[Federal Register Volume 65, Number 64 (Monday, April 3, 2000)]
[Proposed Rules]
[Pages 17474-17477]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-8109]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 111
[Docket No. 95N-0304]
Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in
Part
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule; withdrawal in part.
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SUMMARY: The Food and Drug Administration (FDA) is announcing that it
is withdrawing certain provisions of a proposed rule that published in
the Federal Register of June 4, 1997 (62 FR 30678), relating to dietary
supplements containing ephedrine alkaloids. FDA is taking this action
because of concerns regarding the agency's basis for proposing a
certain dietary ingredient level and a duration of use limit for these
products. Elsewhere in this issue of the Federal Register, FDA is
announcing the availability of new adverse event reports and related
information associated with these products and its plans to participate
in a public forum to discuss this new information at some future date.
In addition, FDA is announcing elsewhere in this issue of the Federal
Register the availability of additional documentation associated with
certain adverse events referenced in the 1997 proposed rule.
DATES: The proposed rule that published on June 4, 1997 (62 FR 30678)
is withdrawn in part for Sec. 111.100(a), (b), (c), (e), and (f) as of
April 3, 2000.
ADDRESSES: Copies of the proposed rule and related comments are
available for public examination in the Dockets Management Branch (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Marquita B. Steadman, Center for Food
Safety and Applied Nutrition (HFS-007), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20852, 301-827-6733.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of June 4, 1997 (62 FR 30678), FDA
published a proposed rule (hereinafter referred to as the ``ephedrine
alkaloids proposal'') to establish that a dietary supplement is
adulterated if it contains 8 milligrams (mg) or more of ephedrine
alkaloids per serving, or if its labeling suggests or recommends
conditions of use that would result in an intake of 8 mg or more within
a 6-hour period or a total daily intake of 24 mg or more of ephedrine
alkaloids (hereinafter referred to as ``dosing level'' or ``dietary
ingredient level''), and to require that the label of such supplement
state that the product is not to be used for more than 7 days
(hereinafter referred to as ``duration of use limit''). The agency also
proposed to prohibit the use of ephedrine alkaloids in dietary
supplements with ingredients, or with ingredients that contain
substances, that have a known stimulant effect, such as caffeine, which
may interact with ephedrine alkaloids; and to prohibit labeling claims,
such as weight loss or body building, that require long-term intake to
achieve the purported effect. In addition, the agency proposed to
require a statement to accompany claims that encourage short-term
excessive intake to enhance a purported effect, such as an increase in
energy, that taking more than the recommended serving may result in
serious adverse health effects; and to require specific warning
statements to appear on product labels.
The agency proposed these actions in response to reports of serious
illnesses and injuries, including a number of deaths, associated with
the use of dietary supplement products containing ephedrine alkaloids
and the agency's investigations and assessment of these illnesses and
injuries. This action was also supported by many of the recommendations
made during the October 1995 meeting of an ad hoc Working Group of the
FDA Advisory Committee (Working Group) and the August 1996 meeting of
the Food Advisory Committee (FAC) and the Working Group concerning the
potential public health problems associated with the use of dietary
supplements containing ephedrine alkaloids and the recommended steps
FDA should take to address the serious health concerns associated with
their use (see Refs. 25 and 27 of the ephedrine alkaloids proposal
(Docket No. 95N-0304)).
The comment period for the June 4, 1997 (62 FR 30678), proposed
rule closed on August 18, 1997. In a notice in the Federal Register of
August 20, 1997 (62 FR 44247), FDA announced its intent to reopen the
comment period after the agency corrected a number of inadvertent
omissions in the administrative record. Subsequently on September 18,
1997 (62 FR 48968), the agency reopened the comment period for an
additional 75 days until December 2, 1997.
The agency received approximately 350 letters regarding the use of
ephedrine alkaloid-containing dietary supplements prior to publication
of the ephedrine alkaloids proposal. These comments have been
considered by the agency along with those commenting in response to the
proposal. The agency received approximately 14,775 comments on the
ephedrine alkaloids proposal. Individual consumers who use ephedrine
alkaloid-containing dietary supplements and independent distributors of
these products submitted most of the comments. Other comments were
received from persons who had, or who knew persons who had, suffered
adverse events or who were reporting adverse events associated with the
use of an ephedrine alkaloid-containing dietary supplement. The
remaining comments included those submitted by medical professionals,
scientists, a scientific association, State and local health
departments, medical associations, government agencies, dietary
supplement manufacturers, Chinese medicine practitioners and
associations, dietary supplement industry trade associations, public
health associations, and consumer groups.
