[Federal Register Volume 65, Number 4 (Thursday, January 6, 2000)]
[Rules and Regulations]
[Pages 1000-1050]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 00-53]



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Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 101



Regulations on Statements Made for Dietary Supplements Concerning the 
Effect of the Product on the Structure or Function of the Body; Final 
Rule

Federal Register / Vol. 65, No. 4 / Thursday, January 6, 2000 / Rules 
and Regulations

[[Page 1000]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. 98N-0044]
RIN 0910-AB97


Regulations on Statements Made for Dietary Supplements Concerning 
the Effect of the Product on the Structure or Function of the Body

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing final 
regulations defining the types of statements that can be made 
concerning the effect of a dietary supplement on the structure or 
function of the body. The regulations also establish criteria for 
determining when a statement about a dietary supplement is a claim to 
diagnose, cure, mitigate, treat, or prevent disease. This action is 
intended to clarify the types of claims that may be made for dietary 
supplements without prior review by FDA and the types of claims that 
require prior authorization as health claims or prior approval as drug 
claims.

DATES: The final rule will become effective February 7, 2000.

FOR FURTHER INFORMATION CONTACT: Ann Marlin Witt, Office of Policy, 
Planning, and Legislation (HF-11), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-0084.

SUPPLEMENTARY INFORMATION:

 I. Introduction

     In the Federal Register of April 29, 1998 (63 FR 23624), FDA 
proposed regulations to identify the types of statements that may be 
made without prior FDA review about the effects of dietary supplements 
on the structure or function of the body (``structure/function 
claims''), and to distinguish these claims from claims that a product 
diagnoses, treats, prevents, cures, or mitigates disease (disease 
claims). FDA received over 235,000 submissions in response to the 
proposed rule. Many of these were form letters, but over 22,000 were 
individual letters from the dietary supplement industry, trade 
associations, health professional groups, and consumers. Almost all the 
comments from the dietary supplement industry and from individuals, 
which made up the vast majority of the comments, objected to all or 
part of the proposed rule, arguing that it inappropriately restricted 
the structure/function claims that could be made for dietary 
supplements. Most of the comments from health professional groups and 
groups devoted to particular diseases supported the proposed rule, or 
believed it did not go far enough in limiting structure/function claims 
for dietary supplements.
     After reviewing the comments, FDA concluded that the comments had 
raised significant questions about some of the key provisions of the 
proposal such that a public meeting was warranted. In the Federal 
Register of July 8, 1999 (64 FR 36824), FDA announced a public meeting 
to be held on August 4, 1999, at which representatives of the dietary 
supplement industry, consumer groups, and health professionals were 
asked to address three major issues raised by the comments. The three 
issues, described in the Federal Register notice, were: (1) Whether to 
finalize the proposed definition of ``disease'' or retain a 1993 
definition of ``disease or health-related condition'' that was in 
effect at the time the Dietary Supplement Health and Education Act 
(DSHEA) was enacted; (2) whether to modify one of the proposed criteria 
for assessing disease claims to permit structure/function claims 
related to certain conditions associated with natural states, such as 
hot flashes associated with menopause and decreased sexual function 
associated with aging; and (3) whether to permit implied disease claims 
structure/function claims. The July 8, 1999, notice also reopened the 
comment period until August 4, 1999, to receive written comments on 
these three issues.
     This document addresses the comments received on the proposed 
rule, as well as comments received in response to the July 8, 1999, 
Federal Register notice. A few comments raised issues that are beyond 
the scope of this rule and generally will not be addressed in this 
document.

 A. Highlights of the Final Rule

     Like the proposed rule, the final rule contains criteria to 
determine when a labeling statement made about a dietary supplement 
constitutes a structure/function claim for which no prior FDA review is 
required and when it constitutes a disease-related claim that requires 
either authorization of a health claim or review under the drug 
provisions of Federal Food, Drug, and Cosmetic Act (the act). FDA has, 
however, made several important changes in the final rule in response 
to comments.
     First, the agency has deleted the proposed definition of 
``disease.'' Rather than creating a new definition of disease, FDA will 
use the preexisting definition of ``disease or health-related 
condition'' in Sec. 101.14(a)(5) (21 CFR 101.14(a)(5)) (formerly 
Sec. 101.14(a)(6)), which was issued as part of the implementation of 
the health claims provisions of the Nutrition Labeling and Education 
Act (NLEA). This change has been made in response to the large number 
of comments that objected to the proposed definition and urged that FDA 
retain the NLEA definition.
     Second, FDA has revised the criterion that applies to conditions 
associated with such natural states or processes as menopause, aging, 
adolescence, and pregnancy. The proposed rule stated that menopause, 
aging, and pregnancy are not themselves diseases but that certain 
conditions associated with them are diseases if they are recognizable 
to consumers or health professionals as abnormal. Many comments 
objected to classifying as diseases such common conditions as hot 
flashes, premenstrual syndrome (PMS), and decreased sexual function 
associated with aging. In response to these comments, FDA has revised 
proposed Sec. 101.93(g)(2)(iii). Common conditions associated with 
natural states or processes that do not cause significant or permanent 
harm will not be treated as diseases under the final rule. For example, 
hot flashes, common symptoms associated with the menstrual cycle, 
ordinary morning sickness associated with pregnancy, mild memory 
problems associated with aging, hair loss associated with aging, and 
noncystic acne will not be treated as diseases under this provision. 
Uncommon or serious conditions like senile dementia, toxemia of 
pregnancy, severe depression associated with the menstrual cycle, and 
cystic acne will continue to be treated as diseases under the final 
rule.
     Third, FDA has revised the criterion that relates to the use in 
labeling of the titles of publications that refer to diseases. In 
response to comments objecting that, as proposed, this criterion would 
hamper manufacturers from providing consumers with information 
substantiating their claims, FDA has revised this criterion. Under the 
revised criterion, the use in labeling of a publication title that 
refers to a disease will be considered a disease claim only if, in 
context, it implies that the product may be used to diagnose, treat, 
mitigate, cure, or prevent disease. Highlighting, bolding, using large 
type size, or prominent placement of a citation that refers to a 
disease use in the title could suggest that the product has an effect 
on disease. Placing a citation to a scientific reference that refers to 
a disease in the title on the

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immediate product label or packaging will be considered a disease claim 
for that product. The agency will also consider whether the cited 
article provides legitimate support for the express structure/function 
statement made for that dietary supplement. Enhancing the bibliography 
with citations to scientific references that refer to a disease in the 
title and that have no reasonable relation to the statement made will 
be considered a disease claim. Similarly, the agency will consider 
whether citations are to bona fide research.

 B. Background

     DSHEA created a new regime for the regulation of dietary 
supplements. These products were previously regulated either as foods 
or as drugs, depending upon whether they had the attributes of food and 
upon their intended uses. Before the passage of DSHEA, a dietary 
supplement for which a health-related claim was made was regulated 
either as a drug, which had to be shown to be safe and effective before 
marketing, or as a food, for which prior authorization to make a health 
claim was required if the claim concerned a disease or health-related 
condition. If the claim concerned a non-disease-related effect on the 
structure or function of the body and the claimed effect derived from a 
food attribute, such as nutritive value, the claim was considered a 
food claim, and prior authorization was not required. Under section 
201(g)(1)(B) and (g)(1)(C) of the act (21 U.S.C. 321(g)(1)(B) and 
(g)(1)(C)), a drug is defined as ``an article intended for use in the 
diagnosis, cure, mitigation, treatment, or prevention of disease,'' or 
``an article (other than food) intended to affect the structure or any 
function of the body.'' Section 505 of the act (21 U.S.C. 355) requires 
that new drugs (see section 201(p) of the act) be shown to be safe and 
effective for their intended uses before marketing. Under sections 
403(r)(1)(B) and (r)(5)(D) of the act (21 U.S.C. 343(r)(1)(B) and 
(r)(5)(D)) and Sec. 101.14, prior authorization is required to make a 
health claim for a dietary supplement. A health claim is a claim that 
``characterizes the relationship of any nutrient * * * in the food to a 
disease or health-related condition'' (section 403(r)(1)(B) of the act; 
see Sec. 101.14(a)(1)).
     DSHEA specifically authorized certain types of claims about the 
uses of dietary supplements, including some claims that formerly would 
have required review by FDA before the claim is made. Section 403(r)(6) 
of the act, added by DSHEA, allows dietary supplement labeling to bear, 
among other types of statements, a statement that ``describes the role 
of a nutrient or dietary ingredient intended to affect the structure or 
function in humans'' or that ``characterizes the documented mechanism 
by which a nutrient or dietary ingredient acts to maintain such 
structure or function.'' Such statements are generally referred to as 
``structure/function claims.'' Because many of these claims would 
previously have been covered by the drug definition in section 
201(g)(1)(C) of the act, section 201(g)(1) was amended by DSHEA to 
provide that a dietary supplement ``for which a truthful and not 
misleading statement is made in accordance with section 403(r)(6) is 
not a drug under clause (C) solely because the label or the labeling 
contains such a statement.''
     Although a dietary supplement manufacturer who wishes to make a 
statement permitted under section 403(r)(6) of the act need not obtain 
prior review of the statement, the manufacturer must possess 
substantiation that the statement is truthful and not misleading, and 
must include in the statement the following disclaimer: ``This 
statement has not been evaluated by the Food and Drug Administration. 
This product is not intended to diagnose, treat, cure, or prevent any 
disease.'' DSHEA also requires the manufacturer of a dietary supplement 
bearing a statement under section 403(r)(6) of the act to notify FDA, 
no later than 30 days after the first marketing of the dietary 
supplement with the statement, that such a statement is being made for 
the product. Regulations implementing these requirements were published 
in the Federal Register of September 23, 1997, and are codified at 
Sec. 101.93 (21 CFR 101.93) (62 FR 49883 at 49886, September 23, 1997).
     DSHEA did not alter the statutory treatment of dietary supplement 
claims related to disease (``disease claims''). Section 403(r)(6) of 
the act, specifically provides that statements permitted under that 
section ``may not claim to diagnose, mitigate, treat, cure, or prevent 
a specific disease or class of diseases,'' except that such statements 
may claim a benefit related to a classical nutrient deficiency disease, 
provided that they also disclose the prevalence of the disease in the 
United States. Consistent with the quoted provision, Congress did not 
modify section 201(g)(1)(B) of the act to exclude disease claims for 
dietary supplements from use as evidence of intended use as a drug, as 
it had done for section 201(g)(1)(C) of the act. Thus, dietary 
supplements ``intended for use in the diagnosis, cure, mitigation, 
treatment, or prevention of disease'' remain within the definition of a 
``drug.'' In enacting DSHEA, Congress also maintained the requirement 
of prior authorization of a claim that characterizes the relationship 
of a nutrient in a dietary supplement to a disease (section 
403(r)(1)(B) and (r)(5)(D) of the act). An interested person may submit 
a petition to FDA requesting the agency to issue a regulation 
authorizing the health claim (see Sec. 101.70 (21 CFR 101.70)). The 
petitioner must demonstrate, among other things, that the use of the 
substance at levels necessary to justify the claim is safe and that 
there is ``significant scientific agreement'' among qualified experts 
that the claim is supported by the totality of publicly available 
scientific evidence (Sec. 101.14(b)(3)(ii) and (c)). The agency notes 
that for health claims to be used on conventional foods, an interested 
person may submit to FDA a notification of an authoritative statement 
by one of certain designated scientific bodies concerning the 
substance-disease relationship to which the claim refers (see section 
403(r)(3)(C) of the act). Unless FDA issues a regulation modifying or 
prohibiting the claim, or a Federal district court finds that 
applicable statutory requirements have not been met, the claim may be 
used 120 days after the notification has been submitted (see section 
403(r)(3)(C)(ii) and (r)(3)(D) of the act). This alternative 
authorization procedure does not apply to dietary supplements by 
statute, but FDA has proposed to extend it to dietary supplements by 
regulation (see 64 FR 3250, January 21, 1999).
     Although FDA believes that dietary supplements have potential 
benefits for consumers, dietary supplements labeled with unproven 
disease claims, i.e., those that have not met the requirements for 
health claim authorization or new drug approval, can pose serious 
risks. Such claims may encourage consumers to self-treat for a serious 
disease without benefit of a medical diagnosis or treatment. They may 
also cause consumers to substitute potentially ineffective products for 
proven ones, foregoing or delaying effective treatment for serious and 
life-threatening illnesses. Reliance on disease prevention claims may 
encourage consumers to feel sufficiently protected from developing 
serious diseases (e.g., cancer or human immunodeficiency virus (HIV) 
infection) that they delay or forego regular screening, and forfeit the 
opportunity for early medical treatment that may be critical to 
survival. Finally, use of dietary supplements to treat

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disease may increase the risk of adverse reactions due to the 
interaction of the dietary supplement with other compounds a consumer 
is taking for that disease or for other conditions, e.g., prescription 
medications.
     This final rule is intended to apply only to structure/function 
claims and disease claims within the meaning of section 403(r)(6) of 
the act. DSHEA, generally, and section 403(r)(6) of the act, 
specifically, apply only to dietary supplements for human consumption 
and were enacted to provide a unique regulatory regime for these 
products. Thus, this rule is neither intended to apply to products 
other than dietary supplements for human consumption nor to interpret 
other provisions of the act.
     The final rule establishes criteria for determining whether a 
statement made about a dietary supplement is acceptable as a structure/
function claim under section 403(r)(6) of the act. The rule is neither 
intended to establish whether any particular structure/function claim 
is appropriate for any specific product, nor whether the claim would be 
permitted under other provisions of the act. Like the labeling of any 
other FDA-regulated product, the labeling of dietary supplements must 
comply with all applicable requirements of the act and regulations. For 
example, an otherwise acceptable structure/function claim might 
nevertheless be false or misleading for other reasons, causing the 
product to be misbranded under section 403(a)(1) of the act.

 C. The Proposed Rule

     The proposed rule defined criteria for determining when a 
statement about a dietary supplement is a claim to diagnose, cure, 
mitigate, treat, or prevent disease (``disease claim''), and thus 
requires prior approval as a drug or prior authorization as a health 
claim. The proposed rule included a definition of ``disease,'' which 
was to replace a definition of ``disease or health-related condition'' 
issued for implementation of the health claims regulations, and 10 
criteria for identifying express or implied disease claims. FDA 
proposed to treat a statement about a dietary supplement as a disease 
claim if the statement claimed, explicitly or implicitly, that the 
product: (1) Has an effect on a specific disease or class of diseases; 
(2) has an effect, using scientific or lay terminology, on one or more 
signs or symptoms that are recognizable to health care professionals or 
consumers as being characteristic of a specific disease or of a number 
of different specific diseases; (3) has an effect on a consequence of a 
natural state that presents a characteristic set of signs or symptoms 
recognizable to health care professionals or consumers as constituting 
an abnormality of the body; (4) has an effect on disease through one or 
more of the following factors: (a) The name of the product; (b) a 
statement about the formulation of the product, including a claim that 
the product contains an ingredient that has been regulated by FDA as a 
drug and is well known to consumers for its use in preventing or 
treating a disease; (c) citation of a publication or reference, if the 
citation refers to a disease use; (d) use of the term ``disease'' or 
``diseased;'' or (e) use of pictures, vignettes, symbols, or other 
means; (5) belongs to a class of products that is intended to diagnose, 
mitigate, treat, cure, or prevent a disease; (6) is a substitute for a 
product that is a therapy for a disease; (7) augments a particular 
therapy or drug action; (8) has a role in the body's response to a 
disease or to a vector of disease; (9) treats, prevents, or mitigates 
adverse events associated with a therapy for a disease and manifested 
by a characteristic set of signs or symptoms; or (10) otherwise 
suggests an effect on a disease or diseases.
     Claims that did not fall within the proposed criteria for disease 
claims and that otherwise complied with the notification and disclaimer 
provisions of Sec. 101.93(a) through (e) were to be eligible for use as 
structure/function claims. The proposed rule also provided examples of 
claims that would be permitted as structure/function claims and those 
that would require prior review as disease claims under each of the 10 
criteria.
     The basis for the proposed rule was the agency's experience in 
implementing section 403(r)(6) of the act, and the final report (the 
report) of the President's Commission on Dietary Supplement Labels 
(Ref. 1), which included a number of recommendations for distinguishing 
structure/function and disease claims and suggested that FDA issue 
further guidance on acceptable structure/function claims.

 II. Comments

 A. General Comments

     (1.) Many comments focused on the impact of the rule on consumers. 
Many comments opposing the proposed rule said that consumers should be 
able to receive truthful and non-misleading information and that the 
proposed rule would curtail or restrict such information or restrict 
the focus of dietary supplements to preventive care and wellness. Some 
comments added that DSHEA, through the dissemination of truthful and 
non-misleading information on health and promotion and disease 
prevention, makes consumers responsible for their own health. Other 
comments said that FDA should let the public educate itself. Other 
comments suggested that FDA simply adopt a ``truthful and non-
misleading'' standard. Some comments added that full disclosure of all 
pertinent information (such as the preliminary status of scientific 
studies substantiating the claim) would be sufficient. Another comment 
questioned whether consumers would, as the preamble to the proposed 
rule stated, benefit from not having to search for information and from 
getting appropriate information. The comment argued that consumers 
would receive less information under the rule and would have to search 
more extensively for information.
     Many comments supporting the proposed rule, including comments 
from nutrition counselors and health professionals, said that the 
proposal would reduce confusion among patients, prevent consumers from 
being misled, diminish the number of inappropriate disease claims, and 
help consumers decide when to seek medical attention. One comment added 
that, while it supported the need for consumers to have choice 
regarding dietary supplements, the choice should be made based on 
accurate information that is supported by appropriate scientific 
investigations. One comment argued that in the absence of valid 
effectiveness data, which does not exist for most dietary supplements, 
it is not possible to provide ``truthful'' information about the 
effects of these products. Some comments said that the proposal would 
protect consumers from harmful or potentially harmful products and save 
consumers from needless suffering and financial loss; others expressed 
concern that inappropriate statements would expose consumers to 
potentially harmful drug-supplement interactions, create ``false 
hopes,'' and lead consumers to stop complying with advice from health 
care professionals or to avoid proven treatments.
     FDA agrees that DSHEA encourages the dissemination of truthful and 
non-misleading information about the uses of dietary supplements to 
affect the structure or function of the body, and encourages full 
disclosure of information about claims authorized by the statute. To 
the extent that truthful and non-misleading information is being 
withheld from consumers in the context of structure/function claims for 
dietary supplements, it is the statute that, in the first instance, 
precludes

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certain information from being included in such claims. Section 
403(r)(6) of the act permits dietary supplement labels to carry 
structure/function claims without meeting the requirements for drug 
approval or health claim authorization, but precludes them from 
carrying unreviewed claims that the product diagnoses, treats, 
mitigates, cures, or prevents disease. (The statute does not ultimately 
prevent dissemination of information about disease uses to the consumer 
in labeling claims or otherwise. Instead, it requires that claims about 
disease uses meet certain standards of substantiation and undergo 
agency review.) This final rule differentiates between structure/
function claims authorized by section 403(r)(6) of the act and disease 
claims that may not be made in dietary supplement labeling under the 
authority of section 403(r)(6). The agency notes that, in response to 
comments, the final rule classifies many more claims as structure/
function claims than would have been so classified under the proposed 
rule, thus increasing the amount of information available to the 
consumer without prior FDA review.
     The agency also declines to adopt a ``truthful and non-
misleading'' standard instead of the final rule. Section 403(a)(1) of 
the act already subjects all food claims, including structure/function 
claims on dietary supplements, to the ``truthful and non-misleading'' 
standard, so promulgating the same standard through regulations is 
unnecessary. In addition, section 403(r)(6)(B) of the act already 
requires dietary supplement manufacturers to have substantiation that 
their statements are truthful and non-misleading. Finally a fundamental 
problem with this approach is that a ``truthful and non-misleading'' 
standard, unlike the final rule, would not provide any criteria for 
differentiating between structure/function claims and disease claims.
    (2.) Some comments focused on product safety. One comment said that 
regulation of claims is unnecessary because dietary supplements are 
safe. Similarly, another comment claimed that ``one million peer-
reviewed studies'' showed that dietary supplements provide benefits, 
whereas a recent medical journal reported deaths and other injuries to 
patients who use prescription drugs. Other comments declared that 
dietary supplements are safer than most regularly-used drug products. 
In contrast, other comments argued that the safety of many dietary 
supplements is unknown, and that risks have been documented with some 
supplements. Some comments claimed that dietary supplements pose risks 
because they can cause consumers to avoid or delay more effective 
treatment. One comment stated that there is a substantial potential for 
public harm because of the unknown or unregulated source materials for 
many dietary supplements, the variety of suppliers, and the lack of 
regulatory production standards and quality control.
     Although this final rule may not appear to be a safety measure 
because it addresses the labeling of dietary supplements rather than 
their composition, protecting consumer health and safety is one of its 
major purposes. Because structure/function claims are not subject to 
the new drug approval standard or the health claim authorization 
standard and do not undergo FDA review before marketing, FDA believes 
it is important to ensure that such claims do not promote products for 
disease treatment or prevention claims. Disease treatment or prevention 
claims can pose serious risks to consumers if they induce consumers to 
substitute ineffective or less effective treatments for proven ones, 
especially if the disease involved is serious or life-threatening. 
Therefore, the agency believes that ensuring that such claims cannot be 
made without a demonstration of safety and effectiveness will protect 
and promote public health.
     FDA also believes that the safety and the effectiveness of 
products intended to promote health, including both dietary supplements 
and drugs, cannot be viewed independently of each other. FDA agrees 
that prescription drugs can and do cause adverse reactions. It is 
important to remember, however, that ``safety'' is relative. Products 
that are capable of treating diseases have powerful effects on the body 
and frequently carry risks. Before prescription drugs are marketed, 
both their risks and their benefits must be carefully investigated and 
documented in adequately designed clinical trials. Prescription drugs 
are permitted to be marketed only when the agency concludes that their 
documented benefits outweigh their known and potential risks. Those 
with significant risks are approved for marketing only if the benefits 
warrant those risks. And they are marketed as ``prescription'' drugs to 
ensure that health professionals manage their risks. Even over-the-
counter (OTC) drugs are evaluated for both benefits and risks and are 
permitted to be marketed only when their established benefits outweigh 
their risks. There is no comparable testing and approval process for 
dietary supplements marketed with structure/function claims. The 
manufacturer must have substantiation of the structure/function claim, 
but this substantiation is not reviewed before the product is marketed 
with the claim. Contrary to the suggestion in the comment, few dietary 
supplements have been the subjects of adequately designed clinical 
trials.
     This does not mean that dietary supplements are unsafe or that 
they do not have benefits. Some have already been shown to be safe and 
to have benefits, and the safety and effectiveness of others are likely 
to be shown in the future. At this time, however, many marketed 
supplements have not been the subjects of adequate studies to establish 
whether or not they are safe or effective, or the nature of the 
benefits they may provide.
    (3.) Many comments asserted that FDA had no authority to issue the 
proposed rule because it was inconsistent with DSHEA and congressional 
intent, in that it restricted rather than increased the amount of 
information given to consumers. Some comments said that Congress 
enacted DSHEA to reverse FDA's ``overly restrictive'' approach towards 
health claims and to increase the dissemination of truthful and non-
misleading health information and that Congress repeatedly expressed 
its displeasure with FDA's regulatory approach. One comment said FDA 
must determine whether a proposed action is consistent with its 
statutory authority before it takes any regulatory action. The comment 
cited excerpts from congressional documents ``condemning the agency's 
repeated penchant'' for restricting statements on dietary supplement 
labels and labeling, and said that, given congressional intent and the 
act's language, FDA has no authority to proceed with rulemaking without 
a grant of authority from Congress. One comment cited section 403B of 
the act (21 U.S.C. 343-2) as evidence that Congress, by exempting 
certain publications from the definition of labeling, barred FDA from 
restricting in ``any way whatsoever'' the dissemination of such 
publications and information.
     FDA agrees that DSHEA was intended to authorize the dissemination 
of more truthful and non-misleading information in dietary supplement 
labeling without the need for prior agency review. In response to 
comments that the proposed rule was too restrictive, FDA has modified 
the final rule to incorporate many of the changes requested by the 
comments, including a return to the preexisting definition of ``disease 
or health-related condition,'' and a less restrictive interpretation of 
the types of structure/function claims

[[Page 1004]]

that can be made about conditions associated with such natural states 
as aging, pregnancy, and the menstrual cycle. The final rule classifies 
many more claims as structure/function claims than the proposed rule 
would have.
     The agency does not agree, however, that section 403(r)(6) of the 
act authorizes dissemination of any and all information about dietary 
supplements without prior review. That section authorizes statements 
about the effects of dietary supplements on the structure or function 
of the body, but not statements that claim to diagnose, mitigate, 
treat, cure, or prevent a specific disease or class of diseases. 
Section 403B of the act exempts from being considered labeling certain 
balanced, third-party publications that are physically separate from 
product labeling and do not promote a particular brand or product. This 
provision does not authorize dietary supplement manufacturers to ignore 
the restrictions in section 403(r)(6) of the act on what structure/
function claims may be made by a manufacturer about its product on the 
product label and in materials that are indisputably part of the 
product's labeling.
     The agency also disagrees with the assertion that separate 
congressional authority is needed for this rulemaking. FDA issued the 
proposed rule, and this final rule, to implement section 403(r)(6) of 
the act. No independent authority to issue these regulations is 
necessary because section 701(a) of the act (21 U.S.C 371(a)) expressly 
gives FDA ``the authority to promulgate regulations for the efficient 
enforcement of this Act, except as otherwise provided in (section 701 
of the act) * * *.'' The proposed rule identified section 701(a) of the 
act as being part of the agency's legal authority (see 63 FR 23624 at 
23628 and 23631), and there is no exception in the act that restricts 
or limits, either expressly or impliedly, the agency's ability to issue 
regulations to implement section 403(r)(6) of the act. Therefore, the 
rule is authorized by law and consistent with FDA's statutory 
authority.
     (4.) Some comments contended that FDA did not provide a sufficient 
justification for issuing the rule. Two comments challenged FDA's 
assertion that the rule would reduce substantial confusion among 
manufacturers. The comments referred to statements in the preamble to 
the proposed rule which said FDA received approximately 2,300 
notifications of structure/function claims and sent objection letters 
to approximately 150 notifications. One comment said the low objection 
rate did not indicate ``substantial confusion'' among manufacturers, 
while the other comment hypothesized that, if FDA objected to a small 
number of claims in each notification, the number of objectionable 
claims was very small. Other comments contended that the Commission 
report did not support the proposed rule. These comments were divided 
in their reasons. Some comments argued that the Commission exceeded its 
statutory mandate under section 12 of DSHEA or failed to perform its 
statutory obligations. Thus, the comments stated, FDA cannot base any 
regulation on the Commission's findings, guidance, or recommendations 
and has no authority to proceed with the rulemaking. Other comments 
stated that FDA relied on statements from individual Commission members 
rather than the report itself, that the report did not suggest that FDA 
issue regulations, and that the report did not suggest that FDA issue a 
new definition of disease. One comment said that the Commission did not 
support a need for regulations. Another comment noted that the 
Commission did not recommend regulations and asserted that FDA had 
publicly said that DSHEA is self-implementing.
     FDA does not agree that there is insufficient support for this 
rule. FDA's experience, the Commission report, and FDA's authority 
under section 701(a) of the act to issue regulations implementing 
statutory requirements provide more than adequate support for the rule. 
The preamble to the proposed rule referred to substantial confusion 
among manufacturers and consumers, rather than manufacturers alone. 
Comments received from other sources, particularly physicians, 
dieticians, and health professional organizations, agreed that 
consumers are confused and misled by claims. In addition, the number of 
objection letters is not the sole indicator of manufacturer confusion, 
for three reasons. First, manufacturers and consumers have asked FDA to 
provide clarification on structure/function and disease claims, and 
such requests for clarification would not necessarily have resulted in 
an objection letter from FDA. Second, the agency has repeatedly said 
that the absence of an objection letter does not necessarily indicate 
acceptance of the claim. Third, there are apparently a large number of 
marketed dietary supplement products making claims for which FDA has 
not received 30-day notification letters under section 403(r)(6) of the 
act. (In the proposed rule, FDA estimated that approximately 22,500 
dietary supplement labels carried structure/function claims. FDA had 
received 2,300 notifications at the time of the proposed rule. While 
some notifications contain more than one claim, they do not average 10 
claims per notification.)
     FDA also does not agree that the Commission report was necessary 
to provide support for this rule. The proposal was based not only on 
the Commission report, but also on the agency's experience in reviewing 
30-day notification letters submitted under section 403(r)(6) of the 
act (63 FR 23624 at 23625). Although FDA believes the rule is 
consistent with the views expressed in the Commission report, the 
Commission report was not a necessary prerequisite for the agency to 
issue the rule. FDA issued the proposal under section 403(r)(6) of the 
act (section 6 of DSHEA) and the rulemaking authority of section 701(a) 
of the act, not under section 12 of DSHEA. FDA takes no view on whether 
the Commission met its statutory obligations in issuing its report. To 
the extent that the report is beyond the Commission's authority, FDA's 
experience and section 701(a) of the act provide adequate support for 
the rule. Thus, whether or not the Commission exceeded its mandate is 
irrelevant to the validity of the rule.
     With regard to the issues raised about the consistency of the 
agency's approach with the Commission report, it is true that the 
Commission did not specifically recommend regulations, but the 
Commission did express the view that FDA guidance on claims under 
section 403(r)(6) of the act would be ``appropriate and helpful in 
clarifying the appropriate scope'' of such claims (the report, p. 38).
     As to the agency's public statements that DSHEA is self-
implementing, the comment took those statements out of context. When 
DSHEA was passed, there was confusion in the industry about whether the 
types of statements permitted by section 403(r)(6) of the act could be 
made under the authority of the statute alone, in the absence of 
implementing regulations. To clear up this confusion, at least one 
agency official publicly said that DSHEA was ``self-implementing.'' 
Agency statements to this effect were intended to clarify that 
manufacturers were not required to wait for FDA to issue implementing 
regulations before making claims under section 403(r)(6) of the act; 
however, they were in no way intended to imply that the agency lacked 
authority to issue implementing regulations.
     Contrary to the suggestion in one of the comments, FDA did not 
rely on the views of individual Commission members, but on the official 
7-point

[[Page 1005]]

``guidance'' developed by the Commission ``as to what constitutes an 
acceptable statement of nutritional support of the structure function 
type'' (the report at pp. 38 and 39). The criteria developed by FDA are 
highly consistent with the Commission's guidance. FDA also agrees that 
the Commission did not make any findings or recommendations on the 
definition of disease. As described elsewhere in this rule, the final 
rule does not modify the existing definition of disease found in FDA's 
health claims regulations.
    (5.) One comment said that FDA should have admitted that there is 
and will be some overlap between disease and structure/function claims 
and that the agency should have drafted a rule to prevent extreme 
overlap between structure/function claims and drug or health claims.
     FDA disagrees with this comment. In the proposed rule, FDA 
recognized that section 403(r)(6) of the act leaves open questions 
concerning the distinction between structure/function claims and 
disease claims. Diseases cause, and can be characterized as, 
abnormalities in the structure or function of the body. It would 
therefore be possible to describe almost all products intended to treat 
or prevent disease in terms of their effects on the structure or 
function of the body, without mentioning the disease itself.
     The language of DSHEA, however, does not support treating those 
structure/function claims that are also disease claims as statements 
permitted under section 403(r)(6) of the act. As noted above, section 
403(r)(6) of the act contains two passages that indicate Congress' 
intent to exclude from the scope of structure/function claims any claim 
that is also a disease claim. Section 403(r)(6) of the act provides 
that structure/function statements ``may not claim to diagnose, 
mitigate, treat, cure, or prevent a specific disease or class of 
diseases.'' It also requires structure/function claims to be 
accompanied by a disclaimer stating that the product ``is not intended 
to diagnose, treat, cure, or prevent any disease.''
     In light of the statutory framework, FDA concluded in the preamble 
to the proposed rule that section 403(r)(6) of the act authorizes 
claims related to the effect of a product on the structure or function 
of the body only if they are not also disease claims. FDA's conclusion 
was consistent with the policy guidance offered by the President's 
Commission on Dietary Supplement Labels. In the report the Commission 
offered general guidance on structure/function claims, including the 
following:
     3. Statements indicating the role of a nutrient or dietary 
ingredient in affecting the structure or function of humans may be 
made when the statements do not suggest disease prevention or 
treatment.
(The report, p. 38)
     Accordingly, FDA believes that it is appropriate to define the 
universe of permitted structure/function claims by first identifying 
those claims that should be considered disease claims. Remaining claims 
about the effect of a dietary supplement on the structure or function 
of the body may be acceptable structure/function claims under section 
403(r)(6) of the act, provided that they are consistent with the 
requirement in section 201(ff)(1) of the act that a dietary supplement 
be ``intended to supplement the diet.''
    (6.) Some comments, particularly those received at the public 
hearing or during the reopened comment period, argued that it is 
difficult or impossible to draw principled distinctions between 
structure/function claims and disease claims. Some of these comments 
said that section 403(r)(6) of the act, which is premised on such a 
distinction, is not scientifically based. Other comments argued that it 
is not necessary or practical to draw clear lines between disease 
claims and structure/function claims, and that dietary supplement 
labeling should instead focus on educating consumers about the 
conditions for which a product may be used. According to these 
comments, if there are disease conditions that might be implied by a 
particular claim, the labeling should, for example, inform consumers of 
the symptoms of such conditions, the importance of seeking medical 
attention for them, and their health-related consequences. Other 
comments argued that consumers reading the labels of dietary 
supplements will incorrectly assume that the information provided 
therein has been reviewed by the government and that the claims, 
express or implied, are supported by the kind of scientific evidence 
that supports drugs with similar claims.
     FDA agrees that it may be very difficult to draw clear lines 
between structure/function claims and disease claims. Despite the 
difficulty, implementing section 403(r)(6) of the act requires the 
agency to draw these lines. FDA would not be carrying out its statutory 
obligations if it abdicated responsibility for distinguishing between 
the two types of claims, and instead permitted dietary supplements to 
disseminate information about specific disease states. FDA agrees that 
scientifically valid information about diseases is helpful to 
consumers, if it is delivered consistently and accurately, but does not 
agree that section 403(r)(6) of the act authorizes such dissemination. 
FDA strongly believes that the dissemination of such information on 
dietary supplement labels increases the likelihood that consumers will 
believe that the supplements are intended to treat or prevent the 
diseases described in the labeling. Therefore, it is important that any 
disease claims in dietary supplement labeling continue to be subject to 
prior FDA review to evaluate the safety and effectiveness of the 
product for the use described or suggested by the claim.
     The agency also notes that there may be important health-related 
consequences associated with taking a dietary supplement, even if the 
product does not bear disease claims. For the labeling of a dietary 
supplement to be considered truthful and non-misleading (see sections 
403(a) and (r)(6) and 201(g)(1) of the act), it must include all 
information that is material in light of the claims made for the 
product and the consequences that may result from its use (see section 
201(m)) of the act.
     (7.) Many comments discussed the rule's effect on scientific 
research. Some comments argued that the proposal would discourage 
scientific research on dietary supplements. One comment contended that 
such research might prompt FDA to consider a dietary supplement to be a 
drug. Another comment said the proposal would ``chill'' the 
availability of third-party information on dietary supplements.
     The agency disagrees with the comments. The comments provided no 
evidence, and the agency is aware of none, that establishing criteria 
for distinguishing structure/function claims and disease claims will 
adversely affect the conduct or use of scientific research. In the 
agency's experience, establishing regulatory standards has generated 
more research rather than less. As described below, some comments from 
pharmaceutical companies and from patient organizations expressed the 
contrary concern that allowing dietary supplements to make disease 
claims without FDA review would undermine incentives for rigorous 
scientific research. The agency also notes that nothing in this rule 
would treat scientific research or the publication of research results 
in a scientific journal as evidence that a product is marketed as a 
dietary supplement or is a drug.
     (8.) Several comments addressed the relationship between dietary 
supplements and drug products, and the effects of this regulation on 
drug products and drug development. Some comments suggested that the 
proposal represented an attempt by FDA to

[[Page 1006]]

regulate dietary supplements in a manner that benefits pharmaceutical 
interests or to regulate dietary supplements in a manner that is 
similar to European regulatory systems that apply drug requirements to 
such products.
     In contrast, other comments expressed concern over the negative 
effects of DSHEA and the proposed rule on incentives for pharmaceutical 
drug development. One comment asked FDA to provide an ``unambiguous 
demarcation'' that would preserve research and development incentives 
for drug products and permit evaluation of opportunities in the dietary 
supplement marketplace. According to this comment, section 403(r)(6) of 
the act, and DSHEA generally, were intended to create ``parity'' 
between the dietary supplement and food industries without undermining 
research and development incentives for the pharmaceutical industry and 
to address a perceived failure by FDA to implement the health claims 
provision for dietary supplements in section 403(r)(5)(D) of the act. 
The comment contended that section 403(r)(6) of the act is intended to 
provide a limited statutory safe harbor for certain dietary supplements 
that might otherwise be subject to regulation under the health claim 
rules for food or as unapproved new drugs, but it does not permit any 
and all structure/function statements for dietary supplements. Thus, 
the comment said FDA should have ``parallel interpretations'' of 
sections 201(g)(1)(C) and 403(r)(6) of the act. The comment suggested 
that FDA enforce the requirement of a ``documented mechanism'' imposed 
in section 403(r)(6)(A) of the act, which permits claims that 
``characterize the documented mechanism by which a nutrient or dietary 
supplement acts to maintain'' structure or function and that FDA limit 
claims to ``maintaining,'' rather than ``promoting'' or ``improving'' 
structure or function.
     FDA does not agree that this rule was designed to benefit the 
pharmaceutical industry or to establish rules that are consistent with 
European regulation of dietary supplements. As noted above, some 
pharmaceutical companies believe that the rule will harm them by 
permitting competition by products that have not had to undergo 
rigorous testing or review. Other pharmaceutical companies already 
produce dietary supplements and expressed the same reservations about 
the rule as other dietary supplement manufacturers. There was also no 
attempt to model this rule after European regulation of dietary 
supplements.
     FDA recognizes the importance of maintaining incentives for 
research and product innovation. By establishing criteria for 
determining when a statement may be a disease claim, the final rule 
indirectly contributes towards preserving the incentives for 
pharmaceutical research and development by ensuring that products 
marketed for treatment or prevention of diseases must all meet the same 
regulatory standards. As stated below, FDA believes that if the rule 
were to permit dietary supplements to carry implied disease claims, the 
incentives for new drug development could be significantly undermined.
     FDA agrees with the comment that the structure/function provisions 
of sections 403(r)(6) and 201(g)(1)(C) of the act are similar in scope. 
FDA also agrees that to make a statement about the mechanism by which a 
dietary supplement maintains structure or function, the mechanism of 
action must be ``documented.'' FDA does not agree, however, that this 
is the only provision under which a dietary supplement may claim to 
maintain healthy structure or function. Maintenance claims also can be 
made under the provision that authorizes statements that ``describe the 
role'' of a supplement ``intended to affect the structure or function'' 
of the body (section 403(r)(6)(A) of the act).
     In response to the comment asking FDA to limit claims to 
``maintaining,'' rather than ``promoting'' or ``improving,'' structure/
function, the agency agrees that ``improving'' often suggests some 
abnormality or deficiency that can be treated, so a claim to 
``improve'' a structure or function of the body would be more likely to 
be a disease claim. On the other hand, a claim to improve memory or 
strength would be a permitted structure/function claim, unless disease 
treatment were implied. Use of the term ``promote'' may be acceptable 
under the portion of section 403(r)(6)(A) of the act which authorizes 
claims that ``describe[] the role of a * * * dietary ingredient 
intended to affect the structure or function.'' Whether a claim for 
``promoting'' structure or function is a disease claim will depend on 
the context and nature of the claim. For example, a claim that a 
product ``helps promote digestion'' would be a structure/function claim 
because it does not refer explicitly or implicitly to an effect on a 
disease state, but a claim that a product promotes low blood pressure 
would be considered a disease claim. Both the preamble to the proposed 
rule and the Commission recognized that statements using the word 
``promote'' can be appropriate when the statements do not suggest 
disease prevention or treatment or use for a serious health condition 
that consumers cannot evaluate (see 63 FR 23624 at 23626).
    (9.) A few comments objected to the statement that a dietary 
supplement bearing an appropriate structure/function claim may be 
subject to regulation as a drug if there is other evidence that it is 
intended for the diagnosis, cure, mitigation, treatment, or prevention 
of disease. One comment argued that many dietary supplements are used 
for medicinal purposes and it would be ``easy'' for FDA to find 
evidence that they were intended for this purpose based on consumer use 
of the product.
     Although FDA's longstanding interpretation of section 201(g)(1)(B) 
of the act authorizes the agency to rely on evidence outside the 
labeling and advertising of a product to establish its intended use, 
FDA does not rely on such evidence alone except in unusual 
circumstances. For example, the courts have suggested that if the 
agency seeks to rely solely on evidence that consumers use a product 
for a particular purpose to support a finding of intended use for that 
purpose, consumers must use the product predominantly or nearly 
exclusively for that purpose. (See, e.g., Action on Smoking and Health 
(ASH) v. Harris, 655 F.2d 236, 239-240 (D.C. Cir. 1980); National 
Nutritional Foods (NNFA) v. Weinberger, 512 F.2d 688, 702 (2d Cir. 
1975), cert. denied, 423 U.S. 827 (1975).) The fact that some consumers 
used a dietary supplement for medicinal purposes would not by itself be 
sufficient to establish intended use as a drug, if use for medicinal 
purposes was not the predominant use.
     FDA reiterates, however, that in appropriate circumstances, FDA 
may find that a dietary supplement for which only structure/function 
claims are made in labeling may nevertheless be a drug if there is 
other evidence of intended use to prevent or treat disease.
     (10.) Some comments discussed the ``disclaimer'' statement 
required by section 403(r)(6)(C) of the act. The disclaimer reads as 
follows: ``This statement has not been evaluated by the Food and Drug 
Administration. This product is not intended to diagnose, treat, cure, 
or prevent any disease.'' One comment said the disclaimer resolves any 
consumer confusion between dietary supplement claims and drug claims. 
Another comment said the proposed rule showed that FDA was implicitly 
rejecting the disclaimer's meaning because the proposed rule would 
restrict the amount of information flowing to consumers. One comment 
said the disclaimer reflects

