The Regulatory Continuum

To view the figures 1-5 mentioned in this article click the following links. Figures 1-3 Figures 4&5 (all figures are adobe .pdf files)

The regulatory structure for food and drugs in the United States is unique in the world. The U.S. Federal Food, Drug and Cosmetic Act (FFDCA) established product categories based almost exclusively on the claims made for these products. According to American law, the shape, composition and presentation of the product have less to do with its classification than how it is marketed. Specific exclusions granted to product categories center on the claims more than the presentation of a product. If a product looks like water and tastes like water, yet its label states that the water can lower cholesterol, the Food and Drug Administration (FDA) considers that product to be a drug. The usual "five magic words" in marketing that automatically catapult a product toward drug status are cure, treat, diagnose, prevent and mitigate.

There used to be only two regulatory classifications--foods and drugs. In particular, products claiming to have an effect on a disease or disease state were drugs regardless of composition. With the passage of the Dietary Supplement Health and Education Act in 1994 (DSHEA), and its forerunner, the Nutrition Labeling and Education Act of 1990 (NLEA), the regulatory field became muddied.

With the passage of NLEA, a "health claim" could be applied to a product that "characterizes the relationship of any nutrient ... to a disease or a health-related condition." This section of the law has subsequently been interpreted by FDA to apply exclusively to a substance preventing or, euphemistically, reducing the risk of a disease. The requirements for how such claims may be made are also spelled out in the FFDCA, including having the maker demonstrate Significant Scientific Agreement (SSA) supporting the product's reason for the health claim.

With the passage of DSHEA, "structure/function" claims were also identified. These claims "describe ... the role of a nutrient or dietary ingredient intended to affect the structure or function in humans." Without splitting regulatory hairs concerning what these claims are, FDA issued a final rule in February 2000 contending that virtually all claims for dietary supplements that discuss a substance's remotest effect on the structure or function of the human body fall into this class. In order to use structure/function claims, the manufacturer must notify FDA within 30 days of the claim's first use. Also, in each instance where the claim is used on the label or in labeling of the product, it must carry the disclaimer, "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease."

The disclaimer presents an interesting conundrum. First, it notes that FDA has not evaluated the company's structure/function claims, even though they were submitted for exactly that purpose. Second, since FDA does not involve itself with structure/function claims until it rejects or removes the claim, the way the agency treats the disclaimer sends a clear message that it has not given the claim the time of day.

Currently, supplements, as with all foods, have the ability to make nutrient content claims, statements of nutritional support (structure/function claims) and health claims. They are specifically disallowed, as are all other foods, from making either express or implied drug claims. However, there are products already on the market that fall through the cracks that are somewhere between a food and a drug. If you plotted the distance between "food" and "drug" graphically, gaps of product categories exist between the continuum that includes these three claims classes, which are grouped together according to the requirements behind each claim.

You will notice that there is no overlap in any of these product categories, as seen in Figure 1. This is because the products are sectioned off according to their claim. The product category, "dietary supplements," falls across the divide between food and dietary supplement GMP because it has gone through manufacturing processes specific to its claim's guidelines.

In reality, there are a host of subcategories that are promoted in marketing strategies if not in the government's eyes. Further, the broad category of dietary supplements encompasses a range of products that do not truly fit into their assigned areas. For example, functional foods, nutritional supplements, nutraceuticals, traditional medicines and foodaceuticals have distinct pharmacologic activity that extends beyond the term "nutrition" in the classical sense. Moreover, some foods look very much like ordinary food but offer additional benefits outside the conventional food norm.

Currently, there exist noticeable gaps in this graphed continuum. Products in these gaps are still sold, yet they are prevented from being identified as such from a regulatory perspective. Looking at Figure 1, the left side of the continuum should show products currently known as "functional foods," filling a gap between foods and dietary supplements. The historic understanding of what a dietary supplement is brings to mind vitamin and mineral supplements. These nutritional supplements are the true dietary supplements from a definitional sense of the term. Yet, neither the category of functional foods nor nutritional supplements exists from a regulatory standpoint.

Moving along the continuum toward drugs, there are a variety of substances with clinically demonstrated health benefits. In the opening lines of DSHEA, Congress found "... the benefits of dietary supplements to health promotion and disease prevention have been documented increasingly in scientific studies ..." and that "... there is a link between the ingestion of certain nutrients or dietary supplements and the prevention of chronic diseases such as cancer, heart disease, and osteoporosis ..." Yet, no such product category exists in our current model.

