Manufacturers wish to communicate the benefits of probiotics in advertising and labeling with lawful and adequately substantiated claims. Regulatory and substantiation requirements differ for products intended to cure, treat, prevent, or mitigate a disease; to reduce a healthy individual's risk of developing a disease; or to affect the structure or function of the body. Food labeling is regulated by the US Food and Drug Administration, and advertising is regulated by the Federal Trade Commission; the standards and methods used by these agencies differ. Food manufacturers must design their claims regarding the benefits of probiotics with the regulatory environment in mind and must develop their research plans to provide evidence that satisfies the agencies' substantiation requirements. This article offers an overview of the applicable laws and regulations, what they mandate regarding legitimate claims, and the issues regarding the design of research to substantiate such claims.
There is a variety of different types of health-benefit claims that may be made lawfully for foods and dietary supplements, most importantly claims about structure and/or function and health claims. The US Food and Drug Administration (FDA) has promulgated regulations that define each type of claim and that address substantiation requirements. Before a discussion of allowable claims, however, it is useful to identify one type of claim that is not permitted for foods or dietary supplements: drug claims—that is, any representation that the product might be of use in the cure, treatment, mitigation, prevention, or diagnosis of a disease or health-related condition. No amount of substantiation will render this type of claim legal for a food or dietary supplement. A product for which such a claim is made is regarded by the FDA as a drug, and, if there is no New Drug Application on file, it is an illegal drug. It should also be noted that claims that a product is useful for adjunct therapy—including specific claims about mitigation of the adverse effects of drug therapy that are themselves diseases—are regulated by the FDA as drug claims. Section 101.93(g)(2) of the Code of Federal Regulations title 21  defines the following types of statements (among others) as drug claims not permitted for foods or dietary supplements.
Augments a particular therapy or drug action that is intended to diagnose, mitigate, treat, cure, or prevent a disease or class of diseases [1, paragraph vii].
Treats, prevents, or mitigates adverse events associated with a therapy for a disease, if the adverse events constitute disease [1, paragraph ix].
In the announcement of the final rule that established these regulations in the 6 January 2000 issue of the Federal Register, the FDA specifically addressed the use of probiotic products to counteract the adverse effects of antibiotic therapy:
Although the statement “helps individuals using antibiotics to maintain normal intestinal flora” does not explicitly refer to a disease, there is an implicit claim that use of the dietary supplement while taking antibiotics will prevent or mitigate a disease...developing overgrowth in the gut of a pathogenic organism...[C]laims that the product can be used to maintain normal intestinal flora while taking antibiotics, is...an implied disease prevention claim. [2, p. 1029]
It is possible, of course, to take issue with the FDA's interpretation. Antibiotic treatment does not directly cause the growth of pathogens. Rather, the adverse effect is destruction of the natural intestinal microbiota, which does not constitute a disease; this destruction merely provides the opportunity for pathogens to proliferate. Probiotic products help maintain a beneficial microbiota and do not cure, treat, or mitigate a disease.
The statutory definition of a drug in the Food, Drug, and Cosmetic Act is “an article (other than a food) intended to affect the structure or any function of the body” . The phrase “other than a food” implicitly recognizes that a food or food ingredient can affect the structure or function of the body without thereby becoming a drug. This recognition is the basis for “structure/function” claims, which are statements regarding the effect of a food or dietary supplement on a structure or function of the body or the mechanism by which such an effect is produced. Note that structure/function claims may not address a disease or disorder but may be directed at healthy states that represent the absence of disease. For example, a structure/function claim for a probiotic may not suggest that the product prevents rotavirus infection, but it may state that the product helps support immune function. Consequently, a structure/function claim often can say essentially the same thing as a drug claim, but it must—as the old song goes—accentuate the positive.
A “health” claim, as distinguished from a structure/function claim, is statutorily defined as a statement that expressly or by implication characterizes the relationship of any substance in a food or dietary supplement to a disease or health-related condition. Health claims made for foods or dietary supplements are a specific statutory exemption to the restriction of disease-prevention claims to drugs. The FDA has chosen to limit allowable health claims to one specific type of relationship: a reduction in the risk of incurring the target disease or condition by the currently healthy population.
When choosing whether to develop a health claim or a structure/function claim for a product, it is useful to examine the differences between the substantiation requirements for the 2 types of claims. The data substantiating structure/function claims need not be publicly available and need not be disclosed, whereas the supporting data for health claims must be published, which in turn means that the claim is available for use on any product that meets the requirements associated with the claim. The level of substantiation needed for structure/function claims is widely regarded as significantly lower than that for health claims. Structure/function claims are flexible with regard to the kinds of evidence that can be introduced to support them, whereas health claims must be supported by prospective studies in humans. Furthermore, the studies must be done with healthy people; they cannot be studies of individuals who already have the disease, unless it can be demonstrated that progression of the disease is caused by the same factors as its initial etiology. Structure/function claims never require a qualifying statement revealing the limitations of the data, whereas most health claims (except those that have “significant scientific agreement”; see below) must state that the evidence is limited and not conclusive. Structure/function claims are not prereviewed by the FDA; indeed, those made for food products need not be shared with the FDA, although those made for dietary supplements must be disclosed to the FDA within 30 days after the first marketing. Contrarily, health claims must be preapproved by the FDA.
