In May, the Natural Products Association submitted a letter requesting a public hearing on the FDA’s new draft guidance announcing that the agency is considering what amounts to a clemency period for unregistered dietary supplements, before a later crackdown. Last week, the FDA replied, declining to schedule the meeting.
Regulatory Background: Dietary supplements and New Dietary Ingredients
- The FDA defines dietary ingredients as a “a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of the preceding substances.”
- A dietary supplement is a product “intended to supplement the diet” that contains a dietary ingredient and meets additional qualifications. Dietary supplements are meant to be ingested (rather than injected or inhaled), but must not be “represented for use as a conventional food or as a sole item of a meal or the diet” and should be labeled accordingly. Uncommonly, dietary supplements may also include drug products that were marketed as a dietary supplement prior to being approved as a drug.
- How FDA regulates dietary supplements and ingredients: In 1994 the Dietary Supplement Health and Education Act (DSHEA) gave the FDA authority to regulate finished dietary supplement products and dietary ingredients. Under DSHEA, manufacturers are responsible for ensuring their products are safe and any claims made are substantiated with evidence. Sponsors of dietary supplements may only make claims that their products affect the structure or function of the body and may not make any claim that a supplement is effective at treating or preventing a specific disease. These products do not need approval prior to being marketed – unless they contain a new dietary ingredient (provided they meet other requirements).
- Sponsors of a New Dietary Ingredient (NDI) – defined as a dietary ingredient not marketed before October 15, 1994 – or a dietary supplement containing an NDI are required to submit what is known as a Premarket Safety Notification to the FDA at least 75 days prior to marketing the product. These applications are more commonly referred to as New Dietary Ingredient Notifications, or NDINs. The application must contain information including the amount of the NDI present in a dietary supplement, the proposed conditions of use, evidence to establish the safety of the product (such as evidence regarding a product’s history of use) and proof of a product’s identity.
- In the 75 days between submitting information and marketing, the FDA’s Office of Dietary Supplement Programs (ODSP) will review the information provided in the premarket safety notification (also called new dietary ingredient notifications, or NDINs). The agency will then respond to the sponsor of the NDIN with either of two responses: an acknowledgement letter accepting the notification, or a letter stating that the NDI cannot be used in dietary supplements at this time because of problems with the NDIN in its current form.
- Letters denying NDIs typically cite one of three problems: the evidence provided in the NDIN did not adequately show that the NDI could “reasonably be expected to be safe” under the conditions listed; the NDI in question did not meet the statutory definition of a dietary supplement or ingredient; or the NDIN was incomplete.
- The FDA receives relatively few NDIs each year. According to AgencyIQ’s research from 2021, the agency received between 29 and 96 NDINs per year since 2002, although it typically received between 40 and 50.
- The FDA rejects most of the NDINs it receives, based on AgencyIQ’s research. Of the 231 NDIN letters we analyzed, just 80 received an acknowledgment letter, or a letter where the FDA did not contest the NDI and permitted it to be marketed. This means that 65.4% of all NDIs submitted to the agency during this time period (2017-2021) were denied. In the 151 NDIN denials, the FDA raised concerns about evidence of product safety in 54 and noted legal or regulatory issues that precluded marketing in another 103. Six letters expressed concerns about both safety and legal or regulatory problems.
- But the FDA is perhaps more concerned about the NDIs it’s not aware of. As has long been known to regulators and policymakers, the FDA does not hold dietary supplement manufacturers to the same registration and listing requirements as pharmaceutical manufacturers. As a result, the FDA knows relatively little about the full extent of marketed dietary supplement products available on the market.
- In other words, if a dietary supplement manufacturer doesn’t tell the FDA that its product contains an NDI, the FDA won’t know otherwise unless the product is the subject of enforcement actions or safety concerns. These concerns have prompted some legislators to introduce reforms as part of the Senate’s user fee reauthorization process that would require mandatory listing.
In a draft guidance issued in May, the FDA indicated that it’s prepared to step up its enforcement of NDIs
- In a new draft guidance for industry, Policy regarding certain New Dietary Ingredients and Dietary Supplements Subject to the Requirement for Pre-market Notification, the FDA says it is “aware that some manufacturers and distributors have marketed products for which a premarket NDI notification under section 413(a)(2) of the FD&C Act was required, but never submitted.” According to the FDA’s estimates, there are approximately 3,400 products for which an NDI should have been submitted but has not been.
- FDA’s implied threat to companies that have not yet submitted an NDIN but need to: Act fast or get ready for regulatory enforcement. “To increase the amount of safety information we have about NDI-containing dietary supplements in the marketplace and to promote risk-based regulation, we are informing manufacturers, distributors, and other interested persons of our intent to exercise enforcement discretion, for a limited time and in limited circumstances, to encourage firms to correct past failures to submit an NDI notification.”
- According to the agency, companies will have 180 days from the time the final version – not the draft version – of the guidance is published to submit their NDIN as well as any “other information recommended” in the guidance. Since the products will have been marketed (unlike a traditional NDI product), FDA is asking companies to provide the FDA with information supporting a determination that the product is “reasonably expected to be safe,” including “any evidence related to the history of your product’s use since it has been on the market, including any customer complaints and adverse events (whether serious or non-serious) associated with the product.” This process could add to the company’s regulatory burden if higher-quality safety data are required, since firms may not have those readily at hand.
