its Impact on the Dietary Supplement Industry,” which will be held on Wednesday, September 14, 2011, from 2:00 – 4:00 pm EDT. (Information at Natural Products INSIDER or www.crnusa.org.)
Natural Products Association
The Natural Products Association (NPA), a trade association that represents the natural food retail industry and its suppliers, announced that it was planning to hold a webinar on the subject on Monday, July 11, at 3:30 pm EDT. Speakers will include Daniel Fabricant, PhD, director of the Division of Dietary Supplement Programs at FDA’s Center for Food Safety and Applied Nutrition (CFSAN); Scott Bass, head of the Global Life Sciences Team at Sidley Austin LLP; Cara Welch, PhD, NPA vice-president of scientific and regulatory affairs; and John Gay, NPA executive director and CEO. (Registration for the webinar is available at www.npainfo.org/NDIWebinar.)
On July 6, NPA issued another notice to its members and stakeholders stating that it believes FDA may have exceeded the intent of Congress inherent in the passage of DSHEA (NPA, e-mail, July 6, 2011). The release quotes Dr. Welch of NPA as saying,
We believe the draft guidance does not match Congress’s clear intent that products made from ingredients on the market prior to DSHEA should remain on the market. The FDA is asking for far more from the industry to prove that an ingredient was on the market before 1994 than most makers can probably produce. That was not the intent of DSHEA. These requirements will reduce ingredients meeting the established grandfathered status to a regrettably small number.
In addition to providing early description of the document to its members (see Israelsen comments above), the UNPA, like other trade groups, has been planning an educational program dealing with the NDI issue. UNPA will hold a 2-day seminar in Salt Lake City, UT, on July 26-27. (Registration available at http://unpa.com/login.php.)
*the length of the document may be a bit shorter or longer, depending on individual computer settings
1. Food and Drug Administration. Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues. Federal Register. July 5, 2011. Available at http://www.accessdata.fda.gov/scripts/oc/ohrms/advdisplay.cfm.
2. Natural Products Association. NPA Concerned FDA May Be Overstepping Congress’s Intent as Expressed in DSHEA:
Draft NDI Guidance Tough on Industry, May Lead to Fewer New Products. Natural Products Assn. July 6, 2011.
3. Harrison T, Lewis C. FDA Publishes Draft Guidance on New Dietary Ingredients (“NDIs”) [memo to clients]. Washington, D.C.: Venable LLP, July 5, 2011.
4. McGuffin M, Young A. Premarket notifications of new dietary ingredients - a ten-year review Food & Drug Law Journal. 2004;59:229-244.
5. American Herbal Products Association. AHPA to create “ODI substantiation database” [press release]. Silver Spring, MD: American Herbal Products Association; August 9, 2006.
6. American Herbal Products Association. FDA's NDI Guidance Now Posted;
AHPA to Host NDI Seminar. Silver Spring, MD: American Herbal Products Association, July 1, 2011.
7. Noonan C, Noonan WP. New Dietary Ingredients: DSHEA Provides Protection from Potentially Unsafe New Ingredients with no Prior Market History in the U.S. HerbalGram. 2004;63:70-74. Available at: http://cms.herbalgram.org/herbalgram/issue63/article2716.html.
8. Council for Responsible Nutrition. CRN commends FDA for releasing NDI draft guidance. Washington, D.C.: Council for Responsible Nutrition, July 1, 2011.
Sidebar 1: Additional Comments by Food and Drug Attorney, Justin Prochnow of Greenberg Traurig LLP
[Sent to ABC via e-mail on July 5, 2011. This text has undergone minimal stylistic editing by ABC.]
What follows is commentary by Justin Prochnow of the law firm of Greenberg Traurig on specific areas of the FDA’s draft guidance document:
“While the Q&As under Section VI should provide valuable insight into the FDA’s thinking with respect to history of use and other evidence of safety for those going through the NDI Notification process, I am limiting my comments in this email below to identifying some of the key points set forth in Section IV: “Determining Whether a New Dietary Ingredient Notification is Necessary.”
