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Muscle-Building Workout and Diet

Hello. I’m Kenneth Taylor from the Division
of Dietary Supplement Programs at FDA’s Center for Food Safety
and Applied Nutrition. This division of FDA is responsible for developing policy,
regulations, and providing
regulatory guidance for dietary supplements. In this presentation, I am going
to provide some fundamentals of FDA’s current
regulatory requirements for marketing dietary
supplements in the
United States. The United States Congress enacted The Dietary Supplement
Health and Education Act, or DSHEA, and amended the Federal Food, Drug,
and Cosmetic Act, or the Act, to provide the FDA
with a systematic framework for regulating
dietary supplements apart from conventional
food and drug products. It was also Congress’ intent that information
on dietary supplements would become more readily available
to promote wellness. DSHEA did not exempt supplements
from regulation, nor did it limit FDA’s
enforcement abilities. Furthermore,
DSHEA did not compromise the rigor of new
drug-development incentives, as evidenced
by the nature of claims that may be made
for dietary supplements. This overarching intent
forms the basis for the regulatory approaches
regarding dietary supplements with respect
to acceptable ingredients and the statements
that may be made about them. Successful regulation
of dietary supplements requires that FDA
interpret DSHEA correctly. However, since there is
no detailed legislative history of DSHEA, FDA relies in part on the
plain language of the statute and congressional findings
in its analysis. Additionally, FDA also considers
relevant case law and court decisions. Generally, FDA tries
to balance congressional intent with consumer protection
when developing regulatory policy. DSHEA defines dietary supplements,
including dietary supplements under the Act’s
adulteration provisions, and establishes requirements
for new dietary ingredients that may be used
in dietary supplements. A fundamental principle
of the Act is that the relevant article
of a product in commerce is primarily determined
and regulated by its intended use. Therefore, a requirement
for a dietary supplement is that it must be intended
to supplement the diet. Neither the Act
nor legislative history explains this terminology. Thus, FDA has looked
to ordinary definitions and the congressional findings
of DSHEA to interpret it. To illustrate,
the common definition of “diet” is “the usual food
or drink of humans.” In developing DSHEA, Congress mentioned
the importance of nutrition and the benefits
of dietary supplementation for health promotion
and disease prevention. Therefore, for an article
to be a dietary supplement, FDA interprets that to mean it is to augment the diet
to promote health. In addition to describing the intended use
of dietary supplements, DSHEA also defined the nature
of the substances which can be considered
as dietary ingredients. Dietary supplements are products,
other than tobacco, which contain dietary ingredients
such as vitamins, minerals, amino acids,
herbs or other botanicals, or other dietary substances
to supplement the diet. They can also be concentrates,
metabolites, constituents, extracts, or combinations
of these ingredients. The variety
of dietary ingredients that may be used
for diet supplementation also do not need to have recognized nutritional value
or significance. In other words, a supplement
may contain ingredients that may or may not have established
Daily Reference Values or Recommended Daily Intake. I would like to explain
that the term “dietary substance” is not a catch-all phrase included in the
“dietary supplement” definition to provide for an unlimited universe
of conceivable substances. Again, it is important
to consider the congressional findings
in DSHEA for guidance and determining Congress’ intent to consider
acceptable dietary substances. Statements such as, “improving the health status
of United States citizens,” “appropriate use of safe
nutritional supplements,” “Dietary supplements are safe
within a broad range of intake,” and, “Safety problems
with supplements are relatively rare,” suggest that dietary ingredients are exclusive
of harmful substances. Also, as I mentioned earlier, FDA has relied upon
the ordinary definition of “usual food or drink”
for “diet” or “dietary.” This would indicate
that not every substance, even though it can be present
in the diet, does not automatically qualify it
as a dietary substance. An example
would be a contaminant, such as a pesticide, or filth, such as insect parts. The intended use
of such substances would not be routine consumption
as usual food. There are some additional
requirements that are consistent with the intended use
of dietary supplements — namely, as food, supplements are
supposed to be taken internally and be present in a form that allows them
to be taken internally. Typical delivery systems
of dietary supplements are pills, liquids, and powders. However, the delivery system
for a dietary supplement may have the form
of a conventional food but must not be represented
for use as a conventional food. The key here is to understand
intended use again, as I will come back to momentarily. But other requirements
demonstrating intended use are that supplements
cannot be the sole item of the meal or diet, although they may be used
as part of a meal, and they must be labeled
as a dietary supplement. Two important points
must be considered with respect to the intended use
of dietary supplements and augmenting the usual or common
food and drink of humans. With respect to supplements
being intended for ingestion, the judicial courts
in the United States have looked to
the plain-language meaning of the term “ingestion”
and interpreted it to mean “to take into
the gastrointestinal tract.” Consequently, external products or those taken orally
