In the United States, probiotics remain stuck in a murky regulatory environment, one that stifles innovation and market growth, and, at the end of the day, blocks potential health benefits for the consumer.
In the United States, probiotics remain stuck in a murky regulatory environment, one that stifles innovation and market growth, and, at the end of the day, blocks potential health benefits for the consumer. On December 1 during the Natural Products Association’s (NPA; Washington, DC) The Big Natural virtual conference, a panel of regulatory experts highlighted the ongoing frustration the probiotics industry bears under the weight of an unclear roadmap.
The challenges surrounding probiotics in the dietary supplement space stem from the fact that these live microbial organisms differ from other types of dietary ingredients. “It’s a unique category,” said panelist Amy Smith, PhD, global regulatory strategy lead, probiotics and fibers, DuPont Nutrition and Biosciences (Wilmington, DE). “It’s very different from the traditional ingredient that would be used in dietary supplements and that fits nicely in with DSHEA”—DSHEA being the Dietary Supplement Health and Education Act regulating supplements in the U.S.
She continued: “The probiotic offering in itself is unique in that these are live microorganisms, and live microorganisms bring a dynamic presence where they have the ability to adapt to their environment. They will shut genes off to make and focus their energy on the genes they need to thrive in their environment. And so with that, there can be a slight change in the genetic makeup, even though the strain is the same and has not changed what it’s capable of doing or…how it’s capable of behaving.”
In FDA’s latest, revised New Dietary Ingredient (NDI) draft guidance, which provides FDA’s view on what the agency considers an NDI which would require notification to the agency, the agency reiterated its position in the original 2011 draft of the guidance, which is that microorganisms (probiotics) that have never been consumed in the food supply are unlikely to be considered a dietary ingredient at all. The guidance states that “bacteria that have never been consumed as food are unlikely to be dietary ingredients” and that “a microorganism that is not a dietary ingredient cannot be an NDI.”1
This position, however, doesn’t make sense to those in the probiotics field who have been studying probiotics for their demonstrated and wide-reaching health benefits. After all, while some probiotic strains have indeed long been present in foods and shown a history of safety—for instance, in yogurts and cheeses—not all probiotic strains that have been shown to have a health benefit originate in food.
Panelist Solange Henoud, director of global regulatory affairs, Lallemand Health Solutions (Montreal), pointed out: “We know that there are many new strains coming in, and genetically engineered strains, that have not been used in the food supply…”
Smith said: “As we all know, over time the health benefits have been discovered, and there’s been a lot of science over the past several decades, that would indicate that a healthy microbiome is key to your overall health—and this is where probiotics really come into being able to promote a wellness within our population.”
But, she asked, “What happens when we move to the microbiome side of things where we are uncovering species that have been in the gut? They’re not present in the food supply, but they’re commensals, and they provide benefit. They get in the gut somehow. So, if we are really restricted to what is currently in the food supply, that stifles innovation from a microbiome perspective and puts a damper on our wellness offering as well.”
What probiotic stakeholders like DuPont and Lallemand would like to see is a clear, practical regulatory framework for probiotics, one that is workable from the start. “We don’t want to go to market through a loophole in the regulation,” Smith emphasized.
Unfortunately, a clear regulatory path isn’t what probiotic manufacturers are dealing with now. In fact, stakeholders are often thrown into unclear waters largely stemming from uncertainty among federal agencies about how to classify probiotics. “We as a category are kind of toggled back and forth,” Smith said. “It’s almost as if it’s a hot potato of sorts.”
Which Category for Probiotics?
Currently, probiotics could fall into one of three categories, Smith explained: 1) dietary supplements (regulated by FDA’s Office of Dietary Supplement Programs, or ODSP), 2) food (regulated by FDA’s Office of Food Additive Safety, or OFAS), or 3) biologics (regulated by FDA’s Center for Biologics Evaluation and Research, or CBER).
The panelists provided an example of how probiotic manufacturers currently find themselves receiving confusing messages from the agencies. ODSP, said Smith, “has been very strict in that they expect a probiotic strain to be taken from the food supply.” If a probiotic species or strain hasn’t been shown to be present in the food supply, “ODSP will say, ‘Well, you have to put this in food,’” she said.
On the other hand, OFAS, which regulates food ingredients, has often required manufacturers to remove any mention of the term probiotic from submissions made to its office, so “that we remove any aspect of any sort of wellness benefit that would be provided,” said Smith. “And they tell us to go to ODSP.”