[[Page 1007]]

Congress' understanding of a tension between structure/function and 
disease claims, while another comment asserted that the disclaimers 
required on a label are an attempt to decrease the amount of space on a 
label for a structure/function claim.
     Section 403(r)(6) of the act requires dietary supplement 
manufacturers who wish to make a structure/function statement to 
include the disclaimer, and, since 1997, FDA regulations regarding the 
disclaimer have been codified at Sec. 101.93. However, the disclaimer's 
role does not eliminate the need for this final rule to establish 
criteria for determining whether a statement is a disease claim. 
Section 403(r)(6) of the act provides that a statement for a dietary 
supplement that is made under section 403(r)(6) ``may not claim to 
diagnose, mitigate, treat, cure, or prevent a specific disease or class 
of diseases.'' Had Congress thought the disclaimer, alone, was 
sufficient to distinguish between structure/function claims and disease 
claims, it would not have enacted the restriction against disease 
claims in section 403(r)(6) of the act.
     FDA does not agree with the assertion that the disclaimer, which 
is expressly required by the act, is a scheme to decrease the space for 
structure/function claims on a label. FDA believes that the disclaimer 
is intended to make sure that consumers understand that structure/
function claims, unlike health claims and claims that appear on the 
labels of drugs, are not reviewed by FDA prior to marketing, and to 
caution consumers that dietary supplements bearing such claims are not 
for therapeutic uses.
     (11.) Several comments sought additional statements or language on 
product labels. One comment supported the marketing of dietary 
supplements and other substances whose effectiveness has not been 
established and that have no appreciable toxicity as long as the 
product's label stated that effectiveness had not been proven. Another 
comment said precautions, such as adverse reactions and 
contraindications to certain diseases and medications, are important 
information for labels. The comment also sought a description of a 
dietary supplement product's contents as a percentage of a person's 
recommended daily intake (RDI) and in actual units.
     FDA declines to revise the rule as suggested by the comments. With 
regard to the marketing of dietary supplements with a label statement 
that the product's effectiveness has not been proven, the agency 
advises that dietary supplements that do not do what they claim to do 
are misbranded. The act forbids false and misleading labeling and 
advertising claims and requires businesses to have substantiation for 
any structure/function claims they make for dietary supplements in 
labeling (see section 403(a) and (r)(6)(B)) of the act). The presence 
of a disclaimer indicating that effectiveness has not been established 
cannot vitiate these statutory obligations. Therefore, it would be 
inappropriate for FDA to sanction the use of effectiveness disclaimers.
     Although the act does not prescribe any specific statements 
concerning adverse reactions or contraindications that dietary 
supplements must carry, the agency notes that dietary supplement 
labeling, like the labeling of all other FDA-regulated products, is 
required to include all information that is material in light of 
consequences that may result from the use of the product or 
representations made about it (see sections 403(a)(1) and 201(n) of the 
act).
     As for requiring information on the percentage of RDI and actual 
units for dietary ingredients in dietary supplements, FDA agrees that 
such information is useful. In fact, FDA's nutrition labeling 
regulations for dietary supplements generally require the percentage of 
the RDI or daily reference value (DRV) that a dietary supplement 
contains to be given for dietary ingredients that have an RDI or DRV 
(see Sec. 101.36(b)(2)(iii) (21 CFR 101.36(b)(2)(iii))). In addition, 
the amount in units must be given, regardless of whether an RDI or DRV 
has been established (see Sec. 101.36(b)(2) and (b)(3) (21 CFR 
101.36(b)(2) and (b)(3)). This information can be found on the 
Supplement Facts panel of dietary supplements.
     (12.) One comment objected to referring to structure/function 
statements as ``claims.'' The comment said that, under section 
403(r)(6) of the act, such statements must be truthful and non-
misleading, so they should be called ``statements'' instead of 
``claims.''
     FDA has traditionally used the term ``claim'' to refer to any 
statement made by a manufacturer that recommends or suggests a 
particular use of a product. This term is used for all products 
regulated by FDA, including drugs, foods, devices, and dietary 
supplements. Use of the term ``claim'' is not intended to suggest that 
a statement is untrue or misleading in any way.
     (13.) One comment said that any substance used with 
``pharmacologic intent'' should be classified as a drug or biologic in 
order to ensure the efficacy, potency, and purity of medicines. The 
comment explained that such substances have a potential for therapeutic 
benefit as well as harm, and suggested that existing and new dietary 
supplements that are marketed with health-related claims be required to 
provide scientific evidence of their safety and efficacy as a condition 
of their being marketed as a drug or biologic.
     FDA declines to adopt the comment's suggestion. Section 403(r)(6) 
of the act expressly authorizes certain structure/function claims for 
dietary supplements. Many of these claims may be said to be ``health-
related.'' (The agency is uncertain what is meant by ``pharmacologic 
intent.'') Thus, the act does not require all substances with health-
related claims to be classified as a drug or biologic.
     Regarding safety and effectiveness evidence for dietary 
supplements that bear health-related claims, FDA agrees that such 
evidence should continue to be required where the claim is a health 
claim within the meaning of Sec. 101.14(a)(1) or a claim that subjects 
the product to regulation as a drug under section 201(g)(1)(B) of the 
act. With regard to health-related claims that are authorized by 
section 403(r)(6) of the act, section 403(r)(6)(B) does require 
manufacturers to have substantiation for their claims. However, the act 
does not generally require dietary supplement manufacturers that make 
claims for their products under section 403(r)(6) of the act to provide 
a premarket demonstration of safety and effectiveness to FDA.
     (14.) One comment recommended that FDA not finalize the proposed 
rule because it claimed that the proposal's criteria were based on a 
subjective evaluation of claims and not on objective information from 
market research studies to determine whether consumers are confused by 
the claim. The comment also argued that FDA did not provide data and 
information regarding consumer confusion, and that all interested 
parties should be able to evaluate and comment on any data before FDA 
finalizes the proposal. The comment asserted that a significantly 
revised and limited final rule could provide a basic regulatory 
definition of disease and a ``construct'' for structure/function claims 
so that detailed regulatory criteria would be unnecessary.
     The act does not require market research studies to determine 
whether a particular statement is a structure/function claim or disease 
claim, and it would be both impractical and inefficient to require such 
studies to decide the status of every possible claim that could be made 
under section 403(r)(6) of the act. FDA also does not

[[Page 1008]]

believe that market research studies are necessary to provide a 
reasonable basis for the agency's determinations concerning the meaning 
of labeling claims. The agency has extensive experience in interpreting 
such claims. The agency has, however, modified the second criterion in 
Sec. 101.93(g)(2)(ii) to eliminate reference to recognition of signs 
and symptoms by consumers or health professionals because many comments 
objected that this standard would appear to require consumer testing. 
FDA has replaced the recognition standard with an objective standard.
     (15.) One comment said that it would be inappropriate for FDA to 
issue any regulation that restricted the scope of statements of 
nutritional support related to a nutrient content claim or claims 
pertaining to a classical nutrient deficiency-related disease. The 
comment said that claims such as ``calcium builds strong bones'' are 
acceptable and that FDA should clarify this fact in the final rule.
     FDA agrees that dietary supplements may carry structure/function 
statements concerning the relationship of nutrients and the structure 
or function of the body, such as ``calcium builds strong bones.'' The 
preamble to the proposed rule also specifically acknowledged that 
although statements under section 403(r)(6) of the act generally may 
not claim to diagnose, mitigate, treat, cure, or prevent a specific 
disease or class of diseases, ``such statements may claim a benefit 
related to a classical nutrient deficiency disease, provided that they 
also disclose the prevalence of the disease in the United States'' (63 
FR 23624). The final rule codifies this exception at Sec. 101.93(g)(2), 
which states that ``FDA will find that a statement about a product 
claims to diagnose, mitigate, treat, cure, or otherwise prevent disease 
(other than a classical nutrient deficiency disease) * * *'' (emphasis 
added). Classical nutrient diseases are also specifically excluded from 
the definition of disease in Sec. 101.93(g)(1). Thus, because the final 
rule already contains the exception, no change to the rule is 
necessary.
     (16.) Many comments suggested that FDA issue a guidance document 
instead of regulations. Some of the comments stated that regulations 
are neither desirable nor necessary. Others stated that a guidance 
document would be appropriate because it would permit new information 
to support new structure/function claims or because it would enable FDA 
to conduct consumer research and industry outreach programs before 
imposing new rules. Some comments also requested separate guidance 
documents for specific claims or recommended that FDA create or use 
advisory committees to help draft guidance documents. Two comments said 
that the Commission report only provided guidance and suggestions, so 
FDA did not have to issue the proposed rule. Another comment said that 
publishing a guidance document would consume fewer agency resources and 
that a rule is unnecessary because the industry already knows the 
permissible scope of statements for dietary supplements.
     FDA disagrees with the comments. The final rule creates uniform, 
enforceable requirements for structure/function claims. By doing so, 
the final rule establishes a ``level playing field'' for all members of 
the dietary supplement industry, and permits rational use of FDA's 
limited enforcement resources. In contrast, guidance documents, 
although they represent FDA's best advice on a particular matter, are 
not binding on any party. Relying solely on guidance documents would 
not be as effective in achieving consistency in the regulation of 
structure/function claims on dietary supplements and would lead to 
case-by-case enforcement.
     FDA does, however, intend to issue a guidance document to provide 
additional information regarding structure/function and disease claims. 
The guidance document would complement, rather than substitute for, the 
final rule.
     As for those comments stating that a guidance document would 
permit new information to support new structure/function claims or that 
outreach programs are necessary, FDA notes that interested persons may 
generate such information regardless of the rule. FDA may also conduct 
research or other programs or consult advisory committees or other 
persons if such actions would be helpful. In short, gathering more 
information or conducting research and other programs is not dependent 
on whether FDA issues a guidance document instead of a rule.
     (17.) A few comments stated that FDA should enforce existing laws 
and regulations, remove unsafe products from the market, take action 
against dietary supplements that make ``extravagant, unsubstantiated'' 
claims, or promote educational activities instead of issuing 
regulations. One comment suggested that FDA resources would be better 
spent reviewing notices sent to the agency instead of issuing 
regulations. Another comment suggested that FDA continue to clarify 
issues on a case-by-case basis.
     FDA disagrees with the comments. Regulations offer several 
important advantages that case-by-case clarification, individual 
enforcement actions, and educational activities generally cannot. For 
example, when FDA develops a regulation, it provides notice, obtains 
public comment, considers alternatives, and evaluates the rule's 
potential impacts, costs, and benefits. Individual enforcement actions 
and educational activities are not subject to these considerations.
     Regulations also establish uniform, industry-wide requirements in 
a single administrative proceeding (rulemaking). In contrast, 
individual enforcement actions focus on distinct facts that may not 
lend themselves to uniform application to an entire industry. Moreover, 
enforcement actions are resource-intensive and require multiple steps, 
such as inspections, warning letters, and sometimes litigation, before 
they are completed. Educational activities may deal with general topics 
and provide valuable opportunities for discussing issues with FDA, but 
they do not create uniform requirements.
     Regulations are also easier to locate because they are published 
in the Federal Register when they are issued, are codified and 
published in the Code of Federal Regulations (CFR) and can be found in 
libraries and on government Internet sites (such as the Government 
Printing Office's website at www.gpo.gov). In contrast, agency 
correspondence and results of individual enforcement actions are not as 
widely available and may be difficult for some regulated entities and 
consumers to obtain.
     Thus, when it comes to establishing uniform, industry-wide 
requirements, conserving agency resources, and providing public notice 
and an opportunity to comment, regulations are preferable to individual 
enforcement actions and educational activities.
     (18.) A comment suggested that FDA adopt an approach like hazard 
analysis critical control point (HACCP) instead of issuing the rule.
     FDA disagrees with the comment. HACCP is best suited for issues 
relating to how a product is manufactured. Here, the principal issue is 
the claims made for a product rather than how the product is made.
     (19.) A comment stated that FDA lacks the expertise to determine 
whether a botanical is a drug or a dietary supplement. The comment 
explained that botanicals can be used for medicinal purposes, but that 
they can also be used for promoting general well being and supporting 
the structure or function of the body. According to the

[[Page 1009]]

comment, FDA declared Yellowdock, an herb, to have medicinal purposes 
only, when the herb also had a long history of use as a food source.
     The comment may have misinterpreted the rule. The focus of this 
rule is not on whether a substance has a history of use as a food but 
on claims made in the product's labeling. The rule defines the types of 
statements that may be made concerning a dietary supplement's effect on 
the structure or function of the body. FDA has many years of experience 
in regulating and interpreting health-related product claims.
     (20.) One comment said other countries (naming several European 
nations) and the World Health Organization have established lists of 
ingredients and botanical products that are safe and permitted for 
therapeutic purposes. The comment suggested that FDA consider 
assembling a committee to establish a similar list for the United 
States.
     A list of dietary ingredients and botanical products and their 
therapeutic uses might provide valuable information. Nevertheless, 
section 403(r)(6) of the act permits only structure/function claims for 
dietary supplements that are not also disease claims, and so such a 
list would not be relevant to this rulemaking.
     (21.) Two comments suggested that FDA list examples of structure/
function claims in order to reduce confusion. Another comment would 
have FDA describe both disease claims and structure/function claims.
     FDA intends to issue a guidance document that will provide 
examples of claims that would and would not be considered disease 
claims. This final rule also includes many examples of structure/
function and disease claims.

 B. Permitted Structure/Function Statements (Sec. 101.93(f))

     Proposed Sec. 101.93(f) stated that dietary supplement labels and 
labeling may bear structure/function statements that are not disease 
claims within the meaning of proposed Sec. 101.93(g) and that otherwise 
comply with the notification and disclaimer provisions of 
Sec. 101.93(a) through (e). FDA is revising Sec. 101.93(f) on its own 
initiative to make it clear that a dietary supplement may bear a 
disease claim if it is the subject of an authorized health claim, but 
that otherwise disease claims will subject the product to regulation as 
a drug.

 C. Definition of Disease (Sec. 101.93(g)(1))

     To assist in describing what constitutes a disease claim, the 
proposed rule contained a definition of ``disease.'' The proposed 
definition was based on standard medical and legal definitions of the 
term (Refs. 2, 3, 4, and 5). Proposed Sec. 101.93(g)(1) defined 
``disease'' as:
     any deviation from, impairment of, or interruption of the 
normal structure or function of any part, organ, or system (or 
combination thereof) of the body that is manifested by a 
characteristic set of one or more signs or symptoms, including 
laboratory or clinical measurements that are characteristic of a 
disease.
     The proposed definition would have replaced an earlier definition 
issued in 1993 as part of the regulations implementing the health 
claims provisions of NLEA. The implementing regulations require dietary 
supplement manufacturers to obtain prior authorization of any labeling 
statement that characterizes the relationship between a substance in 
the supplement to a ``disease or a health-related condition'' (section 
403(r)(1)(B) of the act; Sec. 101.14(a)(1)). The phrase ``disease or 
health-related condition'' was defined in those regulations as:
     damage to an organ, part, structure, or system of the body such 
that it does not function properly (e.g., cardiovascular disease), 
or a state of health leading to such dysfunctioning (e.g., 
hypertension); except that diseases resulting from essential 
nutrient deficiencies (e.g., scurvy, pellagra) are not included in 
this definition * * *.
Section 101.14(a)(5) (formerly Sec. 101.14(a)(6)). The definition was 
redesignated as Sec. 101.14(a)(5) effective March 23, 1999 (see 62 FR 
49859, 49867).
     FDA tentatively concluded that it did not want to retain the older 
health claims definition because its use of the term ``damage'' could 
be interpreted to limit the definition to serious or long-term 
diseases, and could imply that there needed to be pathological evidence 
of damage, which is not always present. For example, most mental 
illnesses have no evidence of anatomic damage, yet are clearly 
diseases.
     In the July 8, 1999, Federal Register notice announcing a public 
meeting and reopening the comment period, FDA requested additional 
comment on the definition of disease. The notice listed four questions 
on which it sought specific comment: (1) What are the consequences, 
with respect to the range of acceptable structure/function claims, of 
adopting: (a) The 1993 definition in Sec. 101.14(a)(5), or (b) the 
definition in the proposed rule? (2) If FDA were to retain the 1993 
definition, does the reference to ``damage'' exclude any conditions 
that are medically understood to be diseases? Please provide examples. 
(3) If it does not exclude any such conditions, is the 1993 definition 
otherwise consistent with current medical definitions of disease? (4) 
If it does exclude conditions that are medically understood to be 
diseases, could it be revised in a way that would include such 
conditions?
     (22.) Almost all of the comments from the dietary supplement 
industry and from individuals objected to the new definition of 
disease. Most of these comments argued that the new definition is too 
broad, sweeping in many minor deviations or abnormalities that are not 
diseases. (Many of these comments did not appear to have understood 
that the definition required not only a deviation, but one that ``is 
manifested by a characteristic set of one or more signs or symptoms.'') 
One comment said that under the new definition wrinkles and gray hair 
would qualify as diseases. Some comments objected to the fact that the 
proposed definition was not limited to adverse deviations from normal 
structure or function. Other comments argued that the breadth of the 
proposed definition is inconsistent with the intent of DSHEA. Some 
comments objected to the distinction between normal and abnormal 
functions, and argued that Congress did not intend to limit structure/
function claims to normal structure or function. Some comments 
contended that the definition of disease should not include the phrase 
``structure or function.'' Other comments said that Congress should be 
presumed to have been aware of the 1993 definition of ``disease or 
health-related condition'' and to have intended FDA to use that 
definition. Several comments argued that the new definition of 
``disease or health-related condition'' for health claims would 
inappropriately broaden the scope of health claims for conventional 
foods and concomitantly narrow the scope of acceptable structure/
function claims for foods. One comment said that redefining ``disease 
or health-related condition'' in Sec. 101.14(a)(5) would undermine the 
existing definition of ``statement of nutritional support,'' and would 
violate DSHEA and the First Amendment. Most of the comments from the 
dietary supplement industry and from individuals recommended that FDA 
return to the 1993 definition.
     Most of the comments from health professional groups and groups 
devoted to specific diseases, including those who participated in the 
August 4, 1999, public meeting, supported the new definition of disease 
as more consistent with a medical understanding of disease than the 
NLEA definition. Some of these

[[Page 1010]]

comments criticized the 1993 definition because of its reliance on 
``damage'' and dysfunction and because of its failure to refer to signs 
and symptoms. While many comments from the dietary supplement industry 
said that no recognized diseases would be excluded by requiring 
evidence of ``damage,'' comments from health professionals pointed out 
a number of recognized disease conditions for which it is not currently 
possible to identify physical damage to an organ, part, or system of 
the body, including most psychiatric diseases (depression, bipolar 
disorder, schizophrenia, and obsessive compulsive disorder, among 
others), and the early stages of certain metabolic diseases, including 
diabetes, genetic diseases, and nutritional deficiency diseases.
     A few comments offered alternative definitions of disease. A major 
medical association contended that the proposed definition would be 
improved by the addition of the phrase ``or a state of health leading 
to such deviation, impairment, or interruption.'' An OTC drug and 
dietary supplement trade association offered the following alternative 
definition of disease, which would modify the proposed definition:
     A disease is any adverse deviation from, or impairment of, or 
interruption of the normal structure or function of any part, organ, 
or system (or combination thereof) of the body that is manifested by 
a characteristic set of one or more signs or symptoms that are not 
characteristic of a natural state or process.
 According to this comment, the addition of the word ``adverse'' 
appropriately narrows the nature of the deviation, ``laboratory or 
clinical measurements'' are appropriately deleted because they are 
already included under the concept of ``signs,'' and the exclusion of 
natural states ``encompasses Congress' intent to allow health 
promotion/maintenance claims.'' One comment suggested that, if FDA were 
to retain the 1993 definition, it add the word ``impairment'' after 
``damage'' to cover those recognized disease conditions for which 
evidence of damage is missing. A pharmaceutical trade association urged 
FDA to convene a small workshop of physicians, patients, and other 
stakeholders to develop a consensus on the distinction between disease 
claims and structure/function claims.
     In response to the comments, FDA has reconsidered the proposed 
definition of disease in Sec. 101.93(g)(1), and has concluded that it 
is not necessary to change the 1993 health claims definition, because 
it can be construed in a manner that covers conditions that are 
medically understood to be diseases. In light of Congress' desire to 
increase the number of claims that could be made for dietary 
supplements without subjecting them to drug regulation, FDA is 
persuaded that it is therefore appropriate to retain a narrower 
definition of disease at this time.
     FDA has concluded that the older health claims definition, read as 
a whole, will not exclude any significant conditions that are medically 
understood to be diseases. For example, the requirement of ``damage to 
an organ, part, structure, or system of the body such that it does not 
function properly'' indicates that a condition may be considered a 
disease if there is direct evidence of structural damage to an organ, 
part, structure, or system of the body, or indirect evidence of damage, 
indicated by the failure of the organ, part, structure, or system of 
the body to function properly. This interpretation is appropriate 
because otherwise well-recognized psychiatric diseases, migraine 
headaches, hypertension, blood lipid disorders, and many other well-
accepted diseases, could be excluded from coverage due to the lack of 
direct evidence of physical damage. The reference to ``a state of 
health leading to such dysfunctioning'' also permits the agency to look 
at evidence other than actual damage to an organ, part, structure, or 
system of the body.
     FDA does not believe that it would be constructive to defer a 
decision on the definition of disease and seek a ``consensus'' of 
stakeholders. The agency believes that it is unlikely that diverse, 
strongly-held views expressed in written comments and at the public 
hearing could be forged into a consensus on this issue. FDA also 
believes that it is important to reach a decision as soon as possible 
to permit the issuance of clear, uniform rules that will apply to all 
dietary supplement labeling.
     Accordingly, the final rule does not include a new definition of 
disease, but incorporates the definition of ``disease or health-related 
condition'' in Sec. 101.14(a)(5). If experience shows a public health 
need for a different or broader definition, however, FDA will consider 
initiating a rulemaking to amend that definition.
    (23.) One comment argued that it is unnecessary for FDA to define 
disease at all, but that the agency should use a ``common sense'' 
approach to distinguishing structure/function claims from disease 
claims. According to this comment, dietary supplements should be 
allowed to make any claim that does not contain express references ``to 
specific diseases * * * or which can only be reasonably interpreted to 
refer to a specific disease (e.g., `helps prevent tumors').''
     FDA does not agree that a definition of disease is unnecessary. 
The comment that made this argument went on to use the term disease in 
its ``common sense'' principle, apparently assuming that there is some 
common sense understanding of the term. FDA is not aware of any common 
sense understanding of ``disease,'' and the diversity of comments 
received in this rulemaking on the appropriate definition of disease 
supports FDA's view that a definition is needed if FDA is to enforce 
section 403(r)(6) of the act fairly and consistently.
    (24.) One comment argued that any definition of disease should 
exclude symptoms or diseases that do not normally require a drug or 
doctor's care because these states could be considered part of 
``normal'' living.
     FDA does not agree that DSHEA was intended to permit structure/
function claims about diseases that can normally be treated without a 
physician's care. Nothing in the statute or its legislative history 
suggests that Congress intended to accord different treatment to this 
subset of diseases. Diseases that do not ordinarily require a 
physician's care are generally those for which drugs may be sold over 
OTC. (OTC drug claims include both disease claims and structure/
function claims.) Drugs carrying OTC claims are already regulated under 
rules different from those applicable to prescription drugs. FDA has 
undertaken a comprehensive review of OTC drug claims and published 
monographs on these claims. Had Congress intended to permit dietary 
supplements to make all OTC claims (both disease claims and structure/
function claims) without prior review, it could easily have so 
indicated. Because Congress did not do so, FDA does not believe that 
there is support for treating this subset of diseases differently from 
other diseases. As discussed elsewhere in this document, the structure/
function claims made for OTC drugs also may be made, in appropriate 
circumstances, for dietary supplements under section 403(r)(6) of the 
act.
    (25.) One comment argued that it was irrelevant whether the 1993 
definition excluded conditions that were medically understood to be 
diseases. According to this comment, the definition of disease should 
be based on consumer understanding rather than medical understanding, 
because DSHEA was intended to educate consumers.
     FDA does not agree that its interpretation of a medical term like 
``disease'' should ignore medical definitions of the term, unless there 
is

[[Page 1011]]

clear guidance from Congress that it intended a nonmedical definition 
of the term. In any case, the comment provided no argument or evidence 
that the 1993 definition was based on, or reflects, consumer 
understanding of the term ``disease.''

 D. Disease Claims (Sec. 101.93(g)(2))

    (26.) Many comments agreed with the statement in proposed 
Sec. 101.93(g)(2) that, in determining whether a statement is a disease 
claim, it is appropriate to consider the context in which the claim is 
presented. One comment argued, however, that language of the regulation 
and preamble showed that FDA was biased because the agency would only 
consider the context of a claim to convert a dietary supplement to a 
drug.
     FDA does not agree that it will consider context only to convert 
an otherwise acceptable structure/function claim to a disease claim. 
The context in which a claim appears can provide evidence in either 
direction.
    (27.) One comment argued that the rule should have only the 
following three criteria: (1) The words ``diagnose,'' ``prevent,'' 
``treat,'' ``cure,'' and ``mitigate'' should not be used in a 
structure/function claim; (2) the words ``stimulate,'' ``maintain,'' 
``support,'' ``regulate,'' and ``promote''--or other similar words--may 
be used in a structure/function claim to distinguish the claim from a 
specific disease claim; and (3) clinical endpoints that are 
recognizable to health professionals or consumers as being related to a 
disease may be used in a structure/function claim.
     FDA does not believe that the three suggested criteria provide a 
sufficient basis to distinguish between structure/function claims and 
disease claims. Nothing in these criteria would prevent a structure/
function claim from discussing a specific disease, explicitly or 
implicitly, as long as the claim did not contain the specific verbs 
``diagnose,'' ``prevent,'' ``treat,'' ``cure,'' or ``mitigate.''
     (28.) Several comments from medical and consumer groups supported 
the establishment of criteria for structure/function claims, but were 
concerned that the criteria in the proposed rule were too vague and 
would fail to protect consumers from misleading claims. A major medical 
association contended that some of the structure/function claims listed 
as acceptable in the proposal were debatable and expressed doubt that 
the public health would be adequately protected. Some of these comments 
expressed the view that some of the structure/function claims listed in 
the proposal in fact imply disease prevention. For example, some of 
these comments argued that health maintenance claims imply disease 
prevention. On the other hand, a comment from a major dietary 
supplement trade association argued that the overall impact of the 
criteria restricts the value of structure/function claims in providing 
consumers with useful information about dietary supplements.
     FDA agrees that consumers should have access to, and be allowed to 
evaluate for themselves, as much truthful information about dietary 
supplements as is possible, consistent with the statutory restrictions 
on disease treatment and prevention claims. FDA believes that the 
criteria in this rule strike a reasonable balance between these 
competing goals. Undoubtedly, the criteria will not satisfy everyone. 
For example, some of the claims considered to be structure/function 
claims may imply specific disease prevention to some consumers. Because 
of the importance of the context in which a claim is presented, it will 
not always be possible to draw a line between structure/function and 
disease claims in this rule with great specificity. FDA believes that, 
within these constraints, the criteria, as finalized, adequately 
distinguish between structure/function claims and disease claims. In 
developing final criteria, the agency has tried to pay particularly 
close attention to claims that might relate to serious health 
conditions that patients cannot safely evaluate on their own. The 
question of whether health maintenance claims necessarily imply disease 
prevention is discussed in more detail below.
     (29.) One comment, from a Commission member, said the ``dietary 
relationship'' of a structure/function claim is relevant in considering 
whether such a claim is appropriate. The comment said that statements 
for dietary ingredients should ``relate to the role of the dietary 
ingredient in the diet in achieving effects like those associated with 
the effects of foods.'' The comment added that the claim ``should be 
for an effect that is similar to the non-disease effects of a food on 
the body'' and ``phrased to indicate the role of the dietary ingredient 
in the diet in maintaining or supporting the ordinary functioning of 
the body in a manner similar to that achieved through foods.'' Thus, 
the comment would consider a claim such as ``promotes relaxation'' to 
be appropriate ``only if it is indicated to be similar to the effects 
achieved from foods, such as by indicating that it provides a relaxing 
calming effect like a cup of tea.'' While the preamble to the proposed 
rule considered the claim of ``improves absentmindedness'' to be a 
structure/function claim, the comment viewed the same claim as a 
disease claim ``because of the association of absentmindedness with 
Alzheimer's disease.'' The comment continued, ``That claim should not 
be permissible for the same reason that a claim that a dietary 
supplement is an `oral contraceptive' is not permissible--the claim is 
simply not one for the effects of a dietary ingredient.''
     FDA agrees that dietary supplements must be ``intended to 
supplement the diet'' (section 201(ff) of the act). In interpreting 
section 403(r)(6) of the act, however, FDA believes that it is 
appropriate to focus on the claims made for the product. Unlike section 
201(g)(1)(C) of the act, section 403(r)(6) of the act does not limit 
authorization to make structure/function claims (without triggering 
drug approval requirements) to substances that are ``food.'' FDA notes 
that it is developing an overall dietary supplement strategy and will, 
when a document incorporating the strategy is released, state how the 
agency plans to address the requirement that dietary supplements be 
``intended to supplement the diet.''
     (30.) One comment said FDA should develop a list of ``acceptable 
subclinical, pre-disease, and normal states'' that may be used in 
structure/function claims.
     FDA declines to adopt the comment's suggestion. However, this rule 
contains many examples of acceptable structure/function claims and FDA 
intends to issue further guidance listing acceptable claims.
     (31.) One comment argued that all statements about effects on 
structure or function should be deemed permissible unless they are 
already approved drug claims. The comment noted that ``reduces joint 
pain'' and ``relieves headache'' would not be structure/function claims 
because they are OTC monograph claims.
     FDA does not agree that such a criterion would appropriately 
discriminate between structure/function claims and disease claims. One 
kind of valid drug claim is a claim related to the effect of the 
product on the structure or function of the body (section 201(g)(1)(C) 
of the act) but not related to disease prevention or treatment. In 
other words, not all drug claims are disease claims. Congress 
specifically provided that structure/function claims authorized by 
section 403(r)(6) of the act do not, in themselves, subject a dietary 
supplement to regulation as a drug under 201(g)(1)(C) of the act. It 
thus would not be appropriate to exclude

[[Page 1012]]

from the scope of acceptable structure/function claims OTC monograph 
claims or other approved claims for products classified as drugs under 
section 201(g)(1)(C) of the act.
     (32.) A national pharmacy group stated that the examples of 
structure/function and disease claims in the proposal were reasonable 
and based on good science and logic, but should be evaluated and 
revised as necessary over time.
     FDA agrees that it will be necessary to evaluate the examples over 
time and to revise them as experience dictates.
     (33.) Some comments argued that the types of claims permitted 
under the proposal may discourage serious approaches to substantiation 
because the terms used are not scientifically verifiable. Stating that 
the preferred method of substantiation is an adequate and well-
controlled trial, one comment contended that the claims permitted under 
the rule are not amenable to such proof. According to this comment, 
this rule may preclude companies from meeting the substantiation rules 
of the Federal Trade Commission (FTC). A few comments said that 
manufacturers cannot substantiate claims that a product maintains 
healthy status. One of these comments stated that it was impossible to 
show by adequate studies that ``cranberry extract supports healthy 
urinary tract functioning,'' and that companies should instead be able 
to show that cranberry extract reduces frequency of urinary tract 
infections in susceptible people. Similarly, because it is 
``impossible'' to test whether St. John's Wort ``supports mood'' in the 
general population, companies need to be able to test its effect on 
depressed people.
     FDA agrees that some structure/function claims that are acceptable 
under DSHEA may be difficult to substantiate. For example, some 
structure/function claims currently in the marketplace use terms that 
do not have clear scientific meaning. Other claims concern health 
maintenance in the general population and therefore could require 
studies in a large population for substantiation. FDA believes, 
however, that such claims are within the intended scope of section 
403(r)(6) of the act. Difficulty in substantiating them does not alter 
the terms of the statute. Manufacturers are responsible for determining 
whether claims for their products can be appropriately substantiated, 
and to use only those claims for which they have substantiation. FDA 
does not agree that difficulty in substantiating a particular claim 
justifies the use of express or implied disease claims for which 
methods of substantiation may be more straightforward. Such an approach 
would turn section 403(r)(6) of the act on its head.
     FDA also does not agree that it is impossible to substantiate the 
claims described in the comments. For example, to substantiate the 
claim ``supports mood,'' it is not necessary to study the effects of a 
substance on clinical depression. Instead, it is quite possible to 
assess the effects of a substance on mood changes that do not 
constitute clinical depression.