Under the subheading A"When Is a Dietary Ingredient New?," there are 12 Q&As. While many of these Q&As may not be new revelations, highlights include the following:
• A NDI is defined in 21 USC 350b(c) as "a dietary ingredient that was not marketed in the United States before October 15, 1994.”
• The use of an ingredient in a conventional food before October 15, 1994 does not determine whether the ingredient is a NDI. What matters is whether the ingredient was marketed as a dietary ingredient. An ingredient that was used to make a conventional food before October 15, 1994 is a NDI unless the ingredient was also marketed as a dietary ingredient.
• However, even though an ingredient that was used to make a conventional food before October 15, 1994 may be a NDI, a NDI notification is not required for a dietary supplement containing the NDI as long as the supplement contains only dietary ingredients that have been present in the food supply as articles used for food in a form in which the food has not been chemically altered.
“Essentially, these two read together mean that an ingredient is a NDI unless it was used in a dietary supplement prior to October 15, 1994, but a NDI notification is not required if the ingredient has been used in conventional food and has not been altered. Additionally, the ingredient must meet the adulteration standard as outlined below.
• "Marketing" a dietary ingredient means selling or offering the dietary ingredient for sale (1) as a dietary supplement, (2) in bulk as a dietary ingredient for use in dietary supplements, or (3) as an ingredient in a blend or formulation of dietary ingredients for use in dietary supplements. A dietary ingredient may be "marketed" by physically offering the article for sale at a retail establishment, listing it for sale in a catalog or price list, or through advertising or other promotion, if the promotion makes clear that the article is available for purchase.
“Evidence of marketing in other countries does not establish proof that an ingredient is or is not a NDI; only marketing in the United States is pertinent. Marketing of an ingredient as a conventional food, drug, or any other non-food use is also not relevant to establishing proof of an ingredient marketed as a dietary ingredient prior to October 15, 1994.
• There is no authoritative list of dietary ingredients marketed in the United States prior to October 15, 1994. NNFA’s and CRN’s lists of "grandfathered" ingredients do not constitute proof for FDA because they have not been verified by FDA and are qualified by those trade organizations.
• If changes are made to the manufacturing process of a dietary ingredient that was marketed in the United States prior to October 15, 1994, and those changes alter the chemical composition or structure of the ingredient, the resulting compound is likely a NDI.
• Similarly, if changes are made to the manufacturing process of a NDI for which a NDI notification was filed and an acknowledgement without objection from FDA was received, a new NDI notification must be submitted as the new resulting compound is likely a NDI.
“Changes to the manufacturing processes of ingredients that alter the chemical composition will most likely cause the ingredients to be NDIs, thus requiring a NDI notification.
“Under the subheading B "Exception to Notification Requirement for Certain NDIs with a History of Use in Conventional Food," there are 4 Q&As. Highlights include the following:
• Even though a dietary ingredient may be a NDI, a NDI notification is not required if the ingredient has been listed or affirmed by FDA as GRAS, self-affirmed as GRAS, or approved as a direct food additive in the United States. However, the adulteration standard set forth under 21 USC 342(f)(1)(B) still applies.
• Ingredients marketed in foods outside the United States are exempt from the NDI notification requirement but must also meet the adulteration standard.
“The adulteration standard set forth in 21 USC 342(f)(1)(B) provides that a supplement containing a NDI is adulterated unless there is adequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury. If the intake level of the NDI is the same as or lower than the intake level approved in a food additive regulation or specified in a GRAS regulation, FDA is likely to conclude there is adequate information. If levels are higher, safety analyses would be necessary to establish safety.
• Chemically altering processes
“There are 9 different examples listed in the Draft Guidance for Industry of processes that chemically alter an article of food. Those include processes making or breaking chemical bonds such as hydrolysis or esterification; removal of some components of tincture or solution in water which changes the chemical composition; application of nanotechnology that results in new or altered chemical properties of the ingredient; and use of a botanical ingredient that is at a different life stage than previously used.
