FDA tentatively aims this year to complete its guidance for new dietary ingredient notifications, which industry research shows are largely failing to pass the agency's scrutiny.

Center for Food Safety and Applied Nutrition executive Bill Frankos said during a recent online seminar that he "would like to target" issuing a guidance in 2009.

However, Frankos, director of CFSAN's Division of Dietary Supplement Programs, added he "just can't say what the priorities will be" under the Obama administration and he declined to definitively commit to that schedule.

Discussion during the Dec. 10 seminar demonstrated the need for NDI guidance, as industry experts noted that supplement firms have not understood FDA expectations for notifications.

Frankos said a March 2008 call for industry input on the NDI pre-market notification process has yielded "very useful information" for drafting a guidance (¹ Also see "Request For NDI Input May Portend Much Anticipated Guidance – Industry" - Pink Sheet, 31 March, 2008., p. 6).

He also blamed "competing priorities" for delaying the guidance, which has become a fixture on CFSAN's regulatory agenda and was once slated for completion in fiscal 2008 (² Also see "NDI Notification Failures Concern FDA; Complete Submissions Urged" - Pink Sheet, 15 October, 2007., p. 8).

Council for Responsible Nutrition VP of Scientific and Regulatory Affairs Andrew Shao, who participated in the seminar, said in an e-mail that the guidance has had numerous false starts and he is "hopeful, but not optimistic, that we will see the guidance this year."

Submission Impossible?

Debbie Trinker, VP of regulatory and legal affairs for nutritional ingredient firm Kemin Health, said her analysis of FDA docket data shows the annual number of NDI submissions increased from around 20 in the late 1990s to 72 in 2006 and 60 in 2007.

In the early years of the NDI program, FDA "acknowledged" every submission even if the agency objected to it, she said.

The agency now acknowledges only those NDI notifications to which it does not object, in lieu of an "approval" process.

Trinker said the data show a drop in FDA's acknowledgement rate for first-time NDI submissions from 65 percent in 1998 to 11.4 percent in 2005 to 2.4 percent in 2007. Those rates discount notifications made for combinations of previously acknowledged dietary ingredients, she said during the seminar.

NDI submissions have become more sophisticated over the years, evolving from early notifications that were "just literature stapled together," Trinker added in an interview.

She said the acknowledgment rate has dropped over the years not simply because the process has changed, but also because FDA has stepped up scrutiny of the submissions.

Dan Levy, acting supervisor for CFSAN's NDI review team, commented during the seminar that NDI submissions are more complete than they once were.

"We are beginning to see detailed manufacturing schemes, detailed specifications" in NDI notifications, Levy said. "That's enormously helpful to us in figuring out the identity of the ingredient."

He advised sharing as much information as possible with FDA about how an ingredient is made. All proprietary information will be redacted before the submission is made public.

Shao said the agency's insufficient resources could be causing low acknowledgement rates for NDI submissions, but praised its recent "renewed commitment to improve the process by hiring new review staff and appointing a new NDI [notification] team leader."

CFSAN says the NDI program serves as a gatekeeper by requiring companies to prove the safety of any ingredient not in the food supply before the passage of the Dietary Supplement Health and Education Act in October 1994 (³ Also see "FDA Analyzing Lead Levels In Multivitamins, Concerned About NDIs" - Pink Sheet, 12 May, 2008., p. 12).

DSHEA added a provision to the Food, Drug and Cosmetic Act that requires manufacturers and distributors to notify the agency at least 75 days before introducing a supplement with an NDI.

No NDI Is An Island

Frankos and Levy clarified that an NDI notification should address an ingredient's intended use, similar to certifying a substance as generally recognized as safe and effective.

"You can't review an ingredient without putting it into the context of the supplement" in which it will be used, Frankos explained.

He added notifiers have "a burden to address the effect of interaction" between an NDI and other ingredients in a supplement - even those ingredients with an established safety profile.

During the seminar, food and drug attorney Claudia Lewis-Eng said FDA officials' comments on how the agency evaluated NDI notifications revealed something industry did not know.

Supplement firms have "been focusing solely for a very long time on the ingredient itself and not the overall safety profile of the supplement in which it is supposed to be applied," Lewis-Eng observed.

Lewis-Eng, a partner in the Washington office of Venable LLP, said in an interview that she has not seen FDA enforcing the stance on NDI evaluation described by Frankos and Levy.

Keys To Success

George Burdock, president of Orlando, Fla.-based Burdock Group consultants, offered suggestions for successful NDI submissions during the seminar, which was organized by the Council for Responsible Nutrition and Virgo Publishing.

Notifications should be "as visual as possible" with charts and tables demonstrating an ingredient's safety, he said.

He also advised avoiding mention of an ingredient's benefit, which FDA could potentially view as a drug claim.

- Dan Schiff (d.schiff@elsevier.com)

NDI Notification Guidance To Assist Puzzled Industry Could Emerge In 2009

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