 E. Effect on Disease or Class of Diseases (Sec. 101.93(g)(2)(i))

     Under proposed Sec. 101.93(g)(2)(i), a statement would be 
considered a disease claim if it explicitly or implicitly claimed an 
effect on a specific disease or class of diseases. FDA included the 
following examples of such disease claims: ``Protective against the 
development of cancer,'' ``reduces the pain and stiffness associated 
with arthritis,'' ``decreases the effects of alcohol intoxication,'' or 
``alleviates constipation.'' FDA included the following examples of 
claims that do not refer explicitly or implicitly to an effect on a 
specific disease state: ``Helps promote urinary tract health,'' ``helps 
maintain cardiovascular function and a healthy circulatory system,'' 
``helps maintain intestinal flora,'' and ``promotes relaxation.'' FDA 
proposed to treat both express and implied disease claims as disease 
claims that could not be made for dietary supplements without prior 
review either as health claims or as drug claims. Implied disease 
claims do not mention the name of a specific disease, but refer to 
identifiable characteristics of a disease from which the disease itself 
may be inferred. There are many possible ways to imply treatment or 
prevention of disease, from listing the characteristic signs and 
symptoms of the disease to providing images of people suffering from 
the disease. Nine of the 10 criteria proposed by FDA for identifying 
disease claims could be considered methods of implying disease 
treatment or prevention.
     In the July 8, 1999, Federal Register notice announcing a public 
meeting and reopening the comment period, FDA sought additional comment 
on the applicability of the rule to implied disease claims. The 
discussion in the notice offered three examples of possible implied 
disease claims: (1) ``shrinks tumors of the lung'' or ``prevents 
development of malignant tumors'' (``treats cancer'' would be the 
corresponding express claim); (2) ``prevention of seizures'' 
(``treatment of epilepsy'' would be the corresponding express claim); 
(3) ``relief of sneezing, runny nose, and itchy watery eyes caused by 
exposure to pollen or other allergens'' (``treatment of hayfever'' 
would be the corresponding express claim). The notice listed four 
questions related to implied disease claims on which the agency sought 
specific comments: (1) If implied disease claims should be permitted, 
has FDA correctly drawn the line between what constitutes an express 
disease claim and what constitutes a permitted implied claim? (2) If 
such claims should be permitted, what are representative examples of 
the types of implied disease claims that should be permitted without 
prior review? (3) Are the examples of implied claims mentioned in the 
July 8 notice appropriate structure/function claims? (4) Is a claim 
that a product ``maintains healthy function'' an implied disease claim 
in all cases? If not, under what circumstances is such a claim not an 
implied disease claim?
     (34.) Many comments agreed with proposed Sec. 101.93(g)(2)(I) that 
structure/function statements should not explicitly or implicitly 
mention specific diseases or class of diseases. These comments 
contended that consumers cannot distinguish between implied and express 
disease claims and that permitting implied disease claims poses 
significant dangers to consumers with diseases. According to these 
comments, permitting implied disease claims on dietary supplements may 
cause consumers to delay or forego effective treatment for serious 
diseases without assurance that the dietary supplement that has been 
substituted is safe or effective for the disease. Some comments also 
argued that permitting implied disease claims on dietary supplements 
will undermine the drug approval process by permitting dietary 
supplement manufacturers to market products for essentially the same 
indications for which pharmaceutical companies have spent millions of 
dollars obtaining approval.
     Many other comments objected to treating implied disease claims as 
disease claims, arguing that dietary supplements should be allowed to 
carry any truthful claim that does not explicitly refer to a specific 
disease. Some comments argued that Congress intended consumers to have 
access to as much information about supplements as possible. Other 
comments contended that barring implied disease claims eliminates any 
meaningful claims for dietary supplements. Other comments argued that 
treating implied claims as disease claims gives FDA ``unlimited 
discretion'' to treat structure/function

[[Page 1013]]

claims as disease claims. Some comments, however, agreed that disease 
claims may be implied as well as express, and said that it is 
appropriate to consider a structure/function statement in context to 
determine whether it conveys a disease claim.
     FDA continues to believe that structure/function claims should not 
imply disease treatment or prevention. Most disease treatment or 
prevention claims, including claims about serious and life-threatening 
diseases, can be described in a manner that will be easily understood 
by consumers without express reference to a specific disease. The 
following examples of implied disease claims demonstrate that it is not 
difficult to convey prevention or treatment of a specific disease or 
class of diseases without actually mentioning the name of the disease, 
which are given in parentheses: ``Relieves crushing chest pain'' 
(angina or heart attack), ``prevents bone fragility in post-menopausal 
women'' (osteoporosis), ``improves joint mobility and reduces joint 
inflammation and pain'' (rheumatoid arthritis), ``heals stomach or 
duodenal lesions and bleeding'' (ulcers), ``anticonvulsant'' 
(epilepsy), ``relief of bronchospasm'' (asthma), ``prevents wasting in 
persons with weakened immune systems'' (AIDS) (acquired immune 
deficiency syndrome), ``prevents irregular heartbeat'' (arrhythmias), 
``controls blood sugar in persons with insufficient insulin'' 
(diabetes), ``prevents the spread of neoplastic cells'' (prevention of 
cancer metastases); ``antibiotic'' (infections), ``herbal Prozac'' 
(depression). The distinction between implied and express disease 
claims is thus, in many cases, a semantic one that has little, if any, 
practical meaning to consumers. The argument that Congress intended to 
encourage the free flow of information about dietary supplements and 
therefore intended to permit implied disease claims is illogical. If 
Congress wanted to ensure that consumers receive information about how 
these products can treat or prevent diseases, it is difficult to 
imagine why it would have specifically denied the right to make such 
claims expressly, and allowed manufacturers to make the claims only by 
implication.
     There are also serious public health questions raised by implied 
disease claims. Treatment and prevention of disease are serious 
matters, and the statute reflects a congressional judgment that 
consumers deserve to have claims for such uses reviewed by experts for 
proof of safety and effectiveness. In addition, permitting dietary 
supplement manufacturers to make implied disease claims without prior 
review would allow them to compete unfairly with prescription and OTC 
drugs, which are required to establish their safety and effectiveness 
for disease treatment and prevention before being marketed. 
Pharmaceutical manufacturers, faced with this competition, might be 
less likely to undertake future research and development, compromising 
one of the nation's most important sources of therapeutic advances. Had 
Congress intended to allow implied disease claims when it authorized 
dietary supplement manufacturers to make structure/function claims 
without prior review, it could easily have made clear its intention 
through express statutory language or legislative history. As discussed 
below, Congress did not do so.
     FDA does not agree that the final rule eliminates all meaningful 
claims for dietary supplements. FDA believes that there are many 
meaningful structure/function claims that can be made without implying 
disease treatment or prevention, and has listed a number of such claims 
in this preamble.
     FDA does not agree that treating implied claims as disease claims 
gives the agency unfettered discretion to treat all structure/function 
claims as disease claims. The purpose of this rule is to clarify which 
claims are structure/function claims permitted under section 403(r)(6) 
of the act and which are disease claims. Both in the proposed rule and 
in this final rule, FDA has provided many examples of specific claims 
that would be acceptable structure/function claims.
     (35.) Many comments pointed to three provisions of DSHEA as 
evidence that Congress intended to include implied disease claims among 
structure/function claims permitted under section 403(r)(6) of the act. 
First, the ``Findings'' section of DSHEA refers to the relationship 
between dietary supplements and disease prevention. Many comments 
argued that Congress would not have made statutory findings linking 
dietary supplements to disease prevention if it intended that FDA could 
prohibit such references.
     Second, section 403(r)(6) of the act states that structure/
function statements may not ``claim'' to treat or prevent disease, and, 
according to the comments, this term should be read to refer only to 
express claims. Some comments noted that section 403(r)(6) of the act 
does not use the word ``implied'' to qualify the term ``claims,'' and 
contrasted the language of the drug definition in section 201(g)(1)(B) 
of the act (``articles intended for use in the diagnosis, cure, 
mitigation, treatment, or prevention of disease'') with the language of 
section 403(r)(6)(C) of the act, which states that a structure/function 
statement may not ``claim'' to diagnose, cure, mitigate, treat, or 
prevent disease. One comment agreed with the proposal's statement that 
while DSHEA authorizes structure/function claims that are not also 
disease claims, but nevertheless asserted that the statute authorizes 
structure/function claims that imply ``some protection against 
disease.'' This comment reasoned that the act, as amended by DSHEA, 
allows dietary supplements to be ``intended'' to affect the structure 
or function of the body, provided that the product does not ``expressly 
claim to prevent, etc. disease'' (emphasis in original) and the product 
bears ``an express, formal disclaimer of an intent to prevent, etc. 
disease.'' The comment also said that the Commission report only 
referred to express claims.
     Third, DSHEA requires structure/function claims to be accompanied 
by a disclaimer that reads, in part: ``[T]his product is not intended 
to diagnose, treat, cure, or prevent any disease.'' According to some 
comments, Congress understood that specific disease treatment or 
prevention effects can also be described as effects on the structure or 
function of the body, and resolved the tension by requiring the 
disclaimer. In contrast, however, another comment argued that the drug 
definition in section 201(g)(1)(B) of the act still applies to dietary 
supplements because the exemption for dietary supplements added to 
section 201(g)(1) applies only to the structure/function definition in 
section 201(g)(1)(C). Many comments argued generally that DSHEA was 
intended to promote the free flow of truthful information about dietary 
supplements, and that prohibiting implied disease claims is contrary to 
this legislative goal.
     FDA does not agree that DSHEA authorizes dietary supplement 
manufacturers to make implied disease claims without prior review of 
the claims. There is no express provision of DSHEA that authorizes 
implied disease claims, and a construction of DSHEA that permitted such 
claims would be fundamentally incompatible with important provisions of 
the act that were squarely before Congress when it passed DSHEA, 
including the definitions of ``drug'' and ``new drug'' and the health 
claims provisions of NLEA.
     As described above, Congress created a partial exemption for 
dietary supplements from the definition of drug in section 201(g)(1)(C) 
of the act by providing that truthful and non-misleading claims under 
section

[[Page 1014]]

403(r)(6) of the act do not in themselves trigger drug regulation. 
Congress did not, however, create any exemption from section 
201(g)(1)(B) of the act for dietary supplements. Thus, dietary 
supplements that are ``intended for use in the diagnosis, cure, 
mitigation, treatment, or prevention of disease'' are subject to 
regulation as drugs under the act. It has been FDA's longstanding 
interpretation of section 201(g)(1)(B) of the act that the phrase 
``intended for use'' refers to the objective intent of the 
manufacturer, which is not limited to a manufacturer's express 
representations. See Sec. 201.128 (21 CFR 201.128); NNFA v. Weinberger, 
557 F.2d 325, 334 (2d Cir. 1977) (``the FDA is not bound by the 
manufacturer's subjective claims of intent,'' but may establish intent 
``on the basis of objective evidence''). Evidence of objective intent 
can come from a variety of sources, and may include both implied and 
express claims (United States v. Undetermined Quantities * * * Pets 
Smellfree, 22 F.3d 235 (10th Cir. 1994); United States v. Storage 
Spaces Designated Nos. ``8'' and ``49'', 777 F.2d 1363, 1366 (9th Cir. 
1985) (``intent may be derived or inferred from labeling, promotional 
material, advertising, or any other relevant source''), cert. denied, 
479 U.S. 1086 (1987); United States v. Kasz Enterprises, Inc. 855 F. 
Supp. 534, 539, 543-44 (D.R.I. 1994), modified on other grounds, 862 F. 
Supp. 717 (D.R.I. 1994); United States v. Articles of Drug * * * 
Neptone, 568 F. Supp. 1182 (N.D. Ca. 1983); United States v. * * * 
Vitasafe, 226 F. Supp. 266 (D.N.J. 1964); United States v. 14 105 Pound 
Bags * * * Mineral Compound, 118 F. Supp. 837 (D.C. Idaho 1953); United 
States v. 43 1/2 Gross Rubber Prophylactics, 65 F. Supp. 534, 535 (D. 
Minn. 1946), aff'd sub nom. Gellman v. United States, 159 F.2d 881 (8th 
Cir. 1947); 59 FR 6084, 6088 (February 9, 1994) (terms 
``antibacterial,'' ``antimicrobial,'' ``antiseptic,'' or ``kills 
germs'' constitute implied drug claims that cause products carrying 
them to be drugs); 58 FR 47611, 47612 (September 9, 1993) (labeling 
indicating that ``hormones'' are present in a product constitutes 
implied drug claim); 58 FR 28194, 28204 (May 12, 1993) (products 
carrying term ``sunscreen'' are drugs because ``sunscreen'' implies 
disease prevention, even if not expressly promoted for prevention of 
skin cancer)).
     Thus, interpreting section 403(r)(6) of the act as permitting 
implied disease claims would be irreconcilable with FDA's longstanding 
interpretation of section 201(g)(1)(B) of the act, which treats such 
claims as drug claims.
     Permitting implied disease claims as structure/function claims 
would also conflict with the health claims scheme established in 
section 403(r)(1) through (r)(1)(5) of the act, which requires food and 
dietary supplement manufacturers to obtain health claim authorization 
before making a claim ``which expressly or by implication'' 
characterizes the relationship of a nutrient to a disease or health-
related condition. Under this provision, a claim that characterized, by 
implication, the relationship between a dietary supplement ingredient 
and a disease would require authorization as a health claim. 
Interpreting section 403(r)(6) of the act as permitting the same 
implied claim without authorization of a health claim directly 
conflicts with 403(r)(1) through (r)(1)(5) of the act.
     None of the statutory provisions relied on by the comments 
provides persuasive support for the conclusion that structure/function 
claims can imply disease treatment or prevention.
     FDA agrees that the Findings section of DSHEA includes statements 
linking dietary supplements and disease prevention. However, in 
addition to the types of claims authorized for dietary supplements in 
section 403(r)(6) of the act, the act specifically authorizes dietary 
supplements to bear health claims. Health claims are expressly 
described in the statute as claims that characterize the link between a 
nutrient and a disease or health-related condition (section 
403(r)(1)(B) of the act). The statements in the ``Findings'' section of 
the DSHEA are entirely consistent with this scheme and do not compel 
the conclusion that claims linking dietary supplements and disease 
prevention may be made as structure/function claims.
     The use of the word ``claim'' rather than ``intended for use'' in 
section 403(r)(6) of the act also does not show that Congress intended 
to permit implied disease claims. First, the comment cites no 
authority, and FDA is aware of none, for the proposition that the 
meaning of the word ``claim'' is limited to ``express claim.'' More 
importantly, section 403(r)(6) of the act does not stand by itself. As 
Congress recognized when it provided that dietary supplements making 
appropriate claims under section 403(r)(6) of the act do not thereby 
become drugs under section 201(g)(1)(C) of the act, section 403(r)(6) 
must be read in conjunction with section 201(g)(1). As described above, 
section 201(g)(1)(B) of the act continues to apply to dietary 
supplements and treats them as drugs if they are ``intended for use in 
the diagnosis, cure, mitigation, treatment, or prevention of disease.'' 
FDA has interpreted section 201(g)(1)(B) of the act to cover both 
express and implied claims for more than 50 years. Had Congress 
intended 403(r)(6) of the act to permit any claims covered by section 
201(g)(1)(B) of the act, it would have had to provide an exemption from 
the latter section.
     Further, FDA does not agree that the Commission report referred 
only to express claims. In its guidance on statements under section 
403(r)(6) of the act, the Commission specifically said that such 
statements ``should be distinct from NLEA health claims in that they do 
not state or imply a link between a supplement and prevention of a 
specific disease or health-related condition'' (the report, p. 38) 
(emphasis added). In addition, the Commission cautioned that claims 
using terms such as, e.g., ``support,'' ``maintain,'' or ``promote'' 
are appropriate only if they do not ``suggest disease prevention or 
treatment or use for a serious health condition that is beyond the 
ability of the consumer to evaluate'' (the report, p. 38) (emphasis 
added). Clearly, the Commission was concerned about implied claims as 
well as express claims.
     FDA also does not agree that the required disclaimer demonstrates 
an intention to permit implied claims. To the contrary, FDA believes 
that the disclaimer language (``This product is not intended to 
diagnose, treat, cure, or prevent any disease''), which is virtually 
identical to the language of section 201(g)(1)(B) of the act, provides 
further evidence that Congress did not intend section 403(r)(6) of the 
act claims to overlap section 201(g)(1)(B) claims. As a practical 
matter, it is unreasonable to interpret section 403(r)(6) of the act as 
inviting a communication to consumers like the following: ``This 
product prevents bone fractures in post-menopausal women due to bone 
loss. This product is not intended to diagnose, treat, cure, or prevent 
any disease.'' The comments suggested that the addition of the 
disclaimer would somehow clarify the product's purpose to consumers. 
The comments provided no support, however, for their view that 
consumers reading the disclaimer would interpret it as eliminating 
implications in the remainder of the labeling that the product treats 
or prevents disease. FDA believes that the two statements simply 
contradict one another and could confuse consumers. Indeed, FDA is 
concerned that juxtaposing two such contradictory statements is likely 
to cause consumers to ignore the disclaimer required by section 
403(r)(6) of the act, undermining its effectiveness.

[[Page 1015]]

     (36.) A few comments addressed the examples of implied claims 
listed in the July 8, 1999, Federal Register notice. Some comments said 
that all of the examples were appropriate structure/function claims. 
Two comments suggested that ``shrinks tumors,'' ``prevents development 
of malignant tumors,'' and ``prevents seizures'' are express disease 
claims because they employ ``synonyms'' for specific diseases. 
According to these comments, ``tumor'' is a synonym for cancer, and 
``seizure'' is a synonym for epilepsy. Another comment said that FDA 
should treat as implied disease claims only those claims ``where there 
is a direct causal relationship between the structure/function 
parameter identified in the claim and a specific known disease.'' 
According to this comment, a tumor is a ``direct manifestation of 
cancer'' and therefore reference to a tumor is a disease claim. In 
contrast, risk factors for disease, in which the comment includes 
elevated cholesterol, are not direct manifestations of a disease, and 
therefore may be the subject of structure/function claims. Another 
comment contended that disease claims should be limited to express 
claims and to terms or measurements that are ``surrogates for the 
disease itself.'' According to this comment, tumors are a surrogate for 
cancer, but elevated cholesterol is not a surrogate for heart disease. 
One comment argued that ``relief of sneezing, runny nose, and itchy 
watery eyes caused by exposure to pollen or other allergens'' is an 
acceptable structure/function claim, but did not explain why.
     FDA has considered these comments, but does not believe that any 
of them have provided a principle that distinguishes between claims 
that consumers will understand as disease claims and those that will 
not be understood as disease claims. According to the comments, some of 
the claims that FDA offered as examples of implied disease claims 
should not be allowed as structure/function claims. FDA agrees that 
claims that refer to synonyms for disease, direct manifestations of 
disease, and surrogates for disease are disease claims. Each of these 
principles, however, would permit many types of implied disease claims 
that would be clearly understood by consumers as disease claims, e.g., 
``Herbal Prozac'' and ``antibiotic.''
     (37.) Some comments argued that it is impossible to construct a 
structure/function claim that does not imply disease prevention or 
treatment. Several of these comments claimed that health promotion 
claims inevitably imply disease prevention.
     FDA does not agree that every structure/function claim implies 
disease prevention or treatment. In the proposed rule, FDA provided 
examples of many types of claims that the agency would not consider 
implied disease claims, and has expanded that list in the final rule.
     (38.) Some comments disagreed with FDA's examples of disease 
claims in the proposed rule. These comments stated that intoxication 
and constipation are not in and of themselves diseases, and that these 
conditions are not readily understood by consumers as diseases. A few 
comments argued that alcohol intoxication is a ``self-induced 
condition'' and not a disease.
     FDA continues to believe that alcohol intoxication, like all 
poisonings (mushroom, digitalis, or any drug overdose), meets the 
definition of disease, albeit a transient disease. The definition in 
Sec. 101.14(a)(5), which FDA is incorporating in this rule, states, in 
part, that a disease is ``damage to an organ, part or structure, or 
system of the body such that it does not function properly * * *'' All 
poisonings, like alcohol intoxication, cause dose-related 
dysfunctioning and damage, ranging from mild impairments to death. 
Alcohol intoxication causes temporary damage to brain function, causing 
impairments of judgment, attention, reflexes, and coordination. The 
fact that it is ``self-induced'' does not remove it from the definition 
of disease. Deliberate barbiturate overdoses are also self-induced, but 
clearly meet the definition of disease.
     FDA has considered the comments on constipation and agrees that 
certain constipation claims should not be treated as disease claims. 
Constipation has a variety of causes, many of them unrelated to 
disease. For example, constipation can be caused by changes in diet and 
schedule, and by travel. Constipation can also, however, be a symptom 
of such serious diseases as bowel obstruction and irritable bowel 
syndrome. FDA is aware that there may be differences of opinion about 
whether occasional constipation, alone, constitutes a disease, but 
believes that treating it as a disease would not be consistent with the 
intent of DSHEA. ``For relief of occasional constipation'' would 
therefore not be considered a disease claim under the rule. The 
labeling of a product that claimed to treat occasional constipation 
should make clear, however, that the product is not intended to be used 
to treat chronic constipation, which may be a symptom of a serious 
disease.
     (39.) One comment questioned whether a claim that begins, 
``According to the National Cancer Institute'' would be a disease claim 
because it used the word ``cancer.''
     Although the National Cancer Institute (NCI) is associated with 
the treatment and prevention of cancer, such a statement will be 
considered a disease claim only if, within the context of the total 
labeling, the statement can be reasonably understood to relate the 
product to the disease listed in the organization's name, e.g., cancer. 
For example, FDA would regard as a disease claim ``According to the 
National Cancer Institute, ingredient X protects smokers' lungs.''

 F. Signs or Symptoms of Disease (Sec. 101.93(g)(2)(ii))

     Under proposed Sec. 101.93(g)(2)(ii), a statement would be 
considered a disease claim if it explicitly or implicitly claimed an 
effect (using scientific or lay terminology) on one or more signs or 
symptoms that are recognizable to health care professionals or 
consumers as being characteristic of a specific disease or of a number 
of diseases. FDA provided as examples of such disease claims: 
``Improves urine flow in men over 50 years old,'' ``lowers 
cholesterol,'' ``reduces joint pain,'' and ``relieves headache.'' 
Stating that claims of an effect on symptoms that are not recognizable 
as characteristic of a specific disease or diseases would not 
constitute disease claims, FDA provided the following examples of 
acceptable structure/function claims: ``Reduces stress and 
frustration,'' ``inhibits platelet aggregation,'' and ``improves 
absentmindedness.'' The agency also stated that if the context did not 
suggest treatment or prevention of a disease, a claim that a substance 
helps maintain normal function would not ordinarily be a disease claim. 
Examples included: ``Helps maintain a healthy cholesterol level,'' or 
``helps maintain regularity.''
     FDA specifically requested comment on the distinction between 
maintaining normal function, which is potentially the basis for an 
acceptable structure/function claim, and preventing or treating 
abnormal function, which is potentially a disease claim. FDA noted that 
the members of the Commission were divided on this issue, but that the 
final report concluded that ``statements that mention a body system, 
organ, or function affected by the supplement using terms such as 
`stimulate,' `maintain,' `support,' `regulate,' or `promote' can be 
appropriate when the statements do not suggest disease prevention or 
treatment or use for a serious health condition that is beyond the 
ability of the consumer to evaluate'' (the report, p. 38). Recognizing 
that

[[Page 1016]]

claims relating to maintaining healthy cholesterol levels raise 
particularly difficult issues, FDA sought specific comment on these 
claims.
    (40.) Many comments from manufacturers and individuals objected to 
proposed Sec. 101.93(g)(2)(ii). Some of these comments argued that 
basing the criterion on which signs and symptoms were ``recognizable'' 
to health care professionals or consumers was too vague, and that it 
was unclear what proportion of health care professionals or consumers 
would be necessary to establish recognition. Some comments asked 
whether FDA expected manufacturers to conduct consumer surveys. Other 
comments urged that FDA itself conduct consumer surveys to determine 
which signs and symptoms were recognizable to consumers as implied 
disease claims. Other comments argued that the proposed provision would 
create a moving target because ``as soon as consumers understood that 
certain signs and symptoms are characteristic of a disease--that is, as 
soon as consumers understood why they should take a particular 
supplement--FDA could * * * prohibit a product label from bearing the 
substantive claims information.''
     FDA agrees with these comments that the proposal's focus on 
recognition of signs and symptoms by consumers or health professionals 
might have made the provision difficult to apply, both for 
manufacturers and for the agency. Accordingly, the agency has 
substituted a more objective criterion. The final rule eliminates the 
reference to recognition, and focuses simply on whether the labeling 
suggests that the product will produce a change in the characteristic 
signs or symptoms of a specific disease or class of diseases. FDA 
believes that it will be easier for manufacturers to verify whether 
symptoms are in fact characteristic of a disease. FDA and manufacturers 
may look to medical texts and other objective sources of information 
about disease to determine whether a label implies treatment or 
prevention of disease by listing the characteristic signs and symptoms 
of a disease or class of diseases.
     FDA notes that the standard in the rule may be met if 
characteristic signs and symptoms are referred to either in technical 
or lay language. It also would not be necessary to mention every 
possible sign or symptom of a disease to meet this standard. Instead, 
the standard focuses on whether the labeling suggests that the product 
will produce a change in a set of one or more signs or symptoms that 
are characteristic of the disease.
    FDA does not agree with the comment that objected to the 
recognition standard because it would prohibit a claim ``as soon as 
consumers understood that certain signs and symptoms are characteristic 
of a disease--that is, as soon as consumers understood why they should 
take a particular supplement * * *.'' This comment assumes that the 
only reason people take dietary supplements is to treat or prevent 
disease and that it is appropriate to market supplements by implying 
that they can do so. Many people take dietary supplements for health-
related reasons that do not involve treatment or prevention of specific 
diseases. As discussed elsewhere in this document, FDA does not believe 
that the act permits structure/function claims to imply treatment or 
prevention of specific diseases.
     (41.) Several comments contended that the recognition standard was 
too restrictive because all signs or symptoms relating to the structure 
or function of the body are potentially recognizable to health care 
professionals and educated consumers as characteristic of some specific 
disease. Another comment argued that the proposal to treat references 
to signs and symptoms as disease claims was arbitrary and artificial. 
The comment said that specific examples of disease claims used in the 
proposal could as easily refer to nondisease states, e.g., ``reduces 
joint pain'' could refer to over-exercise. Conversely, ``stress and 
frustration'' could refer to anxiety and depression. Another comment 
contended that ``reduces joint pain'' is an acceptable structure/
function claim if other language or graphics in the labeling clearly 
communicated treatment of conditions unrelated to arthritis. One 
comment asked whether ``helps support cartilage and joint function'' 
would constitute a permissible structure/function claim. Some comments 
said that references to signs and symptoms should not be evidence of a 
disease claim because signs and symptoms can be associated with a 
number of varying conditions. One comment claimed that ``inhibits 
platelet aggregation'' does not mean anything to most consumers. On the 
other hand, some medical groups, groups devoted to specific diseases, 
and others expressed concern that the examples of structure/function 
claims provided by FDA permitted references to signs or symptoms that 
imply disease treatment or prevention. According to one comment, 
``inhibits platelet aggregation'' could be interpreted to mean 
``prevents heart attack,'' and ``improves absentmindedness'' could be 
interpreted as a treatment for Alzheimer's disease.
     FDA believes that removing the reference to recognition by 
consumers or health professionals from Sec. 101.93(g)(2)(ii) will 
permit a clearer distinction between those signs and symptoms that 
imply a disease and those that do not. The focus will be on whether 
specific signs or symptoms are characteristic of a disease, based on 
objective sources. FDA does not believe that ``improves 
absentmindedness'' or ``relieves stress and frustration'' are 
characteristic of the specific diseases mentioned in the comments. FDA 
agrees that some signs and symptoms are associated with such a wide 
variety of diseases and nondisease states that they may not imply a 
specific disease or class of diseases. For example, FDA would not 
interpret ``improves absentmindedness'' as implying treatment of 
Alzheimer's disease because absentmindedness is not as serious as the 
type of memory loss characteristically suffered by Alzheimer's 
patients; absentmindedness is, in fact, suffered predominantly by 
people who do not have Alzheimer's disease or any other disease. Stress 
and frustration, while associated with some anxiety disorders, are not 
the characteristic symptoms of those disorders; in addition, these 
symptoms are equally associated with many other nondisease states.
     The agency does agree, however, with the comment that ``inhibits 
platelet aggregation'' is an implied disease treatment or prevention 
claim. Although platelet aggregation is a normal function needed to 
maintain homeostasis, inhibiting or decreasing platelet aggregation is 
a well-recognized therapy for the prevention of stroke and recurrent 
heart attack (see, e.g., 63 FR 56802, October 23, 1998 (final rule for 
professional labeling of aspirin for cardiovascular, cerebrovascular, 
and rheumatologic uses); 53 FR 46204, November 16, 1988, (internal 
analgesic tentative final monograph)). Inhibiting or decreasing 
platelet aggregation is the mechanism of action of a number of drug 
products approved for the treatment or prevention of stroke and heart 
attack. Thus, the agency would consider a claim to inhibit normal 
platelet function to be an implied claim to treat or prevent these 
disease conditions.
     FDA also believes that ``joint pain'' is characteristic of 
arthritis. According to the Merck Manual, joint tenderness is the most 
sensitive physical sign of rheumatoid arthritis (Ref. 6). The claim 
``helps support cartilage and joint

[[Page 1017]]

function,'' on the other hand, would be a permissible structure/
function claim, because it relates to maintaining normal function 
rather than treating joint pain.
     (42.) One comment suggested that claims about a physiologic marker 
or symptom should be regarded as disease claims in two situations: (1) 
If the physiologic marker or symptom of a disease is described as being 
quantifiably linked to that disease in an official government health 
agency summary statement or consensus report, or (2) if most clinicians 
treating patients with the condition prescribe prescription drugs to 
modify the marker and historically do so without including nutritional 
or dietary intervention as part of the treatment. According to this 
comment, references to cholesterol lowering or blood pressure reduction 
would be regarded as disease claims under the first suggested 
criterion, and white cell counts and fever would be disease claims 
under the second. This comment also suggested that FDA develop a list 
of disease markers and symptoms that fall under each of the proposed 
criteria.
     FDA agrees in part and disagrees in part with this comment. The 
agency agrees that references in dietary supplement labeling to 
physiologic markers or symptoms of a disease that are quantifiably 
linked to that disease in an official government health agency summary 
statement or consensus report would be appropriately treated as implied 
disease claims. Indeed, in the cases described, elevated blood pressure 
(hypertension) and elevated cholesterol (hypercholesterolemia) are 
diseases themselves, with subsequent events (heart attack, stroke) the 
late consequences of those diseases. Although FDA agrees that fever and 
elevated white cell counts are almost always evidence of a disease, FDA 
does not agree that the second criterion appropriately describes the 
remaining circumstances in which references to signs or symptoms should 
be treated as disease claims. The appropriate test is whether: (1) The 
condition to be treated or prevented is a disease and (2) the signs and 
symptoms referred to in the labeling, in context, are characteristic of 
a disease and thus permit the inference that the product is intended to 
treat or prevent the disease. The second criterion offered by the 
comment does not provide information on either of these elements.
     (43.) Some comments that objected to the proposed definition of 
disease argued that the inclusion of ``signs or symptoms'' as part of 
the definition of disease should not mean that a reference to the signs 
and symptoms of a disease in dietary supplement labeling constitutes a 
disease claim. Another comment argued that because signs and symptoms 
do not appear in the definition of ``drug,'' FDA is not authorized to 
treat a reference to characteristic signs and symptoms as a drug claim.
     The health claims definition of ``disease or health-related 
condition'' in Sec. 101.14(a)(5), which is being adopted as the 
definition of ``disease'' in this regulation, does not include 
reference to the signs and symptoms of disease. Nonetheless, dietary 
supplement labeling that refers to the characteristic signs or symptoms 
of a specific disease or class of diseases will still be considered to 
have made an implied disease claim. Labeling that claims a product 
``prevents bone fragility in post-menopausal women,'' clearly implies 
that the product prevents osteoporosis. Similarly, labeling that claims 
a product ``prevents shortness of breath, an enlarged heart, inability 
to exercise, generalized weakness, and edema'' has made a congestive 
heart failure claim.
     The basis for determining whether such a reference to signs or 
symptoms constitutes an implied disease claim is not whether the 
definition of disease includes mention of signs or symptoms. Rather, 
FDA looks at whether the objective evidence shows that the product is 
``intended for use in the diagnosis, cure, mitigation, treatment, or 
prevention of disease'' within the meaning of section 201(g)(1)(B) of 
the act and Sec. 201.128, or the claim constitutes a health claim 
within the meaning of section 403(r)(1)(B) of the act and 
Sec. 101.14(a)(1). For example, Sec. 201.128 provides that the 
objective intent of those responsible for the labeling of drugs ``is 
determined by such persons' expressions or may be shown by the 
circumstances surrounding the distribution of the article.'' Section 
101.14(a)(1) provides that ``[i]mplied health claims include those 
statements, symbols, vignettes, or other forms of communication that 
suggest, within the context in which they are presented, that a 
relationship exists between the presence or level of a substance in the 
food and a disease or health-related condition.'' Both of these 
provisions permit FDA to look at whether a reference to the 
characteristic signs or symptoms of a disease constitute an implied 
disease claim.
     (44.) Many comments argued that the distinction between claims 
that a product maintains healthy function and that it prevents or 
treats abnormal function is artificial, and that consumers understand 
both types of claims as disease treatment or prevention claims. 
Comments from dietary supplement manufacturers and some consumer groups 
argued that both types of claims should be permitted either because 
they are not implied disease claims or because implied disease claims 
are permissible. Conversely, most of the comments from health 
professional groups, groups devoted to specific diseases, 
pharmaceutical companies, and other consumer groups argued that neither 
type of claim should be permitted, because permitting implied disease 
claims to be made without prior review would jeopardize the public 
health by encouraging substitution of unproven remedies for proven 
ones. One comment argued that analysis of health maintenance claims is 
no different than analysis of any other structure/function claim: They 
are disease claims if they imply disease prevention or treatment. 
According to this comment, health maintenance claims are permissible 
unless they relate to endpoints that are understood to be disease 
markers, such as blood pressure and cholesterol. Comments from a former 
Commission member and from a consumer group argued that many health 
maintenance claims will be perceived as disease treatment or prevention 
claims, and urged that FDA follow the Commission's guidelines, under 
which the seriousness of the condition and the ability of the consumer 
to evaluate it are key factors in deciding whether a disease claim has 
been made. One comment argued that FDA may not prohibit a claim that a 
dietary supplement ``maintains normal function'' even if it implies a 
disease claim because 403(r)(6)(A) of the act expressly authorizes such 
claims.
     One comment said that the proposed rule would frustrate the 
``orphan drug'' process. The comment contended that if dietary 
supplement labeling may claim to promote or maintain ``healthy'' 
endpoints that are related to signs and symptoms of specific diseases, 
then incentives to conduct research on orphan drugs would be 
undermined. The comment explained that dietary supplements do not 
require the same financial investment as drugs do (because drugs must 
be approved as safe and effective for their intended uses and meet 
quality controls), and could undercut sales of a more heavily regulated 
and more expensive approved drug. The comment said that a dietary 
supplement manufacturer's ability to make a disease prevention claim by 
characterizing the product as promoting good health ``cannot become a 
license to sell an active ingredient in a product

[[Page 1018]]

that is functionally a drug but is labeled as a dietary supplement.''
     FDA has carefully considered these comments and has concluded that 
the distinction drawn in the proposal between maintaining normal 
function and treatment or prevention of abnormal function is supported 
by the statute and the Commission report. FDA does not agree that 
health maintenance claims must always be treated as implied disease 
claims. Section 403(r)(6)(A) of the act demonstrates that Congress 
intended to treat as structure/function claims some claims concerning 
maintenance of normal structure or function, because it expressly 
permits statements that ``characterize the documented mechanism by 
which a nutrient or dietary ingredient acts to maintain such structure 
or function.''
     FDA also believes that many claims concerning the maintenance of 
``normal'' or ``healthy'' structure or function do not imply disease 
prevention in the context of dietary supplement labeling, unless other 
statements or pictures in the labeling imply prevention of a specific 
disease or class of diseases. There may be cases, however, in which a 
statement of health maintenance can be understood only as a claim of 
prevention of a specific disease, in which case it will be considered a 
disease claim. Thus, any reference to ``maintaining a tumor-free 
state'' would be a disease claim. Similarly, a claim to ``maintain 
normal bone density in post-menopausal women'' is a disease claim 
because post-menopausal women characteristically develop osteoporosis, 
a disease whose principal sign is decreased bone mass.
     FDA has added a sentence to Sec. 101.93(g)(2) clarifying that the 
criteria in that paragraph are not intended to preclude structure/
function claims that refer to the maintenance of healthy structure or 
function, unless they imply disease treatment or prevention.
     For the reasons described elsewhere in this document, however, FDA 
does not believe that DSHEA permits claims concerning treatment or 
prevention of abnormal function, where such abnormal function implies a 
specific disease or class of diseases. Accordingly, FDA believes that 
the statutory scheme is consistent with treating many health 
maintenance statements as structure/function claims, while treating as 
health claims or new drug claims statements that imply disease 
treatment or prevention by reference to an effect on abnormal structure 
or function.
     The Commission report also supports the distinction drawn by FDA 
between maintaining healthy function and preventing or treating 
abnormal function. The report's Guidance states:
     4. Statements that mention a body system, organ, or function 
affected by the supplement using terms such as ``stimulate,'' 
``maintain,'' ``support,'' ``regulate,'' or ``promote'' can be 
appropriate when the statements do not suggest disease prevention or 
treatment or use for a serious health condition that is beyond the 
ability of the consumer to evaluate.
     5. Statements should not be made that products ``restore'' 
normal or ``correct'' abnormal function when the abnormality implies 
the presence of disease. An example might be a claim to ``restore'' 
normal blood pressure when the abnormality implies hypertension.
(Report at pp. 38 and 39.)
     FDA agrees that if a health maintenance claim implies disease 
treatment or prevention, it would not be acceptable. (In FDA's view, a 
claim promoting ``use for a serious health condition that is beyond the 
ability of the consumer to evaluate'' is simply one form of implied 
disease claim.) FDA believes that many health maintenance claims are 
acceptable. In some cases, a health maintenance claim could use terms 
that are so closely identified with a specific disease or that so 
clearly refer to a particular at-risk population that FDA would 
consider the claim to be an implied disease prevention claim, e.g., 
``maintains healthy lungs in smokers'' would imply prevention of 
tobacco-related lung cancer and chronic lung disease. ``Maintains 
healthy lung function,'' alone, however, would be an acceptable 
structure/function claim.
     In response to the comment contending that dietary supplements 
undercut sales of orphan drugs by making health promotion claims for 
active ingredients already approved as orphan drugs, FDA notes that 
section 201(ff)(3) of the act excludes from the definition of ``dietary 
supplement'' articles that have been approved as drugs or for which 
substantial clinical investigations conducted under an investigational 
new drug application (IND) have been made public, before they were 
marketed as dietary supplements or foods.
     (45.) Many comments responded to FDA's specific request for 
comment on whether it is appropriate to treat ``maintains healthy 
cholesterol levels'' as a permissible structure/function claim, while 
treating ``lowers cholesterol'' as a disease claim. A few comments 
supported the distinction drawn in the proposed rule. Many did not, 
however. One comment from a major trade association claimed that the 
distinction between lowering and maintaining cholesterol levels is 
ambiguous, asking ``What is a healthy cholesterol level, but a lower 
cholesterol level?'' Another comment from a food industry group 
contended that ``cholesterol'' itself is a sign or symptom, and thus 
that both types of claims refer to a sign or symptom of disease. 
Several comments argued that lowering cholesterol is inextricably 
linked to cardiovascular disease. Some comments argued that the 
distinction between maintaining normal cholesterol and lowering 
cholesterol is arbitrary because both have as their purpose preventing 
heart disease, and consumers link cholesterol levels with disease 
prevention. Other comments, however, argued that cholesterol claims do 
not imply disease prevention. A comment from an organization devoted to 
prevention and treatment of heart disease argued that if any 
cholesterol claims were to be permitted, a claim like ``promotes 
cholesterol clearance'' would be a more accurate structure/function 
statement than ``maintains healthy cholesterol'' and less likely to 
imply disease prevention. Two comments contended that changing a claim 
from ``lowers cholesterol'' to ``maintains healthy cholesterol levels'' 
does not change the effect of the product or its use. Some comments 
argued that ``lowers cholesterol'' claims should be permitted for 
cholesterol levels that are not ``abnormal'' or are below 
hypercholesterolemia.
     FDA does not agree that claims concerning maintenance of normal 
cholesterol levels necessarily constitute implied disease claims. 
Although an elevated cholesterol level is a sign of 
hypercholesterolemia and an important risk factor for heart disease, a 
cholesterol level within the normal range is not a sign or risk factor 
for disease. Moreover, maintaining cholesterol levels within the normal 
range is essential to the structure and function of the body for 
reasons other than prevention of heart disease. Although many people 
think of cholesterol solely in terms of the negative role of elevated 
cholesterol in heart disease, normal cholesterol levels play a positive 
role in maintaining a healthy body. Cholesterol is a necessary 
constituent of cell membranes and of myelin, the sheath that coats 
nerves. Cholesterol is also required for the synthesis of steroid 
hormones, which are essential for life. Finally, cholesterol is 
required for the production of bile in the liver, making possible 
absorption of dietary fat and fat soluble vitamins. Thus, a claim that 
a dietary supplement helps maintain cholesterol levels that are already 
within the normal range does not necessarily imply disease

[[Page 1019]]

treatment. FDA also believes that Congress intended to permit dietary 
supplements to carry claims of this type under section 403(r)(6)(A) of 
the act.
     The agency has concluded, however, that references to ``healthy'' 
cholesterol may be misleading to consumers because the phrase ``healthy 
cholesterol'' is now frequently used to refer to high density 
lipoproteins (HDL), a specific cholesterol fraction believed to be 
beneficial. To avoid this confusion, FDA has concluded that an 
appropriate structure/function claim for maintaining cholesterol would 
be ``helps to maintain cholesterol levels that are already within the 
normal range.''
     FDA continues to believe that ``lowers cholesterol,'' however 
qualified, is an implied disease claim. As many comments argued, 
lowering cholesterol is inextricably linked in the public mind with 
treating elevated cholesterol and preventing heart disease. The agency 
also believes that ``promotes cholesterol clearance'' is an implied 
disease claim because it is directed at lowering cholesterol rather 
than maintaining levels already determined to be within a normal range. 
FDA will review all cholesterol claims to determine whether the 
labeling as a whole implies that the product is intended to lower 
elevated cholesterol levels. In such cases, FDA would consider the 
labeling to create an implied disease claim.
     (46.) A comment from a former Surgeon General of the United States 
argued that, given the importance of preventing cardiovascular disease, 
dietary supplements should be permitted to make claims for cholesterol 
reduction, because ``our citizens deserve the opportunity to know when 
safe and effective dietary supplements are available to lower 
cholesterol.'' A comment from the Nutrition Committee of the American 
Heart Association argued that current scientific evidence does not 
support added benefits of dietary supplementation with nutritive 
substances for prevention of cardiovascular disease in the general 
population, and expressed concern that dietary supplements also carry 
risks.
    FDA agrees that prevention of heart disease is an extremely 
important public health goal. Lowering cholesterol with certain drugs 
has been conclusively shown to be effective in reducing mortality from 
coronary artery disease. Indeed, the evidence linking the lowering of 
elevated cholesterol with preventing heart disease is so strong that 
identifying and using effective therapies to lower cholesterol in 
patients with elevated cholesterol levels has become of compelling 
importance. With this in mind, use of possibly ineffective therapies in 
persons with elevated cholesterol, which can delay or prevent effective 
treatment, poses significant public health risks. Although DSHEA 
requires that manufacturers who make structure/function claims have 
substantiation, manufacturers are not currently required to submit that 
substantiation to FDA for premarket review, nor does FDA have the 
resources to inspect and review the quality of the substantiation in 
most cases. For this reason, FDA does not believe that permitting 
``lowers cholesterol'' claims on dietary supplements without prior 
review serves the public health.
     (47.) A few comments argued that FDA may not prohibit ``lowers 
cholesterol'' claims because the agency had earlier issued an advisory 
letter permitting such claims if the claim stated that the product was 
useful in the context of a healthy diet. One of these comments 
contended that the agency may not change its advice or guidance because 
it has cited no studies in this rulemaking to support the view that 
``lowers cholesterol'' implies disease treatment.
     FDA does not agree that it may not change its position on whether 
particular cholesterol claims imply disease treatment. The record and 
analysis in this rulemaking, as well as FDA's experience in 
implementing DSHEA, provide an ample basis for the conclusions that the 
agency has reached on cholesterol claims.

