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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 *** Energy Drink,
Free *** Energy Drink, and Cut *** 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 ***
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.