NDI Does Not Stand for Numbing, Difficult and Impenetrable

NDI Does Not Stand for Numbing, Difficult and Impenetrable

by Suzanne Shelton

As the Food and Drug Administration (FDA) inches towardfull implementation of the Dietary Supplement Health and Education Act of 1994(DSHEA) in bits and pieces, one of the most significant recent developments isthe agencys attention to the new dietary ingredient (NDI) component of thelaw.

A year ago, FDA published Regulatory Strategy for theFurther Implementation and Enforcement of the Dietary Supplement Health andEducation Act of 1994, which addresses three components: safety, quality and labeling.

In the document, FDA expressed concern that there wereproducts on the market not in compliance with the NDI requirements. Some products contain ingredients that were not on the marketpre- DSHEA and no NDI application was submitted. Others contain ingredients forwhich an NDI application was submitted and FDA subsequently expressed safetyconcerns, but the products are still being marketed. The agency announced plansto bring enforcement actions against marketed dietary supplements thatcontain NDIs for which required notification has not been submitted.

The agency issued a notice in the FederalRegister on Oct. 20, 2004, Dietary Supplements:Pre-market Notification for New Dietary Ingredient Notifications, that raiseda number of questions. When FDA subsequently held a public meeting and asked forcomments, industry companies and trade associations were very thorough in theirresponses in order to mitigate onerous demands. FDA is still evaluating thecomments, but the status quo regarding NDIs may be about to change.

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and Sen. RichardDurbins assertions to the contrary, prior to DSHEA, FDA regulated dietarysupplements as foods to ensure they were safe and wholesome, and that theirlabeling was truthful and not misleading. FDA evaluated new ingredients forsafety under the 1958 Food Additive Amendments to the Federal Food, Drug, andCosmetic Act (FD&C Act).

With the passage of DSHEA, Congress amended the FD&C Actto include several provisions that apply specifically to dietary supplements andtheir ingredients. Nutritional ingredients in dietary supplements are notsubject to the same pre-market safety evaluations required of other new foodingredients, or for new uses of old food ingredients. However, other newingredient safety provisions were put into place, including the NDI provision;its main purpose is to serve a safety function.

The magic date is Oct. 15, 1994, when DSHEA was passed. Olddietary ingredients, those marketed prior to the passing of DHSEA, aregrandfathered in and safety data on them does not have to be gathered andsubmitted to FDA. Many of them, particularly herbs, are GRAS (generallyrecognized as safe) for use as a food, and have a history of safe usage.

A dietary supplement that contains a dietary ingredient notmarketed for dietary supplement use in the UnitedStates prior to that point may be designated adulterated if FDA determines thereis inadequate information to provide reasonable assurance that the ingredientwill not present a significant or unreasonable risk of illness or injury. This happened in March 2004 when FDA declared productscontaining androstenedione adulterated.

Ingredient manufacturers are required to notify FDA at least75 days before marketing products containing NDIs and provide the agency withthe information on which the company has based its conclusion that a dietarysupplement containing the NDI will reasonably be expected to be safe. Noone did this for andro, conveniently eliminating a product that had become bythat time a political hot potato in the steroid controversy.

Generally the burden of filing an NDI application falls uponthe ingredient supplier, because NDI applications focus on dietary ingredients,not finished products. Manufacturers using the ingredient of a raw materialsupplier who received an NDI are afforded the same status of no comment atthis time, which is FDAstyle acceptance, for the ingredient, said ChrisNoonan, MPH, an industry consultant.

Companies that have submitted NDIs note the process iscritical. We were fortunate that we had a lot of science, lots oftoxicity data and pharmacokinetic information, said Dan Murray, associatedirector of nutrition at Lonza Inc., which submitted an NDI notification forzinc carnosine (which it supplies as PepZin GI) in the summer of 2002. Weworked with consultants Anthony Almada and Patrick Noonan of IMAGINutrition, andthe application was successful. Supplement manufacturers are more comfortable when they knowtheir ingredient supplier has completed the NDI process.

A bonus to being in compliance with the law is that when aningredient is also protected by a patent, the NDI application is further proofof the uniqueness of the ingredient and can help a company protect itsintellectual property (IP). We can use the NDI to support any IP lawsuits wehave, because the NDI supports the assertion that our molecule is unique, andhas never before been offered for sale, Murray said. If someone intends to copy our product, wehave the support of this history.

Chrysantis Inc. also worked with IMAGINutrition to ensure itsNDI application was complete and submitted correctly. The company received wordthat its application for natural zeaxanthin was accepted in June 2005. Westarted our NDI submission 18 months ago, said Manuel Pavon, general managerat Chrysantis, supplier of EZ Eyes zeaxanthin.We had to provide enoughevidence to prove the safety of zeaxanthin in general and zeaxanthin coming frommarigolds specifically. Fortunately, there is a lot of science that has beendone about zeaxanthins potential to prevent AMD and its safety when sourcedfrom fruits and vegetables.We also had to also prove that the other carotenoidsin the product are safe. But our NDI was accepted and approved at first shot,even though FDA has increased the rigor of the process and are looking at theevidence very closely.