This huge gap between dietary supplements and drugs contains products that have pharmacologic effects that are offered by naturopathic doctors or other practitioners on a daily basis. Nonetheless, they remain trapped in the bubble of dietary supplements and treated as nutritional support rather than as "alternative medicine." The U.S. drug model virtually mandates single-chemical-entity presentation. Products comprised of a host of chemicals that work in concert, and in many instances may lack the subsequent negative effects found in their pharmaceutical counterparts, do not fit into this model. Instead, only single-chemical entities exhibiting strong effects and a larger risk for adverse events can be classified as drugs. The government has no classification for substances that offer subtler and less harmful effects than those in the "classic" drug model.

Referring back to the continuum, the pharmaceutical therapies that can use the "magic" words are readily available over-the-counter after passing certain requirements, such as being filed for a New Drug Application (NDA). "Alternative" therapies, which may offer the same if not gentler "pharmaceutical" effects, have become an over-generalized and homogenized area of dietary supplements where drug status is a no man's land. The end result is that the industry sells a broad product range across a broad continuum that does not match up with the definitional mandates imposed by the current FFDCA regulations. There are no claims classes in existence to allow for the proper and appropriate description of what many of these products do. This challenge is not yet being confronted on a formal basis, but it needs to be.

Closing the Gaps

Bear in mind that companies have an obligation to substantiate the validity of any claims they make. It is an overriding concept that rules over the claims classes. Current substantiation requirements range from nutrient content verification to NDA filings for drug status.

In order to close the gaps that exist and to openly discuss and market beneficial products that fill the gaps along this potholed continuum, substantiation requirements must be met while carving out claims classes to describe the products that are actually being sold. When the industry identifies these claims classes, it defines the additional product categories that need to be created.

The first step in filling the gaps is to insert the product categories currently being sold into the continuum. You will find that some of these categories overlap. New, more specific nomenclature is also created to help avoid the confusion that exists today through the overly broad application of the term "dietary supplements." Figure 2 places the new product categories along the continuum and includes the necessary nomenclature changes that more accurately identify vitamin and mineral supplement products.

Getting from Here to There

Figure 2's continuum show the products presently being marketed today. The awkward term, "preclusive supplements," is staying within the boundaries of the law by avoiding the magic word "prevent." Filling in the product category gaps merely gives form to market reality; it does not address the issue of how to achieve this.

The law, in terms of structure/function claims, allows for discussion of the relationship between a dietary substance and its role on the structure or function of the human body. Using these claims as guidelines, they allow for discussion and presentation of information as to the relationship of a nutrient to disease or disease states. By using these claims as the origins for the claims classes, you can begin to fill in the product gaps. It would be folly to assume that only the products our industry sells that fall under the current regulatory schema can make the claims selected. Indeed, FDA has stretched current boundaries by allowing that some OTC claims are appropriate "structure/function" claims. The reverse should also be true.

Filling in the gaps among the claims classes generates subsets of what already exists. Reading the law specifically, the role a nutrient plays on a disease or disease state does not automatically mean it is only a prevention claim. The following two classes sidestep FDA's hot button, "prevent:"

* Risk Reduction Claims: This category of claims applies to products that have demonstrated a literal preventive effect. However, since the word "prevent" is statutorily excluded from use except for drug products, the phrase "risk reduction" is more acceptable. These claims also require a different burden of proof than health claims (discussed later).

* Remedial Claims: These claims reflect the positive impact that substances can have in the literal treatment or mitigation of a disease or disease state. Notably, they apply to those products that are understood to provide medicinal benefits, although they are not considered medicine in the confines of the current regulatory scheme. The application of these particular claims is shown in Figure 3.

Examination of this figure reveals the reach of product categories across the entire continuum. What is also evident is how overlap exists with some of these substances. It is important to recognize the continuum's two realities: 1) this dispersion of claims applies the tenets of the law as it is written and 2) the overlap that already exists reflects the marketplace.

Once the product and claim gaps are bridged by the industry, the next step is substantiation. The Europeans are deft at handling this step, having dealt with these product categories far longer than the United States. This is reflected in the European Union's (EU) regulation of herbal remedies and is further reflected in the FAO/WHO guidelines. Following in Europe's footsteps may be a benefit to the American industry.