Whereas labeling of foods, drugs, and dietary supplements is regulated by the FDA—including both the label itself and the sources of information in close physical association with the product, such as shelf placards and Web sites at which customers can buy a product—advertising claims, including claims made on the Internet, are regulated by the Federal Trade Commission (FTC). In evaluating advertising claims, the FTC does not classify them by type as does the FDA; drug claim, health claim, and structure/function claim are FDA categories and are not used by the FTC. The FTC merely requires that the advertiser have a reasonable basis for all express and implied claims and that the information substantiating the claim be available before its first dissemination. Claims must be based on the totality of the evidence, and the standard for claim substantiation under FTC purview is competent, reliable scientific evidence based on accepted norms in that particular field.
For structure/function claims, the FDA has adopted the FTC standard—that is, the manufacturer must have substantiation, accepted by experts in the field, that the statement is truthful and not misleading. In judging the substantiation of health claims, on the other hand, the FDA actually has several standards, the first for health claims that need no disclaimers regarding the limited state of the science. These claims require what the FDA terms “significant scientific agreement” , meaning that scientific consensus exists that, although there may be refinements in our understanding in the future, the claim is not going to be found to be completely invalid. As a result of court decisions, the FDA has also developed interim criteria for “qualified” health claims—those based on less-secure scientific foundations—which must include words that indicate the tentative nature of the evidence . The standard for such claims is that there must be “credible evidence” supporting the claim .
There are 4 areas of expertise needed to develop a lawful and successful claim: marketing, legal, science, and consumer research. Marketing specifies the target audience(s) and determines what claims are most effective in selling the product. Legal identifies what claims can be made lawfully under the statutes and the regulatory environment. Science provides the substantiation of the substance-benefit relationships that form the basis of the claims. Finally, consumer research is essential to learn how consumers understand the stated claim, which may help identify any implied claims that go beyond the expressed claim. This last area is important because the FTC's evaluation of the meaning of a claim is based on the “reasonable consumer” standard—how a reasonable person would understand the claim under the circumstances .
In December 2003, the FDA adopted the FTC's “reasonable consumer” standard for evaluating the meaning of claims. Previously, under a 1969 court decision, labeling claims were judged by their potential for misunderstanding by “the ignorant, the unthinking, and the credulous” . The change of standard has several implications. First, the previous standard sharply limited what marketers could say on a label; now, labels can be used for more-sophisticated claims that may help to educate consumers. Even more important is that there is now a rational way of resolving disagreements between the marketer and the FDA about whether a claim is misleading. Previously, the FDA could argue that a claim was misleading because there were undoubtedly at least a few people in the country who would misunderstand it. There was no way to dispute such an argument. Under the “reasonable consumer” standard, disputes about the meaning of a claim can be resolved by means of a well-designed consumer survey. The FDA has shown itself to be responsive to this kind of evidence when there has been a question about how consumers will interpret a claim.
When the evidence needed to adequately substantiate a claim is assembled, it is helpful if a plausible biological mechanism can be identified. Probably, most scientists are more confident that an observed effect is real when it has theoretical underpinnings. It is also essential to have independent replication of results; the FDA has rarely regarded a single clinical study as adequate, no matter how well designed and executed. The gold standard for clinical studies is the randomized double-blind placebo-controlled trial, followed by longitudinal cohort studies. In reality, only these 2 types of studies are determinative for the substantiation of proposed health claims, although animal and in vitro studies can help establish the mechanism. However, it is important to use an appropriate animal model, and that may be a particular challenge with probiotics because there has been little published research demonstrating that rats, mice, or other frequently used laboratory animals are valid models for the safety or efficacy of probiotic microorganisms in the human. The need for appropriate models also applies to human studies. The study participants must be appropriate in terms of age, sex, racial and ethnic characteristics, health and nutrient status, dietary patterns, and other factors. If research is conducted outside the target country, it is necessary to ensure that the population studied does not differ from the target population in ways that might invalidate the applicability of the findings.
As noted earlier, research intended to help substantiate a health claim must employ currently healthy individuals. It can include individuals at an elevated risk but not individuals who already have the target disease. The FDA has properly refused to accept research that indicates that an intervention may reduce the progression of a disease or ameliorate its symptoms as a demonstration of the ability of that intervention to lower the risk of developing the disease among currently healthy individuals, unless it can be demonstrated that the factors involved in the etiology of the disease are the same as those involved in its progression.
It is extremely desirable to establish a dose-response relationship between the test substance and the end point. One weakness of research on probiotics is that few studies include multiple dose levels to allow an understanding of dose response. It is not sufficient merely to establish that a given number of microorganisms is effective in a controlled study—that is, that it produces a significant difference between the test group and the controls. First, it is likely that there are individual variations in the effects produced by different dosage levels. Second, no food ingredient, including probiotics, is regarded as safe unless it is used under the guidelines for good manufacturing practice, which require, among other things, that the ingredient be used at the minimum level required to produce the desired effect. It is also vital to describe fully the test microorganism, with complete phenotypic and genotypic characteristics to identify the strain.
It is hoped that the discussions in this supplement will help to address the challenges in establishing sound scientific approaches to the demonstration of the health benefits of probiotic products and in making true, nonmisleading, and appropriate claims to communicate these benefits to consumers.
Supplement sponsorship. This article was published as part of a supplement entitled “Developing Probiotics as Foods and Drugs: Scientific and Regulatory Challenges,” sponsored by the Drug Information Association, the National Institutes of Health National Center for Complementary and Alternative Medicine (1R13AT003805-01 to Patricia L. Hibberd), the California Dairy Research Foundation, Chr. Hansen, the Dannon Company, General Mills, Institut Rosell, and Yakult International.
Potential conflicts of interest. J.T.H.: no conflicts.