Not all ingredient manufacturers file NDI applications fornew, even patented, ingredients. We have never submitted a NDI applicationfor any of our products, said one well-known ingredient supplier. We werelooking to do so about a year ago, but were advised by a consulting group that had successfully putseveral NDIs through FDA that with no definitive criteria on what kinds ofinformation, and in what format, we would be best served to sit on the sidelinesuntil this tightened up a bit. However, we were looking at one of our productsthat had been on the market for over five years. I dont think they had areasonable feel for the possible outcome in a situation like this. Their reasonfor this advice was due to the lack of clarity of protocols in the NDIsubmission process. Until things become a little more clear, we will probably gowith the status quo on products we have been selling.

The status quo may be changingif slowly. FDA iscurrently in the process of developing clearer guidance on NDIs that hopefullywill make the notification process more transparent and predictable, said Farah Ahmed, an attorney with Collier Shannon Scott and aformer FDA staffer. In the interim, I certainly understand a companystrepidation in submitting an NDI notification, especially given the increasednumber of rejections we are seeing,

Despite the trepidation, the law is still clear, said W.Patrick Noonan, another industry attorney. The fact that some may considerthe requirements for filing an NDI notification to be confusing does not negatethat the notice is legally required, he said. Any dietary supplement thatcontains an NDI that has not complied with the regulations is adulterated as amatter of law. If a company cannot prove its dietary ingredient is old andtherefore grandfathered under DSHEA, or is present in the food supply asthe actual article used for food that has not been chemically altered, then itis a new dietary ingredient. Whether it is confusing or not, this is the law.Companies that do not comply are subject to regulatory action by FDA and if theingredient were to cause harm, lack of compliance would be persuasive evidencein a product liability lawsuit.

Ahmed agreed, noting, My hope is ingredient suppliers willconsider the ramifications of not submitting. FDA has stated that it intends touse its authority under the NDI provisions of the FD&C Act to considerwhether a product currently on the market is required to, but did not, submit anNDI notification. These products would automatically be considered adulterated,regardless of their safety. One way to help avoid rejection of an NDI notification is tocommunicate effectively with FDA before and during the process. At the veryleast, this could prove very effective in preventing rejections based on smallgaps in information or technicalities.

The American Herbal Products Association (AHPA) has long beeninvolved in trying to both clarify the NDI notification process for industry andencourage FDA to provide more clarity in what it expects. The group tackled amore technical and controversial aspect of what constitutes an NDI with recentcomments to FDA on how the agency should address NDIs. These comments make adistinction between new dietary ingredients that are unprocessed and those inthe form of semi-purified extracts.

AHPAs position is that, in the case of an unprocessed herbor botanical, a single complete NDI notification is sufficient, and thatthere should be no requirement for any other distributor of exactly the samebotanical ... to submit a separate notification. By unprocessed, AHPAdescribes botanical ingredients that have had only minimal post-harvestprocessing, limited to cleaning, dehydration and milling for size reduction.

However, semi-purified extracts of botanicals that are NDIsare produced by using unique proprietary processes and may result insignificantly different end products even if made from the same herbalingredient. The information that serves as a basis for a conclusion that dataand information establishing that one semipurified extract of a new herb willreasonably be expected to be safe may not be relevant to another, saidMichael McGuffin, president of AHPA. Each manufacturer of such extractsshould submit an NDI notification with the requisite safety information.

Tony Young, partner with Kleinfeld, Kaplan & Becker andgeneral counsel for AHPA, explained the reasoning. The concept is that if Ibring you sunflower and it is just ground up petals with no special processing,just the herb, and I file an NDI on it, it should apply generically to everyone,he said. But if I make Youngs Sunflower Extract and you make SheltonsSunflower Extract using different methods, the extracts are different from eachother and from basic ground up sunflower petals. They warrant their own NDIs.

Chris Noonan noted FDAs concern is that companies arerelying on other NDIs to prove their ingredients are safe, when there isno real basis for that expectation. One persons manufacturing andextraction procedures may yield different actives, different constituents,making the ingredient biologically different, he said.

Sid Hulse, vice president of marketing and sales with ValensaInternational, a branded ingredient company, also agreed with AHPAsassessment. Absolutely, suppliers should have to have an NDI for each newprocess, he said. A raw material and an extract are not the same thing.Apple seeds are just lovely. Apple seed extracts become cyanide. Valensafiled an NDI in early 2005 on the companys ZANTHIN® astaxanthin oleoresinextract. Previously, the company filed and received approval on the E.U.(European Union) equivalent, a novel food ingredient application. FDA had noobjection to Valensas NDI application, which is the agencys way ofaccepting NDI applications.

