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Dietary
Supplements

Dietary
Supplement Labeling Guide

-

Guidance for Industry: Substantiation for Dietary
Supplement Claims Made Under Section 403(r) (6) of the Federal Food, Drug, and
Cosmetic Act

Contains Nonbinding Recommendations

December 2008

Additional copies are
available from:
Office of Nutrition, Labeling, and Dietary
Supplements
HFS-800
Center for Food Safety and Applied Nutrition
Food
and Drug Administration
5100 Paint Branch Parkway
College Park, MD
20740
(Tel)
301-436-2375 (Updated phone:
240-402-2375)
http://www.cfsan.fda.gov/guidance.html

You may submit written or electronic comments
regarding this guidance at any time. Submit written comments on the guidance to
the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov/. All comments
should be identified with the docket number listed in the notice of availability
that publishes in the Federal Register.

U.S. Department of Health and Human
Services
Food and Drug Administration
Center for Food Safety and Applied
Nutrition
December 2008

OMB Control No. 0910-0626
Expiration Date: 08/31/2011
See additional
PRA statements in Section
III of this guidance

Contains Nonbinding Recommendations

Table of Contents

Introduction

Discussion

Paperwork
Reduction Act of 1995

Contains Nonbinding Recommendations

Guidance for Industry(1)
Substantiation for Dietary Supplement Claims Made
Under Section 403(r) (6) of the Federal Food, Drug, and Cosmetic Act

This
guidance represents the Food and Drug Administration's (FDA's) current thinking
on this topic. It does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an alternative approach
if the approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the FDA
staff responsible for implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate telephone number listed on the title
page of this guidance.

I. Introduction

A. What Does This Guidance Document Address?

Section 403(r)(6) of the Federal Food, Drug, and Cosmetic Act (the Act) (21
U.S.C. 343(r)(6)) requires that a manufacturer of a dietary supplement making
a nutritional deficiency, structure/function, or general well-being claim(2) have substantiation that the claim is truthful
and not misleading.(3)

This guidance document 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. This guidance document is limited to
issues pertaining to substantiation under section 403(r)(6) of the Act; it
does not extend to substantiation issues that may exist in other sections of
the Act.(4)

FDA's guidance documents, including this guidance, do not establish legally
enforceable responsibilities. Instead, guidances describe the Agency'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 Agency guidances means that something is suggested or
recommended, but not required.

B. Why Is Guidance on Substantiation Helpful?

The Act, as amended by the Dietary Supplement Health and Education Act of
1994 (DSHEA) and the legislative history accompanying DSHEA do not define
"substantiation." For this guidance, we 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 Commission on Dietary Supplement Labels (the Commission), a
seven-member body that was established under DSHEA to "provide recommendations
for...the regulation of label claims and statements for dietary supplements,
including the use of literature in connection with the sale of dietary
supplements and procedures for the evaluation of such claims," held public
meetings around the United States from 1996 through 1997. During these
meetings, several manufacturers asked the Commission to provide guidance
regarding the type of information that manufacturers should have in hand to
substantiate a statement of nutritional support.(5)

Under the Act, FDA has exclusive jurisdiction over the safety, and primary
jurisdiction over the labeling, of dietary supplements. The FTC has primary
jurisdiction over advertisements for dietary supplements. Given these
jurisdictional assignments, we and the FTC share an interest in providing
guidance on what "substantiation" means. In April 2001, FTC issued a guidance
document entitled, "Dietary Supplements: An Advertising Guide for Industry."(6) Our guidance document is modeled on, and
complements, the FTC guidance document.

Dietary supplement manufacturers should be familiar with the requirements
under both DSHEA and the Federal Trade Commission Act that they have
substantiation that labeling and advertising claims are truthful and not
misleading. Our approach provides manufacturers flexibility in the precise
amount and type of evidence that constitutes adequate substantiation.
Providing a standard for substantiation may also help to preserve consumer
confidence in these products. To ensure compliance with the Act, we recommend
that dietary supplement manufacturers carefully draft their labeling claims
and carefully review the support for each claim to make sure that the support
relates to the specific product and claim, is scientifically sound, and is
adequate in the context of the surrounding body of evidence.

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. FDA intends to apply a
standard for the substantiation of dietary supplement claims that is
consistent with the FTC approach. This guidance document, using examples of
claims that might be made for a dietary supplement, describes criteria to be
considered in evaluating the nature of the claim and the amount, type, and
quality of evidence in support of the claim.

II. Discussion

A. What is the Substantiation Standard?

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."(7)

Although there is no pre-established formula as to how many or what type of
studies are needed to substantiate a claim, we, like the FTC, will consider
what the accepted norms are in the relevant research fields and consult
experts from various disciplines. If there is an existing standard for
substantiation developed by a government agency or other authoritative body,
we may accord some deference to that standard.