but absorbed prior to swallowing are excluded
from the statutory definition. Secondly, I indicated earlier
that dietary supplements may have the form
of conventional foods because, in effect, the form
is serving as a delivery system. How a food is represented is derived
from the actual message presented by the packaging
and labeling that conveys intended use — whether or not the product
is either a supplement or a conventional food. The packaging or labeling, through names, pictures, directions,
or other means, may suggest that
the intended use of the product is a conventional food
rather than a supplement. There have been
several instances by which FDA has articulated
its position with manufacturers who have misrepresented
conventional foods as dietary supplements. As examples,
while a dietary supplement may be in either the form
of a cereal or soup, actually labeling them as “cereals”
or “supplement soups” makes them conventional foods
because these are terms that are inextricably linked
with conventional food use. Similarly, chewing gum
and drinking water are respectively defined
in the Act and regulation as conventional food. FDA has also published a draft
guidance for public comment describing its current thinking
as to whether a liquid product may be labeled and marketed
as a dietary supplement. Data taken from the 2005-2006 National Health and Nutrition
Examination Survey on daily intake of drinking water
and other beverages in the United States suggests that the total
daily fluid intake per person is about 1.2 liters. Therefore, FDA has concluded
that liquid products that suggest through
their serving size, packaging, or Recommended Daily Intake that if they are intended
to be consumed in amounts that provide all
or a significant part of the entire
daily drinking-fluid intake of an average person
in the United States, then they are represented
as beverages and not dietary supplements. In addition,
the name of a product can represent the product
as a conventional food. Product or brand names
that use conventional food terms such as “beverage,” “drink,” “water,” “juice,”
or similar terms represent the product
as a conventional food and not a dietary supplement. Lastly, under the drug
exclusion clause of DSHEA, a substance cannot become
a dietary supplement if it is approved or authorized
for investigation as a drug unless it was first marketed
as a food or supplement. This exclusion clause is intended primarily
to protect incentives for sponsors to develop
and get approved new drugs and to protect consumers
from having failed drugs subsequently marketed
as dietary supplements. Note that over-the-counter drugs
with an approved monograph may be marketed
as dietary supplements provided that there has not been
a new drug application or an investigational new drug prior to marketing
as a supplement. The underlying principle
of the prior market clause that substances which have been
studied for a drug indication or have gained recognition
in the marketplace as new drugs may not be incorporated into or
marketed as dietary supplements is critical that has significantly
influenced FDA regulatory policy. In making regulatory decisions,
identifying the relevant article and determining if it belongs
within one of the defined categories of dietary ingredients
is crucial. Both of the terms “active ingredient”
and “active moiety” are defined in regulation. The active ingredient
and active moiety are similar in that they pertain
to conferring physiological or pharmacological activity. The difference between
these terms, however, is that “active ingredient” pertains to the entire
relevant article or component, whereas “active moiety” refers to the actual portion
of an active ingredient that has physiological significance. The active ingredient
and the active moiety may be the same or may differ. Two matters in particular — the court decision involving
the Pharmanex product Cholestin and FDA’s response to Biostratum’s Citizen Petition
about Pyridorin — demonstrate
the Agency’s approach to determining the relevant article
in a dietary supplement or a related drug product. In the case of Pharmanex,
the product Cholestin was marketed
as a dietary supplement. The sole ingredient in Cholestin
was red yeast rice, which is a dietary ingredient. However, unlike traditional
red yeast rice, the red yeast rice of Cholestin had been manufactured to contain
high amounts of lovastatin, which is also
the active ingredient of the prescription drug Mevacor. Mevacor is an approved drug
to lower cholesterol. In addition to manufacturing
Cholestin to contain lovastatin, Pharmanex also marketed Cholestin
for its lovastatin content. In this situation, FDA determined
that lovastatin was an article approved as a new drug
within the prior market clause because it is the active ingredient
in Mevacor. Also, by marketing Cholestin
for its lovastatin content, Pharmanex was marketing lovastatin, and therefore
lovastatin was an article marketed as a dietary supplement
under the prior market clause. Therefore, FDA concluded
that Cholestin was excluded from the
“dietary supplement” definition because the approval of Mevacor
as a new drug preceded marketing of lovastatin
as a dietary supplement. The Pharmanex case did not present
the active-moiety issue because the active ingredient and the active moiety
of the article were the same. However, with the Investigational
New Drug Application, or IND, for Pyridorin, the active ingredient
and the active moiety differ. Although pyridoxamine
dihydrochloride is the substance that is actually described
in the IND for Pyridorin, the substance
that is actually being studied for physiological
or pharmacological activity is pyridoxamine,
which is the active moiety. There is no verifiable
contemporaneous evidence documenting that
pyridoxamine dihydrochloride or any other compound containing pyridoxamine
as the active moiety was marketed
