“Food” can be loosely defined as any substance that people or animals eat or drink, in order to maintain life and growth, satisfy hunger, or simply in response to hedonistic impulses. On the other hand, functional foods (or ingredients) have been defined as those foods or ingredients that supply a benefit beyond that of the traditional (i.e., mainstream) nutritive value. A prime example of a functional food ingredient can be seen in probiotics – the definition of probiotics by the World Health Organization (WHO) in 2001 is “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host.”[1]Therefore, application of the term “functional” beyond that of traditional nutritive value is an expressed (not implied) claim. That is, the seller is offering a product that will affect the structure or function of the body, otherwise it would not be “functional” and no one would purchase the product. It follows then, that the seller must substantiate his claim, proving the functionality through clinical trials – the type and rigor of which has increasingly become the subject of controversy and confusion between the two controlling Federal agencies, the Food and Drug Administration (FDA) and Federal Trade Commission (FTC).
As stated above, a functional food provides physiological benefits beyond that of traditional nutritive value. But the type of “benefit” defines the types of data needed to prove that the food is actually “functional.” If the food (or food ingredient) is functional by affecting the normal structure or function of the body, then FDA would look upon the claim associated with the functional food as a structure/function claim (SFC). The claim may characterize the means by which a nutrient or dietary ingredient acts to maintain such structure or function, for example, “fiber maintains bowel regularity,” or “antioxidants maintain cell integrity.” However, inconsistencies arise when functional food ingredients are added to dietary supplements or to conventional foods. Structure/function claims for conventional foods must focus on effects derived from nutritive value of the ingredient, but if the ingredient has no nutritive value such as the polyphenols in cranberry juice, the claim must be based on the nutritive value of the food – the cranberry juice and its effect on urinary tract health. In contrast, structure/function claims for dietary supplements may focus on non-nutritive or nutritive effects – for example, a healthy urinary tract claim can be based on the non-nutritive polyphenols extracted from cranberries. Therefore, “functional foods” that claim benefits beyond nutritive value, or having no nutritive values of their own technically cannot utilize a structure/function claim when used as a food.
Structure/function claims are not pre-approved by FDA, but the manufacturer must have substantiation that the claim is truthful and not misleading and must submit a notification with the text of the claim to FDA no later than 30 days after marketing the dietary supplement with the claim. FDA does not require manufacturers of conventional food to notify FDA about their structure/function claims. In addition, structure/function claims may not (explicitly or implicitly) link the claimed effect of the nutrient or dietary ingredient to a disease or state of health leading to a disease. But if “nutritive value” is necessary for a SFC for conventional food, how can claims be made for indigestible fiber, which does not, by definition (i.e., “indigestible”) have nutritive value? And for the example above, probiotic bacteria are not consumed for their “nutritive value,” although they do, when substantiated by studies, both benefit the body and affect the function of the body. FDA has, in effect, painted itself into a corner, with its insistence on bright lines separating nutrient and non-nutrient substances as a basis for claims, a strategy that is clearly not working. Therefore, FDA should abandon the policy allowing SFC for conventional foods based only on the nutritive value of the substance.
In certain instances, scientific evidence may indicate that there is a relationship between a functional food and a reduced risk of a disease or health-related condition. In this case, FDA requires that a Health Claim petition be submitted to the FDA if a seller wants to make a claim in that respect, along with the substantiation for this Health Claim, which includes clinical trials. FDA will evaluate the evidence submitted to determine the quality and strength of the scientific evidence, and compare with other evidence found in the scientific literature. FDA may then determine if there is “significant scientific agreement” (SSA) for the Health Claim, or only “emerging evidence” available for the claim. Unfortunately, the distinction between FDA’s “significant scientific agreement” and “emerging evidence” definitions have never really been quantified by FDA nor by the FTC, the Agency that evaluates the truthfulness of product advertising, in coordination with the FDA). FDA guidance suggests that significant scientific agreement should be defined as an amount and quality of data provided upon which qualified experts would likely agree that the scientific evidence supports the substance/disease relationship that is the subject of a proposed Health Claim, with a high level of confidence in the validity of the substance/disease relationship, and that the validity of the relationship will not, in all likelihood, be reversed by new and evolving science.[2] “Emerging science”, is defined by FDA as the point “…where data and information permit an inference, but before the point of unanimous agreement with in the relevant scientific community that the inference is valid.”[3] However, the difference in the amount of evidence necessary for a “significant scientific agreement” claim versus an “emerging evidence” claim has never been stated… is it the difference between one clinical trial and two clinical trials? Or is the difference between the types of clinical trials conducted the key? Neither the FDA nor the FTC have provided a bright line describing the rigor of evidence separating the two or provided a readily identifiable tipping point.