In determining whether the substantiation standard has been met with
competent and reliable scientific evidence, we recommend that firms consider
the following 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.

Each of these issues is discussed further in this guidance.

B. Identifying the Meaning of the Claim

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
to clearly identify each implied and express claim. When a claim may have more
than one reasonable interpretation, we recommend that a firm have
substantiation for each interpretation. 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.

Example 1: The label of a dietary supplement
containing "X" uses the following claims: "The amino acid 'X' is the chemical
precursor to nitric oxide. Blood vessel cells contain enzymes that produce
nitric oxide. Nitric oxide is important in maintaining blood vessel tone."
Assuming this statement were supported by sound science so that each
individual statement was substantiated, the "message" conveyed by the claims,
when considered together, is that taking oral "X" will affect nitric oxide
production and blood vessel tone. Therefore, we recommend in this case that
the dietary supplement manufacturer have substantiation that taking the amount
of "X" provided by the product affect nitric oxide production and blood vessel
tone under the product's recommended conditions of use.

The firm's clear understanding of the meaning of the claim is useful in
ensuring that the evidentiary basis for substantiation is appropriate for the
claim. Understanding the claim's meaning will help identify the appropriate
study hypotheses and measurable endpoints, which can be used to ensure that
the firm has appropriate studies to substantiate the claim. For example, a
firm making a claim that a dietary supplement "helps maintain blood vessel
tone" or "supports healthy immune system" should have a clear understanding of
the claim's meaning to develop endpoints that could be measured and replicated
in studies used as a basis for substantiation.

Example 2: The labeling of a dietary supplement
includes the statement "promotes weight loss." The dietary supplement contains
various vitamins and minerals and a botanical extract. The manufacturer relies
on a randomized controlled double blind clinical study showing that subjects
who took the botanical extract had a small but significant increase in
metabolism over subjects taking a placebo over a 24 hour period. The study did
not examine the effect of the extract on subjects' weight and there is no
research showing that a short term increase in metabolism will translate into
any measurable weight loss. The weight loss claim would likely not be
adequately substantiated.

Example 3: The labeling for a dietary supplement
contains a statement saying, "Recommended by Scientists," in connection with
the product's claim. The statement gives consumers the impression that there
is a body of scientists, qualified experts, who believe that the claim being
made is supported by evidence. Consumers might also reasonably interpret the
statement as meaning that there is general scientific agreement or consensus
regarding the claim. If the manufacturer does not possess evidence to
demonstrate such a consensus, the claim may not be substantiated. The opinion
of a single scientist or small group of scientists is probably not adequate
substantiation for such a claim.

Example 4: The labeling states, in connection
with the product's claim, that the dietary supplement has been "studied for
years" in a particular country or region and is the subject of clinical or
"university" research. Here, the labeling conveys the impression that the
product has been studied and also conveys the impression that there is a
substantial body of competently conducted scientific research supporting the
claim. We recommend that manufacturers possess evidence to substantiate both
the express statements and their implied meaning.

C. The Relationship of the Evidence to the
Claim

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 that
is the subject of the claim? We recommend that the studies being used
as substantiation for dietary supplement claims identify a specific dietary
supplement or ingredient and serving size and that the conditions of use in
the studies are similar to the labeling conditions of the dietary supplement
product. Factors that would tend to indicate a stronger relationship between
a substance that is the subject of a study and the substance that is the
subject of the dietary supplement claim includes 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.

Example 5: To illustrate this issue, assume that
a firm has high quality studies that are also consistent with the totality of
the scientific evidence. The firm would like to use these studies to
substantiate a claim that its dietary supplement has a particular effect on
the human body, but the studies involved the impact of a specific ingredient
in foods on the human body, and did not involve the dietary supplement product
itself. In this instance, although the studies might be of high quality, the
results of these studies of conventional foods are not applicable to the
specific dietary supplement product.(8)

Have the studies appropriately specified and measured the
nutritional deficiency, structure/function, or general well-being that is
the subject of the claim? We recommend that the studies clearly
identify the endpoints that are to be used to substantiate the claimed
effect.

Were the studies based on a population that is similar to that which
will be consuming the dietary supplement product? For example, if the
study involved young adults, but the product's claims involve conditions
seen only in the elderly, the study might not be applicable to the claims.

Does the claim accurately convey to consumers the extent, nature, or
permanence of the effect achieved in the relevant studies and the level of
scientific certainty for that effect?

A note on foreign research: 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 at issue. 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, or patterns of use, 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.