 G. Conditions Associated With Natural States (Sec. 101.93(g)(2)(iii))

     The proposed rule stated that natural states such as aging, 
menopause, pregnancy, and the menstrual cycle, are not themselves 
diseases, but can be associated with abnormal conditions that are 
diseases. FDA proposed in Sec. 101.93(g)(2)(iii) to treat as a disease 
claim a statement that a product had an effect on a condition 
associated with a natural state if the condition presented ``a 
characteristic set of signs or symptoms recognizable to health care 
professionals or consumers'' as an ``abnormality.'' FDA provided as 
examples of such abnormal conditions the following: Toxemia of 
pregnancy; premenstrual syndrome; hot flashes; and presbyopia, 
decreased sexual function, and Alzheimer's disease associated with 
aging.
     In the July 8, 1999, Federal Register notice announcing a public 
meeting and reopening the comment period, FDA asked for additional 
comment on this provision of the proposed rule. The agency sought 
specific comment on the following three questions: (1) If FDA were to 
treat some conditions associated with natural states as diseases (e.g., 
toxemia of pregnancy and Alzheimer's disease) but not others (e.g., hot 
flashes, common symptoms associated with the menstrual cycle, and 
decreased sexual function associated with aging), what would be an 
appropriate principle for distinguishing the two groups? (2) For 
example, would it be appropriate to consider the severity of the health 
consequences if the condition were to go without effective treatment? 
(3) If so, how should ``severity'' be defined?
     (48.) Although some comments from disease-specific organizations 
and health professionals supported this provision, most of the comments 
strongly objected to classifying common conditions associated with 
natural states as diseases. None of the objecting comments argued that 
toxemia of pregnancy or Alzheimer's disease are not diseases. Almost 
all of these comments, however, contended that PMS, hot flashes, and 
various conditions associated with aging, such as decreased sexual 
function, are so common that they should be considered neither abnormal 
nor diseases. Some comments argued that any condition suffered by more 
than 50 percent of the population should be considered normal and not a 
disease, and gave as an example benign prostatic hypertrophy. Other 
comments cited prevalence rates for conditions such as PMS and hot 
flashes, and contended that the cited rates were too high for these 
conditions to be considered abnormal. A large number of comments 
asserted that the proposed rule would treat pregnancy, menopause, and 
aging as diseases. A few comments argued that if menopause, aging, and 
pregnancy are not diseases, then signs and symptoms associated with 
these states cannot be diseases. One comment argued that conditions 
related to natural states are not diseases but ``health-related 
conditions'' and that DSHEA permits statements about health-related 
conditions.
     In response to the questions in the July 8, 1999, Federal Register 
notice, many comments argued that the severity of the condition 
associated with a natural state was not an appropriate principle for 
distinguishing diseases from nondiseases. These comments generally 
argued that the severity of the symptoms (rather than the severity of 
the consequences of going without effective treatment) was not an 
adequate basis to distinguish diseases from nondiseases. One comment 
from a food industry group argued that this was an inappropriate 
principle because ``all

[[Page 1020]]

natural states can have severe consequences if left unattended.'' This 
comment suggested that conditions that were ``universal'' should not be 
treated as diseases. This comment and one other also suggested that the 
distinguishing principle was whether the cause of the condition was 
``pathological.''
     FDA has reconsidered proposed Sec. 101.93(g)(2)(iii), and has 
concluded that it is not appropriate, under DSHEA, to treat certain 
common, nonserious conditions associated with natural states as 
diseases. There are a wide variety of conditions representing impaired 
function of an organ or system that are associated with particular 
stages of life or normal physiologic processes. These stages and 
processes include adolescence, the menstrual cycle, pregnancy, 
menopause, and aging. (FDA notes that, contrary to the comments, the 
proposed rule would not have classified these stages or processes 
themselves as diseases; it classified only certain abnormal conditions 
associated with these stages or processes as diseases.) The conditions 
associated with these stages or processes can vary from common, 
relatively mild abnormalities, for which medical attention is not 
required, to serious conditions that can cause significant or permanent 
harm if not effectively treated.
     For example, pregnancy is associated with common and mild 
abnormalities such as morning sickness and leg edema that cause no 
permanent harm if left untreated, as well as with such serious 
conditions as hyperemesis gravidarum, toxemia of pregnancy, and acute 
psychosis of pregnancy, which can be life-threatening if not 
effectively treated. The menstrual cycle is commonly associated with 
mild mood changes, edema, and cramping that do not cause significant or 
permanent harm if left untreated, but also, more rarely, with serious 
cyclical depression that can result in significant harm if not 
effectively treated. Aging is almost invariably associated with 
characteristic skin and scalp changes, such as wrinkles and hair loss, 
which do not need medical attention. It is also, however, associated 
with serious diseases that will result in significant, often 
irreversible damage, many of which can be effectively treated. These 
diseases include osteoporosis, glaucoma, and arteriosclerotic diseases 
of coronary, cerebral, and peripheral vessels. Adolescence is commonly 
associated with mild acne, which does not cause significant or 
permanent harm if not treated, and, rarely, with cystic acne, which can 
produce severe physical and psychological scars if not effectively 
treated.
     Whether all of these conditions represent diseases is, in part, a 
matter of definition and, in part, depends on the consequences of the 
conditions if not effectively treated, and on how commonly they occur, 
i.e., whether they may be considered ``normal.'' Although most people 
consider the more serious or infrequent conditions referred to above to 
be diseases, views vary with respect to the common, milder conditions. 
FDA has reconsidered the position it took in the proposed rule and 
agrees with the comments that treating as diseases the common, mild 
symptoms associated with normal life stages or processes would not be 
consistent with the intent of DSHEA.
     FDA does not believe that the frequency with which a condition 
associated with a natural state occurs is, by itself, sufficient to 
distinguish diseases from nondiseases. The severity of the consequences 
of disease, as well as the consequences of ineffective treatment, must 
also be considered. As noted above, whether common, minor conditions 
associated with natural states are diseases is a matter of debate, but 
FDA has decided not to treat them as diseases because the agency 
believes this approach is consistent with the intent of DSHEA. FDA does 
not, however, believe that DSHEA was intended to permit unreviewed 
claims about serious conditions that could cause significant or 
permanent harm, particularly where effective treatment is available. 
FDA also does not agree that ``all natural states can have severe 
consequences if left unattended.'' FDA has listed a large number of 
conditions associated with natural states that commonly do not have 
serious consequences even if not effectively treated. FDA also does not 
agree that it is helpful in this context to distinguish between 
diseases and nondiseases by asking which have a ``pathological'' basis. 
The term ``pathological'' is itself defined by reference to disease, 
namely, ``caused by or involving disease; morbid'' (Ref. 7).
     Accordingly, for purposes of this rule, mild conditions commonly 
associated with particular stages of life or normal physiological 
processes will not be considered diseases. Therefore, 
Sec. 101.93(g)(2)(iii) now states that a statement will be considered a 
disease claim if it claims that the product ``has an effect on an 
abnormal condition associated with a natural state or process, if the 
abnormal condition is uncommon or can cause significant or permanent 
harm.'' Ordinarily, FDA would follow the suggestion in the comments 
that conditions associated with a stage of life or a normal 
physiological process be considered common if they occur in more than 
one-half of those experiencing that stage or process.
     The following are examples of conditions about which structure/
function claims could be made under Sec. 101.93(g)(2)(iii): (1) Morning 
sickness associated with pregnancy; (2) leg edema associated with 
pregnancy; (3) mild mood changes, cramps, and edema associated with the 
menstrual cycle; (4) hot flashes; (5) wrinkles; (6) other signs of 
aging on the skin, e.g., liver spots, spider veins; (7) presbyopia 
(inability to change focus from near to far and vice versa) associated 
with aging; (8) mild memory problems associated with aging; (9) hair 
loss associated with aging; and (10) noncystic acne. The following are 
examples of conditions that would remain disease claims: (1) Toxemia of 
pregnancy; (2) hyperemesis gravidarum; (3) acute psychosis of 
pregnancy; (4) osteoporosis; (5) Alzheimer's disease, and other senile 
dementias; (6) glaucoma; (7) arteriosclerotic diseases of coronary, 
cerebral or peripheral blood vessels; (8) cystic acne; and (9) severe 
depression associated with the menstrual cycle.
     FDA has not included benign prostatic hypertrophy (BPH) on either 
of these lists, because the agency does not believe that BPH should be 
considered a consequence of aging. Like many other diseases, e.g., 
diabetes, prostate cancer, and heart disease, the incidence of BPH is 
much higher among older men. This does not mean that BPH or prostate 
cancer is caused by the aging process. Even if BPH were considered a 
direct consequence of aging, however, claims to treat or prevent it 
would still be treated as disease claims because failure to obtain 
effective treatment can cause significant or permanent harm.
     FDA notes that it does not base the exclusion of the mild common 
conditions associated with natural states from Sec. 101.93(g)(2)(iii) 
on the argument advanced by one of the comments that these are 
``health-related conditions'' and that DSHEA permits structure/function 
claims about health-related conditions. FDA believes that a ``health-
related condition'' is a state of health leading to disease. As FDA has 
said previously, ``diseases'' and ``health-related conditions'' are 
``so closely related that no bright-line distinction is practicable'' 
(58 FR 2478, 2481 January 6, 1993). There is nothing in DSHEA, its 
legislative history, or in the definition of ``disease or health-
related condition'' that would suggest that common conditions 
associated with natural states

[[Page 1021]]

are ``health-related conditions'' within the meaning of section 
403(r)(1)(B) of the act. Further, FDA does not agree that section 
403(r)(6) of the act authorizes structure/function claims about 
``health-related conditions.'' Had Congress intended to authorize 
structure/function claims about ``health-related conditions'' it could 
easily have used that terminology, but did not.
    (49.) Some comments concerned specific claims under proposed 
Sec. 101.93(g)(2)(iii). One comment sought concurrence that the 
following are acceptable structure/function claims: ``supports a 
normal, healthy attitude during PMS'' and ``supportive for menopausal 
women.'' Another comment argued that a statement that a product 
provides nutrients that diminish the normal symptomatology of 
premenstrual syndrome or menopause is a permissible structure/function 
claim. Another comment asked whether ``helps to maintain normal urine 
flow in men over 50 years old'' is a permissible structure/function 
claim. One comment urged that only products proven safe when used as 
directed should be permitted for sale for enlarged prostate and that 
such products should recommend that a man see his physician. Another 
comment argued that the claim ``for men over 50 years old,'' which FDA 
had proposed as an acceptable structure/function claim, is vague and 
ambiguous and is of no use to consumers.
     FDA agrees that ``supports a normal, healthy attitude during PMS'' 
and ``supportive for menopausal women'' are appropriate structure/
function claims. ``Supports a normal, healthy attitude during PMS'' is 
acceptable because PMS is generally a common, mild condition associated 
with a normal physiologic process. ``Supportive for menopausal women'' 
is acceptable because it is a general statement that does not refer to 
symptoms of any conditions at all. Claims about diminishing the normal 
symptomatology of premenstrual syndrome or menopause would also be 
acceptable structure/function claims, if they did not suggest, for 
example, prevention or treatment of osteoporosis, or another disease 
associated with these states. ``Helps to maintain normal urine flow in 
men over 50 years old,'' however, is an implied disease claim because, 
as many comments pointed out, the average or ``normal'' state in men 
over 50 years old is diminishing urine flow, in most cases due to BPH, 
so that the apparent ``maintenance'' really represents a claim of 
improvement (treatment).

 H. Generally (Sec. 101.93(g)(2)(iv))

     Under proposed Sec. 101.93(g)(2)(iv), FDA stated that a statement 
would be considered a disease claim if it claimed explicitly or 
implicitly to have an effect on disease through one or more of the 
following factors: (1) The name of the product (e.g., ``Carpaltum'' 
(carpal tunnel syndrome), ``Raynaudin'' (Raynaud's phenomenon), 
``Hepatacure'' (liver problems)). Names that did not imply an effect on 
a disease, such as ``Cardiohealth'' and ``Heart Tabs,'' would not 
constitute disease claims; (2) statements about the formulation of the 
product, including a claim that the product contained an ingredient 
that has been regulated by FDA predominantly as a drug and is well 
known to consumers for its use in preventing or treating a disease 
(e.g., aspirin, digoxin, or laetrile); (3) citation of a publication or 
other reference, if the citation refers to a disease use. For example, 
labeling for a vitamin E product that included a citation to an article 
entitled ``Serial Coronary Angiographic Evidence That Antioxidant 
Vitamin Intake Reduces Progression of Coronary Artery 
Atherosclerosis,'' would create a disease claim under this criterion; 
(4) use of the term ``disease'' or ``diseased;'' or (5) otherwise 
suggesting an effect on disease by use of pictures, vignettes, symbols, 
or other means (e.g., electrocardiogram tracings, pictures of organs 
that suggest prevention or treatment of a disease state, or the 
prescription symbol (Rx)). The proposed rule stated that a picture of a 
body would not constitute a disease claim under this criterion.
     (50.) A few comments stated that the phrase ``has an effect on'' 
in proposed Sec. 101.93(g)(2)(iv) is vague and could be interpreted by 
the agency to mean almost anything. Some of these comments argued that 
disease claims should include only those that use the specific terms 
``diagnose,'' ``prevent,'' ``treat,'' ``mitigate,'' or ``cure.''
     FDA does not agree that the phrase ``has an effect on'' is 
inappropriately vague. FDA believes that it is necessary to use a 
phrase that encompasses synonyms for the terms ``diagnose,'' 
``prevent,'' ``treat,'' ``mitigate,'' or ``cure.'' If disease claims 
were limited to those that used the specific terms in the statute, it 
would be possible to make obvious and explicit disease claims simply by 
using terms that are similar in meaning to the statutory terms, e.g., 
``relieves arthritis pain'' rather than ``treats arthritis pain,'' or 
``eliminates the risk of cancer'' rather than ``prevents cancer.''

 I. Product Name (Sec. 101.93(g)(2)(iv)(A))

     (51.) One comment observed that there is an inconsistency between 
the statement in the proposed rule that ``Heart Tabs'' does not imply 
an effect on a disease and Sec. 101.14(a)(1), which states that:
    Health claim means any claim made on the label or in the 
labeling of a food, including a dietary supplement, that expressly 
or by implication, including ``third party'' references, written 
statements (e.g., a brand name including a term such as ``heart''), 
symbols (e.g., a heart symbol) characterizes the relationship of any 
substance to a disease or health-related condition * * *
and requested clarification.
     FDA agrees, in part, and disagrees, in part, with the comment. FDA 
does not agree that Sec. 101.93(g)(2)(iv)(A) and Sec. 101.14(a)(1) are 
inconsistent. Section 101.14(a)(1) was issued in 1993 to implement the 
health claims provisions of NLEA. In Sec. 101.14(a)(1), use of the term 
``heart'' in a brand name and use of the heart symbol in labeling are 
offered as examples of health claims, if in the context of the labeling 
as a whole, the word or symbol suggests that there is a relationship 
between the product and a disease or health-related condition. Thus, 
according to the preamble to that final rule (58 FR 2478 at 2486), the 
heart symbol might appropriately appear in the labeling of a food 
product if, in context, it did not suggest a relationship to heart 
disease, e.g, in conjunction with ``Hey, Fudge Lovers.'' If, however, 
the heart symbol appeared alone on a food, without further explanation 
from context, consumers might conclude that the food was beneficial for 
reducing the risk of developing cardiovascular disease (id.).
     Following the issuance of Sec. 101.14(a)(1), Congress enacted 
DSHEA. DSHEA created a special regulatory regime for dietary 
supplements. That regime, while closely related to the regime for food, 
was not identical to the food regime. Section 403(r)(6) of the act 
specifies certain types of structure/function claims and general well-
being claims that may be made for dietary supplements without first 
obtaining new drug approval or health claim authorization. The types of 
claims listed in section 403(r)(6) of the act are similar, but not 
identical to the claims permitted for foods under section 201(g)(1)(C) 
of the act. Under Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983), 
conventional food claims are limited to structure/function effects that 
derive from the taste, aroma, or nutritive value of the food. Dietary 
supplement claims are not subject to that limitation. Had Congress 
intended the scope of the permitted claims to be identical, it

[[Page 1022]]

could simply have declared that dietary supplements are ``foods.'' In 
light of Congress' intent to expand the types of claims authorized for 
dietary supplements in DSHEA, FDA interprets Sec. 101.14(a)(1) as 
permitting dietary supplements to have brand names that include the 
word ``heart'' or other organs, if, in the context of the labeling as a 
whole, the name does not imply disease treatment or prevention.
     FDA does agree, however, that under .Sec. 101.14(a)(1), a dietary 
supplement name that included the word ``heart'' could be a health 
claim, depending on the context. Thus, a dietary supplement could be 
called ``HeartTabs'' if its claim was ``to maintain healthy 
circulation,'' or some other role related to the structure or function 
of the heart that did not imply treatment or prevention of disease. If, 
however, the product name was not qualified by any further claim in the 
labeling, the product could be considered, under Sec. 101.14(a)(1), to 
be intended for treatment or prevention of cardiovascular disease.
     FDA also believes that the heart symbol has become so widely 
associated with prevention of heart disease that its use in the 
labeling of a dietary supplement would be ordinarily considered an 
implied heart disease prevention claim. Consistent with the examples 
provided in the January 6, 1993, Federal Register document on health 
claims (58 FR 2486), however, there may be unusual cases in which, in 
context, the use of a heart symbol does not imply heart disease 
prevention.
     (52.) Several comments agreed with proposed 
Sec. 101.93(g)(2)(iv)(A) that product names that imply an effect on 
disease, including implying cure or treatment of a disease, should not 
be allowed. The comments, however, requested that the agency provide 
further guidance as to what types of product names are acceptable and 
what types are not. Some comments questioned whether product names such 
as ``CarpalHealth,'' ``HepatoHealth,'' ``HepataCare,'' ``CircuCure,'' 
or ``Soothing Sleep'' would be acceptable under proposed 
Sec. 101.93(g)(2)(iv)(A). Other comments disagreed with the agency's 
examples and stated that it is difficult to distinguish the reasoning 
behind some of the examples cited. For example, a few comments stated 
that both ``Cardiohealth'' and ``Heart Tabs'' imply that the product 
prevents heart disease.
     Two principles formed the basis for the distinctions in the 
proposed rule between product names that were considered structure/
function claims and those that were considered disease claims. First, 
the name should not contain the name, or a recognizable portion of the 
name, of a disease. Second, the name should not use terms such as 
``cure,'' ``treat,'' ``correct,'' ``prevent'' or other terms that 
suggest treatment or prevention of a disease. Thus, ``CarpalHealth'' 
and ``CircuCure'' would be considered disease claims. In some cases, to 
determine whether a product name implies an effect on disease, the 
agency will need to consider the context in which a term is presented 
in the labeling as a whole. Thus, ``Soothing Sleep'' could be 
considered a claim to treat insomnia, unless the labeling made clear 
that the product was intended only for occasional sleeplessness. 
``HepataCare'' and ``HepataHealth'' could also be considered disease 
claims because ``Hepata'' could be read as a reference to hepatitis, 
unless the labeling made clear that the product was intended for 
general liver health and not intended to treat or prevent hepatitis.
     The agency notes that in the near future, FDA will issue for 
public comment a draft guidance to provide additional clarification and 
examples of claims that would and would not be considered disease 
claims under the final rule. FDA will include in the draft guidance 
examples of product names.
     (53.) Another comment stated that proposed 
Sec. 101.93(g)(2)(iv)(A) would prohibit the use of the name of the 
``dispensing institution'' if it had the word ``Cancer'' in it because 
the agency would interpret the labeling as implying an effect on 
disease, when in fact the product was listing the institution where the 
product was dispensed, e.g., ABC Cancer Institute. Other comments were 
concerned that the proposed rule would prohibit the use of their 
company trade name, which includes the use of the word ``prescription'' 
and its abbreviation ``Rx.''
     The agency reiterates that it will view the name in the context of 
the entire labeling to determine whether a disease claim is being made. 
However, a manufacturer may not circumvent the requirements of the act, 
DSHEA, or this final rule by using the name of an institution or the 
manufacturer to imply a disease claim.
     The agency agrees that the use of the word ``prescription'' or its 
abbreviation ``Rx'' in the name of the product should not automatically 
be interpreted as a disease claim. Although these terms imply that the 
product is a prescription drug, some prescription drugs are intended 
for nondisease conditions. Therefore, if nothing else in the labeling 
suggests a disease use, the agency will not consider the use of 
``prescription'' or ``Rx'' to be an implied disease claim. The agency 
notes, however, that the use of these terms on dietary supplement 
products may deceive consumers into thinking that they are purchasing a 
prescription drug without a prescription. Thus, use of the terms 
``prescription'' or ``Rx'' is misleading and will misbrand the product 
under section 403(a)(1) of the act if, in the context of the labeling 
as a whole, the terms imply that the product is a prescription drug.
     (54.) A few comments cited in a proposed rule published in the 
Federal Register of March 27, 1974 (39 FR 11298), in which FDA stated 
that it would challenge brand names only in situations where clarifying 
language is incapable of rectifying FDA's concern with the brand name 
and that excision of a brand name should be a last resort and should be 
pursued only when all other methods of qualifying the name have failed.
     The agency notes that the proposed rule cited in this comment was 
never finalized and was withdrawn on December 30, 1991 (56 FR 67440), 
as part of an FDA initiative to reduce the backlog of outstanding 
proposed rules that have never been finalized. The policies outlined in 
the March 27, 1974, Federal Register notice are not in effect.
     (55.) Several comments sought a statement from FDA that if a 
product brand name becomes synonymous over time with use for prevention 
or treatment of a disease, it will still be permitted. As an example, 
the comments claimed that Kleenex has become synonymous with treatment 
of nasal congestion, but did not provide support for this assertion.
     FDA does not believe that Kleenex is synonymous with treatment of 
nasal congestion and, absent any supportive data, has no reason to 
believe that consumers believe them to be synonymous. The agency would 
agree that Kleenex has become synonymous with ``tissue,'' and that both 
are used in conjunction with nasal congestion. Neither tissue nor 
Kleenex, however, treat, prevent, or otherwise affect nasal congestion 
in any way. Because the agency was not presented with any specific 
examples of, nor is it aware of any, names of products that are not 
intended to treat disease but that have become synonymous with disease 
treatment or prevention, it does not have reason to believe that there 
is a real basis for concern.

 J. Product Formulation (Sec. 101.93(g)(2)(iv)(B))

     (56.) Several comments questioned whether the inclusion of a 
dietary ingredient in the ingredient list of a

[[Page 1023]]

dietary supplement would be interpreted as a disease claim under 
proposed Sec. 101.93(g)(2)(iv)(B). They argued that to provide truthful 
labeling, this information must be included. Another comment stated 
that the proposal fails to distinguish between true claims and false 
claims. Several comments further argued that ingredient information may 
be of value to consumers to alert them to potential adverse effects or 
drug interactions. One comment urged that the presence of a constituent 
that is naturally occurring in a plant and is also regulated as a drug 
does not automatically classify the substance as a drug. The comment 
asserted that 45 percent of drugs are derived from plants, which, 
according to the comment, would classify a number of dietary 
ingredients as drugs.
     Listing a dietary ingredient in the ingredient list of a dietary 
supplement will not be considered to imply an effect on disease unless 
the ingredient is one that has been regulated primarily by FDA as a 
drug and is well-known to consumers for its use or claimed use in 
preventing or treating a disease. (In the proposed rule, the agency 
gave as examples aspirin, digoxin, and laetrile.) Very few dietary 
ingredients meet this test. The agency agrees that a certain percentage 
of drug products are derived from plants. However, only a handful of 
these drugs are well-known to consumers under the name of the plant or 
natural plant ingredient from which they were derived. Instead, they 
are known to consumers under a brand name or generic name, e.g., 
aspirin. Thus, FDA does not believe that listing dietary ingredients 
that happen to be related to well-known drugs will fall under this 
provision, except in unusual circumstances. In those cases where a 
manufacturer does add a drug ingredient that is well-known to treat or 
prevent disease to its product and label its presence, however, FDA may 
consider it a disease claim. The fact that the labeling is truthful 
does not necessarily mean that it falls within the scope of claims 
authorized by section 403(r)(6) of the act. For example, the agency 
believes that there are many dietary ingredients that could be shown to 
treat or prevent diseases, and for which it could thus be truthful to 
state that the product treats or prevents a specific disease. Under the 
act, however, if a manufacturer wants to label its product to treat or 
prevent disease, it must do so under the drug approval provisions or 
the health claim provisions of the act. It may not do so under section 
403(r)(6) of the act. In drafting section 403(r)(6) of the act to 
exclude disease claims, Congress made a judgment that the public health 
will be served by requiring premarket review of such claims.
     FDA agrees that it is important to inform consumers about 
potential adverse effects or drug interactions for specific dietary 
supplement ingredients. In fact, dietary supplement labeling, like the 
labeling of other FDA-regulated products, is required to include all 
facts that are material in light of consequences that may result from 
use of the product or representations made about it (sections 403(a)(1) 
and 201(n) of the act). This provision is not intended in any way to 
preclude truthful adverse event or drug interaction information from 
appearing in a dietary supplement's labeling.
     (57.) A dietary supplement manufacturer asked FDA to clarify the 
effect of Sec. 101.93(4)(ii) on a dietary ingredient found in common 
food(s), whose biological activity is first characterized in a food 
context, but which is subsequently approved as a drug. The comment 
asked whether, if indole-3-carbinol, a compound discovered in broccoli 
and other vegetables, were to be approved as a breast cancer drug, 
claims to the effect that a vegetable-based dietary supplement product 
contains indole-3-carbinol would be permitted as structure/function 
claims under the proposed rule. The comment claimed that the proposed 
rule would classify such claims as disease claims even if the 
biological activity of this dietary ingredient were first identified in 
the food context.
     Where an ingredient has been approved as a drug, section 
201(ff)(3) of the act prohibits marketing of the ingredient as a 
dietary supplement unless the ingredient itself was previously marketed 
as a food (including a dietary supplement), or unless a food containing 
the ingredient was previously marketed for the presence of the 
ingredient. In the example provided in the comment, the isolated 
ingredient indole-3-carbinol could not be marketed as a dietary 
supplement, unless a food containing the ingredient had been marketed 
for the presence of the ingredient before the drug was approved or was 
the subject of substantial investigations that had been made public. 
However, to avoid a conflict between this provision and section 
201(ff)(3) of the act in a situation where the ingredient was marketed 
as a food first, FDA has revised Sec. 101.93(g)(2)(iv)(B) to exclude 
claims about an ingredient that is an article included in the 
definition of ``dietary supplement'' under section 201(ff)(3) of the 
act.
     (58.) One comment misunderstood Sec. 101.93(g)(2)(iv)(B) and 
believed that this provision only applies to the listing of OTC drug 
ingredients recognized by consumers.
     This provision is not limited to the listing of OTC drug 
ingredients. For purposes of Sec. 101.93(g)(2)(iv)(B), the agency may 
consider as a disease claim a claim that the product contains an 
ingredient that has been regulated by FDA as a drug, whether marketed 
over-the-counter or by prescription, and that is well known for its use 
in preventing or treating a disease.

 K. Citation of Publication Titles (Sec. 101.93(g)(2)(iv)(C))

     (59.) Many comments objected to this proposed criterion or sought 
clarification. Many comments said that the proposed criterion 
undermines DSHEA by prohibiting the use of most journals, is not 
required by DSHEA, or is contrary to section 403B of the act (21 U.S.C. 
343-2), which, the comment said, exempts scientific publications from 
labeling rules and is intended to allow consumers to be more informed 
by reading scientific studies. Other comments said that Congress 
intended to encourage the dissemination of scientific research and 
truthful, non-misleading information, so FDA should not prohibit titles 
of scientific studies. Some comments stated that the issue should not 
be whether a publication's title refers to a disease use, but rather 
whether, on balance, the entire presentation, including the product 
label, package insert, and other labeling, represents a disease claim. 
These comments supported the use of complete citations to scientific 
literature, including the titles of scientific articles. Some comments 
suggested that the proposal contradicted earlier FDA positions. One 
comment referred to the September-October 1998 issue of FDA Consumer 
which, the comment stated, suggested that consumers contact companies 
to obtain scientific articles that the company might have to 
substantiate a claim. Another comment said the proposal was contrary to 
FDA policy to recognize and accept valid science. Several comments 
questioned how to provide substantiation of labeling claims, in 
compliance with 403(r)(6)(B) of the act, if the supporting articles 
cannot be cited. One comment stated that there will be more fraud and 
deception in the marketplace because companies will not cite scientific 
support for their statements. Several comments stated that the proposed 
rule will restrict

[[Page 1024]]

access by consumers and the medical community to important new research 
results and discourage companies from investing in research. A dietary 
supplement manufacturer suggested revising the provision to permit 
companies to cite ``bonafide'' textbooks and peer-reviewed scientific 
journals that mention a disease in the title. Another dietary 
supplement manufacturer suggested revising this provision to permit 
citation of a publication or reference if the citation ``is necessary 
to present a balanced discussion of the documented mechanism by which a 
nutrient or dietary ingredient acts to maintain the structure or 
function of the body.''
     FDA agrees that in enacting DSHEA, Congress intended to encourage 
the dissemination of scientific research and truthful, non-misleading 
information. FDA also agrees that consumers can benefit from reviewing 
the scientific support used to substantiate a statement made for a 
dietary supplement under section 403(r)(6) of the act. In keeping with 
these goals, FDA has modified Sec. 101.93(g)(2)(iv)(C) to narrow the 
circumstances under which citation to a scientific reference will be 
considered a disease claim. Based on Congress' explicit prohibition in 
section 403(r)(6) of the act of claims to affect disease, however, FDA 
does not believe that Congress intended to permit scientific references 
to be used in a way that constitutes an implied disease claim. 
Consequently, Sec. 101.93(g)(2)(iv)(C) has been revised to state that 
citation of a title referring to a disease will be treated as a disease 
claim, if, in the context of the labeling as a whole, the citation 
implies treatment or prevention of a disease, e.g., through placement 
on the immediate product label or packaging, inappropriate prominence, 
or lack of relationship to the product's express claims.
     The agency continues to believe that placing a citation to a 
scientific reference that mentions a disease in the title on the 
immediate product label or packaging should be considered a disease 
claim for that product, because of the unusual and unnecessary 
prominence of such placement. For citations to scientific references 
that refer to a disease use in the title and that are included in other 
types of labeling (i.e., other than the product label or packaging) the 
agency will consider the context in which the citation is presented. 
FDA agrees with the comments that the totality of all available 
labeling should be considered to determine the context. One element 
that the agency will look at is the prominence of the citation in the 
labeling. If, for example, the citation is simply listed in the 
bibliography section of the labeling among other titles, it will 
generally not suggest an implied disease claim. On the other hand, 
highlighting, bolding, using large type size, or prominent placement of 
a citation that refers to a disease use in the title could suggest that 
the product has an effect on disease. The agency will also consider 
whether the cited article provides legitimate support for a 403(r)(6) 
of the act statement that appears in the labeling of the dietary 
supplement. Enhancing the bibliography with citations to scientific 
references that refer to a disease in the title and that have no 
reasonable relation to the statement made will be considered a disease 
claim. Similarly, the agency will consider whether citations are to 
bona fide research.
     FDA also agrees that it is important to provide a balanced 
discussion of the scientific literature regarding the claim. FDA 
encourages manufacturers to cite references that provide a balanced 
discussion of the evidence supporting a structure/function claim.
     The agency believes that the final rule strikes a reasonable 
balance between encouraging the dietary supplement industry to inform 
consumers about the substantiation for their claims and preventing 
abuses of section 403(r)(6) of the act.
     (60.) Several comments challenged the basis for the proposed 
restriction of scientific references. One comment from industry said 
the proposed restriction on titles is outside DSHEA because the act 
refers to statements. The comment said titles could be prohibited if 
they were misleading, but said the rule should not contain a blanket 
prohibition.
     The comment is apparently referring to section 403(r)(6) of the 
act, which prescribes the terms under which a ``statement'' may be made 
for a dietary supplement. FDA believes that the comment's reading is 
too literal, however. A ``statement'' does not have to be a declaratory 
sentence but rather is fairly read to include other kinds of 
statements, such as citations of scientific authority. In keeping with 
DSHEA's purpose to broaden the scope of labeling claims that may be 
made for dietary supplements without subjecting them to regulation as 
drugs, FDA believes that Congress intended ``statement'' to refer to 
any claim made that recommends or suggests a particular use of a 
dietary supplement. In addition to being under inclusive, a narrower 
interpretation would not benefit the dietary supplement industry 
because it would limit the scope of claims authorized under section 
403(r)(6) of the act.
    (61.) A few comments stated that the agency did not provide any 
support for the assumption that citations are disease claims rather 
than substantiation for a claim.
     FDA believes that a citation of a title that refers to a specific 
disease can serve both as a disease claim and as substantiation for a 
claim. A citation of a publication title that links the product to a 
particular disease could lead consumers to believe that the product can 
be used to diagnose, prevent, mitigate, treat, or cure a disease, even 
if the title also provides substantiation for the product claims.
     As stated above, citation of a scientific reference will not be 
treated as a disease claim if, in the context of the labeling as a 
whole, the reference lacks prominence and if it is appropriate support 
for the product claim.
     (62.) One comment sought clarification of the effect of this 
provision on multi-ingredient products. The comment asked whether a 
disease claim for the entire product would be created if the labeling 
cited an article about only one ingredient of a multi-ingredient 
product.
     Generally, if a citation is presented in the product labeling in 
such a way as to imply that a specific ingredient can treat or prevent 
disease, the product, as a whole, will be considered to be intended to 
treat or prevent disease.
     (63.) A few comments requested FDA to clarify how proposed 
Sec. 101.93(g)(2)(iv)(C) would operate. The comments questioned whether 
they would have to delete a citation from a list or redact the 
reference to a disease from the title of the article. One comment asked 
whether an article that contains a reference to a disease can be cited 
if the title is not used in the citation. The comments further 
questioned whether they can provide the entire article, with the title 
on it, if requested by a consumer. Some comments asked FDA to clarify 
that a label may cite a title that appears in a publication whose name 
includes a disease (such as the publication titled Cancer) or to 
clarify how scientific studies may be cited. One comment requested that 
the agency issue further guidance to clarify what is and is not covered 
by Sec. 101.93(g)(2)(iv)(C).
     FDA does not expect a manufacturer to redact portions of the 
citation or delete a citation from a list of references or bibliography 
if it is appropriate to include the reference to substantiate a claim. 
As described above, if the citation to a scientific reference refers to 
a disease, the agency will consider the

[[Page 1025]]

context in which the citation is presented, including its prominence in 
the labeling and whether there is a reasonable relationship between the 
reference and the express claim. In most cases, the unredacted 
reference title can be included in the product labeling without 
subjecting the product to regulation as a drug, as long as the 
prominence of the reference does not suggest that it is being used to 
imply disease treatment or prevention. Under revised 
Sec. 101.93(g)(2)(iv)(C), the only reason a publication title would be 
considered a disease claim regardless of prominence would be if the 
reference is not reasonably related to substantiating the product's 
express claim. In that case, FDA believes that the reference would be a 
disease claim, even if the name of the disease is redacted, because the 
only purpose of including the reference would be to suggest use of the 
product for treatment or prevention of the disease discussed in the 
reference.
     With regard to citation of titles from journals whose official 
names include the name of a disease, the same considerations of 
appropriate prominence and reasonable relationship to the product's 
express claims apply. FDA expects that accepted conventions of 
scientific citation will be used for all citations that appear in 
labeling.
     Finally, if specific information about an unlabeled use of a 
product is requested by a consumer, and the request is not solicited by 
the manufacturer, providing articles that are responsive to the request 
will not be considered a disease claim.
     FDA will issue further guidance on Sec. 101.93(g)(2)(iv)(C), if 
necessary.
     (64.) Several comments sought modifications to proposed 
Sec. 101.93(g)(2)(iv)(C). One comment suggested revising the provision 
to permit companies to cite articles or references that use 
``intermediate terms'' (which the comment said were terms or phrases 
that have disease-related endpoints) on the label or labeling.
     Whether a citation that refers to a disease-related endpoint will 
be considered a disease claim under the rule will depend on the context 
in which the disease-related endpoint is referred to and whether the 
reference implies that the product has an effect on disease. For 
example, the title of an article that states that a product was shown 
to maintain cholesterol levels that were already within the normal 
range, with no reference to a disease, would be considered a structure/
function statement about maintenance rather than a disease claim. 
However, if the title of the article states that the product was shown 
to lower elevated cholesterol levels, this implies that the product can 
be used to have an effect on the disease states hypercholesterolemia 
and heart disease, because heart disease is associated with high 
cholesterol levels.
     (65.) A trade association suggested that the title should not be 
considered to be a disease claim unless it uses the terms ``treat,'' 
``cure,'' ``mitigate,'' ``prevent,'' or ``diagnose.''
     As stated elsewhere in this document, FDA believes that a disease 
claim can be made explicitly or implicitly using terms other than those 
listed in the comment. For example, depending on how it was used in a 
product's labeling, a scientific reference entitled ``Using Ingredient 
X For Diabetes'' could constitute a claim that the product can 
diagnose, mitigate, treat, cure, or prevent diabetes, without using any 
of these specific terms.
    (66.) A few comments argued that citation of articles that refer to 
a disease use should be permitted because consumers have access to 
these articles in connection with the sale of dietary supplements under 
section 403B(a) of the act.
     As stated above, FDA has revised the proposed rule's treatment of 
citations to scientific articles. Under the final rule, such citations 
will not always be considered disease claims. FDA does not agree, 
however, that section 403B of the act applies to the citation of titles 
in product labeling. Although section 403B of the act exempts certain 
publications from the labeling provisions of the act, section 
403B(a)(2) states that the exemption applies only when, among other 
requirements, the publication is ``used in connection with the sale of 
a dietary supplement to consumers when it * * * does not promote a 
particular manufacturer or brand of a dietary supplement.'' If the 
reference or the title of the reference was disseminated by a 
particular manufacturer of the dietary supplement discussed in the 
reference, the agency would conclude that it was being used to promote 
that manufacturer's brand of the dietary supplement. Therefore, the 
exemption in section 403B of the act would not apply.
     Furthermore, to qualify for the exemption in section 403B of the 
act, a publication must be ``an article, a chapter in a book, or an 
official abstract * * * reprinted in its entirety'' and must be 
``displayed or presented, or * * * displayed or presented with other 
such items on the same subject matter, so as to present a balanced view 
of the available scientific information of a dietary supplement.'' A 
citation to an article alone could not meet these requirements.