The House Committee on Science requested that the Government
Accounting Office (GAO) examine the scientific bases for the ephedrine
alkaloids proposal and the agency's adherence to the regulatory
flexibility analysis requirements for Federal rulemaking. On August 4,
1999, GAO released its report entitled ``Dietary Supplements:
Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine
Alkaloids.'' A copy of this
[[Page 17475]]
report is available in Docket No. 95N-0304.
Generally, GAO concluded that FDA was justified in determining that
the number of adverse event reports relating to dietary supplements
containing ephedrine alkaloids warranted the agency's attention and
consideration of steps to address safety issues. However, GAO expressed
concerns about the use of the reported adverse events in supporting the
proposed dosing level and duration of use limit, and concluded that the
agency needed additional evidence to support these restrictions.
GAO also concluded that FDA's economic analysis contained the basic
elements expected in a Federal agency's cost-benefit analysis, and the
ephedrine alkaloids proposal complied with regulatory flexibility
analysis requirements under the Regulatory Flexibility Act. GAO noted,
however, that FDA's cost-benefit analysis was not always transparent
regarding why certain key assumptions were made, the degree of
uncertainty involved in those assumptions, or the effect that
alternative assumptions would have had on the agency's estimates of the
costs and benefits of the proposed action.
GAO recommended that FDA ``provide stronger evidence on the
relationship between the intake of dietary supplements containing
ephedrine alkaloids and the occurrence of adverse reactions that
support the proposed dosing level and duration of use limits.'' In
addition, GAO recommended that FDA improve the transparency of its
cost-benefit analysis in its final rulemaking.
In light of GAO's conclusions, comments from others on the
ephedrine alkaloids proposal, and having further considered issues
related to the proposed dietary ingredient level and the duration of
use limit, FDA believes that these aspects of its proposed approach to
regulating these products should be reassessed. Whether there are
appropriate alternative approaches to these aspects of the proposal for
regulating dietary supplements containing ephedrine alkaloids will
require evaluation of additional information not available to the
agency when it issued the proposal. Accordingly, FDA is withdrawing the
provisions of the ephedrine alkaloids proposal relating to the dietary
ingredient level and duration of use limit for these products. This
action will allow FDA to reconsider, with public input, whether any
dietary ingredient level or duration of use limit for these products is
appropriate or whether alternative measures should be considered. The
withdrawn provisions are described briefly below.
II. Withdrawn Provisions of the Ephedrine Alkaloids Proposal
A. Dietary Ingredient Limit for Ephedrine Alkaloids: Per Serving Basis
Sec. 111.100(a)(1)) and Frequency and Per Total Daily Intake Basis
(Sec. 111.100(b))
As stated above, the agency tentatively concluded in the ephedrine
alkaloids proposal that a dietary supplement is adulterated if it
contains 8 mg) or more of ephedrine alkaloids per serving
(Sec. 111.100(a)(1)), or if the labeling suggests or recommends
conditions of use that would result in an intake of 8 mg or more within
a 6-hour period or a total daily intake of 24 mg or more of ephedrine
alkaloids (Sec. 111.100(b)). Having reconsidered the basis for these
limits, including comments on that basis by GAO and others to the
proposal, FDA believes that it should consider additional information
not available to the agency when it issued the ephedrine alkaloids
proposal to determine whether a dietary ingredient limit, or some
alternative approach, would be appropriate to regulate these dietary
ingredients. Therefore, FDA is withdrawing these provisions of the
ephedrine alkaloids proposal.
FDA continues to be concerned about the potential risk for
individuals who are particularly sensitive to the effects of ephedrine
alkaloids, or whose sensitivity or likelihood for adverse effects may
be increased through chronic use of these products or other means
(e.g., physical exercise). FDA expressed this concern in the proposal,
and noted that many members of the FAC agreed.
B. Proposed Compliance Procedures (Sec. 111.100(a)(2))
In the ephedrine alkaloids proposal, FDA stated that it would use a
high performance liquid chromatography method as specified in
Laboratory Information Bulletin No. 4053 to determine the level of
ephedrine alkaloids in a dietary supplement. Without a requirement that
would establish an unacceptable dietary ingredient level for dietary
supplements containing ephedrine alkaloids, this provision, alone, is
no longer necessary. Accordingly, the agency has determined that this
provision should also be withdrawn.