• Changes that don't result in chemical alteration
“Minor loss of volatile components, dehydration, lyophilizaiton, milling and formation of a tincture or a solution in water, a slurry, a powder, or a solid suspension do not chemically alter an ingredient. Examples include leaves or roots of a plant consumed as a conventional food are dried and ground for sale in powder form or a tincture is made by soaking pears in aqueous ethanol and the mixture is then milled and dried into a powder that is placed in a capsule
“Under the subheading C "Other Questions About When a NDI Notification is Necessary," there are 4 Q&As. Highlights include the following:
• If a NDI notification has already been submitted for a supplement, another NDI notification need not be submitted for the same NDI as long as the daily intake level recommended is the same and the new supplement does not have other dietary ingredients that were not included in the original NDI notification.
• It is irrelevant that a NDI has been submitted by another manufacturer; a NDI notification must be submitted for each NDI that necessitates a submission.
“Under the subheading D "Additional Issues to Consider Before Submitting a NDI Notification," there are 11 Q&As. Highlights include the following:
• A synthetic copy of a constituent of a botanical was never a part of the botanical and thus cannot be a constituent of a botanical that qualifies as a dietary ingredient. A synthetic version of a botanical extract is not an extract of a botanical because it was not actually extracted from the botanical.
“This confirms what the FDA has indicated in several recent warning letters and, in our opinion, will likely be the source of litigation between industry companies and FDA in the near future. This position by the FDA has already had significant effect on companies in the bodybuilding and other industries.
• An ingredient that has been approved as a new drug or licensed as a biologic may only be a dietary ingredient for use in a dietary supplement if the ingredient was marketed for use in a dietary supplement or food prior to being approved as a new drug or biologic
• In certain situations, an ingredient that has been clinically tested as a drug but has not been approved can be an ingredient in a dietary supplement.
“There are 4 Q&As regarding dietary ingredients that have been clinically tested pursuant to an IND. We strongly recommend reviewing these Q&As and contacting us if you are considering using an ingredient in a dietary supplement that is also the subject of an IND.”
Sidebar 2: Additional Comments from Food and Drug Law Attorney Jim Prochnow of Greenberg Traurig LLP
[Sent to ABC via e-mail on July 6, 2011. This text has undergone minimal stylistic editing by ABC.]
I briefly read this Guidance document and have these additional comments:
 In our judgment, one effect of this Guidance will be to stifle, not eliminate, the development of new food ingredients and food products. The 14 pages that the FDA uses to describe the requirements for a NDI notification clearly sends a message to the industry that you must be a company with a large amount of cash in order to hire consultants, lawyers and an array of scientists in order to consider, seriously, developing a NDI or using a NDI in a dietary supplement product. In my judgment, the combination of (A) the FDA's increased exercise of its enforcement authority, (B) its very narrow interpretation of Section 201 (ff) (1) (E) , and (C) this new Guidance, will clearly have a major stifling effect on the introduction of innovative products and on the creative talent of this industry.
 In our judgment, the Guidance is woefully lacking in its discussion of what constitutes a "dietary ingredient" in the context of the definition of "dietary supplement." The FDA informs the readers that this Guidance is only in the context of the NDI statute (see page 5, the fourth unnumbered paragraph of Part III of the Guidance) and that the FDA assumes the ingredient to be a "dietary ingredient" for the purposes of its discussion. We encourage the FDA to set out its position on the various substances that can be dietary ingredients.
The only place where the definition of "dietary ingredient" is directly addressed is in the FDA's answers to its Questions IV. D. 1-4. There, the Guidance states that a synthetic version or edition of a botanical or of a substance derived from a botanical does not qualify as a "dietary ingredient," although no explanation is given for that position in this Guidance. Significantly, the Guidance does not preclude the use of synthetic vitamins, minerals or amino acids. The Guidance is silent on that issue. In our opinion, that silence is important; in our opinion, if the FDA’s position is that all synthetic ingredients are precluded from use as dietary ingredients in dietary supplements, it would have declared that position. In our opinion, the FDA’s current regulatory position can be summarized by the phrase “It is what it is.” This means, that if a substance is a vitamin, for example, it is a dietary ingredient whether synthetic or whether derived from an orange. Using that same logic, a synthetic could never be a mirror image of a botanical. We encourage the FDA to discuss its position and confirm that “synthetics” position in the final edition of this Guidance document.
The FDA should discuss in the final Guidance the use of a synthetic substance that is not included in 201(ff)(1)(A, (B), (C), or (D). These special types of substances are new or novel substances created in laboratories and intended for use in food.