 L. Use of Disease or Diseased (Sec. 101.93(g)(2)(iv)(D))

    (67.) Many comments agreed with proposed Sec. 101.93(g)(2)(iv)(D), 
stating that the terms ``disease'' or ``diseased'' should classify a 
statement as a disease claim. Several comments urged that a statement 
referring in a general way to the concept of ``health promotion and 
disease prevention'' not cause the statement to be considered a disease 
claim, as long as no specific disease was mentioned. One comment asked 
that the agency permit general discussions of the concept of disease 
prevention, citing the following example from the U.S. Public Health 
Service Healthy People 2000 initiative: ``Better dietary and exercise 
patterns can contribute significantly to reducing conditions like heart 
disease, stroke, diabetes, and cancer, and could prevent 300,000 
deaths.''
     FDA agrees that general statements about health promotion and 
disease prevention may be acceptable, as long as the statements do not 
imply that a specific product can diagnose, mitigate, cure, treat or 
prevent disease. Accordingly, FDA has revised Sec. 101.93(g)(2)(iv)(D) 
to permit general statements about disease prevention that do not refer 
explicitly or implicitly to a specific disease or class of diseases or 
to the specific product or ingredient. For example, the statement ``a 
good diet promotes good health and prevents the onset of disease'' 
would not be considered a disease claim. On the other hand, the claim 
``Promotes good health and prevents the onset of disease'' would refer 
implicitly to the product and would constitute a disease prevention 
claim. FDA also believes that the particular statement offered by one 
of the commenters would constitute a disease claim. The example cites 
four specific diseases. If that statement were included in the labeling 
for a dietary supplement, a consumer would reasonably assume that the 
statement applies to the product and that taking that dietary 
supplement contributes to preventing the diseases listed. If, however, 
the statement said ``better dietary and exercise patterns can 
contribute to disease prevention and better health,'' FDA would not 
consider it a disease claim.

 M. Pictures, Vignettes, and Symbols (Sec. 101.93(g)(2)(iv)(E))

     (68.) Many comments agreed that certain pictures, vignettes, and 
symbols can explicitly or implicitly convey that the product has an 
effect on disease. A few comments agreed that a diseased

[[Page 1026]]

organ should be considered a disease claim. They argued, however, that 
a picture of a healthy heart, healthy artery, or other healthy organ 
should be permitted because such pictures do not in and of themselves 
depict a disease. A few comments stated that a healthy 
electrocardiogram (EKG) tracing should not be considered a disease 
claim. One comment requested that the agency clarify whether a picture 
of an organ is permitted if the claims are appropriate and within the 
scope of permitted structure/function claims. The comment offered as an 
example a statement that a product maintains cardiovascular health 
accompanied by a picture of a heart and circulatory system.
     FDA agrees that in most cases, a picture of a healthy organ would 
not be considered a disease claim, if, in the context of the labeling 
as a whole, it did not imply treatment or prevention of disease. As 
described in response to comment 51 of section II.I of this document, 
however, there may be symbols for organs, like the heart symbol, that 
have become so widely recognized as symbols for disease treatment or 
prevention, their use in labeling would constitute an implied disease 
claim. FDA also believes that a picture of a healthy EKG tracing is an 
implied disease claim. Because most consumers cannot distinguish a 
healthy EKG tracing from an unhealthy one, both types may be viewed as 
references to diagnosis or treatment of unhealthy heart conditions.

 N. Membership in Product Class (Sec. 101.93(g)(2)(v))

     Some product class names are so strongly associated with use to 
treat or prevent a specific disease or class of diseases that claiming 
membership in the product class implies disease treatment or 
prevention. Under proposed Sec. 101.93(g)(2)(v), a statement would have 
been considered a disease claim if it claimed that the product belonged 
in a class of products recognizable to health care professionals or 
consumers as intended for use to diagnose, mitigate, treat, cure, or 
prevent a disease. The preamble provided the following examples of 
class names that would imply disease treatment or prevention: Claims 
that the product was an ``antibiotic,'' a ``laxative,'' an 
``analgesic,'' an ``antiviral,'' a ``diuretic,'' an ``antimicrobial,'' 
an ``antiseptic,'' an ``antidepressant,'' or a ``vaccine.'' These 
examples were not intended to constitute an exclusive list of product 
class names that convey disease claims. Under the proposed rule, 
claiming that a product was in a class that is not recognizable to 
health care professionals or consumers as intended for use to diagnose, 
mitigate, treat, cure or prevent disease would not have constituted a 
disease claim under this criterion. The preamble provided as examples 
of acceptable structure/function claims: Claims that the product was an 
``energizer,'' a ``rejuvenative,'' a ``revitalizer,'' or an 
``adaptogen.'' In light of the agency's decision that claims for relief 
of ``occasional constipation'' should not be considered disease claims, 
the term ``laxative'' will not be considered a disease claim under the 
final rule, as long as the remainder of the labeling makes clear that 
the product is not intended to treat chronic constipation.
     (69.) Most of the comments on proposed Sec. 101.93(g)(2)(v) were 
generally supportive, but some wanted to ensure that the provision 
would be applied in specific ways. One comment urged that ``appetite 
suppressant'' be treated as a disease claim, while another comment 
urged that ``tonic'' be treated as a structure/function claim.
     FDA does not agree that ``appetite suppressant'' should be 
considered a disease claim. As discussed elsewhere in this document, 
although obesity is a disease, overweight is not. An appetite 
suppressant may be intended for ordinary weight loss, rather than as a 
treatment for obesity. Therefore, ``appetite suppressant'' would only 
be considered a disease claim in a context where it implies use for 
obesity. FDA agrees that ``tonic'' is not a disease claim. ``Tonic'' is 
commonly understood as a general term for anything that refreshes, and, 
by itself, would not be considered to constitute a disease claim.
     (70.) Some comments stated that various class names should be 
allowed when they describe the mechanism by which a supplement has its 
effect, or when they are present in a product and it is truthful and 
not misleading to name them. One comment offered as examples of class 
names that might be used to describe a product's mechanism of action: A 
statement that a product that is soothing to the stomach achieves its 
effects as a result of its ``carminative (antispasmodic) properties'' 
or as a result of its ``anti-inflammatory effect on the 
gastrointestinal tract.'' This comment stated that it is not membership 
in a given class of compounds that should make a product a drug, but 
rather the intended use of the product. One comment asked whether this 
criterion precludes a statement that daily consumption of vitamins and 
minerals may prevent the onset of disease or other physical ailments.
     Nothing in this provision would preclude a manufacturer from 
truthfully declaring the ingredients contained in a product. In fact, 
FDA regulations require the ingredients in a dietary supplement to be 
listed on its label. (See Sec. 101.4(a)(1) and (g) (21 CFR 101.4(a)(1) 
and (g)), and Sec. 101.36). The rationale for Sec. 101.93(g)(2)(v) is 
that certain product class names (not particular ingredients) are so 
strongly associated with use to diagnose, treat, mitigate, cure, or 
prevent disease that claiming membership in the class would constitute 
a disease claim. FDA does not believe that claiming membership in a 
product class is necessary in order to provide an accurate list of the 
ingredients present in a product.
     FDA agrees that dietary supplements may carry statements that 
characterize ``the documented mechanism of action by which a nutrient 
or dietary ingredient acts to maintain * * * structure or function,'' 
but only to the extent that such a statement does ``not claim to 
diagnose, mitigate, treat, cure, or prevent a specific disease or class 
of diseases'' (section 403(r)(6) of the act). In the examples provided 
in the comment, FDA is unaware of evidence establishing that the claims 
actually describe ``documented'' mechanisms by which the products 
``maintain'' a calm stomach. Nevertheless, assuming that these 
statements met the other requirements of section 403(r)(6)(A) of the 
act, FDA would not consider the term ``antispasmodic'' to constitute a 
disease claim because the agency does not believe that it is closely 
associated with treatment or prevention of gastrointestinal disease. 
The term ``anti-inflammatory'' is, however, strongly associated with 
treatment of certain serious gastrointestinal diseases, and would 
constitute a disease claim.
     FDA agrees with the statement that it is not membership in a given 
class of compounds that makes a product a drug, but rather the intended 
use of the product. This criterion sets forth FDA's conclusion that 
claiming membership in certain product classes that are strongly 
associated with use to treat or prevent disease is evidence that the 
product is intended to treat or prevent disease.
     Although this provision does not itself treat as a disease claim a 
statement by a vitamin manufacturer that the product prevents the onset 
of a disease, such a statement would be considered a disease claim 
under Sec. 101.93(g)(2)(I), which covers statements that a product has 
an effect on a specific disease or class of diseases. In addition, a 
general statement that a product prevents the onset of disease would be 
considered a disease claim under

[[Page 1027]]

Sec. 101.93(g)(2)(iv)(D), as noted in the discussion of that provision. 
Claiming membership in the class of vitamins or minerals would not 
constitute a disease claim under this criterion.
     (71.) A food manufacturers' trade association and an individual 
manufacturer opposed the provision, arguing that it goes beyond the 
intent of DSHEA and would prohibit the use of any term associated with 
a drug product.
     FDA does not agree that this provision goes beyond the intent of 
DSHEA nor that it would prohibit the use of any term associated with a 
drug product. DSHEA precludes statements under section 403(r)(6) of the 
act from claiming to treat or prevent disease. This provision 
constitutes FDA's conclusion that some drug class names (but not all 
terms associated with drug products) are so strongly associated with 
disease prevention or treatment that claiming membership in the class 
constitutes a claim that the product, like other members of the class, 
treats or prevents disease.
     (72.) One pharmaceutical company argued that proposed 
Sec. 101.93(g)(2)(v) would violate DSHEA, because DSHEA specifically 
defines as a dietary supplement an article that is approved as a new 
drug under section 505 of the act, if it was, prior to approval, 
marketed as a dietary supplement.
     FDA agrees that the dietary supplement definition includes the 
provision cited by the comment (section 201(ff)(3)(A) of the act), but 
believes that the definition and Sec. 101.93(g)(2)(v) are not 
inconsistent. Section 101.93(g)(2)(v) would treat as a disease claim a 
labeling statement that the supplement is a member of a product class 
when that class is so recognizable for its disease treatment or 
prevention use that the labeling statement would be understood as a 
disease claim for the supplement. The criterion would not treat 
inclusion of an ingredient in a dietary supplement as a disease claim 
merely because the ingredient had been approved under section 505 of 
the act nor would it preclude listing the ingredient in the Supplement 
Facts panel or ingredient list.

 O. Substitute for Disease Therapy (Sec. 101.93(g)(2)(vi))

     Under proposed Sec. 101.93(g)(2)(vi), a statement would have been 
considered a disease claim if it explicitly or implicitly claimed that 
the product was a substitute for another product that is a therapy for 
a disease. FDA offered ``Herbal Prozac'' as an example of such a claim. 
A claim that did not identify a specific drug, drug action, or therapy 
(e.g., ``use as part of your weight loss plan'') would not constitute a 
disease claim under this criterion.
     (73.) There was general support for the provision, particularly 
for considering terms that make a direct connection with an approved 
drug, like ``Herbal Prozac'' and ``Herbal Phen-fen,'' disease claims. 
Several organizations noted that associating dietary supplements with 
regulated drug products is deceptive and dangerous because it can 
signal to consumers that because the product is ``herbal'' it is safer. 
Several medical associations, however, objected to the interpretation 
that ``use as part of your weight loss plan,'' is nonspecific and would 
be acceptable. They maintained that the term implies treatment of a 
disease, obesity. A comment from a manufacturer also strongly objected 
to the statement in the proposal that ``Use as part of your weight loss 
plan'' would be an acceptable structure/function claim. The comment 
contended that the legislative history of the act shows that Congress 
intended weight loss claims to be treated as disease claims. Finally, 
the comment argued that even if FDA decides to permit weight loss 
claims as structure/function claims, the legislative history of the act 
and case law require that FDA classify products containing 
``antinutrients'' as drugs.
     FDA agrees with these comments that obesity is a disease, and that 
obesity claims are not acceptable structure/function claims. Being 
overweight, i.e., being more than one's ideal weight but less than 
obese, however, is not a disease. FDA believes that it is commonly 
understood that ``weight loss plans'' relate to a broad range of 
overweight statuses. Therefore, weight loss plans are not so narrowly 
associated with disease treatment that a reference to use as part of a 
weight loss plan should be considered a disease claim.
     FDA does not agree that either the legislative history of the act 
or the case law interpreting section 201(g) of the act or DSHEA require 
a determination that FDA classify as drugs products making weight loss 
claims. The legislative history of section 201(g)(1)(C) of the act 
shows that Congress added the structure/function definition of ``drug'' 
in part to capture obesity claims that were not covered by section 
201(g)(1)(B) because obesity was not, at that time, considered a 
disease. FDA believes that the legislative history in fact supports 
FDA's view that weight loss claims are properly considered structure/
function claims. Although obesity claims are now covered by section 
201(g)(1)(B) of the act because obesity is now considered a disease, 
section 201(g)(1)(C) was added to cover conditions, like overweight, 
that are not considered diseases, but that affect the structure or 
function of the body. Structure/function claims under section 403(r)(6) 
of the act are closely related to structure/function claims under 
section 201(g)(1)(C) of the act and therefore should encompass weight 
loss claims.
     FDA also does not agree that cases cited by the comment compel the 
conclusion that weight loss products must be regulated as drugs. In 
Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983), American Health 
Products Co. v. Hayes, 574 F. Supp. 1498 (S.D.N.Y. 1982), aff'd, 744 
F.2d 912 (2d Cir. 1984), and United States of America v. Undetermined 
Quantities Of ``CAL-BAN 3000'', 776 F. Supp. 249 (E.D.N.C. 1991), the 
courts held that certain weight loss products were drugs under section 
201(g)(1)(C) of the act because they were labeled to affect the 
structure or function of the body, and did not qualify for the ``food'' 
exception to section 201(g)(1)(C). At the time these cases were 
decided, the only issue was whether these products were ``foods'' or 
``drugs.'' Since then, however, DSHEA created a new statutory category 
of products, dietary supplements. Section 403(r)(6) of the act, which 
was added by DSHEA, permits structure/function claims to be made for 
dietary supplements without subjecting them to regulation as drugs, 
even if they could not qualify for the ``food'' exception in section 
201(g)(1)(C) of the act. Therefore, these cases do not establish that 
dietary supplements making weight loss claims must be regulated as 
drugs. To the contrary, because the products were held to be drugs 
under section 201(g)(1)(C) of the act rather than section 201(g)(1)(B), 
these cases support treatment of weight loss claims for dietary 
supplements as structure/function claims authorized under section 
403(r)(6) of the act.
     Finally, FDA does not agree that, under United States v. Ten 
Cartons, More or Less, of an Article * * * Ener-B Vitamin B-12, 72 F.3d 
285 (2d Cir. 1995), dietary supplements making weight loss claims must 
necessarily be regulated as drugs. The court in Ener-B held that a 
dietary supplement that makes a structure/function claim may 
nevertheless be regulated as a drug, under certain circumstances. In 
that case, the court found that FDA could regulate a product as a drug, 
based on its method of intake (nasal administration). Nothing in that 
case suggests that FDA must regulate dietary supplements making weight 
loss claims as drugs.

[[Page 1028]]

     (74.) Several comments reiterated that general statements about 
the nature of a product or its mechanism of action should not be 
disease claims, or should be structure/function claims as long as they 
are truthful and not misleading. One comment objected to the provision 
as duplicative of proposed Sec. 101.93(g)(2)(v). Another comment sought 
to delete the provision, arguing that dietary supplement manufacturers 
have the right to communicate to consumers that their products have 
fewer side effects than drugs.
     FDA does not believe that this provision precludes general 
statements about the function or mechanism of action of a dietary 
supplement. It is not necessary to claim that the product is a 
substitute for a drug or therapy to describe its function or its 
mechanism of action. Nor is Sec. 101.93(g)(2)(vi) duplicative of 
Sec. 101.93(g)(2)(v). Claiming that a product is a substitute for a 
specific drug or therapy, e.g., ``Herbal Prozac,'' is a different means 
of communicating that a dietary supplement is intended to treat a 
disease than claiming that the product belongs to a class of drugs 
associated with treatment or prevention of that disease, e.g., 
``antidepressant.''
     FDA does not agree that section 403(r)(6) of the act permits a 
dietary supplement manufacturer to claim that its product has fewer 
side effects than a drug, if the drug is intended to treat or prevent 
disease, because the clear implication is that the dietary supplement 
is intended for treatment or prevention of the same disease. If, 
however, the drug is not intended to treat or prevent disease, a 
dietary supplement manufacturer is free to make truthful, non-
misleading comparisons between the drug and the dietary supplement.

 P. Augmentation of Therapy or Drug for Disease 
(Sec. 101.93(g)(2)(vii)))

     Under proposed Sec. 101.93(g)(2)(vii), a statement would have been 
considered a disease claim if it explicitly or implicitly claimed that 
the product augmented a particular therapy or drug action. The preamble 
offered the following example of a disease claim under this criterion: 
``Use as part of your diet when taking insulin to help maintain a 
healthy blood sugar level.'' A claim that did not identify a specific 
drug, drug action, or therapy would not constitute a disease claim 
under this criterion. The preamble gave the following example of an 
acceptable structure/function claim: ``use as a part of your weight 
loss plan.''
     (75.) Several comments supported this provision. A few comments 
requested that FDA withdraw the provision, arguing that dietary 
supplements are often useful in providing nutritional support to 
complement drug therapy or medical treatment and that the agency should 
encourage such information to be communicated to consumers. One comment 
stated that as long as the statement makes it clear that the product is 
being recommended for its nutritional impact on structure or function 
``as part of the therapy and not as the therapy itself,'' FDA should 
permit the statement. According to the comment, ``use as part of your 
diet when taking insulin to help maintain a healthy blood sugar level'' 
should be acceptable because the product is being recommended for its 
nutritional impact on structure or function as part of the therapy and 
not as the therapy itself. Another comment asked whether removing the 
words ``when taking insulin'' from the statement would make it an 
acceptable structure/function claim.
     The agency agrees that dietary supplements may be useful in 
providing nutritional support. Associating such a statement with an 
express or implied claim that the dietary supplement augments a therapy 
or drug action, however, implies that the dietary supplement has a role 
in treating or preventing the disease for which the drug or other 
therapy is used.
     The agency does not agree that the proposed claim involving 
insulin is an acceptable structure/function claim. Persons who take 
insulin have a disease, namely, diabetes. By referring to the use of 
the dietary supplement in conjunction with and for the same purpose 
(``to maintain a healthy blood sugar level'') as a drug (insulin), 
which is used to for a disease (diabetes), the statement implies that 
the dietary supplement will help treat diabetes.
     A general statement that a dietary supplement provides nutritional 
support would be an acceptable structure/function claim, provided that 
the statement does not suggest that the supplement is intended to 
augment or have the same purpose as a specific drug, drug action, or 
therapy for a disease. In the example, if the statement were changed to 
``use as part of your diet to help maintain a healthy blood sugar 
level,'' the claim would be considered acceptable. Deleting the 
reference to the drug, insulin, would remove the implication that the 
dietary supplement is used to augment the insulin to treat, mitigate, 
prevent, or cure diabetes.
     On its own initiative, FDA is modifying Sec. 101.93(g)(2)(vii) to 
limit its applicability to claims for augmentation of drugs or 
therapies that are intended to diagnose, mitigate, treat, cure, or 
prevent disease.
     (76.) Another comment noted that the agency did not address the 
use of synonyms for ``augment,'' such as ``strengthen,'' ``reduce,'' 
``improve,'' ``modify,'' ``inhibit,'' ``protect,'' or ``defend.''
     Use of these terms may be appropriate in some contexts, i.e., when 
the statements do not suggest disease prevention or treatment use. If, 
however, the use of these terms implies that the dietary supplement 
augments a particular therapy or drug action or otherwise suggests an 
effect on disease, the agency will consider the statement a disease 
claim.
     (77.) A trade association maintained that under the proposal, 
bread, crackers, and other baked goods used in conjunction with 
prescription drugs and/or other therapy would not be considered a food, 
but a drug, under certain circumstances.
     Section 101.93 is intended to provide regulatory criteria for 
statements made for dietary supplements. Under section 201(ff)(2)(B) of 
the act, a dietary supplement does not include a product represented 
for use as a conventional food or as a sole item of a meal or the diet. 
If statements made for breads, crackers, and other baked goods 
characterize the relationship between a substance in the food and a 
disease or health-related condition, they must comply with the health 
claims provisions for foods under section 403(r)(1)(B) and (r)(3) 
through (r)(4) of the act.

 Q. Role in Body's Response to Disease or Disease Vector 
(Sec. 101.93(g)(2)(viii))

     Under proposed Sec. 101.93(g)(2)(viii), a statement would have 
been considered a disease claim if it explicitly or implicitly claimed 
a role in the body's response to a disease or to a vector of disease. 
The preamble to the proposal defined a vector of disease as an organism 
or object that is able to transport or transmit to humans an agent, 
such as a virus or bacterium, that is capable of causing disease in 
man. The preamble offered as examples of disease claims under this 
criterion claims that a product ``supports the body's antiviral 
capabilities'' or ``supports the body's ability to resist infection.'' 
A more general reference to an effect on a body system that did not 
imply prevention or treatment of a disease state would not have 
constituted a disease claim under this criterion. FDA provided as an 
example of an acceptable structure/function claim

[[Page 1029]]

under this criterion ``supports the immune system.''
     (78.) Two comments from health associations supported this 
provision. One comment from a manufacturer argued that it should be 
deleted because a number of nutrients and dietary supplements ``have a 
role in the body's response to disease.'' One comment argued that the 
body has natural defenses to disease, that these are normal functions 
of the body, and that therefore, statements such as ``enhances disease 
resistance'' should be allowable as structure/function claims. Comments 
from a consumer organization and a member of the President's Commission 
on Dietary Supplement Labels asserted that the provision made too many 
claims allowable. These comments stated that as long as a claim 
includes a disease-fighting function of the body, e.g., ``supports the 
immune system,'' it should be considered a disease claim, regardless of 
other functions that might be involved.
     FDA agrees that nutrients and dietary supplements may play a role 
in the body's response to disease. This does not mean, however, that 
disease prevention claims are acceptable structure/function claims. The 
act requires dietary supplement manufacturers who wish to make disease 
prevention claims to do so by obtaining authorization for a health 
claim or by obtaining new drug approval. Although FDA agrees that 
claims that a product fights disease, or enhances disease-fighting 
functions of the body, are disease claims, FDA does not agree that 
claims such as ``supports the immune system'' are specific enough to 
imply prevention of disease.
    (79.) Several comments argued that there was no significant 
difference between ``supports the immune system'' (identified as a 
structure/function claim in the proposal) and ``supports the body's 
antiviral capabilities'' (identified as a disease claim in the 
proposal). One view was that both should be considered structure/
function claims. Conversely, other comments contended that ``supports 
the immune system'' is a disease claim, because it could be interpreted 
as a claim for treatment or prevention of human immunodeficiency virus 
(HIV) disease. Another comment recommended that ``supports the body's 
antiviral capabilities'' be allowable as a structure/function claim, 
stating that the broader ``supports the immune system'' statement was 
vague and useless to consumers because the immune system has many 
functions.
     The distinction between the two claims is one of specificity. An 
intact immune system has several functions. In addition to their role 
in the defense against pathogens, certain components of the immune 
system, namely white blood cells, have other important functions. For 
example, white blood cells play an essential role in the phagocytosis 
and disposal of aging red blood cells or otherwise damaged cells. A 
statement of support for the immune system, by itself, conveys no 
specific reference to disease treatment or prevention. The claim that 
vitamin A is necessary to maintaining a healthy immune response does 
not imply that a specific disease or class of diseases will be 
prevented. In contrast, a claim that a product ``supports the body's 
antiviral capabilities'' represents a claim of treatment or prevention 
of a specific class of diseases, those caused by viruses (e.g., colds, 
hepatitis, or HIV infection).

 R. Treatment/Prevention of Adverse Events (Sec. 101.93(g)(2)(ix))

     Under proposed Sec. 101.93(g)(2)(ix), a statement would have been 
considered a disease claim if it explicitly or implicitly claimed to 
treat, prevent, or mitigate adverse events associated with a therapy 
for a disease (e.g., ``reduces nausea associated with chemotherapy,'' 
``helps avoid diarrhea associated with antibiotic use,'' and ``to aid 
patients with reduced or compromised immune function, such as patients 
undergoing chemotherapy''). A claim that did not mention a therapy for 
disease (e.g., ``helps maintain healthy intestinal flora'') would not 
have constituted a disease claim under this criterion.
     (80.) Comments from two large health organizations supported this 
provision, while two large business organizations and several other 
comments criticized it. Those opposing the provision argued that the 
proposal incorrectly categorized adverse reactions as diseases. 
Opposing comments also contended that dietary supplements may be useful 
as an adjunct to therapy by counterbalancing the effects of a drug in 
depleting a nutrient or interfering with the metabolism of a nutrient, 
and that this should be considered a structure/function role.
     FDA believes that some of these comments may have misconstrued the 
provision. The criterion is not intended to capture every adverse event 
claim, but only claims about adverse events that satisfy the definition 
of disease. In the proposed rule, this limitation was conveyed by the 
phrase ``and manifested by a characteristic set of signs or symptoms.'' 
Because the final rule uses a different definition of disease, 
Sec. 101.93(g)(2)(ix) has been revised to state that claims about 
adverse events are disease claims only ``if the adverse events 
constitute diseases.'' FDA believes that a claim that a product is 
useful because it counterbalances the effects of a drug in depleting a 
nutrient or interfering with the metabolism of a nutrient would be 
acceptable as a structure/function statement. Such a claim would not 
suggest treatment of an adverse reaction that meets the definition of 
disease. However, as discussed above, if the claim expressly or 
impliedly suggests that the supplement is intended to augment a 
specific drug, drug action, or therapy for a disease, or serve the same 
purpose as a specific drug or therapy for a disease, then the statement 
may be considered a disease claim.
    (81.) A dietary supplement manufacturer requested that FDA clarify 
why a statement that refers to a drug but not a disease, such as 
``helps individuals using antibiotics to maintain normal intestinal 
flora'' is a disease claim, but a general statement, such as ``helps 
maintain intestinal flora'' is a permissible structure/function claim.
     Although the statement ``helps individuals using antibiotics to 
maintain normal intestinal flora'' does not explicitly refer to a 
disease, there is an implicit claim that use of the dietary supplement 
while taking antibiotics will prevent or mitigate a disease. Persons 
using certain antibiotics are at risk of developing overgrowth in the 
gut of a pathogenic organism because along with fighting the target 
organisms in the body the antibiotic can suppress normal intestinal 
flora that are used to prevent infection in the intestinal tract. A 
firm that markets its product to address this concern, with claims that 
the product can be used to maintain normal intestinal flora while 
taking antibiotics, is making an implied disease prevention claim. 
Conversely, the statement ``helps maintain intestinal flora'' alone, 
without any reference to a disease, drug, drug action, or therapy, does 
not imply an effect on disease and would be considered a structure/
function claim about general health maintenance.

 S. Otherwise Affects Disease (Sec. 101.93(g)(2)(x))

     Under proposed Sec. 101.93(g)(2)(x), a statement would have been 
considered a disease claim if it suggested an effect on a disease or 
class of diseases in a manner other than those specifically enumerated 
in the first nine criteria.
     (82.) A food manufacturers' trade association commented that this 
provision is of no regulatory importance, whereas a dietary supplement 
trade association and

[[Page 1030]]

several other comments considered it an over-reaching ``catch-all'' 
provision that would allow FDA to treat any claim as a disease claim. 
These comments provided examples of a number of claims that they 
believed would be disease claims under this provision, e.g. ``provides 
nutritional support for women during premenstruation by promoting 
proper fluid balances and breast health,'' and ``ginger supports the 
cardiovascular system by inhibiting leukotriene and thromboxane 
synthesis, substances associated with platelet aggregation.''
     FDA believes that this provision is necessary to allow for implied 
disease claims that may not fit into the nine enumerated criteria. The 
nine criteria are examples, and not an exhaustive list, of types of 
claims that the agency believes would constitute disease claims, based 
on past experience. Rather than attempting to evaluate or categorize 
statements that have not yet been presented to FDA, 
Sec. 101.93(g)(2)(x) recognizes the possibility that other types of 
statements may also imply disease treatment or prevention. FDA does not 
believe that the provision will cause the agency to classify any 
structure/function statement as a disease claim. To regulate a 
statement as a disease claim under this provision, the agency would 
have to show that the statement implied an effect on disease. The two 
examples quoted in the comments do not appear to the agency to 
constitute disease claims.

 T. Specific Claims Not Mentioned in the Proposed Rule

     (83.) One comment contended that a dietary supplement called 
``pain free'' or ``pain product,'' that is labeled ``to support and 
maintain joints,'' should not be regulated as an internal analgesic 
drug product under the OTC drug review because it is intended to 
maintain or support ``normal well-being and pain levels.'' According to 
this comment, however, products sold as ``pain relief'' or ``otherwise 
indicated to relieve temporary occurrences of arthritis pain'' could be 
regulated as drug products under the OTC review, because the tentative 
final monograph for internal analgesics requires that such products be 
labeled for the ``temporary relief of minor aches and pains'' (53 FR 
46204). At the same time, this comment argued that pain, in and of 
itself, is not a disease and therefore that pain claims should not be 
regulated as disease claims unless accompanied by an explicit reference 
to a specific disease.
    FDA agrees in part and disagrees in part with this comment. FDA 
agrees that some minor pain relief claims may be appropriate structure/
function claims for dietary supplements. A claim that a product is 
intended to treat minor pain, without reference of any other 
conditions, symptoms, or parts of the body that would imply disease 
treatment or prevention, would be an appropriate structure/function 
claims, because minor pain, by itself, can be caused by a variety of 
conditions, not all of them disease-related.
     FDA does not agree, however that general well-being or health 
maintenance claims would encompass such pain claims. Pain is not a 
normal state, nor are there ``normal pain levels.'' The claim is thus 
clearly one of pain treatment or prevention. FDA also does not agree 
that section 403(r)(6) of the act authorizes a product whose name 
promises freedom from or relief of pain (``pain-free'' or ``pain 
product'') and whose labeling includes claims related to maintenance or 
support of joints. While the latter claims alone are appropriate 
structure/function statements, in conjunction with a name that includes 
the term ``pain,'' the product is clearly making a claim related to 
treatment or prevention of joint pain. As explained elsewhere in this 
document, joint pain is a characteristic symptom of arthritis, and 
joint pain claims are therefore disease claims. Acceptable structure/
function claims could be made, however, for pain associated with 
nondisease states, e.g., muscle pain following exercise.
     (84.) One comment listed several claims and sought concurrence 
that they were acceptable structure/function claims: ``Boosts stamina, 
helps increase muscle size, and helps enhance muscle tone''; ``deters 
bacteria from adhering to the wall of the bladder and urinary tract''; 
and ``dietary support during the cold and flu season.'' Another comment 
asked whether ``promotes general well-being during the cold and flu 
season'' is a permissible claim.
     FDA agrees that ``boosts stamina, helps increase muscle size, and 
helps enhance muscle tone'' are acceptable structure/function claims, 
because they do not refer to any disease. However, the agency notes 
that a claim to increase muscle size implies an effect that may subject 
the product regulation as an anabolic steroid under the Controlled 
Substances Act (see 21 U.S.C. 802(41)). ``Deters bacteria from adhering 
to the wall of the bladder and urinary tract'' is not an acceptable 
structure/function claim because it implies prevention of bacterial 
infections of the bladder and urinary tract. The claims ``dietary 
support during the cold and flu season'' and ``promotes general well-
being during the cold and flu season'' are disease claims because they 
imply that the product will prevent colds and flu or will mitigate the 
symptoms of those diseases.
     (85.) One comment asked that the FDA clarify that dietary 
supplements can bear ``smoking-alternative'' claims if they avoid 
references to nicotine, nicotine withdrawal symptoms, and tobacco-
related disease. The comment sought concurrence that the following 
types of claims were permitted: ``Smoking alternative,'' ``temporarily 
reduces your desire to smoke,'' ``to be used as a dietary adjunct in 
conjunction with your smoking cessation plan;'' and ``mimics the oral 
sensations of cigarette smoke.''
     FDA agrees that certain smoking alternative claims may be 
acceptable structure/function claims, if they do not imply treatment of 
nicotine addiction, relief of nicotine withdrawal symptoms, or 
prevention or mitigation of tobacco-related illnesses. ``Smoking 
alternative,'' ``temporarily reduces your desire to smoke'' and 
``mimics the oral sensations of cigarette smoke'' may be acceptable 
(for products that otherwise meet the definition of a dietary 
supplement), if the context does not imply treatment of nicotine 
addiction, e.g., by suggesting that the product can be used in smoking 
cessation, or prevention or mitigation of tobacco-related diseases. For 
example, such claims would not be disease claims if the context made 
clear that they were for short-term use in situations where smoke is 
prohibited or socially unacceptable. ``To be used as a dietary adjunct 
in conjunction with your smoking cessation plan,'' however, is a 
disease claim because it is a claim that the product aids in smoking 
cessation, thereby implying that the product is useful in treating 
nicotine addiction. As noted earlier, a claim that the product is 
useful in counterbalancing the effects of a drug in depleting a 
nutrient or interfering with the metabolism of a nutrient would be 
acceptable as a structure/function statement.
    (86.) One comment offered as acceptable structure/function claims a 
long list of OTC drug claims provided for in the monographs for 
antacids, antiflatulents (antigas), antiemetics, nighttime sleep-aids, 
stimulants (alertness aids), daytime sedatives, aphrodisiacs, products 
for relief of symptoms of benign prostatic hypertrophy, 
anticholinergics (products that, at low doses, depress salivary and 
bronchial secretions), and products for certain uses. Two comments 
sought clarification that inclusion of a claim in an OTC monograph does 
not preclude its use as a structure/function claim.

[[Page 1031]]

     FDA agrees that some of the claims on the comment's list of OTC 
drug claims may be acceptable structure/function claims, but believes 
that others on the list are disease claims. Of the claims listed in the 
comment from the ``Antacids'' monograph, ``relief of sour stomach'' and 
``upset stomach'' are acceptable structure/function claims, because 
they refer to a nonspecific group of conditions that have a variety of 
causes, many of which are not disease-related. Thus, they are not 
characteristic of a specific disease or class of diseases. Although 
``relief of heartburn'' and ``relief of acid indigestion'' without 
further qualification are not appropriate structure/function claims, 
the agency has concluded that ``occasional heartburn'' and ``occasional 
acid indigestion'' can also be considered nonspecific symptoms, arising 
as they do in overindulgence and other sporadic situations. These 
claims could be appropriate structure/function claims. In contrast, 
``recurrent'' or ``persistent'' heartburn and acid indigestion can be 
hallmarks of significant illness, and are therefore disease claims.
     All of the claims listed in the comment from the 
``Antiflatulents'' (antigas) monograph are acceptable structure/
function claims, because the symptoms in the claims are not 
sufficiently characteristic of specific diseases: ``Alleviates the 
symptoms referred to as gas,'' ``alleviates bloating,'' ``alleviates 
pressure,'' ``alleviates fullness,'' and ``alleviates stuffed 
feeling.'' The claim listed in the comment from the ``Antiemetics'' 
monograph, ``for the prevention and treatment of the nausea, vomiting, 
or dizziness associated with motion,'' is also a permitted structure/
function claim.
     Of the claims listed in the comment from the ``Nighttime'' sleep-
aids monograph, ``for the relief of occasional sleeplessness'' is an 
acceptable structure/function claim, because occasional sleeplessness 
is not a characteristic symptom of a disease. ``Helps you fall asleep 
if you have difficulty falling asleep,'' and ``helps to reduce 
difficulty falling asleep'' are disease claims because, unless the 
context makes clear that the product is only for occasional 
sleeplessness, they imply treatment of insomnia, a disease. The claim 
listed in the comment from the ``Stimulants'' (alertness aids) 
monograph, ``helps restore mental alertness or wakefulness when 
experiencing fatigue or drowsiness,'' is an acceptable structure/
function claim because occasional fatigue and drowsiness are not 
characteristic symptoms of a specific disease or class of diseases. FDA 
notes, however, that chronic fatigue or daytime drowsiness can be 
symptoms of chronic fatigue syndrome and narcolepsy, respectively. 
Products labeled ``to help restore mental alertness or wakefulness when 
experiencing fatigue or drowsiness'' should not imply treatment of 
either of these diseases.
     Of the claims listed in the comment from the ``Daytime'' sedatives 
monograph, almost all are acceptable structure/function claims. 
``Occasional simple nervous tension,'' ``nervousness due to common 
every day overwork and fatigue,'' ``a relaxed feeling,'' ``calming down 
and relaxing,'' ``gently soothe away the tension,'' ``calmative,'' 
``resolving that irritability that ruins your day,'' ``helps you 
relax,'' ``restlessness,'' ``nervous irritability,'' and ``when you're 
under occasional stress, helps you work relaxed'' are all acceptable 
structure/function claims, because all suggest occasional rather than 
long-term or chronic mood changes. Although occasional or acute 
symptoms can be characteristic of diseases in other settings, none of 
the occasional symptoms referred to here is characteristic of a 
specific disease. ``Nervous tension headache'' is a disease claim 
because tension headache meets the definition of a disease.
     Of the claims listed in the comment from the ``Aphrodisiacs'' 
monograph, ``arouses or increases sexual desire and improves sexual 
performance'' is an acceptable structure/function claim because it does 
not imply treatment of a disease. ``Helps restore sexual vigor, 
potency, and performance,'' ``improves performance, staying power, and 
sexual potency,'' and ``builds virility and sexual potency'' are 
disease claims because they use the term ``potency,'' which implies 
treatment of impotence, a disease. If, however, these claims made clear 
that they were intended solely for decreased sexual function associated 
with aging, they could be acceptable structure/function claims. The 
claim from the ``Products for relief of symptoms of benign prostatic 
hypertrophy'' monograph (``To relieve the symptoms of benign prostatic 
hypertrophy, e.g., urinary urgency and frequency, excessive urinating 
at night, and delayed urination'') is a disease claim, because benign 
prostatic hypertrophy meets the definition of a disease.
     The claim listed in the comment from the ``Anticholinergics'' 
monograph is a disease claim. ``Relieve excessive secretions of the 
nose and eyes'' refers to the characteristic signs or symptoms of hay 
fever. Of the claims listed in the comment from the ``Products for 
certain uses'' monograph, ``digestive aid,'' ``stool softener,'' 
``weight control,'' and ``menstrual'' are, by themselves, acceptable 
structure/function claims if the labeling does not otherwise imply 
treatment or prevention of a disease. None mentions a characteristic 
symptom of a disease. ``Laxative'' is a not a disease claim, if the 
labeling makes clear that the intended use is for treatment of 
occasional rather than chronic constipation. ``Nasal decongestant,'' 
``expectorant,'' and ``bronchodilator'' are disease claims. ``Nasal 
decongestant'' is a treatment for a characteristic symptom of colds, 
flu, and hay fever. ``Expectorant'' is a treatment for a characteristic 
symptom of colds, flu, and bronchitis. ``Bronchodilator'' is a 
treatment for bronchospasm, a characteristic symptom of asthma.
     The claim from the ``Products for the treatment and/or prevention 
of nocturnal leg muscle cramps'' monograph (``treatment and/or 
prevention of nocturnal leg muscle cramps, i.e., a condition of 
localized pain in the lower extremities usually occurring in middle 
life and beyond with no regular pattern concerning time or severity'') 
is an appropriate structure function claim. Nocturnal leg cramps do not 
meet the definition of disease.
     As is clear from this response, FDA agrees that inclusion of a 
claim in an OTC monograph does not preclude its use as a structure/
function claim. FDA notes, however, that in light of the statutory 
requirement that dietary supplements bear all information that is 
material in light of consequences that may result from use of the 
product or representations made about it, dietary supplements that 
contain or are labeled as containing ingredients covered by an OTC 
monograph and that are being sold for the claims covered by the 
monograph may be misbranded to the extent that they omit material 
information required under the monograph. For example, if the OTC 
monograph required a label statement that products containing a 
particular ingredient should not be used by persons taking a 
prescription monoamine oxidase inhibitor, a dietary supplement 
containing that ingredient would be misbranded if its label did not 
include such statement.

