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 toward full implementation of the Dietary Supplement Health and Education Act of 1994 (DSHEA) in bits and pieces, one of the most significant recent developments is the agency’s attention to the new dietary ingredient (NDI) component of the law.

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

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

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

The New York Times and Sen. Richard Durbin’s assertions to the contrary, prior to DSHEA, FDA regulated dietary supplements as foods to ensure they were safe and wholesome, and that their labeling was truthful and not misleading. FDA evaluated new ingredients for safety under the 1958 Food Additive Amendments to the Federal Food, Drug, and Cosmetic Act (FD&C Act).

With the passage of DSHEA, Congress amended the FD&C Act to include several provisions that apply specifically to dietary supplements and their ingredients. Nutritional ingredients in dietary supplements are not subject to the same pre-market safety evaluations required of other new food ingredients, or for new uses of old food ingredients. However, other new ingredient 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. “Old dietary ingredients,” those marketed prior to the passing of DHSEA, are grandfathered in and safety data on them does not have to be gathered and submitted to FDA. Many of them, particularly herbs, are GRAS (generally recognized as safe) for use as a food, and have a history of safe usage.

A dietary supplement that contains a dietary ingredient not marketed for dietary supplement use in the United States prior to that point may be designated adulterated if FDA determines there is inadequate information to provide reasonable assurance that the ingredient will not present a significant or unreasonable risk of illness or injury. This happened in March 2004 when FDA declared products containing androstenedione adulterated.

Ingredient manufacturers are required to notify FDA at least 75 days before marketing products containing NDIs and provide the agency with the information on which the company has based its conclusion that a dietary supplement containing the NDI “will reasonably be expected to be safe”. No one did this for andro, conveniently eliminating a product that had become by that time a political hot potato in the steroid controversy.

Generally the burden of filing an NDI application falls upon the ingredient supplier, because NDI applications focus on dietary ingredients, not finished products. “Manufacturers using the ingredient of a raw material supplier who received an NDI are afforded the same status of ‘no comment at this time’, which is FDAstyle acceptance, for the ingredient,” said Chris Noonan, MPH, an industry consultant.

Companies that have submitted NDIs note the process is critical. “We were fortunate that we had a lot of science, lots of toxicity data and pharmacokinetic information,” said Dan Murray, associate director of nutrition at Lonza Inc., which submitted an NDI notification for zinc carnosine (which it supplies as PepZin GI™) in the summer of 2002. “We worked with consultants Anthony Almada and Patrick Noonan of IMAGINutrition, and the application was successful. Supplement manufacturers are more comfortable when they know their ingredient supplier has completed the NDI process.”

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

Chrysantis Inc. also worked with IMAGINutrition to ensure its NDI application was complete and submitted correctly. The company received word that its application for natural zeaxanthin was accepted in June 2005. “We started our NDI submission 18 months ago,” said Manuel Pavon, general manager at Chrysantis, supplier of EZ Eyes™ zeaxanthin.“We had to provide enough evidence to prove the safety of zeaxanthin in general and zeaxanthin coming from marigolds specifically. Fortunately, there is a lot of science that has been done about zeaxanthin’s potential to prevent AMD and its safety when sourced from fruits and vegetables.We also had to also prove that the other carotenoids in 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 the evidence very closely.”

Not all ingredient manufacturers file NDI applications for new, even patented, ingredients. “We have never submitted a NDI application for any of our products,” said one well-known ingredient supplier. “We were looking to do so about a year ago, but were advised by a consulting group that had successfully put several NDIs through FDA that with no definitive criteria on what kinds of information, and in what format, we would be best served to sit on the sidelines until this tightened up a bit. However, we were looking at one of our products that had been on the market for over five years. I don’t think they had a reasonable feel for the possible outcome in a situation like this. Their reason for this advice was due to the lack of clarity of protocols in the NDI submission process. Until things become a little more clear, we will probably go with the status quo on products we have been selling.”

The status quo may be changing—if slowly. “FDA is currently in the process of developing clearer guidance on NDIs that hopefully will make the notification process more transparent and predictable,” said Farah Ahmed, an attorney with Collier Shannon Scott and a former FDA staffer. “In the interim, I certainly understand a company’s trepidation in submitting an NDI notification, especially given the increased number 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 consider the requirements for filing an NDI notification to be confusing does not negate that the notice is legally required,” he said. “Any dietary supplement that contains an NDI that has not complied with the regulations is adulterated as a matter of law. If a company cannot prove its dietary ingredient is ‘old’ and therefore ‘grandfathered’ under DSHEA, or is present in the food supply as the actual article used for food that has not been chemically altered, then it is 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 the ingredient were to cause harm, lack of compliance would be persuasive evidence in a product liability lawsuit.”

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

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

AHPA’s position is that, in the case of an unprocessed herb or botanical, a single complete NDI notification is sufficient, “and that there should be no requirement for any other distributor of exactly the same botanical ... to submit a separate notification.” By “unprocessed,” AHPA describes botanical ingredients that have had only minimal post-harvest processing, limited to cleaning, dehydration and milling for size reduction.