Figure 4 shows what substantiation requirements are necessary for each of the claims classes in order to caulk the gaps between food and drugs. Each step, though, becomes more rigorous as it moves into drug territory. The underpinning of substantiating claims is to have validated science behind each one. The Pearson v. Shalala decision put forward the fact that consumers are capable of understanding messages about the products they consume and that a regulatory agency does not have the right to restrict speech concerning the matter of messages about health. However, FDA has not fully implemented the Pearson decision and is following a 10-year plan before the court decision is fully implemented.

The Claim Process

By considering the present laws and future, as-yet-to-be-implemented court rulings, the requirements concerning levels of substantiation for garnering claims can be summarized as such:

Analysis: For nutrient content claims, analytic verification that a product is high in dietary fiber or low in sodium is already required.

Level 1 and Level 2 Substantiation: These levels of substantiation must exist separately to meet the requirements of nutritional support vs. risk reduction claims. Previously, FDA interpreted the law regarding health claims as limited to risk reduction claims. This is, unfortunately, not how the statute reads. The law states that a claim that "...characterizes the relationship of any nutrient ... to a disease or a health-related condition ..." may be made. Further, review and implementation of the Pearson decision allows for different substantiation requirements and the presentation of qualified claims. One of the relationships that exists between a substance and a disease is reduction of risk. This is not the same as insisting that this is the only such relationship. Holding a level of substantiation that falls short of the requirement for health claims is fully acceptable based on the law and the court decision. Thus, a level of substantiation that falls short of SSA should be applicable to risk reduction claims.

Significant Scientific Agreement: The guidance document that FDA issued concerning this topic requires revisiting. Using the standards presently set in FDA's guidance would require almost scientific unanimity. Still, the application of the guidance as written could apply to this narrow class of claims. This claims class, however, must expand to include characterizations of a substance's relationship to a disease other merely than risk reduction. That is how the law is written.

Monograph: At first glance it may not be obvious that even though this feature already exists, it is not fully implemented throughout the industry. The monographs used for OTC products include specific uses and applications of drugs that existed (in large measure) before 1962. The review proceedings today are not simple when reviewing new OTCs, and some other mechanism must replace it. The monograph presentation of data should be expanded to include monographs that come from other sources. International sources such as WHO or Commission E monographs and domestic sources such as USP-DI, NF or the American Herbal Pharmacopoeia monographs already exist. These include both composition requirements and demonstrated claims that may be made for the products. The obvious added benefit for utilizing these monograph processes is that applicable standards become readily available for the composition of these complex materials. In addition, only product that conforms with a monograph's composition requirements may make claims associated with them. This model also has the added benefit of mandating disclosure of all the warnings and attendant information that typically accompany a monograph claim.

NDA: There is no projected change here for the industry. The data and expense of relating the data to FDA will continue and thus remains unchanged.

The Next Step is Yours

When all the applicable changes are made to the current, gap-laden continuum, the result is a scheme that makes sense (Figure 5). As previously noted, expanding health claims to OTC dietary supplements is the equivalent to FDA's position on OTC drugs being allowed "structure/function" claims.

Finally, the manufacturing industry has an obligation to the industry in practicing Good Manufacturing Practices (GMPs). The mandate from DSHEA was that dietary supplement GMPs be modeled after the GMPs for foods. This is not a truly appropriate standard for products with notable pharmacological effects. The GMP used for drugs is a more germane quality control basis for producing dietary supplements.

The finished continuum (Figure 5) is free of gaps. It identifies and offers regulatory opportunities for the industry to better sell products that already exist in the marketplace but under categories that are now more meaningful because they are based on substantiated claims.

The punch line is that all this can and should be accomplished without legislative action. Legislative action is a risky proposition with an uncertain future. The tenets of NLEA and DSHEA will are worth keeping as they were originally crafted. This new continuum fully implements DSHEA by acknowledging how products are currently being sold and allowing consumers the opportunity to receive accurate information about them. The final result is a regulatory scheme that fulfills the promise of DSHEA, implements the mandates of Pearson v. Shalala and ensures that adequate safeguards exist to assure customers that the products they purchase have benefit. By showing that the continuum can be bridged, it is up to the industry to take action and sell natural products as NLEA, DSHEA and Pearson v. Shalala intended.

Jim Lassiter is president of the Lassiter Group, a regulatory consulting firm based in Laguna Beach, Calif.