as a dietary supplement or food prior to investigation
as a new drug. The mere presence of a substance authorized for investigation
as a new drug that may be a component of a product
found in the food supply does not by itself establish that the substance
has been actually marketed. According to the plain language
of the drug exclusion clause, it must be established that marketing a product containing
such component, the component itself
must also have been marketed. It has been argued that pyridoxamine
is a dietary ingredient because it is one
of the three primary natural forms of vitamin B6. However, this argument
confuses the prior market clause with the requirement
that a dietary supplement contain one or more
dietary ingredients. Pyridoxamine
is a dietary ingredient, but it is also excluded from
the “dietary supplement” definition with respect
to the prior market clause. Because the elements
of the “dietary supplement” definition are phrased conjunctively, a product qualifies
as a dietary supplement only if it satisfies the criteria of all parts
of the statutory definition. As a result, and under
the prior market clause, FDA has concluded that products containing
the active moiety pyridoxamine are not dietary supplements. Aside from just considering
the potential impact for products
that may contain pyridoxamine, this particular precedent indicates that FDA will focus
on the active moiety of substances when making
regulatory decisions. Successful regulatory policy
of dietary supplements also requires consideration
of the products themselves. This includes
combination drug products and establishing
ingredient limits. FDA has not established
definitive policy on drug/dietary supplement
combination products since it is still developing policy
and reviewing combination products on a case-by-case basis. In the January 6, 1993,
preamble of the final rule on General Requirements
for Health Claims for Food, FDA addressed concerns such as
dual labeling, safety, efficacy, and intended use. At that time,
the Agency had no way to harmonize a nutrient-content claim
or a health claim with drug labeling and potentially
conflicting instruction on use. As a result, FDA’s current position,
although not final, is to regulate combinations
of drugs and dietary supplements as unapproved new drugs. FDA has also articulated that products which use terminology
and product labels that refer to illicit street drugs do not meet the definition
for dietary supplements and cannot be legally marketed
as such. Products such as
Cocaine Energy Drink, Free Cocaine Energy Drink,
and Cut Cocaine Energy Drink indicate that these are intended
as alternatives to or associated with
illicit street drugs. Illicit street drugs are not intended
to supplement the diet, but are used
for recreational purposes to affect physiological states. Also, since these products
are identified as drinks, they are represented
as conventional foods and not dietary supplements. However, because such products
may suggest to consumers that they are related to
or mimic the effects of cocaine and that they are intended to affect the structure
or function of the body, they are subject to regulations under the drug provisions
of the Act. Another aspect
that FDA may consider when regulating
dietary supplements is establishing the limits
of certain ingredients. Potassium and iron
are two noteworthy examples. FDA has not established
any upper limit for potassium in dietary supplements. However, FDA withdrew approval
of the New Drug Application in 1992 for oral products
containing potassium chloride due to safety concerns
about small-bowel lesions associated with the use of concentrated
solid oral dosage forms. So even though potassium salts may be generally recognized
as safe, it seems unlikely that potencies associated
with small-bowel injury are within the scope
of safe use. Similarly, the use of iron
in prenatal drugs failed the drug
Good Manufacturing Practices, or GMPs, on inspection. As a result,
without new drug applications, labeling iron products
as a prescription drug would make such products
unapproved drugs. So in the absence
of established limits, dietary-supplement manufacturers are responsible for ensuring
the safety of their products. In the case of iron, if a product is going to
be labeled for prenatal use, then it should reflect
what is recommended by experts qualified
in the field. Dietary ingredients that were not marketed either
as dietary supplements or in food prior to the enactment of DSHEA require a New Dietary Ingredient
Notification. FDA does not maintain
an official list of dietary ingredients. The manufacturer or distributor
is responsible for determining whether or not
a dietary ingredient has been marketed
in the United States. A dietary supplement
is adulterated unless it contains
dietary ingredients that have been present
in the food supply as an article used for food and in a form that has not
been chemically altered. The Act defines “food” to include food or drink
for humans or other animals, chewing gum,
and component articles. There is no definition
for “chemically altered.” However, the Congressional Record
of DSHEA shows that “chemically altered” does not pertain
to physical modifications such as minor loss
of volatile components, dehydration,
lyophilization, milling, a tincture or solution in water,
slurry, powder, or a solid suspension. If the ingredient has not been present
in the food supply without chemical alteration, then a New Dietary Ingredient
Application, or NDI, is required. This notice
serves to demonstrate that the new dietary ingredient is
acceptable for food use under the conditions
suggested in its labeling through establishing
either a history of use or other evidence of safety. Additionally,
the notice must demonstrate that a new food article is one of the six dietary ingredients
