CAMLAW: Complementary and Alternative Medicine Law Blog

FDA Guidance Regarding Structure-Function Claims for Dietary Supplements

The FDA regulation regarding structure-function claims is a good place to start for evaluating whether these claims are permissible or violate the federal Food, Drug & Cosmetic Act.

The entire rule is copied below.

 

http://www.fda.gov/Food/DietarySupplements/GuidanceComplianceRegulatoryInformation/RegulationsLaws/ucm107387.htm

Federal Register Final Rule - 65 FR 999 - January 6, 2000: Regulations on Statements Made for Dietary Supplements Concerning the Effect of the Product on the Structure or Function of the Body

[Federal Register: January 6, 2000 (Volume 65, Number 4)]

[Rules and Regulations]

[Page 999-1050]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr06ja00-17]

[[Page 999]]

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

[[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, 301-827-0084301-827-0084.

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

[[Page 1001]]

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

[[Page 1002]]

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

[[Page 1003]]

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 <divide> 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 <divide> 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 <divide> 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 <SUP>1</SUP>

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

                       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<INF>--</INF>backs/

Feb<INF>--</INF>98/herbusage.html.

     10. Wyngate, P., Consumers Not Supplement Brand Savvy, Natural

Foods Merchandiser, www.nfm-online.com/nfm<INF>--</INF>backs/

Mar<INF>--</INF>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

 


Michael H CohenMichael H Cohen
Founder
The Los Angeles / San Francisco / Bay Area-based Michael H Cohen Law Group provides healthcare legal and FDA legal & regulatory counsel to health & wellness practices and ventures, including health technology companies (medical devices to wearable health and nanotech), healthcare facilities (from medical centers to medical spas), and healthcare service providers (from physicians to psychologists).Our legal team offers expertise in corporate & transactional, healthcare regulatory & compliance, and healthcare litigation and dispute resolution, in cutting-edge areas such as anti-aging and functional medicine, telemedicine and m-health, and concierge medicine.Our Founder, attorney Michael H. Cohen, is an author, speaker on healthcare law and FDA law, and internationally-recognized thought leader in the trillion-dollar health & wellness industry.
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