There is no reason why the FDA should not have seized the opportunity to explain the basis or rationale for its position, as expressed only in concluding fashion in several Warning Letters, that synthetic substances, which are not synthetic vitamins, minerals or amino acids, are not covered by the broad language of Clause (E), "...a dietary substance for use by man to supplement the diet by increasing the total dietary intake." To date, the FDA’s position appears to be that Clause (E) applies only to substances (such as probiotics) that have been commonly used by man for food or drink.
Significantly, what the FDA did do in this Guidance document is to define "dietary substance" on page 24 of the Guidance, as "A substance commonly used as human food or drink." Of course, "commonly used as human food or drink" does not appear in DSHEA. By the inclusion of this definition without discussion, it is not unreasonable to conclude that the FDA is unilaterally attempting to informally amend the FFDCA and DSHEA to conform to its position as the scope of Clause (E), without the specter of a robust industry discussion about the scope of that statutory provision.
Sidebar 3: Comments from Food and Drug Attorneys Todd Harrison and Claudia Lewis of Venable LLP
The complete contents of the 8-page memo to Venable LLP’s clients written by attorneys Todd Harrison and Claudia Lewis, issued on July 5, 2011:
On July 1, 2011, the US Food and Drug Administration (“FDA”) published its long- awaited Draft Guidance on New Dietary Ingredient (“NDI”) notifications (“Draft Guidance”). The Draft Guidance can be found on FDA’s website at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm257563.htm. The notice of availability of the Draft Guidance was published in the Federal Register on July 5, 2011. While comments on the guidance may be submitted to the agency at any time, to ensure consideration by the agency, comments should be submitted by October 3, 2011.
The positions articulated by FDA in the Draft Guidance can be expected to have a significant impact on all those who manufacture or distribute dietary supplement products. The Draft Guidance must be evaluated very carefully to determine the effects it may have on your company. Even those companies that previously submitted NDI notifications that were filed without comment should evaluate whether the use of the NDI is consistent with the four corners of the notification, including the dietary supplement formulation as stated in the original submission.
Please note that the Draft Guidance is a fairly long document, and we did not rehash every issue in this client alert. Rather, the purpose of this client alert is to point out nuances that may have an impact on your company. However, we are happy to discuss with you other issues that are not explicitly discussed below.
By way of background, the federal Food, Drug, and Cosmetic Act (“FDCA”) defines a “new dietary ingredient” as a dietary ingredient that was not marketed in the U.S. prior to October 15, 1994.1 The statute defines a “dietary ingredient” as a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination” of any of the above.2
Importantly, the FDCA requires manufacturers or distributors of an NDI or dietary supplement that contains an NDI to submit a premarket notification to FDA at least 75 days before introducing the supplement into interstate commerce, unless the NDI and any other dietary ingredients in the supplement “have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”3
When an NDI notification is required, it must include a history of use or other evidence of safety for the ingredient. Based on that information, FDA determines whether it will file the notification with no questions asked, respond to the submitter with questions, or refuse to file the notification at all. However, until now, FDA has provided little guidance as to (1) what it considers “present in the food supply” to mean or (2) what type and quantity of evidence is sufficient to demonstrate safety such that the agency will permit the notification to be filed.
B. Important Takeaways from the Draft Guidance
The Draft Guidance contains the following important information:
• Definition of “Marketing.” The Draft Guidance provides a definition of what the agency considers “marketing” for the purposes of establishing that a dietary ingredient was marketed in the U.S. prior to October 15, 1994 (i.e., is a “grandfathered dietary ingredient”). In particular, the agency defines “marketing” as “selling or offering the dietary ingredient for sale (1) as a dietary supplement, (2) in bulk as a dietary ingredient for use in dietary supplements, or (3) as an ingredient in a blend or formulation of dietary ingredients for use in dietary supplements.” The agency clarified that a dietary ingredient may be “marketed” by physically offering the article for sale at retail store, offering it for sale in a catalog or price list, or through advertising or other promotion, if the promotion makes it clear it is available for purchase. “Coming soon” advertisements do not qualify as marketing.