defined in the Act. DSHEA also modified the Act to permit certain claims to be made
for dietary supplements. I am going to provide a brief overview
of the types of claims that may be used in labeling
of dietary supplements. However, I emphasize
that it is important that when claims are made
for a product, manufacturers should review
the underlying statutory provisions, regulations, and guidance
that govern their use. Doing so will provide
a more reliable basis to conclude that a particular claim
is permissible, much better than just relying
on intuition or similar examples that may
be observed in the marketplace. DSHEA does not authorize
statements or claims which suggest
that dietary supplements are intended to diagnose, cure,
mitigate, treat, or prevent disease. Such claims,
whether explicit or implicit, indicate that the intended use
of the article is a drug. FDA has defined
the term “disease” or “health-related condition”
through regulation. Articles which are used
for treatment of damaged and dysfunctional organs,
parts, structures, or other systems are drugs. Health claims describe a relationship
between a substance and the reduction
of risk of a disease. Health claims authorized by the Nutrition Labeling
and Education Act of 1990 are characterized by having
significant scientific agreement to demonstrate their validity. These types of claims are developed
through petitioning FDA and authorized by formal regulation. In order to use a health claim, at a minimum,
a food like a dietary supplement must also contain 10%
of the daily value per serving of the six core nutrients
of vitamins A and C, calcium, iron, protein, and fiber. Statements may also be made
for supplements that also describe
a diet-and-disease relationship when there is insufficient scientific
agreement to support the claim. However,
these qualified health claims must be stated
with sufficient clarity so to avoid
misleading consumers. For such claims, the Agency uses a systematic series
of disclaimers to describe the reliability
of the available scientific evidence which may support
a particular claim. Nutrition support statements,
or structure/function claims, may also be made
for both supplements and conventional foods, but different requirements apply
to each commodity category. Structure/function claims can
be made for conventional foods as provided in section 201(g)(1)(c)
of the Act, which is also one
of the definitions for drugs. That provision defines a drug as, “an article, other than food, intended to affect any structure
or function of the body of man or animals.” The “other than food” exception
is important. Thus a structure/function claim
can be made for a food if the claimed benefit
derives from it being a food. This has been interpreted
to mean that the primary characteristic
for something being a food is that it is used
for its taste, aroma, or nutritive value. Such claims do not require
prior review or approval by FDA. Generally, under DSHEA,
dietary supplements are limited to claims on classical
nutrient-deficiency diseases, effects on structure
or function of the body, mechanism of effect
on structure/function, and general well-being. It is important to note that statements made
for dietary supplements are not limited
to serious health conditions for them to be considered disease
claims, and the criteria
may include signs/symptoms that do not require a drug or doctor. The regulation
for structure/function claims does not define
or provide an exhaustive list of appropriate statements. However, its preamble presents
at length FDA’s consideration into developing
the final rule document and provides some guideline. Nevertheless, these
nutrition support statements can only be made if they can
be adequately substantiated. In order to articulate appropriate
or acceptable evidence to substantiate
a nutrition support statement, FDA published
a guidance document to describe the amount, type,
and quality of evidence recommended for a manufacturer
to have. The guidance does not establish legally enforceable responsibilities
on FDA’s part, but rather describes
the Agency’s current thinking toward substantiating
structure/function claims. In developing
the substantiation guidance, FDA drew upon its own expertise
to the regulations and case law, the U.S. Federal Trade Commission’s
experience and policy on dietary-supplement
claims made in advertising, and recommendations from the Commission
on Dietary Supplement Labels. The Federal Trade Commission,
or 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’s approach
is to apply a standard that is consistent
with the FTC approach. FDA’s guidance describes criteria
to be considered in evaluating the nature of the claim,
as well as the amount, type, and quality of evidence
in support of the claim. FTC case law defines
the standard of competent and reliable scientific
evidence 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.” There is no
pre-established formula as to how many
or the types of studies which are needed
to substantiate a claim. To determine the quantity
and type of appropriate studies necessary for substantiation, FDA considers the accepted norms in consultation with experts
from various disciplines or, if available, an existing standard
for substantiation by either a government agency
or other authoritative body. FDA recommends four areas
of consideration for assessing
if the substantiation standard has been achieved with competent
and reliable evidence. These include the meaning
of the claim, the relationship between
the evidence and the claim, the quality of the evidence,
and the totality of the evidence. In order to determine
what is needed to substantiate a claim
for a dietary supplement, the claim’s meaning
must be understood by identifying each implied
and expressed claim. In situations where a claim may have more than one
reasonable meaning, then there should be substantiation
