FDA today released its long-awaited revised new dietary ingredient (NDI) draft guidance with two major changes the dietary supplement industry will likely hail as good news.
FDA today released its long-awaited revised new dietary ingredient (NDI) draft guidance with two major changes the dietary supplement industry will likely hail as good news. On these two points, FDA and the industry seem to have found middle ground.
FDA will open its two-month public comment period on the draft guidance tomorrow after the guidance is published in the Federal Register. The new draft guidance is a revision of FDA's July 2011 NDI draft guidance.
No Longer NDI Notifications for Every Finished Product
Industry will be relieved to find FDA has dropped its earlier suggestion that companies submit separate NDI notifications for every single finished product on the market containing an NDI ingredient. This provision in the original July 2011 version of the draft guidance sparked huge objections from the industry, with some calling it tantamount to unprecedented-and potentially unlawful-premarket product approval.
In the new draft guidance, FDA said it would instead allow a company to create a single NDI notification (an “NDI master file”) that would cover a wide range of product formulations. The notifier would need to list a range of dosages for the NDI, as well as possible combinations of the NDI with other ingredients, that would still be reasonably expected to be safe.
In addition, the notification would need to list other parameters, including potential daily intake levels, serving sizes, duration of use, frequency of intake, target population, and dosage forms that would still render a product containing the NDI to be reasonably expected to be safe. Companies would only need to submit a new NDI notification if their use of the NDI ingredient fell outside of the original notification’s specifications.
Companies may not be able to anticipate today every future ingredient dose and ingredient combination for an NDI ingredient and may, sometime down the road, need to submit a new notification to account for new uses. Still, this master-file option would drastically reduce the number of NDI notifications industry would need to submit and reduce the cost of submitting multiple NDI notifications.
As is the case today, it's largely expected that ingredient suppliers will be the ones submitting NDI notifications for their ingredients. An ingredient supplier could submit one NDI notification spanning multiple uses for its branded ingredient, for instance, and all companies and distributors using that exact ingredient thereafter could rely on the supplier's master file, as long as their use of the ingredient fell within the notification’s usage parameters.
The supplements industry will no doubt find this master-file proposal a happy compromise.
“I think this absolutely is a place where FDA is trying to move to common ground. They certainly heard our concerns from the marketplace side that what was in the first guidance was not workable,” said Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN; Washington, DC) in an interview with Nutritional Outlook today, noting that his association had proposed the master-file concept over many meetings with FDA.
The solution may not please everyone, but Mister said, “I think it is absolutely a middle ground that the industry should learn to live with."
He elaborated: “Because on the one hand, it protects FDA; they’re concerned about the safety of ingredients, and they want to be sure that if one company comes up with an ingredient and then somebody else comes along with a copycat and says mine is the same, they want some assurance that it is in fact made the same way and has the same safety profile. But from the industry standpoint, we want our finished-product folks to be able to rely on their ingredient supplier. And if the ingredient supplier goes and does all of this work, we want the people who buy from that vendor to be able to rely on [the supplier's NDI notification], as long as they’re buying [that same NDI ingredient] from that vendor.”
“It’s a balancing act,” he said.
FDA's requirements may also help level the playing field between two companies producing similar ingredients. The new draft guidance says that if a company has submitted an NDI notification for its ingredient, another ingredient supplier making what it claims to be a similar ingredient would still need to submit its own NDI notification to prove that its version of the ingredient is safe. There is one exception, however: if a distributor sells a supplier’s ingredient, and the supplier has already submitted an NDI notification for the ingredient, the distributor would not need to submit a duplicative NDI notification.
“If somebody else pops up and says, ‘Oh, I have a me-too, I’m made the same way, buy from me, and I’m cheaper, that company is still going to be required to do a full NDI and show that, yes, in fact they are making it in the same way and that it is as safe as the other ingredient,” Mister said. “And that’s as it should be. But for companies who are buying from the innovator who filed the first ingredient notification, they ought to be able to rely on that, and this appears to be letting them do that.”
For firms worried about submitting NDI data that contains trade secrets, FDA has retained its provision that data marked confidential in an NDI docket will remain confidential. “It should be noted that the original notifier is under no obligation to share with other manufacturers and distributors any trade secrets or confidential commercial information that were part of the basis for a safety conclusion for the original notifier’s product,” the new draft guidance states.
No Longer Holding Supplements to Redbook Safety Standards
FDA has also moved away from requiring NDI ingredients to abide by the stringent Redbook premarket-approval food-safety standard. In its original July 2011 draft guidance, the agency referred specifically to the Redbook and its safety standard of “reasonable certainty of no harm.” But those references are largely absent from the new text.
Industry pushed back forcefully on the Redbook language, underlining that the NDI standard Congress approved under the Dietary Supplement Health and Education Act of 1994 (DSHEA) is the lower-tier “reasonably expected to be safe” standard.