Example 6: A firm claims that its dietary
supplement contains an ingredient shown to promote claim Y. The firm conducts
a literature search and finds several references for carefully conducted,
well-controlled studies demonstrating that the substance appears to be helpful
in persons with claim Y associated with aging when the substance is applied
topically to the affected area. However, there is no information provided
concerning the effect of the substance when taken orally. Although the
evidence may demonstrate that the product is effective when used topically,
this information would generally not be useful to substantiate a claim for a
dietary supplement (by definition, a product that is intended for ingestion
(section 201(ff)(2)(A) of the Act (21 U.S.C. 321(ff)(1)(A))).

Example 7: A dietary supplement firm wants to
promote an amino acid product to improve blood circulation and improve sexual
performance. The firm conducts a literature search and finds many abstracts
and articles about the amino acid's effect on biological mediators of
circulation and a few animal and human studies designed to study the effect of
the amino acid on blood flow. The firm intends to use this list of studies as
substantiation for its claim.

Although the firm appears to have a significant amount of information for
its claim, the list is likely not adequate because the firm has not
demonstrated that the information is directly related to the claim being made.
For example, in this situation we would recommend that the firm provide
information to clarify the meaning of "improves blood circulation" and
"improves sexual performance." We would also recommend that the firm determine
whether the studies examined a dosage of product similar to the firm's product
and whether any study measured outcomes (i.e., improved sexual performance)
other than blood flow/blood circulation. Until the firm has reviewed the
underlying studies, it should not assume that merely finding studies testing
the same substance necessarily constitutes adequate substantiation.

Example 8: A firm wishes to market its mineral
supplement by using a claim that "studies show that the mineral supplement
promotes "Z." The firm has the results of a randomized, double blind,
placebo-controlled study conducted in a foreign country showing that a similar
product did, in fact, promote "Z," although the study indicates that the
foreign study subjects had low blood levels of the mineral at the start of the
study. The general U.S. population does not have such a mineral deficiency.
Although this study is a high quality study, it may not be adequate to
substantiate a claim about the product's use intended for consumers in the
United States because it is confounded by the initial abnormal blood levels of
the mineral. Since the study is not designed to answer the question of whether
the effect would be expected to occur in subjects with normal blood levels of
the mineral, the study may not be adequate evidence to substantiate the
claim.

Example 9: A firm is marketing a product
specifically to reduce nervousness during stressful everyday situations, such
as public speaking. The firm has results from several small studies
demonstrating that the product will raise blood levels of a chemical that is
well known to relax people in stressful situations. The firm also has two
small, randomized, placebo-controlled studies showing that its product
positively affected measurable indices of anxiety in people placed in
stressful situations, including public speaking. These studies may be adequate
evidence to support the product claims. Although the studies may be small in
terms of the numbers of subjects tested, they are well-designed studies that
resulted in statistically significant positive results that are consistent
with the larger body of scientific evidence related to stress anxiety in
public situations.

Example 10: A firm has developed a product to
improve memory and cognitive ability and intends to market the product to
parents for their school-aged children. The firm has several high quality
clinical studies that examined the ingredient's effect in elderly people with
diagnosed, age-related memory problems. These studies alone would likely not
be adequate substantiation for a claim about memory improvement in young
children because the patient population (elderly people with memory problems)
is completely different from the intended population (children) in the
claim.

Example 11: A dietary supplement firm is
marketing an iron dietary supplement with the claim that the dietary
supplement is to correct iron-deficiency anemia in the 10% of menstruating
women with menorrhagia. The firm has not studied the product in this
population of women directly, but has assembled and carefully reviewed the
scientific literature of studies that have investigated the oral dosage and
intestinal absorption of the type of iron used in its product, both in the
population in general, and in women that match the target consumer of the
product. Using this information, the firm has formulated its product to
provide the amount of bioavailable iron needed by this population of women.
Even though the firm did not test its product directly, it has examined the
existing scientific literature and has formulated the product in a manner to
meet the standards of products shown effective in well-controlled studies.
There is, therefore, a basis to conclude that the existing literature is
applicable to the product in the target population in which it is intended.
Thus, the firm's claim that the product will be useful in correcting
iron-deficiency anemia would likely be adequately substantiated.

Example 12: A firm claims that its multi-vitamin,
multi-mineral product "provides the vitamins and minerals needed to promote
good health and wellness." In this case, the firm's claim is likely
substantiated by the substantial scientific evidence showing that certain
vitamins and minerals are essential nutrients that are needed to maintain good
health, even though the firm does not have data from specific scientific
studies to show that its product results in any measurable outcome. Scientific
evidence studying the firm's particular product formulation probably would not
be needed for this claim unless the firm were to make claims that its
formulation is different or superior to other formulations or confers benefits
above and beyond the benefits demonstrated to be associated with adequate
intake of vitamins and minerals.

