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Questions still remain about how practical master files will be in practice.
The dietary supplement industry’s first new dietary ingredient (NDI) master-file notification has now been submitted to FDA. Scientific and regulatory consulting firm AIBMR Life Sciences (Seattle, WA) told Nutritional Outlook it submitted the notification on behalf of a client in early September.
A concept newly introduced in FDA’s revised NDI draft guidance released on August 11, the NDI master-file provision lets multiple firms operate under the umbrella of a single NDI notification (NDIN). John Endres, ND, AIBMR’s chief science officer, said that when his company submitted its master-file notification, FDA “had no standard operating procedures” for submitting a master file. “I think they’re trying to work it out,” he added.
Industry leaders largely support the idea of a master file because it should ease the total number of NDINs industry firms will need to submit. In addition, the new draft guidance gives firms the option of “piggybacking” off of another company’s NDI data in order to build its own NDIN, as long as it has written permission from the original NDIN submitter to do so.
As convenient as these provisions sound, there are still times when taking advantage of them may not be as easy as it seems, and even times when it may not be the right thing to do.
Master Files in Practice
While the majority of the dietary supplements industry has voiced support for the master-file concept, stating that this option will ease the number of NDI notifications companies are required to submit, questions still remain about how practical master files will be in practice.
FDA’s guidance states that if a dietary supplement manufacturer’s product contains the exact same ingredient that is covered by an existing master-file NDIN (same ingredient identity, manufactured in the same way) and uses the ingredient under the same dosage, ingredient-combination, and conditions described as safe in the original notification, the manufacturer does not need to submit its own NDIN and can go about using the ingredient in its product legally.
But is it really possible for, say, an ingredient supplier to anticipate the needs-ingredient combinations, ingredient dosages-of all of its current and potential future manufacturer clients when creating its master file? That remains to be seen.
The creator of a master file will likely want the notification to be as broadly applicable as possible when listing safe usage parameters and ingredient combinations. “We think that FDA should clearly state and in fact encourage companies to submit notifications for the ingredient that broadly describe the conditions of use to the degree that the information that is the basis for the submitter’s conclusion of reasonable expectation of safety can be applied broadly,” said Michael McGuffin, president of the American Herbal Products Association (AHPA), in an August interview with Nutritional Outlook. “The thing that’s logical is if the ingredient company comes into the marketplace with a new ingredient, and they want to sell it to 30, 60, dozens of different brands, one of their valuable properties should become their NDI notification. Then they can go to all of the brands and say, ‘I've got you covered because I've got my NDI notification that I wrote broadly.’”
When it comes to describing ingredient identity, however, a company will want to be very specific, said Dan Fabricant, CEO of the Natural Products Association. “You know the agency," he said. "The first thing they look at is the identity. So if that identity, or identities, aren’t clearly defined, you’re going to have some trouble.”
But Fabricant also advised companies to get specific when describing usage parameters. “[Be] very specific, incredibly specific, in [terms of] the amount [of the ingredient] that’s going to be used and in [terms of] the combinations [with other ingredients],” he said.
AIBMR’s Endres said that creating a master file that will work for a large number of companies is “definitely doable.” However, he conceded there is no established path forward given that this is the first time industry will be submitting master files.
Fabricant said the ease or difficulty of creating a broad master file would be determined on a “case-by-case basis.”
“I see some scenarios where it’s very easy, and I see some scenarios where you probably can’t do it,” he said. “It really depends. If it’s just one ingredient that’s being combined with an excipient, or being combined with alphabet vitamins, that’s pretty easy. If it’s an NDI combined with other NDIs, that’s a bit tricky.”
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When asked whether ingredient suppliers are likely to start investing in studies on more ingredient combinations in order to broaden notifications, Fabricant said that depends on the individual situation as well. “In some cases, they’re going to have to, and in other cases, they’re not going to have to. I mean, if you’re going to combine an NDI with something like vitamin C…there’s probably not a lot limiting…the amount of vitamin C there. Once there’s a safety signal, you’ve satisfied that question. I think people need to be reasonable. [But] if you’re combining something with caffeine or an ingredient that may be used as a stimulant or things like that, then you’re going to have to be very, very specific with your safety data.”
When Does Piggybacking NOT Make Business Sense?
Firms also have the option of piggybacking off of another supplier's existing NDIN. In this case, a company still submits its own notification, only the notification may borrow or cite some data that's already been submitted to FDA as part of another company's NDIN. For instance: if an ingredient supplier's NDI master file doesn't meet all of a product manufacturer's needs-say the ingredient combinations the master file describes exclude some ingredients in the manufacturer's product-then the manufacturer can submit its own NDIN but still include or cite some of the ingredient supplier's data on the supplier's own particular NDI ingredient. This way, the manufacturer is able to account for its use of the NDI ingredient within its specific product formula, without having to perform additional safety studies that an ingredient supplier has already performed on an NDI ingredient. FDA's draft guidance makes clear that companies may only borrow data if they have express written permission from the original notifier to do so.
Initially, this piggybacking option may seem very convenient, especially for product manufacturers. If an ingredient supplier lets a product manufacturer piggyback, “then [the manufacturer] can do a very abbreviated sort of NDI notification electronically based on the master file, as long as the master file received an ‘acknowledgment of no objection’ letter,” AIBMR’s Endres says.
But all companies need to be careful about whom they choose to piggyback off of and, likewise, who they allow to do the piggybacking. During an August Natural Products Association NDI webcast covered earlier by Nutritional Outlook, Kevin Bell, an intellectual property attorney and managing partner at Porzio, Brombery, and Newman, pointed out that a company could end up sharing information with someone who may one day become a competitor.
Plus, he pointed out, piggybacking can make the world of intellectual property more complex in other ways. Here’s one: in a supplement industry grown increasingly litigious around ingredient patents, companies should keep in mind that although FDA allows the master-file holder to redact confidential data when sharing master-file information with other firms, that confidential data could still become public if the two firms sharing NDI data become embroiled in an IP battle one day. Courts may require the NDI data be shared as evidence, Bell said.
He concluded, “I don’t see a true benefit in piggybacking off of someone else’s NDI, certainly not if it risks your IP position.”
Master Files Are Valuable Property
Now that the first master file has been submitted to FDA, more will certainly follow. Most parties still deem the master-file provision a win for the industry. “We think this has a lot of merit and should be looked at with favor,” said Loren Israelsen, president of the United Natural Products Alliance, during a UNPA NDI webcast in August.
“This is an industry where so much of the research is done at the ingredient level, not at the finished-product level,” Steve Mister, president and CEO of the Council for Responsible Nutrition, told Nutritional Outlook. “And I can really see finished-product companies using this piggyback ability so that they don’t have to create new research. It’s really beneficial to them because it means they don’t have to start from scratch."
Also, he said, "It’s really beneficial to the ingredient supplier that does the work because then they’re assured that there will be some reward for doing the research. Companies will have to buy from them.”
In fact, master-file owners can benefit in another way, too-by selling their NDIN information to other companies. This is happening already, said NPA’s Fabricant. “They certainly could-licensing the NDINs. There are companies that do that already. They basically license the ability to use it,” he said.
Master files will therefore become a company’s valued property, he said. “It could be part of their trade dress,” he said. And in the climate of mergers and acquisitions, “it certainly would be viewed as an asset.”
Note: This article was updated on September 27.
Nutritional Outlook magazine