“That’s something we pushed for very much in our comments [to FDA] five years ago,” Mister said, adding that the food-additive standard is “a much higher standard because it was created for synthetic, manufactured food chemicals and food colorings and preservatives where people were creating completely new chemical entities and putting them in foods to make them look better or last longer.”
“We are very pleased to see FDA backing away from references to the Redbook and backing away from that standard, which was not the standard for dietary ingredients,” he said.
Lots More to Dissect
Aside from these two welcome revisions, there's a lot more to unpack from the agency's 100-page new draft guidance. Here are some other takeaways gleaned from a first read-some that industry will not find so welcome. Nutritional Outlook will continue its analysis on these and other draft guidance issues in the weeks to come.
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In the new draft guidance, FDA says it still will not recognize any third-party lists denoting grandfathered ingredients that don’t require an NDI notification.
“Some trade associations and other industry groups have compiled lists of ‘old dietary ingredients,’ though FDA is unable to verify the accuracy of these lists because we have not seen documentation showing that the ingredients on such lists were marketed as dietary ingredients prior to October 15, 1994,” the guidance states.
Instead, FDA says it is “prepared” to create its own “authoritative list of pre-DSHEA ingredients.” To create this list, it says, it would need industry to help provide marketing records and other documentation to prove that ingredients were on the market in dietary supplements in the U.S. prior to October 15, 1994.
Which modern-day manufacturing processes will render an ingredient “chemically altered” and thus require NDI notification? On first glance, the new draft guidance continues to adhere to the DSHEA text that “‘chemically altered’ does not include the following physical modifications: minor loss of volatile components, dehydration, lyoph[i]lization, milling, tincture or solution in water, slurry, a powder, or solid in suspension.”
The new guidance says the following processes, many of which are commonly used in the dietary supplements industry today, are examples that “FDA would likely consider to involve chemical alteration”: hydrolysis, chromatography, distillation, filtration, use of solvents other than water or aqueous ethanol, supercritical fluid extraction, high-temperature baking or cooking not used pre-DSHEA, nanotechnology, “fermentation conditions [that] alter the chemical or molecular composition or structure of the ingredient,” and use of a botanical ingredient at a different life stage than used pre-DSHEA.
Synthetic Botanical Ingredients
The guidance says that synthetic herbal/botanical ingredients are still not considered dietary ingredients. “I’m not surprised by the agency’s position here,” CRN’s Mister said. “We did push back on them, that we felt like synthetic ingredients could be dietary ingredients if they could be shown to be identical. FDA has referenced this provision in a number of warning letters over the last five years, so we have seen evidence that they are not backing down on that. So seeing it in the guidance is not a big surprise.”
However, he said, FDA may be offering some flexibility here. “They are showing at least some willingness to work with industry by signaling that even if it can’t be a botanical or an herbal, it might be able to be a dietary ingredient under one of the other prongs of the statute.” The guidance states: “Because the ‘dietary substance’ category is defined in part by history of use, a synthetic copy of a botanical ingredient may qualify as a dietary ingredient under section 201(ff)(1)(E) if the synthetic copy has been used as a lawfully marketed ingredient in the conventional food supply.” The guidance points to examples of vanillin and cinnamic acid as two botanical derivatives made synthetically as food flavorings that fall in this category.
Companies argued that the original July 2011 draft guidance was vague when it came to probiotics, only stating that “Not all bacterial microorganisms are dietary ingredients, and a microorganism that is not a dietary ingredient cannot be an NDI…” The new draft guidance repeats this language, without much more elaboration provided in the original guidance.
Investigational New Drugs
FDA maintains its position that ingredients that were the subject of an investigational new drug (IND) application before they entered the supplements market are not considered dietary ingredients because they were studied as drugs first. The new draft guidance says the same-even if an IND was withdrawn at some point in time.
Like the original draft guidance, the revised draft guidance states that ingredients with Generally Recognized as Safe (GRAS) status do not require NDI notifications, as long as the ingredient has not been subject to further chemical alteration.
More Clarity Is Good
CRN’s Mister said he was still reading the fine print of the new draft guidance. But he did provide one takeaway:
“I think just having the guidance out is a win for the industry. It’s taken us four years since [FDA] promised to give us a new draft, and I think the fact that we have it at all is going to do a lot towards giving more transparency and more certainty in the industry. It gives the industry a clear roadmap as to what FDA expects.”
“Even if we don’t always agree with everything that FDA says, it’s a big victory just to know what the agency’s interpretation is, with clarity. And I think we’re getting that today.”
Nutritional Outlook will bring you much more coverage the new draft guidance in the coming weeks. In the meantime, be sure to read Nutritional Outlook’s February 2012 article, “Rough Draft: Dietary Supplement Industry Arguments Against FDA's NDI Draft Guidance,” to review the industry’s biggest problems with the original July 2011 draft guidance.
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