D. The Quality of the Evidence

In deciding whether studies substantiate a claim, an important
consideration is the scientific quality of studies. 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. For example,
if the scientific study adequately addressed all or most of the above
criteria, it could 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. The "gold" standard
is randomized, double blind, placebo-controlled trial design. However, trials
of this type may not always be possible, practical, or ethical. There are
several systems available to rate scientific information.(9) Firms making claims are encouraged to refer to
these systems when developing substantiation for claims or relying on existing
information. The following provides some commonly accepted scientific
principles in evaluating the quality of scientific evidence.

What Are the Types of Evidence that May Substantiate a
Claim?

As a general principle, one should think about the type of evidence that
would be sufficient to substantiate a claim in terms of what experts in the
relevant area of study would consider to be competent and reliable. Competent
and reliable scientific evidence adequate to substantiate a claim would
consist of information derived primarily from human studies.

Human studies can be divided into two types: intervention studies
and observational studies.(10) Of these types of studies, 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.

Intervention studies

In intervention studies, an investigator controls whether the subjects
receive the treatment or intervention of interest in order to test whether
the intervention or treatment supports a pre-determined hypothesis. Firms
should determine the hypothesis that should be supported or tested prior to
identifying supportive documentation or developing a study protocol.
Randomized, double blind, parallel group, placebo-controlled trials offer
the greatest assessment of a relationship between a dietary supplement and
an outcome. Although intervention studies are the most reliable studies for
determining a cause-and-effect relationship, generalizing from such evidence
on selected populations to different populations may not be scientifically
valid. For example, as described in Example 10 above, if there is
evidence to demonstrate a relationship in a specific population (elderly
patients with diagnosed age-related memory problems), then such evidence
should not be extrapolated to a different population (children).

Observational studies

In observational studies, the investigator does not have control over the
exposure to the treatment or intervention of interest. In prospective
observational studies, investigators recruit subjects and observe them
before a particular outcome occurs. In retrospective observational studies,
investigators review the records of subjects and interview subjects after
the outcome has occurred. Retrospective studies are usually considered to be
more vulnerable to recall bias (error that occurs when subjects are asked to
remember past behaviors) and measurement error, but are less likely to
require large sample size, cost, or encounter the ethical problems that may
occur in prospective studies. Types of observational studies include:

Case reports, which describe observations of a single subject or a
small number of subjects.

Case-series studies, which are a descriptive account of a series of
"outcomes" observed over time and reported for a group of subjects. No
control group is described.

Case-control studies, which compare subjects with a condition (cases)
to subjects who do not have the same condition (controls). Subjects are
enrolled based on their outcome rather than based on their exposure.

Cohort studies, which compare the outcome of subjects who have been
exposed to the substance to the outcome of subjects who have not been
exposed.

Cross-sectional (prevalence) studies, which compare, at a single point
in time, the number of individuals with a condition who have been exposed
to a substance to the number of individuals without the condition who were
not exposed to the substance.

Time-series studies, which compare outcomes during different time
periods, e.g., whether the rate of occurrence of a particular outcome
during one five-year period changed during a subsequent five-year period.

Epidemiological studies, which compare the rate of a condition across
different populations.

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

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

Animal studies - Animal studies may provide useful background
on the biological effects of a substance. However, they often have limited
or unknown value in predicting the effect of the substance in humans. Care
should be exercised in extrapolating results obtained in animal research
directly to the human condition. The strongest animal evidence is based on
data from studies in appropriate animal models, on data that have been
reproduced in different laboratories, and on data that give a statistically
significant dose-response relationship. Without any data from human studies,
the results of animal studies alone are not sufficient to substantiate a
claim.

In vitro studies are studies that are done outside a living
body. For example, such studies might examine a product's effect on isolated
cells or tissues. These studies are of limited value in predicting the
effect of a substance when consumed by humans. The strongest in vitro
evidence would be based on data that have been reproduced in different
laboratories, but this evidence alone would not substantiate a claim.

Testimonials and other anecdotal evidence - This type of
evidence includes descriptions of experiences of individuals using a dietary
supplement product or ingredient. It might also include descriptions of the
use of the product or ingredient by others, for example, by other cultures
in the past or present. It might consist of an opinion or statement of an
expert or someone who endorses the product. Anecdotal evidence generally
would not be sufficient to substantiate claims regarding a dietary
supplement's effect because each individual's experience might be
attributable to factors other than the dietary supplement itself. For
example, a person might have experienced a placebo or coincidental effect,
rather than an effect attributable to the dietary supplement itself.
Additionally, the "honest opinion" of a consumer testimonial or an expert
endorsement would not be enough to substantiate a claim; rather, the
endorsement should also be supported by competent and reliable scientific
evidence.