 U. Substantiation of Claims

     (87.) Several comments requested that the final rule explicitly 
state that structure/function statements must be adequately 
substantiated and that FDA provide guidance on what constitutes 
adequate substantiation. One comment

[[Page 1032]]

maintained that adequate substantiation is critical to ensuring that 
consumers receive truthful and accurate information about the benefits 
of dietary supplements. Another comment argued that this final rule 
should focus on adequate substantiation of claims rather than on 
delineating the boundaries between structure/function claims and 
disease claims. Other comments maintained that substantiation is not as 
effective in preventing consumer fraud as preapproval of the claims 
because consumers will be using the products long before the label 
claims are investigated.
     FDA agrees that the statutory requirement to substantiate claims 
is important. FDA does not agree, however, that it is necessary to 
state in the regulatory text of the final rule that structure/function 
claims must be adequately substantiated. Section 101.93(a)(3) requires 
a firm notifying FDA of a claim under section 403(r)(6) of the act to 
certify that the firm has substantiation that the claim is truthful and 
not misleading. FDA also does not agree that substantiation is an 
appropriate alternative to distinguishing structure/function claims 
from disease claims. The requirement that structure/function statements 
and other statements for dietary supplements under section 403(r)(6) of 
the act be adequately substantiated is distinct from the requirement 
that such statements not claim to diagnose, treat, mitigate, cure, or 
prevent disease. Both of these requirements are imposed by the statute 
and must be complied with.
     (88.) Several comments offered advice on what types of evidence 
should constitute adequate substantiation. A consumer health 
organization suggested that health claims and structure/function claims 
for dietary supplements be based on the totality of the publicly 
available scientific evidence, including results from well-designed 
studies conducted in a manner consistent with generally recognized 
scientific principles and procedures. The comment added that consumers 
would be better served if standards for support applied to both health 
claims and structure/function claims. Another consumer health 
organization suggested that substantiation be based on ``significant 
scientific agreement.''
     Many of the comments suggested that the agency adopt FTC standards 
for substantiation. A comment from FTC explained that FTC typically 
applies a substantiation standard known as ``competent and reliable 
scientific evidence'' to claims about the safety and effectiveness of 
dietary supplements, after first looking at the overall context to 
determine what the claim is. The comment further stated that FTC's 
approach to substantiation is consistent with the guidance provided by 
the President's Commission on Dietary Supplement Labels, and, because 
FDA concurred with the Commission's guidance on substantiation, the 
comment suggested that FDA refer to the Commission guidance in the 
final rule.
     As stated above, the agency does not believe that this final rule 
is the appropriate venue to address the substantiation requirement. FDA 
does, however, agree that claims under section 403(r)(6) of the act 
should be supported by adequate scientific evidence and may provide 
additional guidance regarding substantiation for 403(r)(6) statements 
at a future date.
     The Commission report included guidance on what quantity and 
quality of evidence should be used to substantiate claims made under 
403(r)(6) of the act. It also contained guidance on the content of the 
substantiation files for such statements, including the 30-day 
notification letter to FDA, identification of the product's 
ingredients, evidence to substantiate the statements, evidence to 
substantiate safety, assurances that good manufacturing practices were 
followed, and the qualifications of the person(s) who reviewed the data 
on safety and efficacy. In a notice published in the Federal Register 
(63 FR 23624 at 23633), FDA stated that it agreed with the guidance of 
the Commission. FDA encourages manufacturers of dietary supplements 
making a 403(r)(6) of the act statement for a dietary supplement to 
follow this guidance.
     (89.) A food manufacturer suggested that the agency require 
dietary supplement manufacturers making structure/function claims to 
disclose in labeling any and all scientific studies supporting the 
claim. In addition, the comment advocated requiring that these studies 
be performed using the marketed formulation. The comment also urged FDA 
to determine how contrary studies should be addressed.
     DSHEA does not require dietary supplement labeling that carries a 
statement under section 403(r)(6) of the act to include in the labeling 
``any and all scientific studies supporting the claim.'' Section 
403(r)(6)(B) of the act requires only that the ``manufacturer have 
substantiation that such statement is truthful and not misleading.'' 
Contrary studies should be considered when deciding whether to make and 
how to word a 403(r)(6) of the act statement to ensure that any 
statements made are truthful and not misleading. Additionally, in 
response to a request for substantiation for the statement, the agency 
would expect manufacturers to provide a requester with contrary as well 
as supporting studies.
     There is no specific statutory requirement that the studies 
substantiating the statement be performed using the actual marketed 
formulation. However, many ingredients and factors influencing the 
formulation can affect the safety and effectiveness of the dietary 
supplement. These variations from the marketed product should be 
considered before using a study to substantiate a statement made for a 
particular product.

V. Enforcement Issues

     (90.) One comment said that the proposal shifts the burden of 
proof to manufacturers to show that their files match and support the 
claims made for their products.
     The regulations issued by this final rule do not address or affect 
the burden of proof during enforcement actions. However, section 
403(r)(6)(B) of the act clearly states that manufacturers must have 
substantiation to show that the statements that they make under section 
403(r)(6) of the act are truthful and not misleading. This indicates 
that manufacturers must be prepared to demonstrate to the court that 
they have support for each claim.
     (91.) One comment predicted widespread noncompliance with the rule 
because of its complexity and limited FDA resources.
     FDA disagrees with the comment. FDA believes that most of the rule 
is straightforward, and the comments received on the proposed rule 
indicate that dietary supplement manufacturers understood the 
provisions of the rule. Moreover, as noted in the Analysis of Impact in 
section VI.E of this document, most of the claims of which FDA has been 
notified are consistent with the final rule. Thus, based on what has 
been provided to FDA, most manufacturers would appear to be already in 
compliance with this final rule. If it becomes apparent that there are 
provisions that are being violated because of true confusion about 
their applicability, FDA will issue clarifying guidance. FDA agrees 
that its enforcement resources are limited, and is issuing this rule in 
part to avoid inefficient use of those resources on case-by-case 
enforcement. FDA believes that the dietary supplement industry will 
make good faith efforts to comply with this rule, once it becomes 
effective.

[[Page 1033]]

 W. Other Comments

     (92.) One comment said FDA should conduct an educational campaign 
to enhance public awareness of the differences between structure/
function claims and disease claims and the meaning of individual 
claims.
     FDA intends to conduct various outreach activities on dietary 
supplement matters.
     (93.) One comment said FDA should amend the tentative final 
monograph on OTC laxatives to be consistent with the rule. The comment 
explained that the tentative final monograph should permit the words 
``help maintain regularity'' on OTC labeling.
     The agency disagrees with the comment. The fact that ``helps 
maintain regularity'' is an acceptable structure/function claim does 
not mean that it satisfies the requirements for inclusion in an OTC 
monograph, including the requirement of a finding of general 
recognition of safety and effectiveness.
     (94.) Several comments addressed manufacturing or related issues. 
One comment said FDA should investigate effects of dissolution on 
product potency and efficacy, while other comments advocated using 
United States Pharmacopeia standards for all dietary supplements on 
matters pertaining to dissolution, disintegration, purity, and potency. 
One comment added that poor product quality would present a health 
threat to consumers and result in economic fraud.
     Another comment said FDA should concentrate on standardization and 
quality control instead of regulating labeling statements, but offered 
no specific suggestions. Some comments, however, made specific 
recommendations. One comment said that product labels should contain 
lot numbers and expiration dates and that manufacturers should conduct 
stability tests to determine accurate expiration dates. Another comment 
said the public should be protected against poor manufacturing 
standards for herbal products. Other comments simply stated that there 
is substantial potential for public harm because there are: Multiple 
sources of dietary supplement ingredients; multiple suppliers; a lack 
of regulatory production standards, or questions concerning product 
safety, efficacy, and manufacturing quality; vigorous product 
promotion; and a sizeable market. One comment simply asked for good 
manufacturing practice regulations for dietary supplements.
     Manufacturing issues are outside the scope of this rule. FDA 
intends to issue a separate proposed rule on current good manufacturing 
practice (CGMP) for dietary supplements, and that proposed CGMP rule 
may address some of the issues raised by the comments.

 III. Legal Authority

 A. Scope of Section 403(r)(6) of the Act

 1. Relationship Between Sections 403(r)(6) and 201(g)(1)(C) of the Act
     (95.) Several comments stated that the proposal mistakenly 
suggests that there is only one type of structure/function claim that 
may be used for dietary supplements. Some of these comments said that 
if a structure/function claim does not trigger drug status for the 
product and is not a health claim, then such a claim may be made in 
labeling for a dietary supplement so long as it is truthful and not 
misleading. These comments asserted that such a claim is not subject to 
the notice, labeling, or disclaimer requirements in section 403(r)(6) 
of the act. As an example, the comments said the claim that ``calcium 
helps build strong bones'' is not a health claim because it does not 
characterize a relationship between the substance and a disease, 
damage, or dysfunction of the body. The comments added that FDA 
recognized this in the final rule that it published in the Federal 
Register on September 23, 1997 (62 FR 49859, 49860, 49863, and 49864), 
when it stated in the preamble that claims that cranberry juice 
cocktail helps maintain urinary tract health or that calcium builds 
strong bones and teeth are not health claims because no disease is 
mentioned explicitly or implicitly. Some comments added that FDA cannot 
say that only those claims falling under section 406(r)(6) of the act 
are structure/function claims because such a result would be contrary 
to the act and would mean that the proposed rule must be withdrawn.
     FDA agrees with these comments in part and disagrees in part. The 
agency agrees that statements such as ``calcium helps build strong 
bones'' are not health claims because they do not characterize the 
relationship between a substance and a disease or health-related 
condition. Rather, such statements are structure/function claims 
authorized by section 403(r)(6) of the act.
     FDA does not agree with the comment's statement that dietary 
supplements may bear structure/function claims without complying with 
the notice, disclaimer, and other requirements of section 403(r)(6) of 
the act. Section 403(r)(6) of the act, by its terms, applies to dietary 
supplements. The other possible source of authority to make structure/
function claims on dietary supplements is section 201(g)(1)(C) of the 
act, which provides that ``articles (other than food) intended to 
affect the structure or any function of the body of man or other 
animals'' are drugs. Under this provision, foods may make claims to 
affect the structure or function of the body without being regulated as 
drugs. By its terms, however, section 201(g)(1)(C) of the act exempts a 
dietary supplement that bears a structure/function claim from drug 
regulation only if it is also a food. The last sentence of section 
201(ff) of the act provides, ``Except for purposes of section 201(g), a 
dietary supplement shall be deemed to be a food within the meaning of 
this Act.'' The clear import of this language is that dietary 
supplements are not foods under section 201(g) of the act and therefore 
cannot qualify for the ``(other than food)'' exception to the drug 
definition in section 201(g)(1)(C). As a result, dietary supplements 
that use structure/function claims may do so only under section 
403(r)(6) of the act and are therefore subject to the disclaimer, 
notification, and other requirements in that section and in FDA's 
implementing regulation.
     The agency acknowledges that it took a contrary position in the 
September 1997 final rule preamble referred to in the comment. In that 
preamble, FDA said that a dietary supplement could bear a structure/
function claim under the ``(other than food)'' exception to the 
definition of ``drug'' in section 201(g)(1)(C) of the act, provided 
that the claim was truthful, non-misleading, and derived from nutritive 
value (see 62 FR 49859 at 49860, 49863, and 49864). However, the agency 
has now reconsidered in light of the plain language of section 201(ff) 
of the act and is revoking its statements on this subject in the 
September 1997 preamble (i.e., the statements at 62 FR 49859 at 49860, 
49863, and 49864 concerning structure/function claims for dietary 
supplements under section 201(g)(1)(C)). It should be noted, however, 
that the agency is not revoking its statements in that preamble 
concerning structure/function claims for conventional foods under 
section 201(g)(1)(C) of the act. As explained in the September 1997 
preamble (62 FR 49859 at 49860), conventional foods may make structure/
function claims under section 201(g)(1)(C) of the act as long as such 
claims are truthful, non-misleading, and derive from the nutritive 
value of the food.
     For a limited transition period, FDA does not intend to take 
enforcement action against firms who have relied on the agency's 
September 1997 final rule preamble statements to make a structure/
function claim for a dietary supplement under section 201(g)(1)(C) of 
the act. To allow a reasonable time for

[[Page 1034]]

the necessary label changes, the transition period will last until the 
applicable compliance date for the rest of the rule; i.e., small 
businesses will have 18 months from publication to comply, and other 
firms will have 12 months. As of the applicable compliance date, firms 
that have been making structure/function claims under section 
201(g)(1)(C) of the act must either remove the claim or comply with the 
requirements of section 403(r)(6) of the act and Sec. 101.93, including 
notifying FDA of the claim and relabeling to add the required 
disclaimer. New structure/function claims are not subject to this 
transition period; any firm that makes a structure/function claim in 
the labeling of a dietary supplement after the effective date of this 
rule must comply with section 403(r)(6) of the act and Sec. 101.93.
     (96.) One comment objected to a sentence in the introductory 
paragraph in the preamble to the proposed rule. The sentence stated 
that, before DSHEA, certain claims could have rendered a product a 
``drug'' under the act. The comment argued that even before DSHEA, 
dietary supplements could make structure/function claims and not be 
considered drugs. The comment said that section 201(g)(1)(C) of the act 
expressly excluded food from the definition of drug and that dietary 
supplements fell within the ``food'' exception. The comment 
characterized DSHEA as limiting and restricting ``what had been the 
unconditional right of dietary supplement marketers to make structure/
function claims.''
     The agency agrees that before DSHEA, dietary supplements that were 
also foods could make structure/function claims under section 
201(g)(1)(C) of the act without being considered drugs. However, the 
passage of DSHEA changed the regulatory framework for structure/
function claims on dietary supplements by adding sections 201(ff) and 
403(r)(6) to the act. As explained in the response to the preceding set 
of comments, section 201(ff) of the act provides that dietary 
supplements are not considered food for purposes of section 201(g). 
Therefore, dietary supplements may no longer make structure/function 
claims under the ``food'' exception to the drug definition in section 
201(g)(1)(C) of the act. FDA therefore agrees with the comment that in 
one respect, DSHEA limited the ability of dietary supplement marketers 
to make structure/function claims.
     The sentence in the introductory paragraph of the preamble to the 
proposed rule correctly stated that ``certain claims''--structure/
function claims for dietary supplements that were not also foods--could 
have rendered the product a drug before the passage of DSHEA (63 FR 
23624). Post-DSHEA, however, dietary supplements may make structure/
function claims under section 403(r)(6) of the act regardless of 
whether they are also foods. Thus, although in one way DSHEA did limit 
the ability of dietary supplement marketers to make structure/function 
claims, it also significantly expanded the opportunity to make 
structure/function claims in another way by removing the limitation 
that dietary supplements must be foods to make structure/function 
claims. Under section 403(r)(6) of the act, claims may be made for 
nondisease effects of a dietary supplement on the structure or function 
of the body, regardless of whether those effects are nutritive, as long 
as the product is intended to supplement the diet as provided in 
section 201(ff)(1) of the act.
 2. Structure/Function Claims for Conventional Foods
     (97.) Several comments sought consistency in the treatment of 
conventional foods and dietary supplements with respect to structure/
function claims and health claims. Some of these comments contended 
that this rule would permit dietary supplements to carry claims that 
would be health claims if made for a conventional food. One comment 
stated that differential treatment of foods and dietary supplements was 
inconsistent with the Commission's recommendations. This comment 
suggested that differential treatment would cause consumers to perceive 
dietary supplements as better sources for safeguarding health than 
conventional foods. One comment expressed the view that the rule should 
apply to claims for conventional foods as well as dietary supplements 
and requested FDA to clarify the rule's scope. Other comments said that 
any structure/function claims that may be made for dietary supplements 
may also be made for conventional foods. The comments explained that 
the history of the act shows that claims that food affect the structure 
or function of the body do not result in the food being classified as a 
drug, citing the district court and appellate decisions in American 
Health Products Co. v. Hayes, 574 F. Supp. 1498, 1501 (S.D.N.Y. 1983), 
aff'd, 744 F.2d 912 (2d Cir. 1984). Another comment stated that 
established case law shows that an article may be a food if it is used 
primarily for taste, aroma, or nutritional value, but that nutritional 
value is not required in all instances. One comment further noted that 
FDA, when it implemented the labeling requirements for DSHEA (62 FR 
49859, 49860, and 49861) said that it was committed to ``as much parity 
between dietary supplements and conventional foods as is possible 
within the statute'' and that FDA has recognized that a dietary 
supplement may lawfully be in conventional food form, but must be 
represented as a dietary supplement (citing 62 FR 49826 at 49837, 
September 23, 1997).
     Given this background, the comments argued that FDA cannot take 
the position that a structure/function claim may be made for a 
conventional food only if the effect derives from the food's 
nutritional value. One comment added that the act does not distinguish 
foods based on their nutritional value and that DSHEA considers 
structure/function claims for all dietary ingredients to be 
``statements of nutritional support.'' The comment said FDA, therefore, 
should recognize that structure/function claims that can be made for 
dietary ingredients when those ingredients are in dietary supplements 
can also be made when those ingredients are in conventional food, but 
added that the disclaimer statement and notification to FDA, as 
required by section 403(r)(6)(C) of the act, apply only to dietary 
supplements and not to conventional food. One comment said that 
requiring structure/function claims for conventional foods to be 
derived from the food's nutritional value would create a marketing 
disparity and put conventional foods at a competitive disadvantage.
     This rule applies to claims for dietary supplements only. Its 
purpose is to implement section 403(r)(6) of the act, which applies to 
dietary supplements only. Therefore, a detailed discussion of the 
regulatory framework applicable to structure/function claims for 
conventional foods, which are made under section 201(g)(1)(C) of the 
act, is beyond the scope of the rule. FDA advises, however, that for 
consistency, the agency is likely to interpret the dividing line 
between structure/function claims and disease claims in a similar 
manner for conventional foods as for dietary supplements. The agency 
also notes that as discussed in the response to comment 1 in section 
II.A of this document, FDA reaffirms the statements about structure/
function claims for conventional foods in the September 23, 1997 (62 FR 
49859), final rule entitled ``Food Labeling: Nutrient Content Claims, 
Health Claims, and Statements of Nutritional Support for Dietary 
Supplements.'' As explained in that rule (62 FR 49859 at 49860, 49861, 
and 49864), the fact that structure/function claims for conventional 
foods

[[Page 1035]]

are limited to effects derived from nutritional value, while structure/
function claims for dietary supplements are not, is a result of 
differences in the language of the exemption for foods in section 
201(g)(1)(C) of the act, as interpreted by the courts (see Nutrilab, 
Inc. v. Schweiker, 713 F.2d 335, 338 (7th Cir. 1983)), and the language 
of section 403(r)(6) of the act.
     (98.) One comment suggested revising the definition of ``disease 
or health-related condition'' in proposed Sec. 101.14(a)(6) to include 
a reference to Sec. 101.93, and also recommended revising the 
definition of ``health claim'' at Sec. 101.14(a)(1) to be consistent 
with Sec. 101.93. Currently, Sec. 101.14(a)(1) reads as follows:
     Health claim means any claim made on the label or in labeling 
of a food, including a dietary supplement, that expressly or by 
implication, including ``third party'' references, written 
statements (e.g., a brand name including a term such as ``heart''), 
symbols (e.g., a heart symbol), or vignettes, characterizes the 
relationship of any substance to a disease or health-related 
condition. Implied health claims include those statements, symbols, 
vignettes, or other forms of communication that suggest, within the 
context in which they are presented, that a relationship exists 
between the presence or level of a substance in the food and a 
disease or health-related condition.
 The comment would revise the definition to read as follows:
     Health claim means any claim made on the label or in labeling 
of a food, including a dietary supplement, that expressly or by 
implication, including ``third party'' references, written 
statements (e.g., a brand name that includes or implies a disease, 
such as ``Raynaudin''), symbols, or vignettes, characterizes the 
relationship of any substance to a disease or health-related 
condition (e.g., disease-indicating electrocardiogram tracings, 
pictures of organs that suggest prevention or treatment of a disease 
state, the prescription symbol, or any reference to prescription 
use). Implied health claims include those statements, symbols, 
vignettes, or other forms of communication that suggest, within the 
context in which they are presented, that a relationship exists 
between the presence or level of a substance in the food and a 
disease or health-related condition.
     As stated in response to comment 51 of section II.I of this 
document, FDA does not believe that Secs. 101.14(a)(1) and 101.93(g) 
are inconsistent. As a result of the special regime for dietary 
supplements under DSHEA, there may be some differences in the treatment 
of dietary supplements and conventional foods under Sec. 101.14(a)(1).
 3. Relationship Between Structure/Function Claims and Health Claims
     (99.) One comment stated that the proposed rule ``improperly 
distinguishes between other health-related claims and structure/
function claims.'' Relying in part on the introduction to section 
403(r)(6) of the act (``For purposes of paragraph (r)(1)(B) * * *''), 
the comment asserted that structure/function claims are a subset of the 
claims authorized by section 403(r)(1)(B) of the act (health claims). 
Consequently, because claims under section 403(r)(1)(B) of the act may 
characterize the relationship of a nutrient to a disease, the comment 
stated that FDA cannot preclude structure/function claims from making 
any contextual references to diseases.
     FDA disagrees with this comment. Structure/function claims are not 
a subset of health claims because, clearly, there are claims about the 
effect of a product on the structure or function of the body that are 
not also health claims. To be a health claim, a claim must refer to the 
relationship between a food substance and a disease or health-related 
condition. FDA interprets ``health-related condition'' to mean a state 
of health leading to disease. Claims such as ``calcium builds strong 
bones'' are not health claims because they do not refer explicitly or 
implicitly to any disease or health-related condition. Therefore, the 
comment is based on an invalid premise.
     (100.) One comment requested that FDA revise Sec. 101.93(f) to 
state that the requirements of section 403(r)(6) of the act, e.g., use 
of the disclaimer and substantiation, apply only to structure/function 
claims that fall within the definition of a ``health claim'' in 
Sec. 101.14(a)(1) and (a)(5). According to this comment, the 
introduction to section 403(r)(6) of the act (``For purposes of 
paragraph (r)(1)(B) * * *'') establishes that structure/function claims 
that do not fall within the definition of health claims are not subject 
to section 403(r)(6), and may be made without complying with any of its 
requirements.
     FDA does not agree and, in fact, believes that the opposite is 
true. As explained elsewhere in this document and in the proposed rule, 
structure/function claims that fall within the definition of health 
claims, or that otherwise constitute disease claims, do not fall within 
the scope of claims authorized under section 403(r)(6) of the act, but 
other structure/function claims do fall within the scope of section 
403(r)(6) and are subject to its requirements. Adopting the 
interpretation advocated by the comment would bring about illogical 
results for dietary supplement labeling claims in two ways. First, 
structure/function claims that are also health claims would not be 
subject to the health claims prior authorization requirements, but 
instead could be made simply by meeting the requirements of section 
403(r)(6) of the act and FDA's implementing regulations. The language 
in section 403(r)(6) of the act excluding claims to affect disease from 
the coverage of that section demonstrates that Congress made a public 
health judgment that claims promoting dietary supplements for disease 
uses should continue to require premarket authorization. It would not 
make sense for Congress to exclude labeling claims pertaining to 
disease uses in one part of section 403(r)(6) of the act, while 
permitting such claims in another paragraph of the same section. 
Moreover, the interpretation advocated by the comment would lead to 
confusing and contradictory labeling. A dietary supplement that bears a 
health claim--a claim that, by definition, is a claim that a substance 
in the supplement in some way has an effect on a disease--would also 
have to bear a contradictory disclaimer that it is not intended to 
treat, mitigate, or prevent any disease. Second, structure/function 
claims that are not also health claims would not be authorized under 
section 403(r)(6) of the act at all. In fact, a structure/function 
claim on a dietary supplement would subject it to drug regulation 
because, as explained in the response to comment 1 in section II.A of 
this document, section 403(r)(6) of the act is the only provision that 
authorizes the use of structure/function claims on dietary supplements.
     The introductory language in section 403(r)(6) (``For purposes of 
[section 403](r)(1)(B) * * *'') does not support the interpretation 
advocated in the comment. If Congress had wanted to subject only 
structure/function claims that are also health claims to section 
403(r)(6) of the act, it could have done so much more directly by using 
language such as ``A statement for a dietary supplement may be made if 
* * * and the statement is a statement of the type governed by 
paragraph (r)(1)(B).'' The ambiguity of the ``For purposes of 
(r)(1)(B)'' language is well demonstrated by the diametrically opposed 
interpretations adopted by this comment and the preceding comment. FDA 
interprets this language as a caution that the category of claims 
covered by section 403(r)(6) of the act is not to be interpreted as 
coextensive with health claims, the category covered by section 
403(r)(1)(B) of the act. Congress may have been concerned that the 
health claims category would swallow the category of claims under 
section 403(r)(6) of the act because all claims

[[Page 1036]]

under section 403(r)(6) could be characterized as referring to a 
``health-related condition'' if that term were defined broadly as ``a 
state of health.'' The result would have been that all structure/
function claims, as claims about the relationship between a substance 
and a health-related condition, would also have been health claims and 
would have required premarket authorization. By including the 
introductory language, Congress effectively forestalled such an 
interpretation.
     (101.) Another comment said the proposed rule does not distinguish 
between structure/function statements that assert health claims and 
those that do not, and said the failure to make this distinction would 
mean that more products would be subject to the rule than necessary.
     FDA does not agree that the rule fails to distinguish between 
structure/function claims that do and do not assert health claims. On 
the contrary, the rule makes clear that only structure/function claims 
that do not assert health claims may be made under section 403(r)(6) of 
the act. To the extent that the comment may be suggesting that 
structure/function claims that are also health claims should be exempt 
from the health claims authorization requirements, the agency disagrees 
for the reasons given in the response to the previous comment.

 B. Miscellaneous Legal Issues

     (102.) Two comments said the proposed rule violated the 
Administrative Procedure Act because it was arbitrary and capricious, 
on two grounds. One comment asserted that FDA failed to consider an 
important aspect of the problem of distinguishing between drug claims 
and dietary supplement claims: The application of the ``general well-
being'' provision of section 403(r)(6) of the act. The comment argued 
that FDA should have considered whether claims relating to normal body 
functions might qualify as ``general well-being'' claims under section 
403(r)(6) of the act before deciding to regulate them as disease 
claims. The comment also argued that FDA's explanation of the need for 
the proposed rule ran counter to the evidence before the agency, in 
that the agency's actions on notifications of claims under section 
403(r)(6) of the act did not support a need for further regulation.
     The ``general well-being'' provision of section 403(r)(6) of the 
act authorizes statements in dietary supplement labeling that describe 
``general well-being from consumption of a nutrient or dietary 
ingredient'' (section 403(r)(6)(A) of the act). FDA did not consider 
whether statements were authorized under this provision in developing 
the proposed rule because the purpose of the rule was to implement the 
structure/function provisions of section 403(r)(6)(A) of the act, not 
other provisions. However, consideration of this provision as applied 
to normal body functions would not have led to a different result. The 
criteria in the rule were developed to identify claims that refer 
directly or indirectly to an effect on disease and do not encompass 
claims that refer only to general well-being. Claims relating to normal 
body functions are authorized under the rule.
     The comment's argument about the use of FDA's actions on 
notifications of claims under section 403(r)(6) of the act to justify 
the rule is addressed in comment 4 of section II.A of this document.
     (103.) One comment claimed that the proposal does not require FDA 
to show any evidence of a manufacturer's intent to find that a dietary 
supplement claim constitutes an illegal drug claim. The comment argued 
that proposed Sec. 101.93(g)(2)(ii), (g)(2)(iii), (g)(2)(viii), and 
(g)(2)(x) run afoul of the recent appellate decision in Brown & 
Williamson Tobacco Corp. v. FDA, 153 F.3d 155 (4th Cir. 1998), 
contending that ``a product is not a drug merely because a consumer 
uses it as one'' and that ``there must be proof as to the 
manufacturer's intent.'' The comment also cited National Nutritional 
Foods Ass'n v. Mathews, 557 F.2d 325 (2d Cir. 1977), to support its 
position that a manufacturer's intent, as determined from labeling or 
advertising, is the primary factor in determining whether a product is 
intended to treat a disease.
     Although FDA disagrees with the Brown & Williamson decision and is 
awaiting the outcome of Supreme Court review, this rule does not depend 
on the resolution of the legal issues in that case. The focus of the 
rule is on express and implied claims made by the vendor in labeling. 
None of the provisions of the rule, including those mentioned in the 
comment, rely on consumer use as a standard for determining whether the 
product is intended to treat or prevent disease.
     The rule is consistent with the decision in National Nutritional 
Foods Ass'n v. Mathews, in which the court said, ``FDA is not bound by 
the manufacturer's subjective claims of intent but can find actual 
therapeutic intent on the basis of objective evidence. Such intent also 
may be derived or inferred from labeling, promotional material, 
advertising, and `any other relevant source''' (557 F.2d at 334 
(citations omitted)). See also Sec. 201.128 (listing evidence FDA will 
consider in determining the intended use of a drug).
     (104.) One comment said that the proposal must be withdrawn 
because, contrary to section 403(r)(6) of the act, it gives 
manufacturers the burden to prove that a claim is not a drug claim 
when, in fact, FDA has the burden, by a preponderance of relevant 
evidence, to establish that a dietary supplement is misbranded. The 
comment cited two court opinions, United States v. 29 Cartons * * * an 
Article of Food (Oakmont), 987 F.2d 33 (1st Cir. 1993) and United 
States v. An Article of Food * * * Viponte Ltd. Black Currant Oil, 984 
F.2d 814 (7th Cir. 1993), for the proposition that, before DSHEA was 
enacted, courts had invalidated an FDA enforcement theory that shifted 
the burden of proof to manufacturers.
     FDA disagrees with this comment. Although the comment is correct 
that FDA has the burden of proving that a dietary supplement--or, in 
fact, any food--is misbranded, the rule does not give manufacturers the 
burden of proving that a claim is not a drug claim. The rule does not 
shift the burden of proof in an enforcement action but rather sets 
forth criteria for what claims are disease claims that may subject a 
product marketed as a dietary supplement to regulation as a drug.
     The two cases cited in the comment are inapposite. They concern 
FDA's efforts to regulate certain dietary ingredients as food additives 
and do not have any relevance to claims issues.
     (105.) One comment said that the proposed rule is inconsistent 
with the act and congressional intent, arguing that, by enacting DSHEA, 
Congress had taken steps to reverse FDA's ``overly restrictive'' 
approach towards claims and had commanded the agency to expand, rather 
than restrict, the amount of health information permitted on dietary 
supplement labels and labeling. According to the comment, the proposal 
``directly and substantially violates the overall statutory scheme and 
the expressed legislative intent'' and FDA ``has no authority to 
proceed with the rulemaking without a grant of authority from Congress 
in light of the Act's language and Congressional intent.''
     The agency disagrees with this comment and believes that the rule 
is consistent with the act and congressional intent. Although Congress, 
in enacting DSHEA, did expand the scope of information in dietary 
supplement labeling by providing for claims to affect the structure or 
function of the body and the other types of claims authorized by

[[Page 1037]]

section 403(r)(6) of the act, Congress also explicitly limited 
statements under section 403(r)(6) to those that do not claim to 
``diagnose, mitigate, treat, cure, or prevent a specific disease or 
class of diseases.'' This rule does not create new restrictions but 
merely implements the provisions of section 403(r)(6) of the act. FDA 
has authority to issue implementing regulations under section 701(a) of 
the act, which authorizes the agency to issue regulations for the 
efficient enforcement of the act.
     (106.) One comment declared that FDA has no legal basis to include 
a broad variety of implied claims.
     FDA disagrees with this comment. The agency has regulated implied 
claims in labeling for many years, in many contexts. (See, e.g., 21 CFR 
104.5(b) and (d) (prohibiting certain implied claims relating to 
compliance with nutritional quality guidelines); 21 CFR 101.13(a) 
(classifying implied claims to characterize the level of a nutrient in 
food as nutrient content claims subject to the same requirements as 
express claims); 21 CFR 101.95 (prescribing conditions under which 
implied claims of freshness may be made for foods); 21 CFR 201.10(c)(3) 
(prohibiting use in ingredient statement of fanciful drug or ingredient 
names that falsely imply that the drug or ingredient has some unique 
effectiveness or composition); 21 CFR 201.302(c) (prohibiting implied 
claims that drugs for internal use that contain mineral oil are for 
administration to infants). The agency has also regulated implied 
claims in prescription drug advertising. (See, e.g., Sec. 202.1(a)(3) 
(21 CFR 202.1(a)(3)) (prohibiting use in advertising of fanciful 
product or ingredient names that falsely imply that the drug or 
ingredient has some unique effectiveness or composition); 
Sec. 202.1(e)(6)(v) (prohibiting implied claims that a study represents 
more widespread experience with the drug than it actually does).) More 
specifically, the agency has repeatedly taken the position that implied 
disease claims in labeling subject a product to regulation as a drug. 
In the animal drug context, Sec. 500.52 (21 CFR 500.52) provides that 
the use of certain terms in the labeling of products intended for use 
in or on animals implies that the product is capable of a therapeutic 
effect and causes the product to be a drug within the meaning of 
section 201(g) of the act. In the human drug context, Sec. 201.56(c) 
(21 CFR 201.56(c)) prohibits ``implied claims or suggestions of drug 
use'' in prescription drug labeling unless the product has been shown 
to be safe and effective for the implied or suggested use. (See also 
Sec. 310.530 (21 CFR 310.530) (use of the word ``hormone'' in labeling 
is an implied drug claim).) Moreover, courts have upheld FDA's 
authority to regulate implied drug claims. (See, e.g., United States v. 
Storage Spaces Designated Nos. ``8'' and ``49'', 777 F.2d 1363, 1366 & 
n. 5 (9th Cir. 1985), cert. denied, 479 U.S. 1086 (1987); Pasadena 
Research Labs., Inc. v. United States, 169 F.2d 375, 383 (9th Cir.), 
cert. denied, 335 U.S. 853 (1948); United States v. Six Dozen Bottles * 
* * ``Dr. Peter's Kuriko'', 158 F.2d 667, 669 (7th Cir. 1947); United 
States v. John J. Fulton Co., 33 F.2d 506, 507 (9th Cir. 1929); Bradley 
v. United States, 264 F. 79, 81-82 (5th Cir. 1920); United States v. 
Kasz Enterprises, Inc., 855 F. Supp. 534, 539, 543-44 (D.R.I. 1994), 
modified on other grounds, 862 F. Supp. 717 (D.R.I.1994); United States 
v. 43 1/2 Gross Rubber Prophylactics, 65 F. Supp. 534, 535 (D. Minn. 
1946), aff'd sub nom. Gellman v. United States, 159 F.2d 881 (8th Cir. 
1947).)
     (107.) Many comments argued that the proposed rule ignored the 
Supreme Court decision in Daubert v. Merrell Dow Pharmaceuticals, Inc., 
509 U.S. 579 (1993).
     FDA disagrees with these comments. The comments did not explain 
how the rule was contrary to or even affected by the decision. Daubert 
involved the admissibility of scientific evidence in a judicial 
proceeding under the Federal Rules of Evidence. This rulemaking does 
not present issues regarding the admissibility of evidence in any 
proceeding, judicial or administrative, nor does it address expert 
testimony (which was at issue in Daubert). Thus, FDA does not agree 
that the rule ``ignores'' or is contrary to the Daubert decision.