• Evidence of Marketing. The Draft Guidance also clarifies what type of documentation the agency would expect in order to demonstrate that a dietary ingredient was marketed in the U.S. prior to October 15, 1994 (i.e., was a grandfathered dietary ingredient). Specifically, the agency indicates that it expects “written business records, promotional materials, or press reports with a contemporaneous date prior to October 15, 1994.” The agency lists the following as examples of adequate evidence of marketing: sales records, manufacturing records, commercial invoices, magazine advertisements, mail order catalogues, or sales brochures. Consistent with the agency’s response to the pyridoxamine citizen petition in 2009,4 the Draft Guidance states that affidavits that are
unsupported by contemporaneously-created written records are not adequate to show that an ingredient was marketed prior to October 15, 1994.
o Industry Lists of “Grandfathered” Dietary Ingredients. Consistent with the agency’s previously-articulated position, the fact that an ingredient appears on one of the industry-complied lists of dietary ingredients that were marketed prior to October 15, 1994 (i.e., lists of “grandfathered” dietary ingredients) is insufficient evidence that an ingredient is not an NDI.
• Changes in Manufacturing Processes
. In the Draft Guidance, the agency states that even for a dietary ingredient that was marketed prior to October 15, 1994, if changes in the manufacturing process since that time have altered the chemical composition or structure of the ingredient, an NDI notification is likely required. The agency gives the following examples of changes to manufacturing processes that would necessitate an NDI notification: (1) an extract of a grandfathered dietary ingredient that is prepared using a solvent (because the final extract contains only a fractionated subset of the constituent substances in the original grandfathered dietary ingredient), (2) using a different part of the plant, or (3) a change producing nano-sized particles5.
• Use in Food
. An NDI notification need not be submitted for NDIs that have been present in the food supply as articles used for food, in a form in which the foods have not been chemically altered.
o FDA interprets “food supply” as including the world food supply, not just that of the U.S.
o The Draft Guidance details what the agency views as chemical
alteration of an article previously used for food, which would trigger the notification requirement:
• Dehydration, lyophilization, milling, and formation of a tincture of solution in water, a slurry, a powder, or a solid in suspension do not chemically alter an ingredient.
• Any process that makes or breaks chemical bonds is considered chemical alteration. For example:
1. Hydrolysis or esterification, unless the bonds created by the process are reversed when the ingredient is dissolved in water or during ingestion;
2. Removal of some of the components of a tincture or solution in water;
3. Use of solvents other than water or aqueous ethanol to make an extract;
4. High-temperature baking or cooking of a previously uncooked ingredient;
5. Changing the manufacturing method such that the
chemical composition is significantly different (see above);
6. Changing agricultural or fermentation techniques to alter the chemical composition;
7. Fermentation using a different fermentation medium from
the one used to make conventional foods in the food supply;
8. Use of a botanical ingredient that is at a different life
stage than previously used, such as making an extract from
unripe rather than ripe apples.
• NDI Submission is Supplement-Specific, Not Ingredient Specific. Each NDI notification must contain information about the dietary supplement in which the new dietary ingredient will be used, including dosage and recommended uses, as well as other ingredients that will be included in the supplement. Because FDA relies on this supplement-specific information in making its determination about ingredient safety, the agency views each NDI submission as supplement-specific, rather than ingredient- specific. This is extremely important because the agency will require a new NDI notification for each specific formulation for which you use the NDI unless you meet all of the following requirements:
(1) The daily intake level recommended or suggested in the labeling of the
new supplement will be equal to or less than that specified in your prior NDI notification;
(2) The new supplement does not have other dietary ingredients that were not
included in or original NDI notification;
(3) The target populations are the same or a subset of the target populations
specified in your original notification;
(4) All other conditions of use are the same as or more restrictive than the
conditions of use described in your prior NDI notification; and
(5) FDA did not express safety or other concerns in response to your prior
O Evaluation of Dietary Ingredients Other Than the NDI. Because the agency will be evaluating the safety of the dietary supplement as a whole, FDA will require that the notification include the No-Observed-Adverse-Effect Level (“NOAEL”) and Acceptable Daily Intake (“ADI”) for each dietary ingredient, describe the toxicity data or adverse events that were the basis for determining the NOAEL, state the basis for the margin of safety for each ingredient, and discuss whether there is any possible synergy or interaction among any or all ingredients that could affect the safety of the dietary supplement. The notification must concisely evaluate known safety concerns and describe how the notifier concluded that the combination of ingredients can reasonably be expected to be safe.