Meta-analysis is the process of systematically combining and
evaluating the results of clinical trials that have been completed or
terminated. Meta-analysis may identify relevant reports, which may provide
substantiation for the claim.

Review articles summarize the findings of primary reports.
Review articles may identify relevant primary reports, which may provide
substantiation for the claim. Review articles may also provide background
information that is useful to understand the scientific issues about the
relationship between the substance and the claimed effect.

Comments and Letters to the Editor usually focus on a
particular issue or issues from a study, presentation at a meeting etc.
Comments generally do not present the results of a study. Comments and
letters to the editor may identify relevant primary reports, which may
provide substantiation for the claim. Comments and letters to the editor may
also provide background information that is useful to understand the
scientific issues about the relationship between the substance and the
claimed effect.

Product monographs are prepared by the manufacturer to convey
specific information about a product such as its specifications. Product
monographs may provide background information that is useful to understand
the scientific issues about the relationship between the substance and the
claimed effect.

Example 13: A dietary supplement claim states,
"Data suggest that including Substance X in the diet may promote brain neuron
health in healthy individuals." The firm cites a study in which rats were fed
diets containing Substance X and the brains of all rats were examined for
ischemia-induced brain damage. The study does not provide a basis that
Substance X would have the same effect on brain health in otherwise healthy
humans. This study alone likely would not provide adequate substantiation of
the claim being made because it relies solely on animal data.

Example 14: A dietary supplement claim states,
"Grain Y has been used effectively for centuries to promote gastrointestinal
health." The firm has no clinical studies in humans, but has an industry
monograph that relies only on historical descriptions of grain Y use by
pre-modern civilizations. Although the monograph may be an accurate review of
the historical use of grain Y, it would likely not constitute competent and
reliable evidence to support the claim because it is not based on objective
scientific evidence. Rather, it is largely anecdotal evidence that cannot be
objectively evaluated to determine if it applies to the consumers who would
use the product.

Example 15: A dietary supplement label claims
that, in laboratory tests (i.e., in vitro tests), the enzymes in the
supplement can digest up to 20 grams of protein and 15 grams of dietary fat,
and the firm is promoting the supplement to assist in breaking down protein
and fat that its users eat. The firm has not tested its product or the
ingredients in the supplement in humans. Although this evidence may be
accurate, it would generally not be adequate substantiation for the claimed
effects on dietary components because it is insufficient for reaching a
conclusion on whether the enzymes, when consumed, would behave equivalently in
the human body. Corroborating evidence from some human studies would likely be
needed to determine if the in vitro findings reflect the outcomes of the
product when consumed by humans.

Example 16: A botanical product label uses the
claim "improves vitality." The substantiation that the firm is relying upon
consists of testimonial experience it has collected from consumers and
descriptions of the botanical product's traditional use. Although the firm may
have testimonial experience to back up the basic claim being made, the claimed
benefit would likely not be adequately substantiated because neither source is
based on scientific evidence. If the firm wants to make a claim of this type,
we recommend that it have scientific evidence that some measurable outcome(s)
associated with the general conditions cited in the claim is (are)
significantly improved.

What Design Factors Affect the Quality of a
Study?

Multiple factors should be considered in study design. These include, but
are not limited to:

Bias, confounders, and other limitations - Potential sources of
bias include lack of appropriate randomization and blinding, the number of
subjects called for in the protocol vs. the number of subjects who actually
participated in the trial, demographics, adequacy of primary variables,
compliance, control agent, drop-outs, statistical procedures, subgroup
analysis, safety issues, and reproducibility of results. Confounders are
factors that are associated with the outcome in question and the
intervention and prevent the measured outcome from being attributed
unequivocally to the intervention. Potential confounders include variability
in the quantity of the dietary supplement being administered or the presence
of other dietary ingredients that may have their own independent effects.
These factors can limit the reliability of the study.

Quality assessment criteria - Factors that contribute to higher
quality studies include:

Adequacy and clarity of the design

The questions to be answered by the study are clearly described at
the outset.

The methodology used in the study is clearly described and
appropriate for answering the questions posed by the study.

The duration of the study intervention or follow-up period is
sufficient to detect an effect on the outcome of interest.

Potential confounding factors are identified, assessed, and/or
controlled.

Subject attrition (subjects leaving the study before the study is
completed) is assessed, explained, and reasonable.

Population studied

The sample size is large enough to provide sufficient statistical
power to detect a significant effect. (If the study is underpowered, it
may be impossible to conclude that the absence of an effect is not due
to chance.)