However, semi-purified extracts of botanicals that are NDIs are produced by using unique proprietary processes and may result in significantly different end products even if made from the same herbal ingredient. “The information that serves as a basis for a conclusion that data and information establishing that one semipurified extract of a new herb will reasonably be expected to be safe may not be relevant to another,” said Michael McGuffin, president of AHPA. “Each manufacturer of such extracts should submit an NDI notification with the requisite safety information.”

Tony Young, partner with Kleinfeld, Kaplan & Becker and general counsel for AHPA, explained the reasoning. “The concept is that if I bring 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 Young’s Sunflower Extract and you make Shelton’s Sunflower Extract using different methods, the extracts are different from each other and from basic ground up sunflower petals. They warrant their own NDIs.”

Chris Noonan noted FDA’s concern is that companies are relying on other NDIs to “prove” their ingredients are safe, when there is no real basis for that expectation. “One person’s manufacturing and extraction procedures may yield different actives, different constituents, making the ingredient biologically different,” he said.

Sid Hulse, vice president of marketing and sales with Valensa International, a branded ingredient company, also agreed with AHPA’s assessment. “Absolutely, suppliers should have to have an NDI for each new process,” he said. “A raw material and an extract are not the same thing. Apple seeds are just lovely. Apple seed extracts become cyanide.” Valensa filed an NDI in early 2005 on the company’s ZANTHIN® astaxanthin oleoresin extract. Previously, the company filed and received approval on the E.U. (European Union) equivalent, a novel food ingredient application. FDA had ‘no objection’ to Valensa’s NDI application, which is the agency’s way of accepting NDI applications.

Still, Hulse is concerned about suppliers not supporting and adhering 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 received NDI objections from FDA,” he said.

Some manufacturers claim they have GRAS status on their new ingredients, and that status negates the NDI notification requirement. Young disagrees. “GRAS status is for food use,” he said. “GRAS status for dietary ingredients does not really exist whether you are an old dietary ingredient or an NDI. It is a carryover from pre-DSHEA days when all products were 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 an ingredient can be added to food. And how can a new product be GRAS? If it hasn’t been around very long, how can it have achieved general recognition?”

INSIDER contacted an FDA official to ask whether GRAS status ever replaces an NDI application, and the response was straightforward—“No. GRAS substances are food additives used for specific reasons at specific dosages,” the official said. “You can include in your product substances that are GRAS, provided you are using them under the same conditions of use for which GRAS determination was made.” He also explained that 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 an NDI. “GRAS assessments are always made for certain conditions of use; it doesn’t mean you can use it any way you want,” he said.

With the existing NDI process not working as well as it needs to and continued confusion existing over how GRAS interacts with NDIs, FDA’s addressing this issue is welcome in most quarters. However, industry trade associations such as AHPA and the National Nutritional Foods Association (NNFA) are working hard to make sure the resulting guidance isn’t a Trojan horse.

“We’ve cautioned FDA that the NDI section of DSHEA should not be used as a tool to begin tinkering with the definition of a dietary supplement, said David Seckman, executive director and CEO of NNFA. “This is clearly not what Congress intended.”

One critical area that NNFA has asked FDA to clarify is how the agency determines whether an ingredient has been “chemically altered” and thus requires an NDI filing. “DSHEA offers only a small bit of clarification on what is meant by the term ‘chemically altered’ and lists just 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 and FDA has not offered industry guidance as to how to determine whether a process would or would not be considered ‘chemical alteration.’”

NNFA has taken the position that a dietary ingredient should meet the “not chemically altered” exemption as long as 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 formulation always result in a change in the chemical structure that would require a NDI filing. “If FDA were to make NDI notification mandatory after any change to a grandfathered ingredient, it would be inundated with notifications,” Seckman said. “This would hardly help the agency meet its goal when it comes to NDIs, which is to ensure their safety.”

At FDA’s November, 2004, public hearing, the agency noted a number of NDI submissions had omissions that included failure on the part of the submitter to adequately describe the identity and composition of the NDI, provide information that stated the basis for a conclusion that the substance is an 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 (47 percent), because the submissions were incomplete or not required, the substance was not actually a dietary supplement, or the data submitted did not convince FDA of the product’s safety.

AHPA and NPIcenter are now collaborating on a database for accessing all of the notifications FDA has received for NDIs. The AHPA NDI Database will be searchable by numerous relevant fields, and will provide concise “outcome statements” so that users can quickly see FDA’s response to every notification, and the problems, if any, that the agency identified for each. Since DSHEA passed in 1994, FDA has posted more than 280 NDI notifications on its dockets Web site. The AHPA NDI Database will be maintained on an ongoing basis so that future NDI filings and FDA responses will be promptly added to the system. Although the launch date has not yet been finalized, this will be a helpful tool.

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

Unfortunately, it may take a while. FDA received more than 50,000 comments on the NDI issue; around 16,000 can be viewed electronically through the agency’s Web portal (www.fda.gov), while all are available for viewing in the FDA’s Rockville, Md., office. An FDA official said the agency is actively reviewing comments and considering options. “We hope to make a decision on how to proceed in the near future,” he said. “In a few months we are coming out with program priorities documents that say what FDA will be working on for fiscal year 2006. If we are proceeding with an NDI guidance document that will be indicated in that document.”

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