o Evaluation of Non-Dietary Ingredients. Because the agency will be evaluating the safety of the dietary supplement as a whole, FDA will require that the notification include a description of the function of each ingredient that is not a dietary ingredient (i.e., each food additive, color additive, and substance that is Generally Recognized As Safe (“GRAS”)), including the technical effect and the quantity needed to achieve that technical effect. FDA also recommends inclusion of references to the applicable food additive, color additive, or GRAS determination.
• Synthetic and Semi-Synthetic Versions of Extracts or Herbs are Not Dietary Ingredients. The Draft Guidance states that synthetic or semi-synthetic versions of substances that are found in botanicals do not qualify as a “botanical” (or extract or constituent thereof) within the definition of a dietary ingredient found in 21 U.S.C. § 321(ff)(1). According to FDA, for example, use of a large amount of a strong oxidizing acid like sulfuric acid to process a botanical mixture may create a new “semi-synthetic” mixture that is no longer a mixture of components that were present in the original plant, and the mixture is no longer a dietary ingredient. This position is consistent with the agency’s recent response to a citizen petition from OVOS Natural Health, Inc. requesting permission to use homotaurine as a dietary ingredient in dietary supplements.6 In that response, FDA indicated that, although homotaurine occurs naturally in some plants, OVOS’s homotaurine was not a botanical (or extract thereof) because it was made synthetically (i.e., it was not extracted from any botanical).
• Definition of “Amino Acid.” The Draft Guidance defines an amino acid as “an alpha- amino carboxylic acid used as a constituent of proteins or peptides.” This is important for what it does not include. Importantly, based on this definition, if a substance is neither an alpha-amino carboxylic acid nor a constituent of proteins or peptides, then it is not an amino acid within the definition of a dietary ingredient and cannot be included in a dietary supplement unless it falls under one of the other categories of substances that qualify as dietary ingredients under 21 U.S.C. 321(ff)(1). This narrow interpretation of the definition of an “amino acid” likely excludes GABA (gamma- amino butyric acid), an ingredient that many dietary supplement companies use in their products. This position is also consistent with the FDA’s recent decision on the OVOS citizen petition.7
• Probiotics. The Draft Guidance states that while certain microbial ingredients may be new dietary ingredients subject to the NDI notification requirement, others may not be dietary ingredients at all. Specifically, the agency is unlikely to view microorganisms that have never been consumed as food as dietary ingredients. This is because probiotics are generally not vitamins; minerals; herbs or other botanicals; amino acids;
6 FDA/CFSAN Response to OVOS Natural Health, Inc.- Petition Denial, Docket ID: FDA-2009-P-0298 (Feb. 23, 2011).
or concentrates, metabolites, constituents, extracts, or combinations thereof. Thus, the only way that a probiotic can meet the definition of a dietary ingredient is if it is a dietary substance for use by man to supplement the diet by increasing the total dietary intake.
FDA has interpreted that to mean that the ingredient was an intentional constituent of food. Thus, bacteria that are used to produce fermented foods and are eaten without cooking or pasteurization may meet the definition of a dietary ingredient. However, others may not be dietary ingredients. The Draft Guidance also provides information on the content of notifications for ingredients produced using fermentation.
o Pathogens. FDA indicated that it does not view pathogenic species of bacteria as dietary ingredients--even though they may have been present in food as contaminants. In addition, the NDI notification for any microbial NDI should identify any human pathogens that are phylogenetically related to the microbial NDI at the species or genus level and should identify any toxins known to be present in the same species or in a phylogenetically related family or genus. The NDI notification should also document the absence (or the amount, if present) of such toxins in the NDI.
o Antimicrobial Resistance. The agency has indicated that if a microbial NDI is resistant to any clinically-relevant antibiotics, the NDI notification should also include an assessment of the ability of the antibiotic resistance genes to mobilize and transfer to human pathogens under the conditions of use of the dietary supplement.
o Pigs as Animal Model for Digestive Tract. If history of use data are inadequate to support the safety of a microbial NDI, studies in humans or animal models should be included. FDA states that it considers pigs to be the most appropriate animal model for the human digestive tract.