Still, Hulse is concerned about suppliers not supporting andadhering to the requirements DSHEA and the FD&C Act set forth. What should concern us are people who are marketing,claiming they have filed their NDI application, even though they have receivedNDI objections from FDA, he said.

The GRAS Question

Some manufacturers claim they have GRAS status on their newingredients, and that status negates the NDI notification requirement. Youngdisagrees. GRAS status is for food use, he said. GRAS status fordietary ingredients does not really exist whether you are an old dietaryingredient or an NDI. It is a carryover from pre-DSHEA days when all productswere foods. A lot of herbs were on the GRAS list as flavors and spices. Today,to say an ingredient is GRAS is really, from a legal context, to say aningredient can be added to food. And how can a new productbe GRAS? If it hasnt been around very long, how can it have achieved generalrecognition?

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contacted an FDA official toask whether GRAS status ever replaces an NDI application, and the response wasstraightforwardNo. GRAS substances are food additives used for specificreasons at specific dosages, the official said. You can include in yourproduct substances that are GRAS, provided you are using them under the sameconditions of use for which GRAS determination was made. He also explainedthat even if a GRAS ingredient was the sole ingredient in a supplement product,it would constitute a different condition of use and, thus, would require anNDI. GRAS assessments are always made for certain conditions of use; it doesntmean you can use it any way you want, he said.

With the existing NDI process not working as well as it needsto and continued confusion existing over how GRAS interacts with NDIs, FDAsaddressing this issue is welcome in most quarters. However, industry trade associations such as AHPA and theNational Nutritional Foods Association (NNFA) are working hard to make sure theresulting guidance isnt a Trojan horse.

Weve cautioned FDA that the NDI section of DSHEA shouldnot be used as a tool to begin tinkering with the definition of a dietarysupplement, said David Seckman, executive director and CEO of NNFA. This isclearly not what Congress intended.

One critical area that NNFA has asked FDA to clarify ishow the agency determines whether an ingredient has been chemically alteredand thus requires an NDI filing. DSHEA offers only a small bit ofclarification on what is meant by the term chemically altered and listsjust a handful of processes that would result in modification of an ingredient,Seckman said. But it is clear many processes have been left off this list andFDA has not offered industry guidance as to how to determine whether a processwould or would not be considered chemical alteration.

NNFA has taken the position that a dietary ingredient shouldmeet the not chemically altered exemption as longas the resulting dietary ingredient is found in nature,because supplements are a subset of food and need to be regulated accordingly.It holds that FDA should not assume that changes in processing or formulationalways result in a change in the chemical structure that would require a NDIfiling. If FDA were to make NDI notification mandatory after anychange to a grandfathered ingredient, it would beinundated with notifications, Seckman said. This would hardly help the agency meet its goal when itcomes to NDIs, which is to ensure their safety.

At FDAs November, 2004, public hearing, the agency noted anumber of NDI submissions had omissions that included failure on the part of thesubmitter to adequately describe the identity and composition of the NDI,provide information that stated the basis for a conclusion that the substance isan NDI and provide adequate safety information.

According to AHPA, in the first decade since DSHEA was passed,FDA received 145 unique notices of proposed NDIs. FDA objected to 68 of them (47percent), because the submissions were incomplete or not required, the substancewas not actually a dietary supplement, or the data submitted did not convinceFDA of the products safety.

AHPA and NPIcenter are now collaborating on a database foraccessing all of the notifications FDA has received for NDIs. The AHPA NDIDatabase will be searchable by numerous relevant fields, and will provideconcise outcome statements so that users can quickly see FDAs responseto every notification, and the problems, if any, that the agency identified foreach. Since DSHEA passed in 1994, FDA has posted more than 280 NDI notificationson its dockets Web site. The AHPA NDI Database will be maintained on an ongoingbasis so that future NDI filings and FDA responses will be promptly added to thesystem. Although the launch date has not yet been finalized, this will be ahelpful tool.

Given the confusion that exists, which is both adding to FDAsworkload in screening applications that are not complete or unnecessary, as wellas resulting in some suppliers who have not gathered and submitted safety dataon new ingredients, it is not surprising that FDA is seeking clarity.

Unfortunately, it may take a while. FDA received more than50,000 comments on the NDI issue; around 16,000 can be viewed electronicallythrough the agencys Web portal (www.fda.gov), while all are available forviewing in the FDAs Rockville, Md., office. An FDA official said the agencyis actively reviewing comments and considering options. We hope to make adecision on how to proceed in the near future, he said. In a few months weare coming out with program priorities documents that say what FDA will beworking on for fiscal year 2006. If we are proceeding with an NDI guidancedocument that will be indicated in that document.

Suzanne Shelton has provided public relations services tonatural products manufacturers and associations since 1989. Her Chicagobasedcompany, The Shelton Group, can be reached at [email protected].