Guidance provided by FDA for SFC states that “the FTC has typically applied a substantiation standard of ‘competent and reliable scientific evidence’ to claims about the benefits and safety of dietary supplements and other health-related products.”[4]“Competent and reliable scientific evidence” is defined by FTC as “tests, analyses, research, studies, or other evidence based on the expertise of professional in the relevant area, that have been conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted in the profession to yield accurate and reliable results.” It was previously thought that FDA may determine, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence are sufficient to establish substantial evidence.[5] The term “substantial evidence” was defined for drugs by FDA (and has been used for food ingredients) in part as evidence from adequate and well-controlled investigations, conducted by experts qualified by scientific training and expertise, upon which it could be fairly and responsibly concluded by such experts that a drug will have the effect it purports or is represented to have when used as recommended. Confirmatory evidence has been thought to include animal studies, pharmacokinetic studies and those clinical trials that are of insufficient quality to stand on their own scientific merit. FDA has not specifically stated a required number of clinical trials necessary to substantiate a claim, although the Federal Trade Commission (FTC) recently stated that two randomized clinical trials (RCT) for advertising for the company POM Wonderful and its pomegranate products were necessary to indicate “competent and reliable evidence” to substantiate the stated health claims.[6] However, it was not clear if this level of substantiation was necessary for all companies, or only the specific claims made by POM Wonderful. What does this mean for functional food claims? Even if the claim is for a food, the evidence to substantiate the claim must be rigorous and solid. Even claims for functional foods such as “immune-boosting” or “enhancing brain health” must be substantiated by “competent and reliable evidence.” FDA has stated in guidance that there is not pre-established formula for the number of type of studies needed to substantiate a claim, but has suggested that: (1) each study or piece of evidence must be directly related to the specific claim; (2) the strengths and weaknesses of each study must be taken into account, including the type of study, the study design, the analysis of the results, and the peer review; (3) when multiple studies have been conducted, the studies with the most reliable methodologies should indicate a particular outcome; and (4) when multiple studies exist, the totality of the evidence should agree with the claim. Congress amended section 505(d) of the Act for drug products to clearly state that the Agency may consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to constitute substantial evidence if FDA determines that such data and evidence are sufficient to establish effectiveness.[5] One would think that FDA could do the same for dietary supplement products.
Recent research has indicated that components of certain foods can influence disease states, but this information may not meet the threshold of “significant scientific agreement” that FDA requires for a Health Claim. A lower scientific quality standard of “emerging evidence” may be utilized to substantiate a Health Claim, as long as it is then “qualified” with limitations on the claims’ reliability; hence, the “Qualified Health Claim” (QHC) was introduced by FDA, in which FDA evaluates a petitioner’s request for a Health Claim and FDA determines that exact language that may be utilized for the claim. FDA typically dilutes the QHC verbiage with caveats so detrimental to the actual claim that very few companies even attempt to submit a QHC petition. While the QHC is still used to show the interaction between a food substance and a risk of exhibiting a disease, by comparison, structure/function claims must be substantiated utilizing only endpoints that indicate a maintenance of health, which limits the ability to show that a food can have a “beneficial” effect on the body (SFCs are only meant to provide a claim that the substance helps “maintain” basic bodily function). In this way, a company must know what type of claim they are trying to substantiate prior to initiating a clinical trial.
Further, the goal posts for establishing efficacy have been moved with time as shown by the slender threads of data on which the Recommended Daily Intakes, Tolerable Upper Limits and other codified landmarks have been based, compared to regulatory agency demands being made today. The FDA and the FTC have been requiring a greater and greater quantity and quality of scientific data to substantiate claims, thereby actually decreasing the ability of industry to convey to the public the potential benefits of “functional” foods. Functional foods are those foods that have been shown, through scientific evaluation, to provide a benefit beyond basic nutrition and, as industry works to substantiate the actions of functional foods, industry must also prepare a long-term plan to substantiate those claims using robust clinical trials with well-established endpoints.
[1] http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf; site last visited May 5, 2014.
[2] However, even within a few years of establishing them, the FDA has called for comments on a re-evaluation of the SSA for dietary lipids (fat) and cancer and, soy protein and risk of coronary heart disease (Federal Register, December 21, 2007).
[3] http://www.fda.gov/Food/GuidanceRegulation/ucm073332.htm; site last visited May 5, 2014.
[4] http://www.business.ftc.gov/documents/bus09-dietary-supplements-advertising-guide-industry; site last visited May 8, 2014.
[5] http://www.fda.gov/downloads/Drugs/…/Guidances/ucm078749.pdf; site last visited May 9, 2014.
[6] http://www.hpm.com/pdf/blog/POM%20-%20FTC%20DC%20Cir%20Brief%20-%202-2014.pdf; site last visited May 5, 2014.