Plus: Will FDA now step up its game of NDI enforcement?
Wondering whether you need to submit a new dietary ingredient (NDI) notification now that FDA finally issued its revised NDI draft guidance last week? If in doubt, it’s better to be safe than sorry, said speakers at yesterday’s Natural Products Association (NPA; Washington, DC) “emergency” NDI webcast.
“I think that companies should submit notifications,” said Ashish Talati, a member of law firm Amin Talati & Upadhye. “There’s just no reason not to.”
“If you’re dealing with an ingredient that’s new to the market and that hasn’t been in the diet before, what’s your basis for not submitting?” said Daniel Fabricant, PhD, NPA’s executive director and CEO. “You always have to think about it from both sides, the basis for submitting and basis for not submitting. I think more folks need to do that and analyze their risk.”
“I think the risk is going to be higher than the reward in not doing so,” said Kevin Bell, managing partner of law firm Porzio, Bromberg & Newman.
Why You Might Want Your Own Notification
Unlike the draft guidance’s original July 2011 version, the revised August 2016 draft guidance allows multiple firms to benefit from a single NDI notification, or what FDA refers to as an “NDI master file.” This set-up is convenient in the case of a distributor/ supplier relationship in which the distributor is selling a supplier’s ingredient that already has its own NDI notification on file.
Still, there may be good reason a firm may want to submit its own notification-for instance, to avoid future conflicts with competitors. While piggybacking off of another supplier’s NDI notification may sound appealing, a firm may want to avoid this, said Bell.
The guidance says that if a company creating an NDI notification would like to base its notification in part on non-public information contained in another company’s NDI notification, the firm may do so as long as the ingredient is the same, the original NDI notification covers the same conditions of use as the new notification, and the borrower has obtained written consent to use the other firm’s NDI data.
But what if the two companies one day become competitors? “I think it’s important for companies to look at how they should act vis-Ã -vis their competitors, whether they’re the first mover to get the NDI or whether they’re the one that wants to consider piggybacking,” said Bell. “I think a lot of times the answer may be to make competitors submit their own NDI. You certainly don’t want to give them access. Somebody who might not be a competitor today may be a competitor tomorrow or next year. So you really need to make conscious decisions when opening things up to allow someone to do that. And I think from a competitive standpoint, from a strategic standpoint, you probably don’t want to do this.”
Plus, if a company already has its own safety and quality data in house, “you really ought to look at submitting,” said Fabricant. “If there’s any question of whether or not it’s an NDI and you have safety data and you didn’t submit it, then why?”
“You have to err on the side of caution,” he continued. Despite the cost burden of creating a NDI notification, the fact of the matter is that failing to do so “is a technical adulteration,” he added. “It’s a box you sometimes have to check.”
The Process and the Cost
Putting together a solid NDI notification isn’t inexpensive, of course. During the NPA webcast, NPA’s senior vice president of scientific and regulatory affairs, Corey Hilmas, MD, PhD, noted that based on NPA’s conversations with its members and industry consultants, a toxicology study alone could cost $178,000–$328,000. Add to that approximately $162,500 in consultant fees, plus other costs, and it’s clear why creating NDI submissions is a big deal, especially to small-sized nutraceutical firms.
“It’s not cheap at all to submit an NDI,” Hilmas said. NPA’s public comments on the draft guidance, once submitted to FDA, will include calls to “have FDA do a thorough economic cost burden for filing these submissions," he said.
Once a company submits a notification to FDA, the agency will respond in one of four ways: 1) an acknowledgement letter, 2) an “inadequate” letter stating that FDA has some questions regarding minor details, 3) an “incomplete” letter, or 4) a “not a dietary ingredient” letter. If a firm receives an acknowledgement letter, and even if it receives an “inadequate” letter, a company is in the clear and can consider its NDI successfully submitted. If it receives either of the latter two letters, then the NDI is not submitted and the firm must resubmit or take other action.
