Q: Why is FDA issuing this draft guidance?

A: The Act requires dietary supplement manufacturers to have substantiation that structure/function, nutrient deficiency, and general well-being claims on the label of a dietary supplement product are truthful and not misleading under section 403 (r)(6) of the Food, Drug, and Cosmetic Act (the Act). 

The draft guidance is intended to describe the amount, type, and quality of evidence FDA recommends a manufacturer have to substantiate a claim under section 403 (r)(6) of the Act.

Q: How does FDA define "adequate substantiation?"

A: The act does not define what constitutes "substantiation."  For this draft guidance, FDA reviewed regulations, case law, the Federal Trade Commission (FTC) experience with its policy on substantiating claims made for dietary supplements in advertising, as well as recommendations from the Commission on Dietary Supplement Labels.

FTC has typically applied a substantiation standard of "competent and reliable scientific evidence" when it applies its policy on substantiating claims made for dietary supplements in advertising.   FDA intends to apply a standard consistent with FTC's approach.

Q: What constitutes "competent and reliable scientific evidence?"

A: FDA considers the following factors important in determining 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 studies or evidence's strengths and weaknesses?
• 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)?

Q: Are manufacturers required to adhere to this draft guidance document?

A: FDA guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe FDA's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word "should" in FDA guidances means that something is suggested or recommended, but not required.   

Q: Why is it important to understand the meaning of a claim?

A: The first step in determining what information is needed to substantiate a claim for a dietary supplement is to understand the meaning of the claim and clearly identify each implied and express claim. Understanding the claim's meaning will help identify the appropriate study hypotheses and measureable endpoints, which can be used to ensure that the firm has appropriate studies to substantiate the claim. 

Q: What if there are a number of ways a claim can be interpreted?

A: When a claim may have more than one reasonable interpretation, FDA recommends that a firm have substantiation for each interpretation.  Consumer testing may be useful to determine consumer understanding of each claim, in context.  FDA recommends that firms not focus on individual statements or phrases, but rather on what expected effect or benefit is 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.           

Q: How will FDA evaluate the relationship between the claim and a dietary supplement product?

A: Whether studies or evidence have a relationship to the specific claim being made or to the dietary supplement product itself is an important consideration in determining if a claim is substantiated.  The following are some threshold questions in determining this relationship:

• Have the studies specified and measured the dietary supplement or dietary ingredient that is the subject of the claim?
• Have the studies appropriately specified and measured the nutritional deficiency, structure/function, or general well-being that is the subject of the claim?
• Were the studies based on a population that is similar to that which will be consuming the dietary supplement product?

Q: Will FDA accept research from foreign sources?

A: Foreign research could be sufficient to substantiate a claim as long as the design and implementation of the foreign research are scientifically sound and the foreign research pertains to the dietary supplement or ingredient at issue.  However, firms should note that in evaluating data from studies conducted in a foreign population, care should be taken in extending the results to what might be expected in consumers in the United States who will use the product. 

Differences between the two populations, such as differences in diets, general health, patterns of use, among other things, could confound the results.  Also, it is important to make sure that the study examined the same dietary ingredient about which the claim is being made since there may be instances where, due to provincial or regional differences in custom, language, or dialect, the same name is given to different substances or different names to the same substance.

Q: How will FDA evaluate the quality of the evidence submitted?

A: In deciding whether human studies substantiate a claim, an important consideration is the scientific quality of studies.  Scientific quality is based on several criteria including study type, 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. If the scientific study adequately addressed all or most of the above criteria, it would be considered of high quality.  Generally accepted scientific and statistical principles should be used to determine the quality of the studies used as evidence to substantiate a claim. 

Q: What kind of studies does FDA consider the best?

A: The "gold" standard is randomized, double blind, parallel group, placebo controlled trial design.  However, trials of this type may not always be possible, practical, or ethical.  Since there are several systems available to rate scientific information, firms are encouraged to refer to these systems when developing substantiation for claims or relying on existing information.

Q: What are the types of evidence that may substantiate a claim?

A:   Competent and reliable scientific evidence adequate to substantiate a claim would generally consist of information derived primarily from human studies.  Human studies can be divided into two types: intervention studies and observational studies. 

Q: What is the difference between an intervention study and an observational study?

A: In intervention studies, an investigator controls whether the subjects receive the treatment or intervention of interest.  Intervention studies provide the most persuasive form of evidence to substantiate the effect of a dietary supplement in humans because they evaluate the product's direct effect in the human body.  Although interventional studies are the most reliable studies for determining a cause-and-effect relationship, generalizing from evidence on selected populations is cautioned. 

In observational studies, the investigator does not have control over the exposure to the treatment or intervention of interest. Observational studies have a more limited ability than intervention studies to distinguish relationships between a substance and the outcomes being evaluated.

Q: What types of information are useful as background to support a claim?

A: The following additional types of information would generally be considered background information, but alone may not be adequate to substantiate a claim.  

• animal studies;
• in vitro studies (studies that are done outside a living body);
• testimonials and other anecdotal evidence;
• meta-analysis (the process of systematically combining and evaluating the results of clinical trials that have been completed or terminated)
• review articles;
• comments and Letters to the Editor; or
• product monographs (documents prepared by the manufacturer to convey specific information about a product such as its specifications). 

Q: What design factors affect the quality of a study?

A: There are multiple factors that should be considered in a study design including, but not limited to:

• bias and confounders;
• study design;
• assessment of intervention or exposure and outcomes;
• data analysis and assessment; and
• peer review.

Q: What kind of data should firms consider when evaluating the evidence to support a claim?

A: In determining whether there is adequate evidence to substantiate a claim, firms 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), consistency, relevance of exposure, and persuasiveness.

Ideally, the evidence used to substantiate a claim agrees with the surrounding body of evidence.  Conflicting or inconsistent results raise serious questions as to whether a particular claim is substantiated.

There is no general rule for how many studies, or what combination of types of evidence, is sufficient to support a claim.  However, the replication of research results in independently conducted studies adds to the persuasiveness of the evidence. 

Although the quality and persuasiveness of individual pieces of evidence are important, each piece should be considered in the context of all available information; that is, the strength of the total body of scientific evidence is the critical factor in assessing whether a claim is substantiated.