• Ester Ingredients. The Draft Guidance indicates that the safety of an ester ingredient in an NDI notification can be inferred if you can provide data to demonstrate that the ingredient is rapidly hydrolyzed in the stomach or intestine into an acid and an alcohol, and that the acid and alcohol each have a long history of safe use in food.
• Comprehensive Safety Profile and Safety Narrative. The Draft Guidance describes two new sections that should be included in every NDI notification: the Comprehensive Safety Profile and the Safety Narrative. The Comprehensive Safety Profile should provide objective summaries of all available human and animal toxicological information and should substantiate the safe use of the NDI in humans under the proposed conditions of use described in the notification. The Safety Narrative should include a concise summary of the scientific basis for your conclusion that the dietary supplement containing the NDI will reasonably be expected to be safe when used under the conditions recommended or suggested in the supplement’s labeling. It should explain how the various pieces of data and information fit together to form the basis for
your conclusions about the safety of the dietary supplement. The Draft Guidance provides detailed information as to what the agency expects in these two sections.
• Thorough Description of Types of Evidence The Agency Will Likely Require. The Draft Guidance provides a thorough description of the types of evidence that the agency will likely expect depending on the intended frequency and duration of use of the supplement, the intended intake levels, and whether the NDI has a documented history of safe use. Table 2 sets out the information in chart form.
o Twenty-Five-Year Minimum for History of Safe Use. The agency specified that it considers 25 years of widespread use to be the minimum required to establish a history of safe use (without additional safety data).
o One-Year Or Two-Year Studies Likely Required If No History of Safe Use. If there is no history of safe use for an NDI, and if the proposed use is either intermittent or daily chronic, among many other requirements, the agency has indicated that it expects either a one-year chronic toxicity study or a two-year carcinogenesis study in at least two animal species.
o Human Studies May Be Required. The Draft Guidance acknowledges that human studies are not explicitly required by statute, but at the same time states that there may be circumstances in which it is required to conclude that an ingredient is reasonably expected to be safe under the proposed conditions of use.
o Highest Dose To Be Used in Animal and Human Safety Studies. Highest dose in animal studies should be the maximum tolerated dose (“MTD”), which is the dose that causes no more than a 10% reduction in body weight and does not produce mortality, clinical signs of toxicity, or pathologic lesions. Typically this is determined by a 14-day range-finding oral study in an appropriate animal model. The highest dose in human studies should be governed by safety considerations, but should be as high as feasible and at least as high as the total daily intake level of the NDI under conditions of use proposed in the notification—preferably higher. The Draft Guidance references several sources of testing protocols.
• Flow Chart for Determining When to Submit an NDI Notification. The agency has provided a flow chart for companies to use in determining whether to submit an NDI notification. The flow chart can be found at Appendix A to the Draft Guidance.
• New NDI Notification Form. The agency has provided a new NDI notification form that may be used but is not mandatory. The form can be found at Appendix B to the Draft Guidance.
C. Next Steps
We urge all companies that manufacture or private label distribute dietary supplement products to engage in a thorough evaluation of each of their products to (1) confirm that all ingredients in the product qualify as dietary ingredients and (2) determine whether an NDI notification is necessary for that product. Even those companies that previously submitted NDI notifications that were filed without comment should evaluate whether the use of the NDI is consistent with the four corners of the notification, including the dietary supplement formulation as stated in the original submission.
1 21 U.S.C. § 350b(c).
2 21 U.S.C. § 321(ff)(1).
3 21 U.S.C. § 350b(a)(1).
4 Letter from Michael A. Chappell, Acting Associate Commissioner for
Regulatory Affairs, to Kathleen M. Sanzo, Esq., January 12, 2009, at 12
(FDA Docket No. 2005-P-0259).
5 FDA notes the lack of safety evidence regarding nanomaterials in
dietary supplements and recommends that notifiers contact FDA prior to
submitting a NDI notification for an NDI that involves the application