On October 20th, the Food and Drug Administration (FDA) published a broad initiative1 announcing the agency's intent to exercise its authority under the Dietary Supplement Health & Education Act (DSHEA) to monitor and evaluate the safety of dietary ingredients contained in dietary supplements. The initiative was promulgated, in part, because of FDA's concern that some dietary supplement products contain ingredients that require new dietary ingredient (NDI) notifications, but have not been submitted through the FDA 75-day premarket notification process. FDA "intends to use the authority of the NDI provisions of the act" to determine, among other things, whether products currently on the market were required to, but did not, submit the required premarket NDI notification and whether there are products currently marketed that were submitted through the NDI process, but for which FDA previously raised safety concerns. This regulatory initiative marks one of the most significant and aggressive actions on behalf of FDA in the post-DSHEA marketplace.

The legal requirements for the safety of new dietary ingredients (NDIs) have been in place since the passage of DSHEA-which amended the Federal Food Drug & Cosmetic Act (FDC Act)-to allow FDA the regulatory authority to control and ensure their safety. The NDI section of DSHEA applies to any dietary ingredient not marketed in the U.S. prior to Oct 15, 19942. Since that date, FDA has rarely exercised its enforcement discretion. This past March, however, this inactivity ended when FDA challenged the marketing of dietary supplement products containing the ingredient androstenedione ("andro") for failing to undergo the NDI notification process (despite the arguments by certain marketers that andro exists in commonly consumed foods). This enforcement action under the NDI provisions of the FDC Act coupled with the new regulatory initiatives for dietary supplements published in October may be an indication that the perceived sleeping regulatory dragon has now awoken from its dormancy.

As part of its challenge to andro marketers, FDA sent warning letters to 23 companies prohibiting the continued marketing and sale of any dietary supplement product containing andro, under the regulatory position that it was an unsafe dietary ingredient. Based on the authority provided under DSHEA3, FDA declared that it was unaware of any evidence that the dietary ingredient an­dro­stenedione was "lawfully marketed" in the U.S. on or before Oct 15, 1994, and as such, is subject to the premarket notification requirement for NDIs (emphasis added). Because no company marketing a product containing andro had submitted the required premarket notification, all similar products were considered adulterated.

The significance of the word "lawfully" before "marketed" cannot be understated. The regulation for NDIs in Section 8 of DSHEA reads "a dietary ingredient that was not marketed in the United States before Oct 15, 19944." By inserting the word "lawfully" before "marketed" FDA implies that not only does a company have to prove with written evidence the marketing of the actual ingredient prior to October 1994, but also that the ingredient itself was either considered generally recognized as safe (GRAS) or was subject to an approved food additive petition by FDA when it was initially marketed.

According to A. Wes Siegner Jr. of the law firm Hyman, Phelps & McNamara, "FDA appears to be developing a policy that would render dietary ingredients such as evening primrose oil, black currant oil, borage seed oil, lin­seed/flaxseed oil, chlorella, lobelia, St. John's Wort, CoQ10, glucosamine and chondroitin sulfate, and most botanicals illegal under DSHEA unless there is proof of 'lawful' marketing or they are first reviewed by FDA under the NDI notification process5."

As of November, less than four of every 10 NDI submissions received by FDA have been deemed acceptable, meaning that for those NDIs that made it through the process the agency has no immediate questions regarding safety6. The NDI process has been even more difficult for botanical NDIs, with less than three out of 10 accepted without further question. In a review of the 249 NDI submissions available for public viewing on FDA's website7, it is apparent that FDA is applying a safety standard as stringent as the GRAS or approved food additive petition standard. Offering her perspective on this matter, Annette Dickinson, PhD, president, Council for Responsible Nutrition (CRN), Washington, D.C., said, "The safety standard for food additives and GRAS substances is to demonstrate 'reasonable certainty of no harm.' Congress, in passing DSHEA, did not choose to use this language but instead crafted a different standard, namely that the ingredient will 'reasonably be expected to be safe8.'" Dr. Dickinson further clarifies that "FDA affirmatively approves food additives, thus putting the agency's official imprimatur on the ingredient. FDA does not formally approve NDIs." Thus, the regulation reads such that it is a reasonable basis of safety that one must achieve before marketing a dietary supplement and not agency approval as in the case of GRAS ingredients or food additives.

On November 15th, FDA held a public meeting to discuss the legal and regulatory issues pertaining to the status of NDIs and the premarket notification process. This was one of three steps that FDA plans to take as part of the regulatory strategy initiative announced on October 20th. Among the issues ad­dressed was the narrow interpretation by FDA of the definition of a dietary supplement9. The sentiment expressed by most industry-affiliated speakers was that this definition was designed to be as broad as possible in order to include any substance that is suitable for consumption as an article of food (excluding substances studied or approved as drugs before being marketed as a dietary supplement). Several NDI submissions have been rejected on the basis they did not meet FDA's interpretation of the definition. While some rejections were for obvious reasons, others were not, leaving many to wonder on what basis FDA is applying this standard to dietary ingredients.

Also in question is whether the "risk/ benefit" analysis that was applied to dietary supplements containing the ingredient ephedra10 will require NDI notifications to prove benefits in addition to safety. As mentioned under Section 402 (f)(1) of the FDC Act, a food is deemed adulterated if among other things it is a dietary supplement that contains a dietary ingredient that presents a significant or unreasonable risk of injury under the labeled conditions of use. In this case, FDA has the burden of proof that the product presents an unreasonable risk of harm. The evaluation of the safety of the ingredient occurs after the ingredient is marketed, with the exception of NDIs. In February of this year, FDA interpreted for the first time the legal "unreasonable risk" standard when it issued the final rule declaring products containing ephedrine alkaloids adulterated. In that rule, FDA states that in determining an unreasonable risk it will use a "risk/benefit" analysis. For products or ingredients that FDA perceives to have little benefit, even a small safety risk from consumption of the ingredient may trigger this rule. This new regulatory initiative by FDA goes beyond enforcement of the "unreasonable risk" standard and for the first time addresses the whole legal NDI process and the perception by FDA that this provision of DSHEA has been, to a great extent, ignored by the dietary supplement industry.