for each interpretation. When determining
a claim’s meaning, focus should not be exclusively
on individual statements, but also on the overall message when all statements
are collectively considered. Consumer testing may be useful to determine
consumer understanding in context. It is also important to consider
the relationship of studies or evidence to a claim. To illustrate,
studies used to support a claim should be similar
in formulation, serving size, length and frequency
of exposure, as well as be conducted
under conditions as those indicated on the labeling
of the actual product. There should be accounting
for the presence of other substances, whether naturally present
in the study as artifacts or in the subject product, that might affect the dietary
supplement’s performance or the study results itself, and if the studies used
an appropriate population. The studies should also specify
measured end points used to substantiate
the claimed effect. Finally,
dietary-supplement manufacturers should evaluate if the claim conveys
the extent, nature, or permanence of the effect and the level
of scientific certainty. The scientific quality
of studies is important when deciding adequate
substantiation of a claim. Scientific quality is based
upon several criteria, including study population factors, including number, age, gender,
and health, how the study is designed
and conducted, including utilization
of placebo controls, data-collection methods,
statistical analysis, and outcome measures. If a scientific study adequately
addresses most or all criteria, then it could be considered
high-quality. The gold standard is randomized,
double-blind, placebo-controlled trial design. However, such trials
may not always be possible, practical, or ethical. Reliable scientific evidence that is adequate
to substantiate a claim will consist of information
primarily derived from human studies. Human studies can be divided
into two categories — intervention studies
and observational studies. Intervention studies
provide direct evidence to substantiate the effect of
a dietary supplement in humans because an investigator controls the subjects’ exposure
to the treatment in order to validate
a predetermined hypothesis. Again, these studies should include
double-blind, parallel, placebo-controlled trials
to offer the greatest assessment between a dietary supplement
and its outcome. However, generalizing
from among populations may not be scientifically valid. Observational studies
do not afford the investigator control of exposure
to the treatment of interest and thus have
a more limited ability than intervention studies to establish the effects
of a substance. A common example
for an observational study is a case-control study, which compares subjects
with a condition to those who do not have
the same condition. Subjects are enrolled based on
outcome rather than exposure. Some information
has limited usefulness to substantiate
dietary-supplement claims. Animal and in-vitro studies may provide useful
background information on the biological effects
of a substance but often have limited
or unknown value in predicting the effect
in humans. Care should be taken when
extrapolating animal research directly to human condition. Multiple factors can affect
a study’s design and should be considered when determining the reliability
of the study. Potential sources of bias include
lack of appropriate randomization and blind controls, the number of subjects,
demographics, and reproducibility of results. Confounders include variability
in dosage quantity or the presence
of other substances that may have
independent effects. Factors that contribute
to study reliability include quality assessment criteria
like population assessment, which considers aspects
like size and if it is representative
of which the claim will be targeted. Assessment of intervention
or exposure outcomes, which addresses parameters like defined and appropriately
measured dosing and efforts to detect harmful,
as well as beneficial effects, tend to support
improving study quality. And finally,
although not required, publication in peer-reviewed journals
also adds some level of assurance that qualified experts
have reviewed the research and found it to be of sufficient
quality and validity, albeit the mere fact that
a study happens to be published is not necessarily an indicator that the research is competent
and reliable evidence to adequately substantiate
a particular claim. When determining
if there is adequate evidence to substantiate a claim, all evidence should
be considered in entirety. This includes considering
all relevant research, whether favorable
or unfavorable. The evidence used
to substantiate a claim should be consistent with
the surrounding body of evidence. As conflicting
or inconsistent results can undermine the validity
of a claim, plausible explanations
should be attempted to reconcile discrepancies. Disagreement among studies
could be attributed to variables such as concentration, assay
methods, or study populations. Lastly,
there is no specific guideline for the number of studies
or the combination of evidence that will sufficiently
support a claim. However, replication
of research results in independently conducted studies increases the likelihood that
the evidence supports the claim. In this presentation
I have tried to show that DSHEA is a complex
and dynamic law. The challenge for FDA to effectively regulate dietary
supplements in the United States involves trying
to balance statutory intent with consumer protection. Establishing regulatory policy
is a multifaceted approach that can present challenges to include determining
relevant articles in products, evaluating
a constantly expanding array of novel products and dosages, and ensuring the validity
of stated claims is based upon
substantiated evidence. Thank you.

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