FDA likely will not issue warnings before taking judicial actions against firms that fail to comply with the new dietary ingredient notification regulation once the agency publishes a long-awaited guidance.

Judicial actions include seizures, injunctions, inspections, search warrants, prosecution and civil penalties, according to FDA's website.

"Once there is a guidance then there is a lot of low hanging fruit for us to go out and pick" to enforce the NDI notification requirement, said Robert Moore, Regulations Implementation Team supervisor with the Office of Nutrition, Labeling and Dietary Supplements in FDA's Center for Food Safety and Applied Nutrition.

At the Drug Information Association's 46 annual meeting in Washington June 15, Moore said enforcement likely "will be judicial actions from square one," and "won't be preceded by warning letters."

Moore explained that NDI notification enforcement will be "much easier" because the guidance will clarify "unresolved issues that make enforcement more difficult," and it will ensure "everyone will be on the same page of the playbook."

He noted FDA enforcement will target "high profile examples" of products that were introduced without submitting NDI notifications. "FDA takes enforcement action ... to induce voluntary compliance on the part of regulated industry, and you get more bang for your buck the bigger and more prominent the examples," Moore explained.

Council for Responsible Nutrition executive Andrew Shao noted FDA has faced criticism for not effectively enforcing the NDI notification requirement.

The lack of enforcement may explain why few firms comply with the requirement to notify the agency at least 75 days before marketing a product containing an NDI, the trade group's senior VP of scientific and regulatory affairs said in an interview. "If companies think there is no penalty or consequence for not filing a notification, they will simply ignore that provision," Shao said.

Moore recognized the guidance is long overdue, and "in a perfect world" expects the agency will publish it by the end of 2010, "assuming no other food poisonings take away reviewers."

FDA Principal Deputy Commissioner Josh Sharfstein, at a recent Senate hearing on supplement safety, also estimated the guidance would be published by year's end (¹ Also see "Harkin, Hatch Reload In Hunt For Full DSHEA Funding, Implementation" - Pink Sheet, 31 May, 2010.).

Industry stakeholders understandably may be skeptical of FDA meeting its goal given the repeated delays in completing the guidance, partly due to food safety outbreaks that demanded immediate attention, such as salmonella in peanut butter.

Once published, however, the guidance will be a "stake in the ground ... that sets forth the basis for" FDA's enforcement, Shao said.

He added that Moore's "hint" at how the agency will enforce NDI notification ought to put the industry on notice that "FDA will come and really scrutinize the status of ingredients."

"Some companies will stick their heads in the sand as they have for the last 16 years and hope that FDA will continue to not enforce things and allow them to fly under the radar screen, and I don't think that is acceptable and it is not transparent," Shao said.

"Hopefully the agency will put its money where its mouth is and do something in the cases where clearly a company should file a notification."

FDA Will Not Wait To Enforce

While a guidance will facilitate more enforcement, the absence of a guidance does not create a safe harbor, Moore said. Nor does it "excuse firms that probably know they have an NDI for which a notification is required" from submitting the information to FDA, he added.

"Even in the absence of a guidance, we would take legal action" if FDA found an NDI marketed without a notification on file, and if the agency was "pretty confident we could establish a violation of the law," Moore said.

For example, at U.S. ports the agency already routinely detains and refuses entry to imported ingredients that inspectors suspect are new or novel that do not have a notification on file.

Moore reminded firms port inspectors have a relatively low burden of proof to justify detaining a shipment. They do not need a preponderance of evidence - rather, they can block entry if the shipment simply appears to violate regulations.

Products that contain an ingredient an inspector does not recognize or cannot pronounce is a common flag that prompts FDA to hold a shipment and check the NDI database for a notification.

Shao said the agency routinely monitors the Internet for companies advertising new products or making illegal drug claims ² Also see "For Ingredient Suppliers, GMP Compliance Means Surviving And Thriving" - Pink Sheet, 11 May, 2009.).

But if firms have documentation that their ingredient is grandfathered, is exempt from the NDI requirement or is the subject of a notification filed with FDA, "it will save them a lot of headaches," Moore said.

An NDI does not need a notification on file if it was used as a food before becoming a dietary ingredient and the food was not chemically altered.

Ingredients lawfully marketed in the U.S. prior to the passage of the Dietary Supplement Health and Education Act of 1994 also are exempt from the notification requirement.

Other Issues On FDA's List

Another issue on FDA's "regulatory list right now because of fairly systemic and ongoing violations" is failure to assess supplement safety in light of new uses, Moore said. "Even if you qualify for the exceptions for the notification, you still have to establish" a product is safe and does not pose unreasonable risk, he said.

Verifying the safety of a new ingredient or supplement "shouldn't be rocket science, but simply saying it has been used for 1,000 years probably isn't an adequate due diligence evaluation," he said.

Another common and unacceptable reason firms cite about why they presume a product is safe is a lack of adverse event reports as evidence of safety.

Moore said firms must evaluate relevant safety endpoints including the relevance of the historical use to the current target population and reason for current use and potential drug interactions.

The other two top supplement-related issues on FDA's regulatory list are pesticide residues and undeclared drug ingredients, Moore said.

"We have issued hundreds of warning letters and recalls for dietary supplements and botanicals that contain undeclared" active pharmaceutical ingredients, said Moore.

Most supplement recalls occur after FDA determines products contain undeclared steroid ingredients or weight-loss and erectile dysfunction APIs (³ Also see "FDA Plans To Step Up Enforcement Actions On Supplement Rx Contaminants" - Pink Sheet, 15 October, 2007.).

While the agency dedicates "a lot of our enforcement" to undeclared APIs, "there are additional resources on the import side" to identify and block the sale of products with pesticide residues, Moore said.

He explained the Environmental Protection Agency established tolerated levels of "approved pesticides in a regulated commodity," but if a product exceeds those levels or contains pesticides for which EPA has not established a tolerance level, FDA will consider the supplement adulterated.

"For the most part, there are no tolerances that were established for botanical ingredients that are typically used in dietary supplements," he said.

A recent Government Accountability Office investigation found trace amounts of at least one potentially hazardous contaminant in 37 of 40 herbal products tested, though none reached levels high enough to pose a toxicity hazard. GAO also pointed out FDA and EPA do not consider trace amounts of the substances in the products a health risk (⁴ Also see "Senate Supplement Hearing Spotlights Self-Regulation, FDA Enforcement" - Pink Sheet, 31 May, 2010.).

Moore also cautioned that some foreign countries tolerate higher levels of pesticides, but "that acceptance does not extend to the U.S. marketplace."

In particular, he warned, the violation rate approaches 40 percent for excessive pesticide levels in Asian and South American botanicals. "It is important that people focus on that," Moore said.

- Elizabeth Crawford ( ⁵ e.crawford@elsevier.com )

FDA Will Enforce NDI Notification Requirement Without Warning

More from Archive

More from Pink Sheet