- This approach – amnesty, effectively – is also intended to draw some well-meaning companies out of the shadows and into the light, according to the draft guidance. “A number of firms have told us informally that they realize they should have previously submitted notifications and have the information ready to be submitted, but they are afraid of drawing attention to themselves with a late submission,” FDA wrote. [Read AgencyIQ’s full analysis of the draft guidance, including questions of FDA capacity, and potential industry response, here.]
Now the FDA has declined a trade association’s call for a public hearing on the draft guidance.
- On July 11, 2022 the FDA released its response to a letter sent by the Natural Products Association (NPA), which represents some dietary supplement manufacturers.
- The NPA’s letter, sent to FDA’s Office of Dietary Supplement Programs on May 24, requested a public hearing under 21CFR Title 21 for clarification of the agency’s “position on new dietary ingredient notification guidance.” The NPA letter characterizes the provisions of the new draft guidance as a “sudden change of policy” that conflicts with precedent, including the requirement under DSHEA for submission of a premarket safety notification to the agency at least 75 days before placing the product into interstate commerce.
- In declining to schedule the hearing requested by NPA, the FDA pointed to the discretion afforded the agency by 21 CFR Part 15. “Unless the Federal Food, Drug, and Cosmetic Act or FDA regulations specifically provide for a hearing on a particular matter, which is not the case here, the decision whether to grant a hearing is entrusted to the Commissioner’s discretion,” wrote the agency in replying to NPA.
- Comments are due by July 19 on the draft guidance, and the FDA’s letter to NPA noted that the public comment period for the draft “provides an opportunity for the public, including your organization, to submit information and views that the FDA will consider before beginning work on any final guidance.” Concluded the agency, “FDA will evaluate the issues, data, and other information that are raised in the comments to the draft guidance and, after considering those comments, decide what our next step(s) should be.”
Industry is also voicing longstanding concerns about imported products riding the coattails of U.S. NDINs
- Separately, a law firm that represents natural products manufacturers submitted comments in support of the NPA letter. The comment from Ullman, Shapiro & Ullman, LLP, also calls into question the FDA’s intended enforcement discretion: “We question the purpose and legal basis for FDA to announce that it will simply not enforce a portion of the FDCA designed to ensure that NDls do not pose a threat to the public health,” wrote the firm, asking why the FDA is now proposing a period of enforcement discretion.
- The law firm’s comment characterizes the draft guidance as “an exercise of regulatory legerdemain designed to distract from FDA’s abject failure to enforce the law as it relates to NDINs and instead focus blame on the dietary supplement industry.” Some of Ullman, Shapiro & Ullman’s clients presented the FDA with evidence of knock-off ingredients being imported by firms who introduce these ingredients after other supplement manufacturers – such as the law firm’s clients – have done the work of “submitting a fulsome NDIN,” according to the comment.
- Also according to the comment, the FDA “declined to take any action” after being “provided with information documenting the identity of the entities importing” the knockoff ingredients, whose biochemical analysis sometimes indicated the presence of formaldehyde or unknown ingredients, or E. coli bacteria. The comment also contains a critique of the FDA’s intent to create a Mandatory Product List that would require all dietary supplements sold in the U.S.
- The NPA included an attachment to its comment: a letter from the FDA declining to investigate an imported supplement as adulterated. The letter gives some insight into the complexity of communication between the natural products industry and the agency around NDI issues. In the April 2021 letter, addressed to the law firm Arnall Golden Gregory LLP, the FDA declined to take enforcement action against companies importing generic beta-alanine that the firm alleged was adulterated because it was not the subject of the NDIN for beta-alanine previously submitted by Natural Alternatives International, Inc.
- In its response, the FDA cited the “threshold matter” of whether imported beta-alanine is a new dietary ingredient and requires submission of an NDIN. “Importantly, to meet this burden, FDA would need to demonstrate that beta-alanine is not present in the food supply as an article used for food in a form in which the food has not been chemically altered.”
- Beta-alanine may be present in the food supply in energy drinks, noted the agency, which would raise the possibility of its being exempted from NDIN requirements. Though the FDA “has not reached a definitive conclusion as to whether beta-alanine would be excepted from the NDI notification process on the grounds that it is present in the food supply as an article used for food in a form in which the food has not been chemically altered,” the possibility exists, leaving “significant questions that would need to be answered before FDA would be in a position to demonstrate that certain imported beta-alanine appears to be adulterated.”
- The letter followed a March 2021 teleconference that involved an attorney from the firm, the NPA’s Daniel Fabricant, and several FDA representatives. According to a footnote in the FDA’s response letter, FDA attendees included representatives from the Office of the Center Director for CFSAN, ODSP, and the FDA’s Office of the Chief Counsel.
- The comment period is scheduled to close on July 19. AgencyIQ will monitor the docket to see whether the comment period is extended, and whether other members of industry weigh in.
Featuring prior research from Alec Gaffney and former AgencyIQ analyst Lily Rosenfield.
To contact the author of this analysis, please contact Kari Oakes ( [email protected]).
To contact the editor of this analysis, please contact Alec Gaffney ([email protected])
Key Documents and Dates
- Comment from Natural Products Association
- Response Letter from FDA OC to Natural Products Association
- Comment from Ullman, Shapiro & Ullman, LLP
- Draft Guidance for Industry: Policy Regarding Certain New Dietary Ingredients and Dietary Supplements Subject to the Requirement for Pre-market Notification