The study population is representative (with respect to factors such
as age, gender distribution, race, socioeconomic status, geographic
location, family history, health status, and motivation) of the
population to which the claim will be targeted.

The criteria for inclusion and exclusion of study subjects were
clearly stated and appropriate.

The study used recruitment procedures that minimized selection bias.

For controlled interventions, the subjects were randomized. If
matching was employed to assign the subjects to control and treatment
groups, appropriate demographic characteristics and other variables were
used for the matching. The randomization was successful in producing
similar control and intervention groups.

Assessment of intervention or exposure and outcomes

The analytical methodology and quality control procedures to assess
dietary intake are adequate.

The dietary supplement serving size is well defined and appropriately
measured.

The background diets to which the dietary supplement was added, or the
control and interventional diets, are adequately described, measured, and
suitable.

In studies with cross-over designs, the "wash-out" period (the period
during which subjects do not receive an intervention) between dietary
supplement exposures is appropriate. Lack of a sufficient wash-out period
between interventions may lead to confusion as to which intervention
produced the health outcome.

The form and setting of the intervention are representative of the way
the product will be normally used.

Other possible, concurrent changes in diet or health-related behavior
(weight loss, exercise, alcohol intake, and smoking cessation) present
during the study that could account for the outcome identified are
assessed and/or controlled.

The study's outcomes are well defined and appropriately measured

Efforts were made to detect harmful as well as beneficial effects.

Data Analysis and Assessment

Appropriate statistical analyses were applied to the data.

"Statistical significance" was interpreted appropriately.

Relative and absolute effects were distinguished.

Peer Review - The nature and quality of the written report of
the research are also important. Although studies or evidence used to
substantiate a claim do not have to be published in a peer-reviewed journal
or publication, such publications do give some level of assurance that
qualified experts have reviewed the research and found it to be of
sufficient quality and validity to merit publication. In contrast, an
abstract or informal summary of an article is less reliable, because such
documents usually do not give the reader enough insight into how the
research was conducted or how the data were analyzed to objectively evaluate
the quality of the research data and the conclusions drawn by the authors.
Moreover, the mere fact that the study was published does not necessarily
mean that the research is competent and reliable evidence adequate to
substantiate a particular claim.

Example 17: A dietary supplement label claims,
"Randomized, double blind, placebo-controlled studies demonstrate that herbal
extract 'Z' is beneficial in relieving menopausal symptoms." The firm is
relying on the results of more than one randomized, double blind,
placebo-controlled intervention study using menopausal women as subjects, and
the results of those studies are in general agreement. The claim would likely
be substantiated because it relies on high quality studies in humans that
directly addressed conditions described in the claim.

E. Consider the Totality of the Evidence

How Well Does the Totality of Evidence Support the
Claims?

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.

To determine whether the available scientific evidence is adequate to
substantiate a claim, it is important to consider all relevant research, both
favorable and unfavorable. 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. If conflicts or inconsistencies exist in the scientific
evidence, one should determine whether there are plausible explanations for
such conflicts or inconsistencies. For example, an inconsistency between two
studies might be attributable to different concentrations of the dietary
supplement, different test methodologies, different study populations,(11) or other factors.

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 makes it more likely that
the totality of the evidence will support a claim.

Although the quality of individual pieces of evidence is 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.

Example 18: A firm intends to promote an herbal
product "X" to "help maintain cognitive performance" of people who are
fatigued. The firm has researched the scientific literature and found many
studies that demonstrate that the botanical ingredient is effective. However,
there are some studies that demonstrate no effect. Still other studies
examined the botanical ingredient combined with other ingredients, typically
caffeine, which demonstrated mixed positive and negative results. Many reports
do not adequately describe the study participants and products examined.
Consequently, it is not possible to explain the disparate results. However,
the firm's review suggests that either the botanical and/or caffeine are the
most likely dietary ingredients that act to maintain better cognition test
results in fatigued study participants. As a result, the firm conducts a
large, randomized, placebo-controlled study to compare the botanical
ingredient against caffeine in the treatment of cognitive performance deficits
associated with fatigue. The results demonstrate that caffeine improved
cognition test results in all of the fatigued subjects that received caffeine,
while test performance was unaffected in all subjects receiving the botanical
ingredient. The study cannot explain the results reported in the earlier
studies; however, it demonstrates that the botanical ingredient studied is
most likely ineffective for improving or maintaining cognitive performance in
fatigued people.

Example 19: A firm plans to promote its herbal
product "to effectively relieve occasional, nocturnal leg cramps." The firm
has one study demonstrating the product to be effective in ameliorating
nocturnal leg cramps. The firm is also aware of several other randomized
controlled trials that do not show a benefit. All these studies are of equal
quality and used similar patient populations and test materials. When
considered as a whole, even though some evidence to support the claim exists,
the totality of the evidence does not support the proposed claim. If no
plausible explanation can be found to explain the disparate results, the
available evidence would probably not be considered adequate to substantiate
the claim.