Meanwhile, the panelists agreed they don’t believe that probiotics should be regulated as biologics. “When FDA tells us maybe this is a biologic, that is really not the intended scope of a probiotic,” said Smith, because a biologic is meant to be given to diseased people whereas probiotic supplements are meant to support health in healthy people.
“So,” said Smith, “you can see this triangle of confusion.”
Perhaps what makes most sense, said Henoud, would be if FDA were to follow other global regulators in setting a different threshold for probiotics, one that does not rely on a food presence.
“There is room for improvement, definitely, and if we look at how probiotics are regulated in the world outside of the United States, we can see, if we consider some successful regulatory models, that there are some principles that can be easily adopted—like, a risk-based approach…” she said. A risk-based approach would mean that a substance “can be something safe for human consumption; it does not necessarily have to be isolated from food.” And if proven safe, the substance should be considered a dietary substance, she said, adding: “The most important thing is: Is it safe for human consumption? Yes or no?”
A Workable Future
Because at the end of the day, the lack of a sensible regulatory framework for probiotics will dampen innovation in the industry and ultimately limit the products that are able to reach consumers.
Said Smith: “We know that there is room within our society for this as an ingredient, and when it comes to innovation, if the strict interpretation—which I don’t believe is exactly in the spirit of DSHEA, to only pull ingredients that are presently in the food supply…there has to be some respect for the safety history of use at the species level that would allow us to be accepted as a dietary ingredient if there is a strain with a slight deviation that then can be clinically studied to demonstrate a benefit for digestive health, say, or immune health—and we put that into a supplement, even though it wasn’t isolated from food.” She continued, “But if we are only expected to take probiotics that are currently found in the food supply, that stifles innovation. That does not allow us to find something either in nature or from the gut or from the GI tract that has adapted and provides a benefit to market…This is really about establishing safe ingredients that benefit the consumer. And I think that the agency has gotten caught on some of those details and maybe a little bit of red tape that are not allowing that to be the focus.”
It’s unclear if and when FDA will ever provide a pathway that stakeholders would find helpful. “It’s unfortunate that [FDA] hasn’t offered much guidance in that space,” said panel moderator Sibyl Swift, PhD, NPA’s senior vice president, scientific and regulatory affairs. “They continue to…throw up more roadblocks than assistance and help in terms of how responsible firms can bring probiotics” to market in a feasible way.
Said Smith: “We leave pre-submission meetings [with FDA], both on the food and the dietary supplement side, without a clear understanding of what is acceptable to FDA, and have been told to really just tell them the story—and, again, deviating from the safety perspective, really being rejected for inclusion in a dietary supplement or a food because of some nuances of the interpretation of the requirements, which again is taken to be either it must be derived from food, or you cannot use the word probiotic because that would imply that there’s an automatic benefit if we grant this as safe and appropriate for use in food. So we don’t always leave those pre-submission meetings with a clear pathway or the guidance that we go to those meetings intending to gain.”
Panelist Emily Gregoire, global regulatory affairs partner, probiotics, for Chr. Hansen (Milwaukee, WI), added, “We’re like this redheaded stepchild in that we don’t know what the best path to compliance is, and we just want to know what we should do to be the most compliant and the most safe—and we look to FDA for that type of guidance.”
Panel moderator Robert Durkin, of counsel at Arnall Golden Gregory LLP (Washington, DC), and former acting director and deputy director of FDA’s Office of Dietary Supplement Programs, added, “There’s a lack of guidance and a lack of leadership, a lack of putting industry on a level playing ground when it comes to understanding how they can comply with maybe some arbitrary and capricious requirements from the agency.”
And lest we forget, the panelists pointed out, if FDA doesn’t make moves to carve out a clearer regulatory path for probiotics, individual states just might. “[T]he lack of leadership by the agency relative to probiotics [creates] a vacuum that the states are now going to step in fill, and we are going to wind up in a situation similar to CBD [hemp cannabidiol] where we have 50 different jurisdictions with 50 different sets of rules—all well-meaning, all good intentions, but slightly different enough where it really causes havoc for firms and companies trying to operate in the space,” Durkin said.
The bottom line, said Smith? “There’s room for improvement in understanding where probiotics belong, how can they be understood a little bit better, because they are so unique and they don’t fit within the dietary supplement box.”
There is also more work that needs to be done in improving consensus when it comes to strains and species, said Henoud. “If all these strains don’t present a safety concern by themselves but belong to a list of species with established safety, [they] ought not to be considered new and ought to be considered dietary substances.”
She continued: “If we can ask FDA to make peace with the past and consider that all these strains belong to this species are not new today, after 25 years of DSHEA, I think we can have a good environment, regulatorily speaking, and set the stage for all the new innovations that are coming.”