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FDA's new dietary supplement strategy: companies should approach claims substantiation and the new dietary ingredients provision of DHSEA with surgical precision.

In November last year, FDA announced a series of initiatives involving dietary supplements. Two of the more interesting developments were the draft guidance document on claim substantiation (intended to be consistent with the FTC's guidance document) and the development of a regulatory approach to new dietary ingredients (NDIs).

Claim Substantiation

After several years of requests to provide guidance on claim substantiation, FDA finally released draft guidance on the issue. The draft guidance does not contain any surprises. In fact, it is consistent with the FTC's guidance document released a few years ago. According to the FTC standard for substantiation, all claims must be backed by competent and reliable scientific evidence. In this regard, FDA takes the position that the best studies to substantiate claims are double-blind placebo-controlled studies. FDA, as well as the FTC, would prefer studies on the specific product being marketed, but, like FTC, FDA understands that reliance on third party studies will likely be the norm in this industry. The short of FDA's draft guidance is as follows:

* Well-controlled studies with blinded subjects and researchers are likely to be given greater weight than nonblinded studies.

* Long-term studies are better than short-term studies.

* The study's result should be statistically significant.

* The nature and quality of the written report is important.

* Studies appearing in reputable peer-reviewed scientific journals are looked upon with favor.

* Studies that are not published in peer-reviewed journals may be used to substantiate claims if they would be considered properly designed and controlled studies by experts in the field.

It is important to remember that both the FDA and FTC require that the scientific studies relied upon to substantiate the claim must be relevant to the product formulation and claims. This means when evaluating any particular study you must consider the following:

* Dosage level and frequency

* Dosage form

* Route of administration

* Formulation

* Total length of exposure

* Frequency of exposure

* Study population

* Relevant endpoints of the study in relation to the claim being made

Companies often rely on foreign research to substantiate claims. While the FDA would likely deny such bias, it has historically looked unfavorably on foreign research. Some of the issues FDA has noted include:

* Differences between populations, such as differences in diet, general health, or patterns of use, could confound results.

* Companies must ensure the ingredients are truly the same--language/dialect could cause the same name to apply to two different substances. For all ingredients, testing and purity must meet U.S. standards.

When reviewing studies it is important to:

* Identify bias

* Confounding factors

* Recognize lack of appropriate randomization and blinding

* Recognize use of poor statistical procedures

* Identify the presence of other dietary ingredients that may have independent effects

The FDA and FTC have also noted the following types of studies are unlikely to substantiate properly qualified claims:

* Animal Studies: These types of studies may be supportive of claims but alone cannot substantiate claims. The animal studies are based on data from studies in appropriate animal models, on data that have been reproduced in different laboratories, and on data that give a statistically significant dose-response relationship.

* In vitro: The studies are most useful when they are based on data that have been reproduced in different laboratories.

* Testimonial/Anecdotal Evidence: An "honest opinion" and anecdotal claims cannot substantiate a claim even if true.

* Meta-Analysis: This type of review may identify relevant reports, which may provide substantiation.

* Product monographs: Monographs may provide background information useful for understanding the relationship between a substance and a claimed effect.

FDA's guidance document is silent on the use of historical or anecdotal evidence to support a claim. This was probably not an oversight on the Agency's part. Historically, it does not provide any weight to such support. However, there is no reason that FDA should not adopt the FTC's position on this issue, which is that historical and traditional use claims are permissible as long as they are consistent with the historical use of the product, the claim makes it clear that it is based on historical or traditional use, and the claim is not related to a serious disease condition such as cancer, AIDS or heart disease. It is important to note that if a particular herb was either traditionally inhaled or used topically, it would be misleading to suggest that it has been traditionally ingested. Moreover, traditional use claims are generally relevant to whole herb use and not constituent parts, so it may be misleading to suggest that standardized extract has been used traditionally when in fact it was not.

It is still unclear whether FDA is intending to step up its enforcement efforts against products that are making unsubstantiated claims. Because of its limited resources, its enforcement priorities are likely to remain targeted against unsafe dietary supplements, with a secondary target of unsubstantiated claims. However, it is also possible that the FDA will decide to target certain claims in order to set an example.