 C. Constitutional Issues

 1. First Amendment
     (108.) Several comments focused on the First Amendment. One 
comment argued that the rule violates the First Amendment because it is 
more restrictive than is necessary to advance FDA's interests. The 
comment conceded that the government may regulate or prohibit 
commercial speech if the speech is inherently false, deceptive, or 
misleading, but argued that the government can only restrict commercial 
speech that is not false, deceptive, or misleading if the government 
shows that the restriction directly and materially advances a 
substantial state interest in a manner that is no more extensive than 
necessary to serve that interest (citing Ibanez v. Florida Dept. Of 
Bus. & Prof'l Regulation, 512 U.S. 136, 142 (1994); Central Hudson Gas 
& Elec. Corp. v. Pub. Serv. Comm'n, 447 U.S. 557, 566 (1980)). The 
comment argued that not all structure/function claims prohibited under 
the proposed rule are inherently false or misleading and that if FDA 
does not review the evidence for a claim, the claim does not become 
false or misleading. Although the comment admitted that FDA has a 
substantial interest in regulating the safety, efficacy, and labeling 
of dietary supplements in order to protect the public health, the 
comment claimed that the regulation was more extensive than necessary. 
The comment argued that a disclaimer is ``the constitutionally mandated 
method of regulating commercial speech.''
     Other comments said the proposed rule violates the First Amendment 
because, using the analysis in Central Hudson Gas & Electric Corp. v. 
Public Service Commission, 447 U.S. 557 (1980), it is not narrowly 
tailored to meet FDA's interests and does not directly and materially 
advance the agency's interests. In general, these comments offered 
various reasons why the proposed rule did not survive scrutiny under 
Central Hudson. For example, under Central Hudson, the government may 
regulate commercial speech that concerns unlawful activity or is 
misleading if, among other things, the government asserts a substantial 
interest in support of its regulation. In brief, the comments said FDA 
failed to assert a substantial interest or construed the government's 
interest to be Congress' interest in increasing the amount of 
information to consumers. Others said that, contrary to Central Hudson, 
the proposed rule was not narrowly tailored and suppressed more speech 
than necessary to protect a possible government interest in protecting 
consumers from fraud and protecting public health and either suggested 
alternatives or said FDA should consider less restrictive alternatives. 
Some comments said the proposal also did not advance the asserted 
government interest because it blurred, instead of clarified, the line 
between drug and dietary supplement claims.
     One comment also asserted that there is no substantial government 
interest involved, because FDA has not shown a concern for consumer 
safety or a danger to public health; according to this comment, the 
proposed rule was a response to confusion by manufacturers and 
consumers about what claims are permitted.
     Some comments also argued that FDA has not shown that the claims 
are misleading or that the commercial speech covered by the proposed 
rule is

[[Page 1038]]

inherently misleading. One comment asserted that, if statements were 
untruthful or misleading, DSHEA would have prohibited them.
     Another comment said the proposal ``trenches on'' the First 
Amendment because consumers have the right to receive, and 
manufacturers have the right to express, non-misleading information. 
The comment cited Washington Legal Foundation v. Friedman, 13 F. Supp. 
2d 51 (D.D.C. 1998) for this proposition. Another comment cited the 
Washington Legal Foundation decision to argue that the proposed rule 
would ``impermissibly curtail'' the flow of information to consumers. 
The comment suggested that less restrictive alternatives, such as 
``allowing implicit, but not explicit, claims,'' establishing 
``categories of diseases that clearly denoted drug claims'' or 
identifying terms that connote ``treatment,'' ``cure,'' or 
``mitigation'' exist.
     A few comments simply claimed that the proposal violates the First 
Amendment because it would decrease the amount of scientific 
information on labels and labeling or because it represents a ``prior 
restraint'' on health claims. Other comments objected to particular 
provisions of the proposed rule on First Amendment grounds, notably 
proposed Sec. 101.93(g)(2)(iv)(C), which provided that citation of the 
title of a scientific reference in dietary supplement labeling would be 
a disease claim if the title referred to a disease use of the product. 
Several comments said that this provision of the proposed rule would 
violate the First Amendment as an unlawful restraint on commercial 
speech. Others characterized the proposed provision as simply a 
restriction on freedom of speech, whether the restriction was on the 
right of companies to provide the information or on the right of 
consumers to receive the information. One comment said that references 
to publication titles could be prohibited if they were misleading, but 
that the rule should not contain a blanket prohibition. Some comments 
added that the agency should reconsider its position on this provision 
in light of Washington Legal Foundation v. Friedman.
     Finally, a comment said that the proposal was contrary to the 
decision of the U.S. Court of Appeals for the District of Columbia 
Circuit in Pearson v. Shalala, 164 F.3d 650 (D.C. Cir. 1999). According 
to the comment, the court of appeals' First Amendment ruling in Pearson 
requires the agency to permit health claims that do not satisfy the 
``significant scientific agreement'' standard as long as the claim can 
be rendered non-misleading by requiring a disclaimer. According to the 
comment, the court's decision also requires FDA to further define the 
``significant scientific agreement'' standard for authorizing dietary 
supplement health claims. The comment said that the proposed rule was 
premature in light of the need to amend the health claims regulations 
to conform to the Pearson decision. The comment also argued that, in 
light of Pearson, FDA may not issue a final rule that prohibits disease 
claims but rather must choose the less restrictive alternative of 
permitting such claims provided that they are accompanied with 
disclaimers.
     FDA does not believe that the rule violates the First Amendment. 
The rule does not prohibit any speech; rather, it clarifies the 
circumstances under which FDA will consider a certain type of speech--
labeling claims--to be evidence of intended use as a drug, absent 
health claim authorization. Thus, the rule does not regulate speech as 
such, but rather as evidence of intended use. The use of speech as 
evidence of a company's intended use for its products is constitutional 
because ``[t]he First Amendment * * * does not prohibit the evidentiary 
use of speech * * * to prove motive or intent'' (Wisconsin v. Mitchell, 
508 U.S. 476, 489 (1993).) (See also Village of Hoffman Estates v. 
Flipside, 455 U.S. 489, 495-96 (1982) (upholding village ordinance 
treating the proximity of drug-oriented literature as evidence that 
items were marketed for use with illegal drugs). Because it is the 
intent and not the speech that triggers a regulatory burden on the 
speaker, there is no First Amendment violation. (See Wisconsin v. 
Mitchell, 508 U.S. at 489; United States v. Articles of Drug * * * B-
Complex Cholinos Capsules, 362 F.2d 923, 927 (3d Cir. 1966) (no 
impingement on free speech for FDA to use statements made by a lecturer 
employed by a manufacturer as evidence of the manufacturer's intent 
that its products be used for therapeutic purposes).)
     Even if the rule were viewed as a direct restriction on speech, it 
would not violate the First Amendment. The marketing in interstate 
commerce of a drug that has not been determined by FDA to be safe and 
effective is illegal (see section 301(a) and (d) of the act (21 U.S.C. 
331(a) and (d)) and 505 of the act. Thus, labeling claims that promote 
a dietary supplement for disease uses promote the product for use as an 
unapproved new drug, which is illegal. Speech promoting an illegal 
activity may be restricted without violating the First Amendment 
(Central Hudson, 447 U.S. at 563-564). In Pittsburgh Press Co. v. 
Pittsburgh Comm'n on Human Relations, 413 U.S. 376 (1973), the Supreme 
Court held that an advertisement could be prohibited where it indicated 
that the advertiser was likely to have an illegal intent while engaging 
in the proposed transaction (id. at 389). There, as here, ``the 
restriction * * * is incidental to a valid limitation on economic 
activity'' (id.).
     Nor does the rule create an unconstitutional prior restraint. FDA 
does not believe that the regulations in Sec. 101.93(f) and (g) are 
properly analyzed as a prior restraint at all. As explained previously, 
the regulations do not restrict speech but rather treat it as evidence 
of a product's intended use. Using speech to infer intent does not 
violate the First Amendment (Wisconsin v. Mitchell, 508 U.S. 476, 489 
(1993)). Thus, the regulations do not prevent speech from happening, 
but, as evidence of intended use, they determine the consequences that 
result from certain types of speech. (See Village of Hoffman Estates v. 
Flipside, 455 U.S. at 495-96 (rejecting head shop's ``exorbitant'' 
claim that village ordinance treating the proximity of drug-oriented 
literature as evidence of intended use was a prior restraint).)
     Although the regulations cannot themselves be considered as a 
direct prior restraint, it is true that claims classified as disease 
claims under the regulations are subject to prior authorization 
requirements that could be considered prior restraints--namely, the 
prior authorization requirement for dietary supplement health claims 
and the new drug approval requirements that are triggered in the 
absence of health claim authorization. In both cases, a disease claim 
cannot be made until FDA has evaluated the safety of the product and 
the evidence supporting the claim. However, labeling claims are 
commercial speech, and the Supreme Court has indicated that the prior 
restraint doctrine may not apply to commercial speech. (See Central 
Hudson, 447 U.S. at 571 n.13 (``[C]ommercial speech is such a sturdy 
brand of expression that traditional prior restraint doctrine may not 
apply to it.''; Virginia State Bd. of Pharmacy v. Va. Citizens Consumer 
Council, 425 U.S. 748, 771-72 n.24 (1976) (greater objectivity and 
hardiness of commercial speech may make prior restraint doctrine 
inapplicable). Commercial speech is ``sturdy'' because of its profit 
motive. ``[S]ince advertising is the sine qua non of commercial 
profits, there is little likelihood of its being chilled by proper 
regulation and forgone entirely'' (Virginia State Bd. of Pharmacy, 425 
U.S. at 771-72 n.24). The same is true

[[Page 1039]]

of labeling. The Supreme Court has expressed approval of prior review 
requirements in commercial speech cases. (See Shapero v. Kentucky Bar 
Ass'n, 486 U.S. 466, 476 (1988) (lawyer may be required to file 
solicitation letter with State in advance, to give it ``ample 
opportunity to supervise mailings and penalize actual abuses'');Central 
Hudson, 447 U.S. at 571 n.13 (State may require ``a system of 
previewing advertising campaigns'').)
     If the prior authorization requirement for dietary supplement 
health claims and the approval requirement for new drugs were to be 
considered prior restraints, they would be constitutional prior 
restraints. The only court of appeals to address the issue in the 
health claims context ruled that the health claims authorization 
process is not an unconstitutional prior restraint. In a recent case 
challenging the NLEA and FDA's health claim regulations for dietary 
supplements, the U.S. Court of Appeals for the Second Circuit held that 
the prior restraint doctrine did apply, but it went on to uphold the 
statute and regulations based on consideration of the Central Hudson 
factors. Nutritional Health Alliance v. Shalala, 144 F.3d 220, 227-28 
(2d Cir.), cert. denied, 119 S. Ct. 589 (1998). In Nutritional Health 
Alliance, the Second Circuit held that the health claims authorization 
process is ``sufficiently narrowly tailored'' and has adequate 
procedural safeguards--including a deadline for final agency action, a 
decision making standard to constrain the agency's discretion, and 
provision for development of a record for judicial review--to render it 
constitutionally valid (144 F.3d at 228; see Sec. 101.70 (procedures 
for petitioning for a health claim)). In upholding the regulatory 
scheme, the court also stressed that matters of public health and 
safety were involved (144 F.3d at 228). The same considerations that 
the court in Nutritional Health Alliance relied on also operate in the 
new drug approval context: Matters of public health and safety are 
involved, and the act and implementing regulations provide many 
procedural safeguards, including a deadline, a decision making 
standard, and the development of an record for judicial review (see 
section 505(c)(1), (d), and (h) of the act and; 21 CFR 314.200.) 
Moreover, as far as FDA is aware, the constitutionality of the new drug 
approval process has never been challenged on First Amendment grounds. 
Therefore, FDA does not believe that the prior restraint argument in 
the comments has merit.
     Many of the comments assumed that the test for restrictions on 
commercial speech set forth by the Supreme Court in Central Hudson 
applies. FDA believes that it is not necessary to reach the Central 
Hudson test because the rule is constitutional under Wisconsin v. 
Mitchell, Pittsburgh Press, and Village of Hoffman Estates; however, 
the rule also easily passes muster under the four-part test in Central 
Hudson. Under that test, the first question is whether the commercial 
speech at issue is false, misleading, or concerns unlawful activity, 
because such speech is beyond the First Amendment's protection and may 
be prohibited. If the speech is truthful, non-misleading, and concerns 
lawful activity, the government may nonetheless regulate it if the 
government interest asserted to justify the regulation is substantial; 
the regulation directly advances the asserted governmental interest; 
and the regulation is no more extensive than necessary to serve the 
government interest (Central Hudson, 447 U.S. at 566). The Supreme 
Court has explained that the last element of the test is not a ``least 
restrictive means'' requirement, but rather requires narrow tailoring--
``a fit that is not necessarily perfect, but reasonable'' between means 
and ends (Board of Trustees of the State Univ. of N.Y. v.Fox, 109 S. 
Ct. 3028, 3032-35 (1989)). In subsequent decisions, the Court has also 
clarified that ``misleading'' in the first element of the test refers 
to speech that is inherently or actually misleading. Thus, if the 
speech to be regulated is not inherently or actually misleading, the 
remainder of the test applies. (See In re R.M.J., 455 U.S. 191, 203 
(1982).)
     As previously discussed, FDA believes that claims for disease uses 
that have not been found to be safe and effective are speech related to 
an unlawful activity, and therefore there is no need to reach the 
remaining elements of the Central Hudson test. The agency also 
considers such claims inherently misleading because, when accompanied 
by a disclaimer that directly contradicts the claim by stating that the 
product is not intended to have an effect on disease, they are 
inherently likely to confuse consumers rather than provide them with 
useable information. Speech that is ``more likely to deceive the public 
than to inform it'' is not protected by the First Amendment (Central 
Hudson, 447 U.S. at 563). If not inherently misleading, claims for 
disease uses that have not been found to be safe and effective are at 
least potentially misleading because of the confusion caused by the 
disclaimer. Such claims also may lead consumers to believe that the 
product has benefits in treating or preventing disease, even if that is 
not the case.
     Even if the remaining elements of the Central Hudson test are 
reached, the rule and the statutory provisions that it implements are 
constitutional. As previously noted, this rule restricts no speech 
directly. Rather, it determines what types of speech in dietary 
supplement labeling will trigger other statutory provisions and 
regulations that may be considered restrictions on speech. To the 
extent that this rule, the statute, and the drug and health claim 
regulations restrict speech by requiring either health claim 
authorization or new drug approval before a business may make a disease 
claim for a dietary supplement, that restriction directly advances the 
substantial government interest in protecting and promoting the public 
health by helping to ensure that products intended to have an effect on 
a disease are safe and effective for that intended use. That interest 
is an interest both in preventing direct harm from such products--i.e., 
protecting the public from adverse events that such products might 
cause--and in preventing the indirect harm to health that is caused 
when an ill person foregoes medical care in favor of ineffective self-
treatment.
     Requiring prior FDA review and authorization of disease claims 
ensures that such claims will be evaluated by a public health agency 
that has scientific and medical expertise so that only products that 
are safe and effective will be permitted to be sold for therapeutic 
purposes. As a government agency with no financial stake in either 
permitting or denying claims, FDA is in a position to evaluate the 
strength of the safety and efficacy evidence objectively.
     The rule and the other components of the regulatory framework for 
drugs and health claims also advance the related substantial government 
interest in protecting consumers from fraud. If products are marketed 
for disease uses only after they have been demonstrated to be safe and 
effective for such uses, consumers will not suffer economic harm from 
spending money on worthless remedies.
     Moreover, the rule is not more extensive than necessary. The 
agency does not believe that the alternatives mentioned in the 
comments, or any other alternative, would adequately further its 
substantial interest in protecting and promoting public health by 
ensuring the safety and efficacy of products intended to have an effect 
on disease. For example, allowing implicit disease claims, but not 
explicit ones, would merely allow companies to do indirectly what they 
cannot do

[[Page 1040]]

directly--to market products for disease uses without demonstrating 
their safety and efficacy. Likewise, identifying specific terms that 
connote treatment, cure, or mitigation would not accomplish the goal of 
requiring proof of the safety and effectiveness of products marketed 
for disease uses. Merely regulating synonyms for those terms would 
leave unregulated those claims that achieve the same effect without 
using such a synonym, such as the claims ``herbal Prozac'' and ``for 
cancer.'' The suggestion in one comment that FDA establish ``categories 
of diseases that clearly denote drug claims'' is not a workable 
alternative either. Section 403(r)(6) of the act provides that the 
category of structure/function claims excludes claims to affect any 
category of disease, not just certain categories.
     Permitting disease claims under section 403(r)(6) of the act as 
long as they are accompanied with a disclaimer, as suggested by the 
comment that cited the Pearson decision, would be an untenable 
alternative. If companies could avoid the time and expense of complying 
with the new drug provisions of the act merely by attaching a 
disclaimer to a disease treatment or prevention claim, the longstanding 
system of drug regulation in this country would be eviscerated, with 
serious public health consequences. Nothing in Pearson requires such a 
result. Indeed, the Pearson court recognized that its ruling did not 
apply to drugs (164 F.3d at 656 n. 6). Because the act classifies 
products on the basis of intended use, dietary supplements that make 
disease claims are drugs, unless the disease claim is also an 
authorized health claim for which the product qualifies (see section 
201(g)(1) of the act).
     The Washington Legal Foundation decision is not to the contrary. 
That case involved the dissemination of information on ``off-label'' 
(unapproved) uses for approved drugs and devices to physicians by means 
of scientific and educational symposia, reprints, and textbooks. The 
U.S. District Court for the District of Columbia held certain FDA 
guidance documents that described acceptable ways of disseminating such 
information unconstitutional under the Central Hudson test. While 
recognizing the substantial government interest in having off-label 
uses for drugs and devices found to be safe and effective by FDA, the 
court held that the guidance documents violated the First Amendment 
because it believed that they ``restricted'' speech in a manner that 
was more extensive than necessary to further that interest. (See 13 F. 
Supp. 2d at 73.) (Subsequent to the 1998 decision cited by the 
comments, the court rendered another decision adverse to FDA 
(Washington Legal Foundation v. Henney, 1999 WL 557679 (D.D.C. July 28, 
1999)). That decision concerned the constitutionality of certain 
provisions of the FDA Modernization Act of 1997 involving the same 
subject matter as the guidance documents, and the court's First 
Amendment rationale was similar to its rationale in the 1998 decision 
pertaining to the guidance documents.)
     FDA disagrees with the district court decision in Washington Legal 
Foundation and has appealed. In any event, however, the outcome in 
Washington Legal Foundation does not determine the outcome here for 
several reasons. First, in Washington Legal Foundation the court found 
a less restrictive alternative that it concluded would more precisely 
address the government's regulatory concerns: Requiring manufacturers 
who disseminate information about off-label uses to physicians through 
scientific reprints or educational symposia to disclose: (1) Their 
interest in drugs or devices that are the subject of such activities, 
and (2) the fact that the use discussed has not been approved by FDA. 
Here, as explained previously, there are no less restrictive 
alternatives to this rule that would further the government's 
substantial public health interest. Second, in Washington Legal 
Foundation physicians were the intended audience of the commercial 
speech at issue. In contrast, consumers are the primary audience for 
dietary supplement labeling. Although the marketplace includes 
consumers of varying levels of sophistication, the average consumer 
does not possess the medical and scientific expertise necessary to 
evaluate claims about the effect of a product on disease. (See American 
Home Products Corp. v. FTC, 695 F.2d 681, 698 (3d Cir. 1983); 
Association of Nat'l Advertisers, Inc. v. Lungren, 44 F.3d 726, 733-34 
(9th Cir. 1994), cert. denied, 516 U.S. 812 (1995).) Finally, in 
Washington Legal Foundation, it was undisputed that the products 
involved were drugs (or, in some cases, devices) to be used in treating 
or preventing disease. In contrast, the purpose of this rule is to 
distinguish between products that are intended to affect disease and 
products that are not.
     The agency does not believe this rule is premature in light of the 
need to reassess the regulatory regime for health claims under Pearson. 
Since health claims and structure/function claims are regulated 
separately, there is no need to wait for any post-Pearson changes for 
health claims to be complete before proceeding with this rulemaking on 
structure/function claims. Moreover, since the agency has decided not 
to amend the health claims regulations as part of this rulemaking, 
there is no potential conflict between the two.
     The First Amendment issues raised in comments on 
Sec. 101.93(g)(4)(iii) (proposed Sec. 101.93(g)(2)(iv)(C)), concerning 
citations to scientific references in labeling, are not different from 
those raised by comments on the rule as a whole and are addressed in 
the preceding analysis. FDA also notes that, as discussed elsewhere in 
this document, Sec. 101.93(g)(4)(iii) has been revised to narrow the 
circumstances under which the agency will consider citations to 
scientific references in labeling to be disease claims.
     (109.) Another comment further asserted that the prohibition 
against implied disease claims violates the First Amendment because it 
does not advance the safety of dietary supplements. The comment 
acknowledged that some dietary supplements ``may present serious safety 
risks,'' but said ``these risks will not be lessened by prohibiting 
truthful, non-misleading structure/function claims * * *.'' The comment 
suggested that other provisions in DSHEA address the safety of dietary 
supplements and that FDA can bring an enforcement action if it has 
safety concerns.
     FDA agrees with this comment in part and disagrees in part. The 
agency agrees that prohibiting truthful, non-misleading structure/
function claims would not lessen the safety risks posed by some dietary 
supplements. The rule is aimed at the safety risks posed by unapproved 
drug claims and unauthorized health claims on dietary supplements. 
Unproven disease claims on a product marketed as a dietary supplement 
may induce consumers to treat themselves with the supplement instead of 
seeking treatments that are known to be effective. Such claims may also 
dissuade consumers from seeing a doctor. These are very real safety 
risks. To the extent that safety risks are caused by the composition of 
a dietary supplement rather than by claims made for it, the agency 
agrees that other provisions in DSHEA and the act are the appropriate 
remedy.
2. Equal Protection
     (110.) One comment claimed the rule violates the equal protection 
clause of the Fourteenth Amendment because it supposedly gives more 
protection to the ``labeling rights and speech'' of pharmaceutical 
manufacturers than to dietary supplement manufacturers.

[[Page 1041]]

     First, it should be noted that the equal protection clause of the 
Fourteenth Amendment applies only to the States, not to the Federal 
Government. However, the due process clause of the Fifth Amendment 
contains an equal protection component that is equivalent to the equal 
protection clause of the Fourteenth Amendment (Schweiker v. Wilson, 450 
U.S. 221, 226 & n. 6 (1981)). Even if the comment is interpreted to 
refer to equal protection under the Fifth Amendment, FDA disagrees with 
it. First, the comment does not explain in what manner the rule gives 
more protection to the labeling rights and speech of pharmaceutical 
manufacturers than to those of dietary supplement manufacturers. 
Second, even if the rule does treat these two classes of manufacturers 
differently, treating different regulated groups differently does not 
in itself violate the equal protection clause. Unless a regulatory 
classification jeopardizes the exercise of a fundamental right or 
classifies upon inherently suspect grounds such as race or religion, it 
is subject to the least exacting form of equal protection review: 
Whether the classification it draws bears a rational relationship to a 
legitimate government interest. (See Nordlinger v. Hahn, 505 U.S. 1, 10 
(1992).)
     This rule neither jeopardizes the exercise of a fundamental right 
nor creates a suspect classification. The purpose of the rule is to 
clarify the statutory distinction between products that are intended 
for use in treating or preventing disease and products that are 
intended for use in affecting the structure or function of the body. 
Products intended to treat or prevent disease are subject to regulation 
as drugs, unless they qualify for an authorized health claim. Products 
intended to affect the structure or function of the body may be 
regulated as dietary supplements, subject to certain conditions. 
Products regulated as drugs must meet strict requirements for a 
premarket demonstration of safety and efficacy (see sections 201(p) and 
505 of the act); these requirements do not apply to dietary 
supplements. The distinction that the statute and this rule draw 
between products that are intended to have an effect on disease and 
those that are intended only to affect the structure or function of the 
body is clearly rationally related to the legitimate government 
interest of ensuring that products intended to have an effect on a 
disease are safe and effective for that intended use.
 3. Takings Under the Fifth Amendment
     (111.) Several comments claimed that the proposal violates the 
Takings Clause of the Fifth Amendment because it would prohibit the use 
of specific terms that now appear in product names, trademarks, trade 
names, symbols, and company logos, or would harm companies that use 
such terms in their corporate names. One comment said FDA must provide 
compensation for each taking, but that the proposal failed to do so.
     FDA disagrees with these comments. The Takings Clause forbids the 
government from taking private property for public use without just 
compensation. However, FDA believes that no taking will occur as a 
result of this rule.
     The first issue to be considered is whether the categories of 
names, words, and symbols identified in the comments on this issue are 
property within the meaning of the Takings Clause. The Constitution 
itself does not define what qualifies as property. Rather, ``existing 
rules or understandings derived from an independent source,'' such as 
State or Federal law, define the interests that qualify for protection 
as property under the Fifth Amendment (Lucas v. South Carolina Coastal 
Council, 505 U.S. 1003, 1030 (1992)).
     The categories of names, words, and symbols mentioned by the 
comments are intangible property interests. As discussed below, 
trademarks and trade names are property to the extent that they are 
associated with business goodwill. A trademark is a word, name, symbol, 
device, or combination thereof that a person uses, or intends to use 
and has applied to register, to identify and distinguish his or her 
goods from others on the market and to indicate their source (15 U.S.C. 
1127). A trade name is the name a person uses to identify his or her 
business (15 U.S.C. 1127) and may include corporate, partnership, and 
other names. Symbols and logos, when used to identify a product or 
company, may be property insofar as they are trademarks or trade names. 
Likewise, product names may be property if they are protected by a 
trademark or trade name. For brevity, in the remainder of this 
discussion the categories of names, words, and symbols mentioned by the 
comments on the takings issue will be referred to collectively as 
``trademarks and trade names.''
     Trademarks and trade names are property, but only insofar as they 
are associated with the goodwill of an ongoing business. (See American 
Steel Foundries v. Robertson, 269 U.S. 372, 380 (1926).) They have no 
intrinsic value. The purpose of a trademark or trade name is to prevent 
confusion with the products of another manufacturer. (See United Drug 
Co. v. Theodore Rectanus Co., 248 U.S. 90, 97 (1918).) Trademarks and 
trade names are given legal protection to prevent one manufacturer from 
passing off its goods as the goods of another and thus taking advantage 
of the latter's goodwill (American Steel Foundries, 269 U.S. at 380; 
United Drug, 248 U.S. at 97).
     The Supreme Court has declined to prescribe a ``set formula'' for 
identifying takings and instead has characterized takings analysis as 
an ``essentially ad hoc, factual'' inquiry (Penn Central Transp. Co. v. 
City of New York, 438 U.S. 104, 124 (1978)). Nonetheless, the Court has 
identified three factors for consideration in assessing whether a 
regulatory taking has occurred: The character of the governmental 
action; the regulation's economic impact; and the extent to which the 
regulation interferes with reasonable investment-backed expectations 
(Ruckelshaus v. Monsanto Co., 467 U.S. 986, 1005 (1984)). The force of 
any one of these factors may be ``so overwhelming * * * that it 
disposes of the taking question'' (Monsanto, 467 U.S. at 1005). When 
examined in light of these three factors, the rule does not effect a 
compensable taking under the Fifth Amendment.
     a. The character of the government action. With respect to the 
first factor, the character of the government action, courts are more 
likely to find a taking when the interference with property can be 
characterized as a physical invasion by government than when the 
interference is caused by a regulatory program that ``adjust[s] the 
benefits and burdens of economic life to promote the common good'' 
(Penn Central, 438 U.S. at 124). The Supreme Court has held that, when 
a governmental action is taken in order to protect the public interest 
in health, safety, and welfare, this factor weighs heavily against 
finding a taking. (See Keystone Bituminous Coal Ass'n v. DeBenedictis, 
480 U.S. 470, 488 (1987).) Regulatory actions taken to protect the 
public health are rarely, if ever, held to constitute takings. (See 
Porter v. DiBlasio, 93 F.3d 301, 310 (7th Cir. 1996) (action taken to 
protect public health falls within class of property deprivations for 
which Fifth Amendment does not require compensation); Jarboe-Lackey 
Feedlots, Inc. v. United States, 7 Cl. Ct. 329 (1985) (seizure of 
adulterated meat not a taking).)
     Although these regulations will restrict the use of certain terms, 
including terms that appear in some trademarks and trade names, this 
restriction does not rise to the level of a taking. Governmental 
restrictions on the uses individuals can make of their

[[Page 1042]]

property are ``properly treated as part of the burden of common 
citizenship'' (Keystone, 480 U.S. at 491 (citation omitted)). These 
burdens are ``borne to secure `the advantage of living and doing 
business in a civilized community''' (Andrus v. Allard, 444 U.S. 51, 67 
(1979) (quoting Pennsylvania Coal Co. v. Mahon, 260 U.S. 393, 422 
(1922) (Brandeis, J., dissenting)). Moreover, these regulations are not 
without benefit to manufacturers. (See Keystone, 480 U.S. at 491 
(``While each of us is burdened somewhat by such restrictions, we, in 
turn, benefit greatly from the restrictions that are placed on 
others.'').) The regulations will help ensure a level playing field in 
the dietary supplement market because no manufacturer will be able to 
make an implied disease claim without prior FDA review under the health 
claim or new drug standard. Previously, unreviewed implied disease 
claims on dietary supplements proliferated, in part because of 
uncertainty about the line between structure/function claims and 
disease claims.
     These regulations are rationally related to, and substantially 
advance, FDA's legitimate interest in promoting and protecting the 
public health by ensuring the safety and efficacy of products promoted 
for use in treating or preventing disease. (See Keystone, 480 U.S. 470 
at 485; Monsanto, 467 U.S. at 1007.) By clarifying that such products 
may not be marketed under the structure/function claim regime, FDA is 
seeking to ensure that they are regulated through the drug approval or 
health claims authorization process, as appropriate.
     The effect of the regulations cannot be characterized as a taking 
of property. Dietary supplement companies will not be precluded from 
using terms that imply a disease claim in their trademarks and trade 
names. If they wish to continue using trademarks and trade names that 
imply a disease claim, they may do so, provided that they first meet 
the safety and efficacy standards and other regulatory requirements 
applicable to drugs or, in appropriate cases, provided that they obtain 
authorization to make a health claim. (As discussed below, only non-
misleading trademarks and trade names may be used.)
     Even if these regulations could be said to prevent a business from 
using a trademark or trade name on its dietary supplements, such a 
result still would not constitute a taking of the trademark or trade 
name. The purpose of giving trademarks and trade names legal protection 
is to prevent one manufacturer from passing off its goods as the goods 
of another (American Steel Foundries, 269 U.S. at 380). This regulation 
will not allow one manufacturer to use another's trademark or trade 
name; rather, all manufacturers will be precluded from using trademarks 
and trade names that contain an implied disease claim unless they have 
obtained new drug approval or health claim authorization. Thus, 
manufacturers will not suffer any competitive injury.
     Moreover, deprivation of a trademark alone is not a deprivation of 
property. Because the trademark is ``merely a protection for the good 
will'' (Hanover Star Milling Co. v. Metcalf, 240 U.S. 403, 414 (1916)), 
only if a regulation takes the owner's goodwill as well would the 
regulation be a taking. It is not apparent, however, that these 
regulations will deprive manufacturers of any goodwill. Manufacturers 
will be faced with a choice as to whether to change their trademark or 
trade name or to seek approval for their products as drugs. In some 
cases, they will also have a third option: Seeking authorization to 
make a health claim. If they are able to obtain drug approval for the 
intended use suggested by the trademark or trade name, they will not 
have to change the trademark or trade name, provided that the name is 
not confusingly similar to the name of another drug or otherwise 
misleading (see section 502(a)(1) of the act (21 U.S.C. 352(a)(1)); and 
Sec. 201.10(c)(3) and (c)(5).) Similarly, if they are able to obtain 
authorization to make a health claim for the intended use suggested by 
the trademark or trade name, they will not have to change the trademark 
or trade name unless it is misleading. (See section 403(a)(1) of the 
act.) Even if a manufacturer chooses to change its trade name or 
trademark, it will not be deprived of the goodwill underlying them but 
only of that particular symbol of the goodwill. The manufacturer will 
still be able to transfer the goodwill associated with its products to 
another trade name or trademark.
     Case law on the treatment of goodwill under the Takings Clause 
supports the view that no taking will occur as a result of these 
regulations. The general rule is that the owner of a place of business 
to which the government takes title is not entitled to compensation for 
loss of goodwill (United States v. General Motors Corp., 323 U.S. 373, 
379 (1945)). The reason for the rule is that the business may reopen at 
another location to which the goodwill may be transferred (Kimball 
Laundry Co. v. United States, 338 U.S. 1, 11-12 (1949)). Only where the 
government operates the business, thereby depriving the owner of its 
``going-concern value,'' is there a compensable taking of goodwill. In 
Kimball, the Supreme Court held that the government owed compensation 
for the loss of goodwill associated with the temporary taking of a 
laundry during World War II. This action was held to be a taking of 
goodwill because the government not only physically took but also 
operated the laundry during the war (Kimball, 338 U.S. at 12-13). Thus, 
during the period that the government operated the laundry, there was 
no business to whose benefit the goodwill associated with the private 
laundry business could inure. Here, the government is not taking any 
trademark or trade name for its own use, nor is it shutting down the 
businesses that own them. Therefore, the goodwill symbolized by the 
trademark or trade name will remain with these businesses.
     Finally, although trademarks and trade names can be property when 
they symbolize and protect the goodwill associated with a business, 
there can be no property interest in an illegal product. Dietary 
supplements that bear claims to treat or prevent disease are misbranded 
and are also unapproved new drugs (unless the claim is an authorized 
health claim). As such, they may not legally be sold in interstate 
commerce (see section 301 (a) and (d) of the act. There can be no 
taking of an illegal article. (See Meserey v. United States, 447 F. 
Supp. 548, 554 (D. Nev. 1977) (``Plaintiff has not been denied his 
property. He is denied the right to introduce his goods into commerce 
unless they are in compliance with the [Federal Food, Drug, and 
Cosmetic] Act.'').) Moreover, it has always been illegal to market 
dietary supplements or other foods with disease claims, except that 
since 1990 the act has permitted authorized health claims. These 
regulations merely clarify the line between acceptable structure/
function claims and prohibited disease claims. (See Lucas, 505 U.S. at 
1030 (``The use of [property] for what are now expressly prohibited 
purposes was always unlawful, and * * * it was open to the State at any 
point to make the implication of those background principles of * * * 
law explicit'' without paying compensation) (emphasis in original).) 
For this reason and the other reasons previously discussed, the first 
factor of the takings analysis indicates that these regulations effect 
no takings.
     b. The economic impact of the government action. The second factor 
to consider is the economic impact of the government action. This 
impact is not to be considered piecemeal by dividing a property 
interest ``into discrete

[[Page 1043]]

segments and attempt[ing] to determine whether rights in a particular 
segment have been entirely abrogated'' (Penn Central, 438 U.S. at 130). 
The analysis involves looking not just at what has been lost, but at 
the nature and extent of the interference with rights in the property 
as a whole. (See  Penn Central, 438 U.S. at 130-31; Andrus v. Allard, 
444 U.S. at 65-66.) Thus, here the total impact of the regulations on 
property rights should be considered, rather than only whether a 
business can or cannot continue to use a particular trademark or trade 
name. It is clear that a regulation's economic impact may be great 
without rising to the level of a taking. (See Pace Resources, Inc. v. 
Shrewsbury Township, 808 F.2d 1023, 1031 (3d Cir.), cert. denied, 482 
U.S. 906 (1987) (citing Hadacheck v. Sebastian, 239 U.S. 394 (1915) 
(reduction in value from $800,000 to $60,000); Euclid v. Ambler Realty 
Co., 272 U.S. 365 (1926) (75 percent diminution in value)).)
     In assessing whether a regulation effects a taking, the Supreme 
Court has considered whether the regulation denies an owner the 
``economically viable'' use of its property. (See, e.g., Keystone, 480 
U.S. at 499.) Although it is undeniable that compliance with these 
regulations will cost money and may mean that certain trademarks and 
trade names must be altered, companies will not be denied the 
economically viable use of their property. As previously discussed, 
some firms may be able to obtain new drug approval or health claim 
authorization for those products that bear trademarks or trade names 
that include disease claims. If approved as new drugs or authorized to 
bear a health claim, in many cases these products could continue to 
bear the original trademark or trade name. This approach would, 
however, require the company involved to make significant expenditures 
of time and money to submit a new drug application (NDA) or health 
claim petition to FDA. The financial burden required to comply with 
such requirements is not a taking under these circumstances, however, 
just as it is not a taking to require other companies to comply with 
applicable requirements before marketing a new drug or a food bearing a 
health claim. Obtaining new drug approval or authorization to make a 
health claim may be costly, but it is not the kind of economic impact 
that leads to a taking. ``Requiring money to be spent is not a taking 
of property'' (Atlas Corp.) v. United States, 895 F.2d 745, 756 (Fed. 
Cir.), cert. denied, 498 U.S. 811 (1990)).
     As previously noted in the discussion of the first factor of the 
takings analysis, case law indicates that the regulations will cause no 
loss of goodwill even in cases where a trademark or trade name must be 
changed because new drug approval or health claim authorization cannot 
be obtained. Even if the regulations do cause a loss of goodwill, 
however, FDA believes that the economic impact of that loss of goodwill 
is outweighed in the takings analysis by lack of reasonable investment-
backed expectations in being able to make disease claims in trademarks 
and trade names.
     c. Interference with reasonable investment-backed expectations. 
The final factor to consider is whether a company has a reasonable 
investment-backed expectation in continuing to use a trademark or trade 
name. To be reasonable, expectations must take into account the power 
of the state to regulate in the public interest (Pace Resources, 808 
F.2d at 1033). Reasonable expectations must also take into account the 
regulatory environment, including the foreseeability of changes in the 
regulatory scheme. ``In an industry that long has been the focus of 
great public concern and significant government regulation,'' Monsanto, 
467 U.S. at 1008, the possibility is substantial that there will be 
modifications of the regulatory requirements. ``Those who do business 
in the regulated field cannot object'' if the regulatory scheme is 
``buttressed * * * to achieve the legislative end'' (Connolly v. 
Pension Benefit Guar. Corp., 475 U.S. 211, 227 (1986) (citation 
omitted)). The lack of a reasonable investment-backed expectation can 
outweigh the other takings factors and be determinative in whether a 
taking has occurred (Monsanto, 467 U.S. at 1005).
     Companies that use trademarks or trade names that include disease 
claims lack a reasonable investment-backed expectation that they will 
be able to continue to use those trademarks and trade names. First, the 
Supreme Court has said that it is unreasonable to have high 
expectations in personal property (i.e., property other than land): 
``[I]n the case of personal property, by reason of the State's 
traditionally high degree of control over commercial dealings, [the 
property owner] ought to be aware of the possibility that new 
regulation might even render his property economically worthless * * 
*.'' (Lucas v. South Carolina Coastal Council, 505 U.S. at 1027-28). 
Second, the dietary supplement and drug industries are a ``focus of 
great public concern and significant government regulation'' (Monsanto, 
467 U.S. at 1008). A product that bears a disease claim, whether that 
claim appears in a trademark, trade name, or elsewhere, has been 
subject to regulation as a drug since 1906, except that since 1990 the 
act has permitted conventional foods and dietary supplements to bear 
authorized health claims without drug approval. Since 1938, drugs (with 
certain narrow exceptions) have been subject to a premarket approval 
requirement. Given this longstanding history of close regulation, it 
cannot be reasonable for a manufacturer or distributor to expect to be 
able to make disease claims without prior authorization from FDA.
     Moreover, it has always been illegal to market dietary supplements 
or other foods with disease claims, except that since 1990 authorized 
health claims have been permitted. These regulations merely clarify the 
line between acceptable structure/function claims and prohibited 
disease claims. (See Lucas, 505 U.S. at 1030 (``The use of [property] 
for what are now expressly prohibited purposes was always unlawful, and 
* * * it was open to the State at any point to make the implication of 
those background principles of * * * law explicit.'').) Companies in 
the dietary supplement industry should have been aware that FDA was 
likely to issue such a clarification, not only because of the 
regulatory environment generally but also for several specific reasons. 
First, the passage of DSHEA, which added section 403(r)(6) to the act, 
created a likelihood that FDA would issue regulations ``to achieve the 
legislative end'' of permitting structure/function claims without 
premarket review, while continuing to prohibit disease claims lacking 
FDA authorization (see Connolly, 475 U.S. at 227 (citation omitted)). 
Second, the Commission on Dietary Supplement Labels specifically 
encouraged FDA to clarify the appropriate scope of structure/function 
statements (Ref. to Commission report, p. 38). Third, the rapidly 
expanding dietary supplement market and the proliferation of implied 
disease claims in labeling should have put the industry on notice that 
FDA might take action.
     For all these reasons, there can be no reasonable investment-
backed expectations with respect to trademarks and trade names that 
include disease claims. Thus, the third factor of the takings analysis 
weighs strongly against finding a taking of property that requires 
compensation under the Fifth Amendment. Moreover, the three factors, 
taken together, show that these regulations do not effect such a 
taking. Therefore, FDA concludes that the comments arguing the contrary 
are unpersuasive.

