FDA/Center for Food Safety and Applied Nutrition (CFSAN) has issued a guidance document for industry regarding claim substantiation required by Section 403(r) (6) of the Federal Food, Drug and Cosmetic Act.

Under this section, manufacturers of a dietary supplement making a nutritional deficiency, structure/function, or general well-being claim must offer substantiation that the claim is truthful and not misleading. However, the Federal Food, Drug, and Cosmetic Act and the legislative history accompanying DSHEA do not define “substantiation.”

According to FDA, for this guidance, the agency “drew upon our own expertise with respect to the regulations and case law regarding substantiation of various statements that may be made in the labeling of dietary supplements, conventional foods, and drug products (recognizing that conventional foods and drugs are regulated differently from dietary supplements), the Federal Trade Commission’s (FTC) experience with its policy on substantiating claims made for dietary supplements in advertising, and recommendations from the Commission on Dietary Supplement Labels.”

The FTC standard of competent and reliable scientific evidence has been defined in FTC case law as “tests, analyses, research, studies, or other evidence based on the expertise of professionals in the relevant area, that has 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.”

In determining whether the substantiation standard has been met with competent and reliable scientific evidence, FDA recommends that firms consider four issues in their assessment: the meaning of the claim(s) being made; the relationship of the evidence to the claim; the quality of the evidence; and the totality of the evidence.

When a claim may have more than one reasonable interpretation, FDA recommends that a firm have substantiation for each interpretation. According to its guidance: “Consumer testing may be useful to determine consumer understanding of each claim, in context. We recommend that firms not only focus on individual statements or phrases, but also on what expected effect or benefit are being promoted when all of the statements being made for the product are considered together. Although it is important that individual statements be substantiated, it is equally important to substantiate the overall ‘message’ contained when the claims are considered together.”

With respect to the relationship of the evidence to the claim, the studies being used as substantiation for dietary supplement claims should identify a specific supplement or ingredient and serving size and the conditions of use in the studies should be similar to the labeling conditions of the product. Research should focus on similarities in formulation, serving size, route of administration, total length of exposure, and frequency of exposure. Manufacturers should be aware that other substances involved in the study or included in the dietary supplement product itself might also affect the dietary supplement’s performance or the study results, according to FDA.

Scientific quality of studies is also an important consideration. Scientific quality is based on several criteria including study population, study design and conduct (e.g., presence of a placebo control), data collection (e.g., dietary assessment method), statistical analysis, and outcome measures. Intervention studies can provide causal evidence to substantiate the effect of a dietary supplement in humans because they can evaluate the product’s direct effect in the human body. Observational studies have a more limited ability than intervention studies to distinguish relationships between a substance and the outcomes being evaluated and cannot provide causal evidence.

Information useful as background to support a claim may also include animal studies, in vitro studies, testimonials and other anecdotal evidence, meta-analysis, review articles, comments and letters to the editor, as well as product monographs.

In determining whether there is adequate evidence to substantiate a claim, one should consider the strength of the entire body of evidence, including criteria such as quality, quantity (number of various types of studies and sample sizes), relevance of exposure, and consistency and replication of the findings.

According to its guidance, FDA also considers the following factors important to establish whether information would constitute “competent and reliable scientific evidence”:

•    Does each study or piece of evidence bear a relationship to the specific claim(s)?
•    What are the individual study’s or evidence’s strengths and weaknesses? Consider the type of study, the design of the study, analysis of the results, and peer review.
•    If multiple studies exist, do the studies that have the most reliable methodologies suggest a particular outcome?
•    If multiple studies exist, what do most studies suggest or find? Does the totality of the evidence agree with the claim(s)?