Under FDA's regulatory initiative steps two and three have significant, if not intimidating implications for all individuals and companies involved in the dietary supplement industry. As part of step two FDA plans to bring enforcement actions against marketed dietary supplements that contain NDIs for which the required notification has not been submitted. This affirms that FDA intends to exercise its authority under the NDI provisions of the FDC Act to determine which dietary ingredients do not qualify as "old" dietary ingredients and are currently marketed in dietary supplements. The potential ramifications of this new enforcement initiative are alarming. If an FDA market review were to be conducted, it is quite possible that a significant number of dietary ingredients currently marketed would be eliminated from the marketplace unless they met the newly enforced and rigid premarket requirements for marketing NDIs. Further, if FDA prevails in applying the "lawfully" marketed requirement for the enforcement of the NDI provision, a large number of ingredients currently being sold (under the assumption of being an old dietary ingredient) would be considered adulterated until they have met the requirements of the premarket NDI notification process.

The third step describes FDA's plans to bring enforcement action against dietary supplements containing ingredients that failed to meet the NDI review process but are nonetheless still being marketed and sold. This means that for the 60% plus ingredients that did not receive NDI clearance, FDA will deem these ingredients unlawfully marketed and prohibited from sale until the NDI requirements have been met. It is apparent from all three steps that FDA intends to use the NDI notification process as its safety gatekeeper. If the agency is able to implement these steps in a manner similar to the way it has been evaluating NDIs, the number of dietary ingredients on the market will be significantly reduced.

The FDA meeting held on November 15th was a first step toward open dialogue between the dietary supplement industry and FDA on how to define certain aspects of the NDI regulatory process in order to better clarify what is required of marketers of NDIs. Industry has expressed its significant concern about certain FDA interpretations that have been issued in the past and current NDI process. A majority of industry experts feel FDA's role as gatekeeper must ensure that the legal requirements for dietary ingredients be viewed in terms of a "gate" and not as a "barrier."

So what can the industry do? It should send comments to FDA regarding how to improve the NDI process before Dec 20th (many have petitioned FDA to extend this date in consideration of the upcoming need to review the final rule for current good manufacturing practices-cGMP's-for dietary supplements and the recent release of the strategy document and draft substantiation guidance11.

Although the NDI regulations apply to the marketing of dietary ingredients, the burden of submission and substantiation will most likely fall upon the raw material suppliers. Should the end result favor FDA's current regulatory approach and interpretation, finished good manufacturers and marketers will likely require any NDI to have previously obtained NDI legal status, or at least demonstrate that the scientific documentation to support the safety of the ingredient is significant enough to meet FDA's stringent standard.

Alternatively, if a unified majority of dietary supplement leaders can collectively agree on how to define the NDI process in a manner consistent with the intent of DSHEA, the result can be a more functional and transparent review system that allows truly innovative, safe products to be sold to the American public. Whatever the result, the undeniable truth is that the dietary supplement industry will change and so must those who wish to remain a part of it.NW

About the authors: W. Patrick Noonan is an attorney and registered pharmacist, who specializes in matters concerning products regulated by FDA and is based in Woodland Hills, CA. He can be reached at 818-887-5600; E-mail: pat@wpnpc.com; Website: www.wpnpc.com. Chris Noonan, MPH., formerly the president of HealthGuidance, recently joined Imaginutrition, Inc. He can be reached at 310-458-2502; E-mail: chris@imaginutrition.com; Website: www.imaginutrition.com. Patrick and Chris are also managing partners in Mercura LLC, Website: www.mercuraip.com.


References:
1. 69 Fed. Reg. 61680, 61682 (October 20, 2004).
2. The other exemption in Section 413 of the Food, Drug and Cosmetic Act (FDC Act) is that a dietary supplement that contains only dietary ingredients that have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.
3. Section 402 (f)(1)(B) and Section 413(a)(2) of the FDC Act and the FDA regulation at 21 CFR Section190.6 (new dietary ingredient requirements).
4. See Section 413(a) & (c) of the FDC Act.
5. A. Wes Siegner, Jr. Hyman, Phelps & McNamara, P.C. "New Dietary Ingredients and Food Additives: What They Have in Common" Presented at the FDA Nov 15, 2004 Public Meeting titled "Dietary Supplements: Premarket Notification for New Dietary Ingredient Notifications." More information available at www.hpm.com
6. The agency takes the position that because all research on the ingredient has not been reviewed, FDA will make no statement regarding the ingredient's safety.
7. FDA's website: www.fda.gov.
8. Annette Dickinson, PhD, Council for Responsible Nutrition (CRN). Re Docket No. 2004N-0454: Initial Comments of the Council for Responsible Nutrition on Six Major Topics Outlined by FDA Regarding New Dietary Ingredients. Presented at the FDA November 15, 2004 Public Meeting titled "Dietary Supplements: Premarket Notification for New Dietary Ingredient Notifications." Reprints available at www.crnusa.org.
9. 21 U.S.C. § 321(ff)(1)(E).
10. 21 U.S.C. § 342(f)(1)(A).
11. www.cfsan.fda.gov/~dms/ds3strat.html.