Example 20: An herbal product is promoted "to
help you get to sleep when you have difficulty falling asleep." The firm has
one randomized, placebo-controlled study in volunteers who had trouble falling
asleep. The study showed that those who used the product decreased the amount
of time needed time to fall asleep. There are several other high-quality
studies, however, that found that the herbal ingredient used in the product
did not consistently help people get to sleep. It is not clear whether the
different results of the various studies are a consequence of differences in
product formulation or dosage or some other factor. Even though the firm's
single study is positive, it may not provide adequate substantiation because
the totality of existing evidence suggests that the herbal ingredient does not
decrease time to fall asleep in persons who have trouble falling asleep. Given
the contrary evidence against the claim, it is unlikely that this
sleep-related claim would be substantiated for this product.

Example 21: A company plans to promote its
product containing ingredient X to athletes "to improve endurance
performance." There are some well-designed published studies demonstrating
that other products containing ingredient X are effective, but other
well-designed studies show no effect for certain products containing
ingredient X. The firm sponsored a randomized, blinded, six-month study
comparing its product to four other products containing ingredient X in a dose
(serving size)-response fashion. The findings demonstrate that the firm's
product and two other products that provided the highest amount of ingredient
X per day produced substantial, statistically significant improvements in
athletic endurance. When the firm compared the results of this study to prior
studies, the firm concluded that the explanation for previous conflicting
study results is that when the serving size of ingredient X is below a certain
amount, there is no measurable benefit. Taken together, the positive results
from their study, and the identification of a plausible explanation to explain
why some studies showed no positive effects, would likely provide evidence to
substantiate adequately the endurance performance claim for the dietary
supplement.

F. Conclusion

Section 403(r)(6) of the Act requires dietary supplement manufacturers to
have substantiation that structure/function, nutrient deficiency, and general
well-being claims on a dietary supplement product's labeling are truthful and
not misleading. To meet this statutory requirement, we recommend that
manufacturers possess adequate substantiation for each reasonable
interpretation of the claims. We intend to apply a standard that is consistent
with the FTC standard of "competent and reliable scientific evidence" to
substantiate a claim. We consider 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)?

III. Paperwork Reduction Act of 1995

This guidance contains information collections that are subject to review by
the Office of Management and Budget (OMB) under the Paperwork Reduction Act of
1995 (44 U.S.C. 3501-3520).

The time required to complete this information collection is estimated to
range from 44 to 120 hours per response, depending on the nature of the claim,
including the time to review instructions, search existing data sources, gather
the data needed, and complete and review the information collection. Send
comments regarding this burden estimate or suggestions for reducing this burden
to:

Office of Nutrition, Labeling, and Dietary Supplements,
HFS-800
Center for Food Safety and Applied Nutrition
Food and Drug
Administration
5100 Paint Branch Parkway
College Park, MD 20740

An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays a
currently valid OMB control number. The OMB control number for this information
collection is 0910-0626 (expires 08/31/2011).

(1) The Office of Nutrition, Labeling, and Dietary
Supplements in FDA's Center for Food Safety and Applied Nutrition prepared this
guidance document.

(2) Under section 403(r)(6)(A) of the Act (21 U.S.C.
343(r)(6)(A)), such a statement is one that "claims a benefit related to a
classical nutritional deficiency disease and discloses the prevalence of such
disease in the United States, describes the role of a nutrient or dietary
ingredient intended to affect the structure or function in humans, characterizes
the documented mechanism by which a nutrient or dietary ingredient acts to
maintain such structure or function, or describes general well-being from
consumption for a nutrient or dietary ingredient...."

(3) Comments to the Draft Guidance published November
9, 2004 (69 FR 64942), questioned the constitutionality, under the First
Amendment, of the substantiation requirement in section 403(r)(6), as
interpreted by the Draft Guidance. This Guidance offers FDA's non-binding
interpretation of what constitutes substantiation and does not change the
statutory or Constitutional requirement in any way. We believe the statutory
substantiation requirement in section 403(r)(6) is constitutional under the
Supreme Court's analysis governing commercial speech in Central Hudson Gas &
Electric Corp. v. Public Service Commission of New York (447 U.S. 557 (1980)).
Claims made under section 403(r)(6) are misleading when made without
substantiation. The misleading nature of a claim made under section 403(r)(6)
that is not substantiated cannot be cured by a disclaimer stating that the claim
lacks support. For example, a product cannot claim "to promote the structure and
function of the skeletal system" and then attempt to cure the misleading nature
of the claim with a statement "no evidence exists that this product promotes the
structure and function of the skeletal system." However, nothing in this
Guidance addresses the circumstances under which a claim made under section
403(r)(6) that includes qualifying language may be substantiated.