NDI Enforcement

It is still unclear where FDA is headed with this initiative. However, in reading the tea leaves (no pun intended), it appears that FDA is concerned about the safety and proliferation of unique dietary ingredients presently available in the marketplace. Some in the industry view this move by FDA to be an ominous sign of things to come. Indeed, it has been suggested that FDA may attempt to block the marketing of dietary ingredients that were available prior to October 15, 1994, but may have been considered unlawful by FDA because the dietary ingredient was neither an FDA-approved food additive or generally recognized as safe (GRAS) for human consumption. Under this broad interpretation, FDA would be able to ban dietary supplements containing evening primrose or glucosamine sulfate. These concerns have been raised because FDA stated in warning letters to androstenedione ("andro") manufacturers and private label distributors that it had no evidence andro was "lawfully marketed" prior to October 15, 1994. This date is important because dietary ingredients that were marketed prior to October 15, 1994 are not subject to new dietary ingredient premarket notification provision of the Federal Food, Drug, and Cosmetic Act (FFDCA).

While the reference to "lawfully marketed" is curious, it is doubtful that FDA is attempting to eliminate dietary ingredients that were marketed prior to October 15, 1994, on the basis that those ingredients were neither FDA-approved food additives nor GRAS when marketed prior to that date. Indeed, if FDA were to take such a broad view, the vast majority of herbal dietary ingredients, as well as other dietary ingredients that are not essential nutrients, could presently be subject to adverse regulatory action because a premarket submission has not been submitted to FDA and the herbal ingredients have not been used as food in chemically unaltered form.

Indeed, if it were FDA's intention to deal with unapproved NDIs in this fashion, it could have removed ephedra from the marketplace a long time ago. Accordingly, it is doubtful it is FDA's intention to require that all dietary ingredients marketed prior to October 15, 1994, be either FDA-approved food additives or GRAS.

Furthermore, with regard to andro, neither the FDA nor the Drug Enforcement Administration (DEA) have made a determination that andro could ever be legally marketed under the Controlled Substances Act.

That said, FDA could attempt to define NDIs that are subject to premarket notification broadly or narrowly. In fact, FDA's new initiative could become a high stakes match that has significant ramifications for many new herbal ingredients and extracts on the market. For instance, FDA could decide that traditional herbal medicines that were not part of a particular culture's food supply are subject to premarket notification. Similarly, constituents that have been extracted from dietary ingredients that were marketed prior to 1994 could likewise be considered NDIs that are subject to the notification provisions because the constituent was not marketed by itself prior to October 15, 1994 as a dietary supplement or a food.

One window into FDA's thinking may be found in its pursuit of red yeast rice (RYR), which was standardized to include higher levels of a constituent part that is chemically identical to lovastatin. With regard to these RYR extracts, FDA has taken the position that RYR extracts that were standardized to increase their lovastatin content were not available as food prior to lovastatin's approval. Thus, under the Act, it could not be marketed as a dietary supplement because (1) lovastatin was not marketed as a dietary supplement prior to lovastatin's approval and (2) standardized RYR was not available in the food supply prior to lovastatin's approval. FDA after initially losing this case ultimately prevailed.

While the provisions impacting the RYR case are found in a different part of the FFDCA, the language is strikingly similar to the NDI provisions of the FFDCA (i.e., "must be marketed as a dietary supplement or used as food in chemically unaltered form ..."). Thus, it is possible that FDA might interpret the NDI notification provisions in a similar manner.

The consequences of this interpretation may be quite significant. For instance, extracts that are no more than a constituent part of an otherwise old dietary ingredient would require premarket notification and scientific evidence to demonstrate that there is a reasonable likelihood of safety before they may be marketed. FDA could also adopt the position that herbal ingredients that were used in traditional cultures do not require notification as long as its use is consistent with its traditional use. This position would allow FDA to permit the marketing of the whole herb, but not a standardized herbal extract that emphasizes one constituent over the other. FDA could also take a middle position that would permit extracts that emphasize a particular constituent but not permit the marketing of the individual constituent without a premarket notification being submitted to the Agency.

As one can see, the breadth of ingredients subject to notification can be broad or more narrowly tailored. Hopefully, FDA's position will be based on constructive input from industry. However, bureaucratic inertia being what it is, the more FDA believes that industry is being unreasonable, the more likely it is for FDA to strike its own course. Thus, industry should determine a unified and reasonable approach to this issue and work carefully with FDA to bring meaningful clarity to this issue.

Todd Harrison is partner with Venable, which is located in Washington, D.C. He advises food and drug companies on a variety of FDA and FTC matters, with an emphasis on dietary supplement, functional food, biotech, legislative, adulteration, labeling and advertising issues. He can be reached at 575 7th St. NW, Washington, D.C. 20004; 202-344-4724; E-mail:
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Title Annotation:Food and Drug Administration
Author:Harrison, Todd
Publication:Nutraceuticals World
Geographic Code:1USA
Date:Jan 1, 2005
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