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Firms receiving an “inadequate” letter but who really want the full acknowledgment letter can always choose to resubmit data to FDA. Fabricant, who previously served as Director of FDA’s Division of Dietary Supplement Programs, and Hilmas, who was Chief of the FDA Dietary Supplement Regulation Implementation Branch, both stressed that firms can benefit from maintaining open dialogue with FDA throughout the process in order to draw a clear bead on what information the agency is looking for.
Examining five years’ worth of NDI submission data, Hilmas estimated that of 61 acknowledgment letters FDA sent during that five-year period (ending in 2014), only two were achieved without the company having talked to FDA; the others were sent to companies that had communicated with the agency. Of companies that received an “inadequate letter,” Hilmas said that 27% of companies chose to resubmit and, of those, nearly half who maintained open dialogue with the agency went on to get acknowledgment letters.
“Certainly sticking with it and engaging the agency and maybe doing some additional safety studies seems to work to get to an [acknowledgment letter],” Fabricant said. And, he pointed out, if a company received an “inadequate” letter, meaning FDA only has minor questions remaining, “you do meet the regulatory burden, so at that point, it’s a lot easier to engage the agency.”
The key, Fabricant stressed, is to submit your notification in the first place if one is needed. “It’s critical. By notifying the agency, consistent with 21 CFR 190.6, the burden really is on FDA to demonstrate the product is unsafe” thereafter, he said. “If you notify the agency, and unless you receive an incomplete letter in response that your data wasn’t complete to 21 CFR 190.6 and that you didn’t in fact meet the burden for filing, you’ve effectively notified the agency.”
“Without notifying the agency,” however, Fabricant said “it’s a technical adulteration for failing to submit a NDI notification and providing appropriate safety data. I don’t think anyone who’s a responsible corporate citizen is going to want to have that as how they’re viewed out there in the sphere.”
“If your company even thinks you should file, this should push you in the right direction,” he said.
Will FDA Enforce NDIs More Heavily?
Although FDA draft guidance is not binding by law, it provides a solid map to how FDA may go about enforcing NDI provisions in the future. Now that the agency has laid forth its current thinking, will it aggressively go after companies not meeting their NDI burdens?
NPA webcast speaker Cara Welch, PhD, senior advisor at FDA’s Office of Dietary Supplements, repeated what FDA has said in the past-that the agency believes there may be a high percentage of companies in the market who have not submitted notifications when they should have.
“We believe, more anecdotally than anything, that more notifications should have been submitted over the last 20 years than actually have been submitted, and so it’s important to us to ensure that industry is aware of our expectations of when notifications should be submitted,” she said.
“Once finalized, the guidance will set the stage for future actions for those that are not complying with the requirements,” Welch added.
Fabricant said firms should also consider product categories already on FDA’s enforcement radar as areas ripe for NDI enforcement as well.
“If you look at past history, look at where the focus has been,” Fabricant said. “There’s been a lot [of attention] on sports nutrition. There’s been a lot on weight loss. Those are the areas where there tends to be kind of an interest in pushing the line somewhat with newer molecules, so I think people in those areas just need to be careful in terms of what they bring to market.”
Will FDA also have more resources to fund broad-scale enforcement now that the dietary supplements division is a full-blown office within the agency? That remains to be seen, Fabricant said, adding that NPA also plans to inquire about this.
“In terms of the agency priorities and funding, now that the agency is an Office and the strategic plan has since expired-this is 2016-when will we see a new strategic plan from the agency on dietary supplements, and what will be the plan for enforcement of NDIs and statutory authority there? I think everyone wants to see the agency enforce the NDI provisions in full and really pick those items out that shouldn’t be out on the market as dietary supplements or dietary ingredients.”
The agency seems to feel the same. “The NDI notification process is very important to the FDA. The notification process is FDA’s only premarket opportunity to review products, to review the formulation and the safety of products, and we take that seriously,” Welch said.
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