(4) This guidance does not discuss the criteria to
determine whether a statement about a dietary supplement is a structure/function
claim under section 403(r)(6) of the Act or a disease claim. Please see the
Federal Register of January 6, 2000 (65 FR 1000, codified at 21 CFR
101.93) (www.cfsan.fda.gov/~lrd/fr000106.html)
for the final rule defining structure/function claims for dietary supplements
and the January 9, 2002 Small Entity Compliance Guide for structure/function
claims (www.cfsan.fda.gov/~dms/sclmguid.html)(Updated
web reference: Structure/Function
Claims; Small Entity Compliance Guide).

(5) See Report of the Commission on Dietary Supplement
Labels, November 1997, at page 42. The Commission's recommendations on
substantiation are at pages 42 through 45 of the report.

(6) See Bureau of Consumer Protection, Federal Trade
Commission, "Dietary Supplements: An Advertising Guide for Industry," April 2001
(hereinafter referred to as "FTC Advertising Guide"), available at
www.ftc.gov.

(7) See, e.g. Vital Basics, Inc., C-4107
(Consent April 26, 2004); see also In Re Schering Corp., 118 F.T.C.
1030, 1123 (1994).

(8) For example, a study using a conventional food or a
multi-nutrient supplement would not substantiate a single ingredient dietary
supplement claim. When the substance studied contains many nutrients and
substances, it is difficult to study the nutrient or food components in
isolation (Sempos, et al., 1999). It is not possible to accurately determine
whether any observed effects of the substance were due to: 1) the substance
alone; 2) interactions between the substance and other nutrients; 3) other
nutrients acting alone or together; or 4) decreased consumption of other
nutrients or substances contained in foods displaced from the diet by the
increased intake of foods rich in the substance at issue. Furthermore, although
epidemiological studies based on the recorded dietary intake of conventional
foods have indicated a benefit for a particular nutrient, it has been
subsequently demonstrated in an intervention study that the single ingredient
nutrient-containing dietary supplement did not confer a benefit or actually was
harmful. See Lichtenstein and Russell, 2005. We note that the D.C. Circuit Court
in Pearson v. Shalala, 164 F.3d 650, 658 (D.C. Cir. 1999) indicated
that FDA had "logically determined" that the consumption of a dietary supplement
containing antioxidants could not be scientifically proven to reduce the risk of
cancer where the existing research had examined only foods containing
antioxidants as the effect of those foods on reducing the risk of cancer may
have resulted from other substances. The court, however, concluded that FDA's
concern with granting antioxidant vitamins a qualified health claim could be
accommodated by simply adding a prominent disclaimer noting that the evidence
for such a claim was inconclusive given that the studies supporting the claim
were based on foods containing other substances that might actually be
responsible for reducing the risk of cancer. Id. The court noted that FDA did
not assert that the dietary supplements at issue would "threaten consumer's
health and safety." Id. at 656. As the agency has stated in the context of
qualified health claims, that is, claims regarding the relationship between a
substance and the reduced risk of a disease, there is a more fundamental problem
with allowing qualified health claims for nutrients in dietary supplements based
solely on studies of foods containing those nutrients than the problem the D.C.
Circuit held could be cured with a disclaimer. As noted in endnote 3, even if
the effect of the specific component of the food constituting the dietary
supplement could be determined with certainty, recent scientific studies have
shown that nutrients in food do not necessarily have the same beneficial effect
when taken in the form of a dietary supplement. Such studies established either
that there was no benefit when the nutrients are taken as a supplement and some
studies even showed an increased risk for the very disease the nutrients were
predicted to prevent. We would expect similar issues with structure/functions
claims made under § 403(r)(6). Thus, an observational study based on food does
not provide competent and reliable scientific evidence for a dietary supplement
and, and therefore, cannot substantiate a claim made under § 403(r)(6).

(9) See "Systems to Rate the Strength of Scientific
Evidence. Evidence Report/Technology Assessment Number 47, "Agency for
Healthcare Research and Quality and Research (AHRQ), Publication No. 02-E016,
April 2002.

(10) See Spilker, B. Guide to Clinical
Trials. Raven Press, New York, 1991.

(11) For example, with respect to human drug products,
it is fairly well known that children and the elderly may experience different
drug effects compared to those seen in the adult population. These differences
may be due to physiological differences (such as hormonal differences,
differences in kidney function, etc.) between children, adults, and the
elderly.

This document supercedes the previous (draft) version, issued November
2004.

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