[[Page 1044]]

 IV. Implementation Plan

     The preamble to the proposed rule discussed FDA's tentative 
conclusions regarding the effective date of a final rule and the 
agency's implementation plan. In general, the preamble to the proposed 
rule stated that a final rule would become effective 30 days after the 
date of the final rule's publication in the Federal Register. Any 
product that is marketed for the first time after publication of the 
final rule, and any new claims made for an existing product for the 
first time after the publication of the final rule, will be expected to 
be in compliance beginning 30 days after publication of the final rule. 
However, small businesses that marketed a product as of the date of 
publication of a final rule would have had an additional 17 months to 
bring existing claims (i.e., claims already in the products's labeling 
on January 6, 2000 for those products into compliance, provided that 
the small business had notified FDA of the claim as required by section 
403(r)(6) of the act and Sec. 101.93(a) and that FDA had not objected 
to the claim. For all other products that were on the market as of the 
date of publication of a final rule, FDA would have allowed an 
additional 11 months beyond the effective date to bring existing claims 
for those products into compliance, provided that the firm had notified 
FDA of the claim as required by section 403(r)(6) of the act and 
Sec. 101.93(a) and that FDA had not objected to the claim. Any product 
marketed for the first time after the date of publication of the final 
rule, and any new claim made for an existing product for the first time 
after publication of the final rule, would have been expected to be in 
compliance beginning 30 days after the date of publication of a final 
rule.
     (112.) Two comments suggested extending the compliance period to 6 
months after the date of publication of a final rule. The comments also 
advocated that there be no distinction between large and small 
businesses for compliance dates. The comments further suggested that 
FDA give businesses whose products were on the market as of the date of 
publication of a final rule 15 months (instead of 11 or 17 months) to 
comply. Another comment suggested that the final rule become effective 
12 months, rather than 30 days, after its publication date.
     FDA believes that the proposed compliance periods of 11 and 17 
months following the effective date of the final rule are reasonable 
and fair, and that the distinction between large and small businesses 
is appropriate. FDA has decided, however, that it will not treat 
manufacturers who have not notified the agency of their claims 
differently from other manufacturers. At least some of those 
manufacturers who did not submit 30-day notifications to the agency may 
have failed to do so believing that notification was not necessary 
under section 201(g)(1)(C) of the act. Therefore, all manufacturers 
will have 11 months after the effective date of the final rule to come 
into compliance, and small businesses will have 17 months after the 
effective date of the final rule. The agency believes that these 
compliance periods, uniformly applied, are sufficiently long that it is 
not necessary to extend the effective date to 6 months after 
publication in the Federal Register.
     For a limited transition period, FDA does not intend to take 
enforcement action against firms who have relied on the agency's 
September 1997 preamble statements to make a structure/function claim 
for a dietary supplement under section 201(g)(1)(C) of the act. To 
allow a reasonable time for the necessary label changes, the transition 
period will last until the applicable compliance date for the rest of 
the rule; i.e., small businesses will have 18 months from publication 
to comply, and other firms will have 12 months. As of the applicable 
compliance date, firms that have been making structure/function claims 
under section 201(g)(1)(C) must either remove the claim or comply with 
the requirements of section 403(r)(6) of the act and Sec. 101.93, 
including notifying FDA of the claim and relabeling to add the required 
disclaimer. New structure/function claims are not subject to this 
transition period; any firm that makes a structure/function claim in 
the labeling of a dietary supplement after the effective date of this 
rule must comply with section 403(r)(6) of the act and Sec. 101.93.

 V. Environmental Impact

     The agency has determined under 21 CFR 25.30(h) and (k), that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

 VI. Analysis of Impacts

 A. Background

     FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The Regulatory 
Flexibility Act requires agencies to examine the economic impact of a 
rule on small entities. The Unfunded Mandates Reform Act requires 
agencies to prepare an assessment of anticipated costs and benefits 
before enacting any rule that may result in an expenditure in any one 
year by State, local and tribal governments, in the aggregate, or by 
the private sector, of $100 million (adjusted annually for inflation).
     FDA concludes that this final rule is consistent with the 
principles set forth in the Executive Order and in these two statutes. 
The agency has determined that the rule is a significant regulatory 
action as defined by the Executive Order, because it raises novel 
policy issues. FDA has further determined that the final rule may have 
a significant economic impact on a substantial number of small 
entities. This section constitutes the agency's final regulatory 
flexibility analysis as required under the Regulatory Flexibility Act. 
Because this rule imposes no mandates on government entities and will 
not result in private expenditures of $100 million in any one year, the 
Unfunded Mandates Reform Act does not require the agency to prepare a 
cost-benefit analysis.

 B. Benefits of the Labeling Requirements

     The primary purpose of the rule is to provide a consistent 
standard for distinguishing between claims that may be made in labeling 
without prior review by FDA and claims that require prior authorization 
as health claims or prior review as drug claims. The larger goal is to 
ensure that information about non-disease-related effects of a dietary 
supplement on the body may be freely disseminated in labeling, while at 
the same time guaranteeing that claims for use of a dietary supplement 
to treat or prevent disease are not made without prior review to ensure 
that the supplement is safe and effective for that use.
     Although dietary supplements can play a valuable role in consumer 
health, the agency recognizes that, when inappropriately labeled, they 
can pose unnecessary risks. Such risks arise when the product labeling: 
(1) Encourages consumers to self-treat for a serious disease without 
the benefit of a medical diagnosis, or to self-treat for a

[[Page 1045]]

serious disease by substituting a dietary product of uncertain value 
for a medical therapy that has been shown to be safe and effective; (2) 
encourages consumers to feel sufficiently protected from a serious 
disease (e.g., cancer) that they delay, or possibly forego, regular 
screening or early medical attention that may be critical to improved 
odds of patient survival; or (3) increases the risk of adverse 
reactions due to interactions with other chemical compounds (e.g., 
prescription medications) taken by the patient. As consumer spending on 
dietary supplements continues to rise, the need for an information 
standard that minimizes these risks becomes more acute.
    The rule may also benefit consumers by encouraging manufacturers of 
dietary supplements to develop the safety and effectiveness data needed 
to support a health or drug claim. Where disease claims can be made 
without this demonstration of safety and effectiveness, product 
manufacturers have less incentive to develop the substantial 
documentation needed to receive this agency authorization. The 
availability of additional products with authorized health or drug 
claims would be extremely useful to the many consumers who have 
difficulty distinguishing among the variety of products now marketed 
for particular health concerns.
     The dietary supplement industry has grown rapidly, with estimated 
sales in 1996 of $10.4 billion for all dietary supplements, including 
$4.9 billion for vitamins and $3.0 billion for nonprescription herbal 
products (Ref. 8). FDA has limited information on the number of 
products and quantities sold, or on the age, gender, and disease status 
of persons currently using dietary supplements. However, a 1997 survey 
of 43,000 households, conducted by the Hartman and New Hope research 
organization, indicates that approximately 70 percent of all households 
reported using vitamins, minerals, or herbal supplements in the past 6 
months (Ref. 9). Among survey respondents, those under age 30 accounted 
for only 8 percent of all households with a member using dietary 
supplements; ages 30 to 39 accounted for 21 percent, ages 40 to 49 
accounted for 22 percent, ages 50 to 59 accounted for 18 percent, and 
ages 60 or older accounted for 30 percent (Ref. 10). Although the 
oldest group of survey respondents were, on the whole, less 
knowledgeable about individual products, they reported more regular 
product use and more use for specific conditions than younger 
respondents.
     FDA anticipates, therefore, that the final rule will clarify the 
dividing line between acceptable structure/function claims and disease 
claims, and thereby reduce the number of inappropriate disease claims 
in dietary supplement labeling. The defined standard for structure/
function claims under section 403(r)(6) of the act will help to avoid 
instances of inappropriate substitution of dietary products for timely 
disease screening or medical treatment, and of adverse interactions or 
contraindications of drug-supplement combinations. In addition, the 
rule may promote the development of data and information for the 
support of new health or drug claims. Although FDA cannot quantify 
these regulatory benefits, the agency expects that this standard will 
positively support the effective integration of dietary supplements 
into consumers' overall programs of wellness and self-care.

 C. Costs of Compliance

    The costs to industry are the direct costs of compliance, which are 
primarily the costs of the needed product relabeling; and the indirect 
costs of compliance, which include the potential loss of product sales 
due to the elimination of disease claims. The following section details 
the agency's calculation of the direct costs of compliance. FDA has 
been unable, however, to estimate the extent of the indirect costs of 
this rule. As explained below, the agency estimates that over 800 
dietary supplement products will need to be relabeled due to this rule. 
The substitution of a valid structure/function claim for a disease 
claim may, in fact, lead to a decrease in the sale of certain products. 
The magnitude of this impact, however, is unknown, as most firms will 
replace the disease claim with a structure/function claim that appeals 
to many of the same consumers. It is also possible that some firms will 
avoid a potential drop in sales by developing the safety and 
effectiveness data needed to obtain either a new drug approval or 
authorization from FDA to make a health claim. The agency cannot 
quantify the probability of these occurrences, however, and no industry 
comment includes such data.

 1. Proposed Rule
     In the preamble to the proposed rule (63 FR 23624), FDA had 
projected that the direct costs of compliance would range from $0.1 
million to $8.5 million. This figure largely reflected agency estimates 
of the average cost of relabeling a typical dietary supplement product 
multiplied by the number of dietary supplement products that would need 
to be relabeled to conform with the proposed criteria for structure/
function claims. The cost categories included administrative, 
analytical, and inventory disposal activities.
     FDA acknowledged that estimates of the number of dietary 
supplement products were approximate, but projected that the proposed 
rule would cover about 29,000 products, with about 75,000 distinct 
labels, or stock keeping units (SKU's). The agency also explained that 
the rule would directly affect from 500 to 850 manufacturers of dietary 
supplement products.
    To estimate the lower-bound costs of the proposed rule, FDA assumed 
that the 2,300 notifications initially received from dietary supplement 
manufacturers adequately represented the number of products with 
structure/function claims. The agency had already objected to 150 
notifications because they contained obvious disease claims, but 
identified an additional 60 notifications containing one or more claims 
that might not have met the newly proposed criteria for structure/
function claims. Consequently, FDA's lower-bound direct cost estimate 
included label changes for 60 dietary supplement products. The 
estimated administrative, redesign, and inventory losses associated 
with these 60 label changes totaled between $91,400 and $123,400.
     FDA also presented an upper-bound $8.5 million estimate of the 
direct costs of the proposed rule, based on the likelihood that many 
additional dietary supplements are marketed with structure/function 
claims. For this estimate, the agency concluded that about 30 percent, 
or 22,500, of the estimated universe of 75,000 dietary supplement 
labels contain structure-function claims. Assuming that the proportion 
of disease claims on all labels containing structure/function claims 
equals the proportion of disease claims in the 2,300 notifications 
containing structure/function claims, the agency calculated that up to 
585 labels (60/2,300 x 22,500) could need to be changed if the proposed 
rule became final. The higher costs of the upper-bound estimate 
resulted both from the substantially increased assumed number of 
affected labels and from the impact of the significantly shorter 
compliance period (30 days) for manufacturers that had not notified FDA 
of their structure/function claim by the publication date of the final 
rule.

 2. Final Rule
     A number of the comments submitted in response to the proposed 
rule specifically addressed FDA's analysis of compliance costs. As a 
result, the

[[Page 1046]]

agency has altered several of its cost assumptions. In addition, FDA 
has adjusted its analysis to reflect the modified provisions of the 
final rule. As described below, the agency estimates the total direct 
costs of the final rule to be about $3.73 million, but presents 
sensitivity analysis to indicate that the costs could rise to as much 
as $10.35 million under certain worst-case assumptions.
     Although several industry comments suggested that FDA had 
underestimated the costs of relabeling, no comments objected to the 
specific elements that were considered, i.e., administrative, redesign, 
and inventory disposal activities. In response, FDA has retained this 
format for its analysis of the final rule. One comment claimed that FDA 
had underestimated the number of products that would be affected, but 
provided no evidence or basis for determining a more accurate count. 
Another comment stated that the agency's cost estimates were not well 
explained and that all assumptions were not disclosed. Consequently, 
FDA has revised its analysis to; (1) Simplify the cost-estimating 
methodology, (2) clearly present and describe each assumption, (3) 
fully explain the derivation of the estimated direct costs of 
compliance, and (4) conduct sensitivity analysis for the remaining 
areas of significant uncertainty.
     a. Cost of designing new labels. Dietary supplements will no 
longer be able to make claims whose status was previously unclear, but 
which now have been defined as disease claims. Firms may comply either 
by obtaining new drug approval, by receiving authorization from FDA to 
make a health claim, or by revising their product labeling to eliminate 
disease claims. Because the cost of submitting adequate documentation 
to obtain new drug approval or health claim authorization far exceeds 
the cost of modifying a label, this analysis assumes that the direct 
costs of the rule will be the costs of modifying labels with disease 
claims. As explained above, FDA recognizes that some firms may choose 
to obtain health claim authorization or new drug approval as an 
alternative means of compliance, or to improve the marketability of 
their products. The agency believes, however, that it is unlikely that 
the rule would be the determining factor in a large number of 
instances.
     No public comments provided alternative estimates of the number of 
affected dietary supplement products. As noted above, FDA had estimated 
that the industry markets approximately 29,000 covered products with 
about 75,000 distinct labels. The agency has used this estimate for its 
analyses of dietary supplement rules over the past several years (e.g., 
60 FR 67211 December 28, 1995) and has received no indication from 
industry that better estimates were available. Although the agency's 
preliminary analysis reported that an estimated 30 percent of the 
products (8,700) carry structure/function claims, more recent data from 
a random survey conducted for FDA by RTI of about 3,000 dietary 
supplement products indicates that this percentage may have been too 
low (Ref. 11). Although RTI notes that the surveyed sample is too small 
to support quantitative inferences for the population of dietary 
supplements, FDA finds the data to be the best available. The RTI 
report actually shows that 69 percent of the products in its sample 
have claims, but this percentage includes ``diet supplementation'' 
claims. When adjusted to exclude ``diet supplementation'' only 62 
percent of the products in the RTI data base include relevant claims. 
Even this 62 percent figure is too high, however, because RTI over-
sampled herbal products, which have a higher probablity of claims and 
would not exceed 60 percent and has used this figure as its final 
estimate.
    Of the first 2,300 notifications of structure/function claims 
reviewed by FDA, no more than 60, or 2.6 percent of the products with 
claims, would have needed labeling changes due to the criteria 
described in the proposed rule. Since that time, the total number of 
notifications with structure/function claims submitted to the agency 
has increased to about 5,200. A subsequent review of all of the 
submitted claims indicates that the final rule could require about 1.9 
times as many label modifications as the proposed rule, owing largely 
to the revised criteria for cholesterol claims in the final rule. FDA 
estimates that the final rule may require revised labels for about 4.81 
percent of the 17,400 dietary supplement products (29,000 x 60 percent 
currently estimated as marketed with structure/function claims (Refs. 
15 and 16). (Excluding cholesterol claims would reduce this figure to 
1.74 percent of the products with claims.)
     The resulting label cost calculations are straightforward. First, 
the agency found that revised labels (for all claims including 
cholesterol) may be needed for approximately 837 products (17,400 
products with claims x 4.81 percent). Because each product may contain 
roughly 2.6 distinct SKU's (75,000 SKU's  29,000 products), 
labels for an estimated 2,164 SKU's may need to be modified (837 
products x 2.6 SKU's/product). As described in its earlier analysis, 
based on an average of the estimates provided in comments to earlier 
rules, FDA determined that the average label redesign cost is about 
$1,700 per dietary supplement SKU for a 12-month compliance period, and 
$1,300 for an 18-month compliance period. No industry comment 
questioned the reasonableness of these unit cost estimates.
     The final rule sets compliance periods of 1 year for large firms 
(revenues above $20 million) and 18 months for small firms (revenues 
below $20 million), except that new claims (i.e., claims not made 
before the publication of the final rule) must be in compliance as of 
the effective date. Such claims will not necessitate relabeling, 
however. FDA does not know the size of the firms that will need to make 
label changes. RTI (Ref. 12) reports that 95 percent of the firms in 
the industry are small, but that the 5 percent that are large account 
for 80 percent of industry sales. The RTI product data base also 
indicates that approximately 25 percent of the sample products were 
manufactured by just 5 percent of the companies. Thus, FDA has assumed 
that approximately one-quarter of the affected products will come from 
large firms and three-quarters from small firms. Consequently, the 
total estimated label redesign costs equal about $3.03 million (i.e., 
$1,700 x 0.25 x 2,164 SKU's + $1,300 x 0.75 x 2,164 SKU's).

     b. Administrative costs. One industry comment contended that FDA 
had not adequately explained the basis for its company-specific 
administrative costs, estimated at $425 and $320 respectively, for 12-
month and 18-month compliance periods. These figures were derived from 
data presented in a 1991 RTI report on the cost of FDA's food labeling 
regulations (Ref. 13). They included costs associated with interpreting 
a regulation, determining the manner of compliance and managing the 
compliance method. RTI had estimated that, on average, small firms 
would bear administrative costs of $850 to comply with the new food 
labeling rules for a 1-year compliance period, and $650 for a 2-year 
compliance period. For its analysis of the proposed rule, FDA reduced 
this figure by fifty percent, based on the smaller administrative 
effort that would be needed to comply with the proposed rule, compared 
to the conventional food labeling regulations evaluated by RTI in 1991. 
The regulations that were the subject of the 1991 RTI evaluation 
involved a broader range of administrative options and tasks, such as 
nutritional testing and

[[Page 1047]]

product reformulation. (The $320 estimate for the 18-month compliance 
period was determined by interpolating between the estimates for 12 and 
24 months.) The agency has raised these costs by about 27 percent to 
$540 and $407, respectively, to account for salary inflation since 1991 
(Ref. 14).
     FDA had initially estimated that 500 to 850 firms manufacture 
dietary supplements. The recent RTI study, however, has identified 
1,050 manufacturers (Ref. 12). This higher number probably 
overestimates the size of the industry covered by this rule, because it 
includes homeopathic products, which are drugs by statutory definition, 
and ``functional foods'' and sports nutrition products, which may be 
either conventional foods or dietary supplements depending on how they 
are marketed and used. For this final analysis, FDA has assumed that 
1,000 companies manufacture the dietary supplement products covered by 
this rule. Although only a small fraction of these establishments will 
need to implement changes in labeling due to this rule, the agency 
anticipates most firms will review the final rule to assess whether 
their labeling will be affected.
     The administrative costs of the final rule would likely be higher 
for those firms that will need to revise labels and lower for those 
firms that do not. Nevertheless, FDA assumes that, on average, all 
large dietary supplement manufacturers would incur costs of $540 and 
all small dietary supplement manufacturers would incur costs of $407. 
As noted above, RTI found that about 95 percent of the firms in this 
industry are small. Thus, the agency calculated administrative costs to 
equal about $413,000 (i.e., 950 small firms x $407 + 50 large firms x 
$540). FDA notes that these estimates may overstate the incremental 
administrative costs of this final rule, because dietary supplement 
firms must already comply with DSHEA and this rule is meant to clarify 
the meaning of that act, rather than to add new requirements. 
Nevertheless, the agency's sensitivity analysis, presented below, 
doubles the above cost estimates.
     c. Costs of inventory losses. The final cost component involves 
the value of lost inventory. FDA's preliminary analysis relied on 
information from an earlier nutrition labeling rule that affected the 
entire dietary supplement industry. That information indicated that 
inventory disposal costs for the entire industry would be about $8 
million for an 18-month compliance period and $15 million for a 12-
month compliance period. As explained above, FDA estimated that about 
2.89 percent of the dietary supplement products will require new labels 
as a result of this rule (837  29,000) and that about three 
quarters of the affected products are manufactured by small firms. 
Thus, total inventory disposal costs are calculated at $281,000 (i.e., 
$8 million x 2.89 percent x 0.75 + $15 million x 2.89 percent x 0.25).
     d. Total direct compliance costs. As described above, FDA has 
assumed the direct compliance costs of this rule to be the costs 
associated with relabeling those dietary supplements whose labeling 
claims are considered disease claims under the newly defined criteria. 
Redesign costs are estimated at $3.03 million, administrative costs at 
$413,000, and inventory disposal costs at $281,000. In sum, therefore, 
the total estimated direct compliance costs equal almost $3.73 million.
     In addition, there may be costs associated with the discussion in 
the final rule concerning structure/function claims made under section 
201(g)(1)(C) of the act. (See response to comment 95 in section III.A.1 
of this document.) The agency believes that some firms have been making 
structure/function claims for dietary supplements without including a 
disclaimer statement or notifying FDA, based on FDA's statements in a 
1997 preamble (62 FR 49859 at 49860, 49863, and 49864). Because the 
agency has not repudiated these statements, any firm that has relied on 
them to make a claim for a dietary supplement will need to add the 
disclaimer to all applicable labels, as well as to notify FDA, 
according to the requirements of this section 403(r)(6) of the act and 
Sec. 101.93. Because firms making such claims have not identified 
themselves to FDA, the agency does not have a reliable database on 
which to base a cost estimate of the number of firms and products that 
may incur costs to comply with this new provision.
     The costs to industry of the final rule are substantially 
different from the costs of the proposed rule, because of two important 
changes to the proposed requirements. First, the final rule requires 
more product labels to be changed, because it includes more specific 
parameters for acceptable structure/function claims about cholesterol. 
This change increases the direct compliance costs of the final rule. 
Second, the proposed rule required needed label modifications to be 
completed within 30 days after publication of the final rule, for those 
products without a properly submitted claim notification. Roughly 70 
percent of all products with claims may have fallen into this group (1-
5,200 products without notifications  17,400 products with 
claims). Because relabeling costs are reported to double for each 
halving of the compliance period, compliance costs would have been 
eight times greater for those products. For the final rule, all large 
firms will be expected to comply within 12 months, and all small firms 
within 18 months, regardless of whether the firm has notified FDA of 
the structure/function claims on its products. This change 
significantly reduces the direct compliance costs of the final rule.

    4 e. Sensitivity analysis. Due to uncertainty with respect to 
several factors in the agency's direct cost model, FDA has prepared a 
sensitivity analysis of other possible cost scenarios. First, FDA 
tripled the percentage of product notifications assumed to be out of 
compliance with the new criteria for structure/function claims. This 
change results in almost tripling the total direct compliance costs of 
the regulation, raising the estimate from about 3.73 million to about 
10.35 to about $5.93 million. Second, FDA doubled its estimate of 
administrative costs. This change raises the inital cost estimate to 
about $4.14 million. Changing both assumptions simultaneously raises 
the total estimated costs to about $11 million. Finally, under the 
initial scenario, if all of the needed label changes were assumed to 
affect only small businesses, the total cost estimate rises to about 
$3.46 million. This sensitivity analysis indicates that the total 
direct costs of this rule would not impose a major burden on this 
industry even if the most uncertain cost factors are doubled or tripled 
from FDA's best estimates.

D. Other Industry Comments

     Several comments insisted that FDA had not conducted a 
comprehensive cost-benefit analysis of the proposed rule, as required 
under Executive Order 12866. These comments stated that FDA's economic 
analysis ignored both the potential savings in consumer health care 
expenditures that would be lost by restricting important labeling 
information, as well as the likely negative effect of the proposal on 
the growth of the dietary supplement industry. One industry comment, 
for example, declared that a substantive cost-benefit analysis ``must 
identify the potential health benefits that are lost as a consequence 
of reduced consumer access to useful information about the health-
related properties of dietary supplements and ingredients.'' It noted 
that FDA's analysis ``fails to consider the public health benefits 
associated with ingesting dietary supplements as

[[Page 1048]]

well as the losses to public health that could result from consumers 
failing to take appropriate dietary supplements due to uninformative 
structure/function claims.'' That comment also maintains that ``FDA's 
failure to assess and consider such benefits (and costs) stands in 
contrast with the specific finding of DSHEA that `appropriate use of 
safe nutritional supplements will limit the incidence of chronic 
diseases, and reduce long-term health care expenditures'.'' The comment 
also points out that FDA has performed such analyses in other 
rulemakings, e.g., tobacco, nutrition labeling, and ephedra 
regulations.
     FDA disagrees. Although Executive Order 12866 directs agencies to 
assess the costs and benefits of economically significant rules, the 
quantification of these expected costs and benefits is required only 
``to the extent feasible'' (58 FR 51735 at 51741, October 14, 1993). As 
described above, FDA believes that its final rule strikes the 
appropriate balance with respect to health-related claims in dietary 
supplement labeling. The rule classifies certain claims as acceptable 
structure/function claims that may be made without prior FDA review. 
Although the provision of structure/function information to consumers 
may reduce health care expenditures, no health organization, industry 
association, or any other interested public or private group has 
presented information or data that would allow the agency to develop a 
quantifiable estimate of the health care benefits. The rule classifies 
other claims as disease claims that are subject to existing 
requirements for new drug approval or health claim authorization before 
a product may be marketed with the claim. FDA believes that classifying 
claims into a category that requires FDA review of safety and efficacy 
evidence, where appropriate, will similarly reduce long-term health 
care expenditures. Again, however, the agency has no means of 
quantifying the probable health outcomes of this aspect of the rule and 
therefore has no means of quantifying its impact on health care 
expenditures. Because this analysis discusses the types of benefits and 
costs reasonably expected, and quantifies those that can be 
``feasibly'' quantified, the agency has, in fact, complied with the 
direction of Executive Order 12866.
     FDA has attempted to quantify the benefits of some of its previous 
regulations. The agency's estimated benefits of the tobacco rule relied 
on a widely established risk assessment published by the American 
Cancer Society. Estimated benefits of the proposed ephedra rule were 
based on incidents identified in the agency's adverse event database. 
Estimated benefits of the nutrition labeling rule were derived from 
epidemiological studies of the consequences of dietary fat. In each 
case, the agency believed that it had a reasonably reliable data base 
upon which to base conclusions, and each risk assessment dealt with the 
risks of a single substance (tobacco, ephedra, and dietary fat). In 
contrast, this structure/function rule governs structure/function 
claims in the labeling for all dietary supplements. Although the agency 
could conceivably analyze a few of the claims covered by the rule, 
adequate data on the benefits and risks of most of these products are 
not available. Consequently, the agency believes that this rule will 
improve the nation's health, but concludes that it cannot feasibly 
quantify the effects of the rule on the nation's health expenditures.
     One industry comment suggested that the regulatory system could 
impede firms from conducting research to substantiate structure/
function claims, if DSHEA is construed so narrowly that it excludes 
meaningful health-related benefits. This comment noted, however, that 
the absence of an enforceable legal standard for substantiation would 
discriminate against companies that do research to support their claims 
and would deter science-based companies from entering the market. 
Similarly, a patient organization and several pharmaceutical companies 
expressed concern that the rule would permit some products to escape 
regulation as drugs and therefore diminish incentives for the costly 
clinical research conducted by pharmaceutical companies and academic 
scientists.
     As stated previously in the document, FDA is not aware of any 
evidence that would indicate that the establishment of criteria for 
distinguishing structure/function claims from disease claims will 
adversely affect the conduct of scientific research. In fact, FDA 
believes that the final rule accords with the intent of DSHEA in 
promoting the enhancements to consumer health expected from the broad 
dissemination of structure/function information, while reducing the 
risks to consumer health associated with the promotion of disease 
treatment and/or prevention uses for products whose safety and efficacy 
have not been demonstrated.

E. Regulatory Alternatives

     FDA has considered several major alternatives to the proposed rule 
as part of the rulemaking process. These include: (1) Taking no new 
regulatory action; (2) treating a statement about a dietary supplement 
as a disease claim only if the statement included an express reference 
to a specific disease; and (3) treating a statement about a dietary 
supplement as a disease claim if the statement mentions an abnormality 
of the structure or function of the body, even if the abnormality was 
not characterized by a set of signs or symptoms recognized as the 
disease. These alternatives are fully discussed in the preamble to the 
proposed rule (63 FR 23624 at 23630) and alternative (2) is also 
discussed extensively in section II.E of this document. In brief, FDA 
finds that the public comment does not include evidence or arguments 
sufficient to persuade the agency to support these alternatives.
     Within the broad framework of the final rule, FDA weighed other 
policy changes that could affect the compliance costs. One option would 
have set the compliance period for all firms at 6 months and another at 
12 months from the publication date of the final rule. Other options 
would have extended the compliance period beyond 18 months for small 
businesses, or completely exempted small businesses from the rule. 
Finally, the proposed rule would have permitted firms 12 or 18 months 
to comply, depending on whether they were large or small firms; but 
only if they had submitted timely notifications of their structure/
function claims to FDA and FDA had not objected to the claims. Other 
firms had only a 30-day compliance period.
     Based on its model of food labeling costs, FDA assumes that 
compliance costs double for each halving of the compliance period (Ref. 
13). Thus, the first option, which set a 6-month compliance date for 
all firms, results in average relabeling costs twice as high as that of 
the 12-month compliance period. FDA decided that this additional burden 
was not warranted. The option of a 12-month compliance period for small 
as well as large firms was rejected because of the additional burden to 
small firms, which may find it more difficult to effect rapid shifts in 
labeling procedures. The final rule provides small firms with an 
additional 6 months to introduce these labeling changes. Extending the 
compliance date for small firms beyond 18 months was rejected, because 
the agency did not believe that the delayed consumer benefits would be 
balanced by the relatively modest additional cost saving. Exempting all 
small firms was not acceptable, because most firms covered by this rule 
are small. The final option, which was to include the compliance 
periods specified in the proposed rule, required label changes within 
30 days for

[[Page 1049]]

products bearing claims of which FDA had not been notified or claims to 
which FDA had already objected. This option was rejected because it 
could have increased costs per label for many small firms by a factor 
of eight.

 F. Small Business Impacts

     As stated above, the Regulatory Flexibility Act requires agencies 
to analyze regulatory options that would minimize any significant 
impact of a rule on small entities, unless the rule is not expected to 
have a significant economic impact on a substantial number of small 
entities. With this final rule, FDA is defining the types of statements 
that can be made concerning the effect of a dietary supplement on the 
structure or function of the body. It also establishes criteria for 
determining when a statement represents a claim to diagnose, cure, 
mitigate, treat, or prevent disease and thus is not acceptable as a 
structure/function claim. The regulation was prepared in response to 
the dietary supplement industry's request for clarification from FDA 
with respect to the distinction between structure/function and disease 
claims, and to guidance in the Commission report suggesting that FDA 
provide such clarification to industry.
     For its analysis of the proposed rule, FDA had estimated that 
between 500 and 850 firms were involved in dietary supplement 
manufacturing. A more recent industry survey reports that 1,050 
companies manufacture dietary supplements; although as explained above, 
some of these companies may manufacture products not covered by this 
rule. FDA has projected the industry size for this rule at about 1,000 
firms. The Small Business Administration (SBA) has determined that 
dietary supplement manufacturers with fewer than 500 employees are 
small businesses. Because most data sources characterize firms in this 
industry by sales revenues rather than employment size, and because 
company revenues of less than $20 million correlate reasonably well 
with a 500 employee threshold, FDA has received approval from the SBA 
to use a less-than-$20 million sales revenue standard to represent 
small dietary supplement manufacturers. Table 1 displays the reported 
size distribution of the dietary supplement manufacturing industry.
     As described above, FDA assumes that all small manufacturers of 
dietary supplements will incur administrative costs of about $407 per 
firm. In addition, a number of small manufacturers of dietary 
supplements will need to alter some product labels, at an average 
redesign cost of about $1,300 per SKU, and an average inventory cost of 
about $107 per SKU. FDA further analyzed the dietary supplement product 
data base described in the October 1999 RTI report (Ref. 11) to 
determine how these products may be distributed among small businesses. 
As noted earlier, FDA estimates that about 628 of the 837 products (75 
percent) needing revised labels due to this rule are manufactured by 
small firms. If these 628 products were randomly distributed among the 
950 small businesses, less than 0.1 percent of the small firms (1 firm) 
would be likely to have more than 4 of these products and only about 3 
percent (30 firms) to have more than 2 of these products.
     A small firm that needs to redesign labels for three products 
(about eight SKU's) due to the rule will incur estimated one-time 
direct compliance costs of about $11,650. A small firm that needs to 
redesign labels for 4 products (about 10 SKU's) would incur costs of 
about $14,950, or roughly 1.2 percent of average company revenue. Thus, 
the assumption that these products are randomly distributed among small 
firms indicates that very few small businesses would be likely to incur 
relabeling costs that are greater than 1 percent of average small 
company revenue. It is possible, however, that some firms will have a 
disproportionate number of labels to be revised. In the RTI database of 
3,000 randomly selected products, only 3 companies (all large) have 
more than 24 products. Although the data base sample show a number of 
small companies with up to 24 products, it is very unlikely that all of 
these product labels would need to be changed due to this rule. If a 
small company needed to revise 10 products, however, its direct costs 
of compliance would be about $37,000. Moreover, although FDA cannot 
quantify the likelihood, some small firms could lose product sales due 
to the necessary removal of a disease claim from a product label. Thus, 
FDA finds that this rule may have a significant economic impact on a 
substantial number of small companies.

   Table 1.--Estimated Number of Dietary Supplement Manufacturers and
                      Revenues, by Size Category 1
------------------------------------------------------------------------
                       Number of       Revenues ($ in     Percentage of
  Size Category        Companies          billions)          Market
------------------------------------------------------------------------
>$100 million      16                 3.32              55%
$20 to $100        38                 1.54              25%
 million
<$20 million       996                1.19              20%
Total              1,050              6.05              100%
------------------------------------------------------------------------
\1\ Research Triangle Institute, ``Economic Characterization of the
  Dietary Supplement Industry,'' March 1999, pp. 5-15.

 VII. Paperwork Reduction Act of 1995

     This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

 VIII. References

     The following references have been placed on display in the 
Dockets Management Branch (address above) and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.
     1. Commission on Dietary Supplement Labels, Report to the 
President, Congress, and the Secretary of the Department of Health 
and Human Services, November 1997.
     2. Dorland's Illustrated Medical Dictionary, 28th ed., W. B. 
Saunders Co., Philadelphia, p. 478, 1994.
     3. Stedman's Medical Dictionary, 26th ed., Williams & Wilkins, 
Baltimore, p. 492, 1995.
     4. The Encyclopedia Americana, International Edition, Grolier 
Inc., Danbury, p. 168, 1985.
     5. Black's Law Dictionary, 6th ed., West Publishing Co., St. 
Paul, p. 467, 1990.
     6. The Merck Manual, 17th ed., Merck Research Laboratories, 
Whitehouse Station, NJ, p. 416, 1999.
     7. Webster's Encyclopedic Unabridged Dictionary, p. 1057, 1989.
     8. Economic Characterization of the Dietary Supplement 
Industry, prepared for DHHS/FDA/CFSAN by Research Triangle 
Institute, Center for Economics Research under Contract No. 223-96-
2290: Task Order 3, Final Report, p. 5-2, March 1999.
     9. Herb and Supplement Usage Nears 70 Percent, Natural Foods 
Merchandiser, www.nfm-online.com/nfm--backs/
Feb--98/herbusage.html.
     10. Wyngate, P., Consumers Not Supplement Brand Savvy, Natural 
Foods Merchandiser, www.nfm-online.com/nfm--backs/
Mar--98/brandsavvy.html.
     11. Dietary Supplement Sales Information, prepared for DHHS/
FDA/CFSAN by Research Triangle Institute, Center for Economics 
Research Under Contract No. 223-96-2290:

[[Page 1050]]

 Task Order 4, Final Report, pp. 5-8, October 1999.
     12. Research Triangle Institute, Economic Characterization of 
the Dietary Supplement Industry, p. 5-15.
     13. Research Triangle Institute, ``Compliance Costs of Food 
Labeling Regulations,'' prepared for CFSAN/FDA by RTI under Contract 
No. 223-87-2097, final report, pp. 5-3, 5-4, January 1991.
     14. U.S. Department of Labor, Bureau of Labor Statistics, BLS.
     15. Memorandum from R. J. Moore, FDA, to file, review of 
notifications made pursuant to 21 U.S.C. 343(r)(6).
     16. Memorandum from J. Lienesch, FDA, to file, calculation of 
relabeling cost estimate for final rule on statements made for 
dietary supplements concerning the effect of the production on the 
structure or function of the body, December 22, 1999.

 List of Subjects in 21 CFR Part 101

     Food labeling, Nutrition, Reporting and recordkeeping 
requirements.
     Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 101 is amended as follows:

 PART 101--FOOD LABELING

     1. The authority citation for 21 CFR part 101 continues to read as 
follows:

     Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 342, 
343, 348, 371.

     2. Section 101.93 is amended by revising the section heading and 
by adding paragraphs (f) and (g) to read as follows:


Sec. 101.93   Certain types of statements for dietary supplements.

* * * * *
     (f) Permitted structure/function statements. Dietary supplement 
labels or labeling may, subject to the requirements in paragraphs (a) 
through (e) of this section, bear statements that describe the role of 
a nutrient or dietary ingredient intended to affect the structure or 
function in humans or that characterize the documented mechanism by 
which a nutrient or dietary ingredient acts to maintain such structure 
or function, provided that such statements are not disease claims under 
paragraph (g) of this section. If the label or labeling of a product 
marketed as a dietary supplement bears a disease claim as defined in 
paragraph (g) of this section, the product will be subject to 
regulation as a drug unless the claim is an authorized health claim for 
which the product qualifies.
     (g) Disease claims. (1) For purposes of 21 U.S.C. 343(r)(6), a 
``disease'' is damage to an organ, part, structure, or system of the 
body such that it does not function properly (e.g., cardiovascular 
disease), or a state of health leading to such dysfunctioning (e.g., 
hypertension); except that diseases resulting from essential nutrient 
deficiencies (e.g., scurvy, pellagra) are not included in this 
definition.
     (2) FDA will find that a statement about a product claims to 
diagnose, mitigate, treat, cure, or prevent disease (other than a 
classical nutrient deficiency disease) under 21 U.S.C. 343(r)(6) if it 
meets one or more of the criteria listed below. These criteria are not 
intended to classify as disease claims statements that refer to the 
ability of a product to maintain healthy structure or function, unless 
the statement implies disease prevention or treatment. In determining 
whether a statement is a disease claim under these criteria, FDA will 
consider the context in which the claim is presented. A statement 
claims to diagnose, mitigate, treat, cure, or prevent disease if it 
claims, explicitly or implicitly, that the product:
     (i) Has an effect on a specific disease or class of diseases;
     (ii) Has an effect on the characteristic signs or symptoms of a 
specific disease or class of diseases, using scientific or lay 
terminology;
     (iii) Has an effect on an abnormal condition associated with a 
natural state or process, if the abnormal condition is uncommon or can 
cause significant or permanent harm;
     (iv) Has an effect on a disease or diseases through one or more of 
the following factors:
     (A) The name of the product;
     (B) A statement about the formulation of the product, including a 
claim that the product contains an ingredient (other than an ingredient 
that is an article included in the definition of ``dietary supplement'' 
under 21 U.S.C. 321(ff)(3)) that has been regulated by FDA as a drug 
and is well known to consumers for its use or claimed use in preventing 
or treating a disease;
     (C) Citation of a publication or reference, if the citation refers 
to a disease use, and if, in the context of the labeling as a whole, 
the citation implies treatment or prevention of a disease, e.g., 
through placement on the immediate product label or packaging, 
inappropriate prominence, or lack of relationship to the product's 
express claims;
     (D) Use of the term ``disease'' or ``diseased,'' except in general 
statements about disease prevention that do not refer explicitly or 
implicitly to a specific disease or class of diseases or to a specific 
product or ingredient; or
     (E) Use of pictures, vignettes, symbols, or other means;
     (v) Belongs to a class of products that is intended to diagnose, 
mitigate, treat, cure, or prevent a disease;
     (vi) Is a substitute for a product that is a therapy for a 
disease;
     (vii) Augments a particular therapy or drug action that is 
intended to diagnose, mitigate, treat, cure, or prevent a disease or 
class of diseases;
     (viii) Has a role in the body's response to a disease or to a 
vector of disease;
     (ix) Treats, prevents, or mitigates adverse events associated with 
a therapy for a disease, if the adverse events constitute diseases; or
     (x) Otherwise suggests an effect on a disease or diseases.

    Dated: October 26, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 00-53 Filed 01-5-00; 8:45 am]
BILLING CODE 4160-01-F