C. Proposed Limitations on Duration of Use (Sec. 111.100(c))
FDA proposed in Sec. 111.100(c) to require that the label of
dietary supplements that contain ephedrine alkaloids state ``Do not use
this product for more than 7 days.'' FDA intended to require this
provision in conjunction with the 8 mg per serving dietary ingredient
limit proposed in Sec. 111.100(a)(1). FDA noted in the ephedrine
alkaloids proposal that concern about serious adverse events with the
long-term use of ephedrine alkaloids led several members of the Working
Group (see Ref. 27 of the ephedrine alkaloids proposal) and of the FAC
(see Ref. 25 of the ephedrine alkaloids proposal (Docket No. 95N-0304))
to recommend that, in conjunction with a per serving dietary ingredient
limit, FDA require a statement on the label of ephedrine alkaloid-
containing dietary supplements to warn consumers not to use the product
for a period longer than 7 days. FDA also cited evidence from the
scientific literature about the adverse effects of long-term use of
ephedrine alkaloids (62 FR 30678 at 30695).
FDA remains concerned with the long-term use of such products and
the potential adverse effects such use has in combination with the use
of other ingredients that have a stimulant effect. However, having
reconsidered the basis for the proposed duration of use limit,
including the comments on that basis by GAO and others to the proposal,
FDA believes that it should consider additional information not
available to the agency when it issued the ephedrine alkaloids proposal
to determine whether any duration of use limit, or some alternative
approach, is appropriate to regulate these products. In addition, the
agency is also withdrawing the proposed 8-mg dietary ingredient limit.
Therefore, the agency has determined that the proposed labeling
requirement concerning duration of use should also be withdrawn.
D. Prohibition on Claims (Sec. 111.100(e) and (f))
FDA stated in the proposal that restrictions on claims are
necessary to maintain the integrity of the limit on the level of
ephedrine alkaloids in dietary supplements that it proposed and of the
other proposed restrictions on the conditions of use of these dietary
supplements. For example, because safe and significant weight loss and
body building cannot be achieved in a 7-day period, FDA tentatively
concluded that claims that promote these uses promote long-term use of
ephedrine alkaloid-containing dietary supplements, which have been
associated with serious adverse events. For this reason, FDA
tentatively concluded that any claims that promote long-term use of
ephedrine
[[Page 17476]]
alkaloid dietary supplements, such as those for weight loss and body
building, promote conditions of use that present a significant and
unreasonable risk of illness and injury. Consequently, FDA proposed in
Sec. 111.100(e) to require that no dietary supplement that contains
ephedrine alkaloids may purport to be, or be represented as, either
expressly or implicitly, for use for long-term effects, such as weight
loss or body building.
Similarly, many claims found on the labels of, or in the labeling
for, ephedrine alkaloid-containing dietary supplements, including
increased energy, increased mental concentration, and enhanced well-
being, encourage the consumer to take more of the product than is
indicated on the label to achieve more of the purported effect.
Consequently, FDA tentatively concluded that claims that promote
excessive consumption are inconsistent with the dietary ingredient
limit for these products. Accordingly, FDA proposed in
Sec. 111.100(f)(1) that the label or labeling for dietary supplements
that contain ephedrine alkaloids that purport to be or are represented,
either expressly or implicitly, to be used for short-term effects, such
as increased energy, increased mental concentration, or enhanced well-
being, must state ``Taking more than the recommended serving may cause
heart attack, stroke, seizure or death.'' FDA proposed in
Sec. 111.100(f)(2) certain requirements on the size, type, and
placement of this statement on the label. Because FDA is withdrawing
the proposed dietary ingredient limit and duration of use limit, FDA
has determined that the proposed provisions in Sec. 11.100(e) and (f)
should also be withdrawn. FDA believes that it should consider
additional information not available to the agency when it issued the
ephedrine alkaloids proposal before finally determining whether such
provisions with respect to claims, or some alternative approach, is
appropriate to regulate these products. Nonetheless, FDA remains
concerned that adverse effects are associated with long-term
consumption of such products and with consumption of such products in
excess of labeled serving sizes.
III. Current Provisions of the Ephedrine Alkaloids Proposal
Despite this action to withdraw the proposed dietary ingredient
level and duration of use limit, and related provisions of the
ephedrine alkaloids proposal, there remain provisions that the agency
is not withdrawing in this notice. These provisions concern FDA's
proposed prohibition on the use of ingredients with stimulant effects
with dietary supplements containing ephedrine alkaloids
(Sec. 111.100(d)) and the proposed warning statement (Sec. 111.100(g)).
FDA proposed in Sec. 111.100(d) to require that no ingredient, or
ingredient that contains a substance, that has a known stimulant effect
(e.g, sources of caffeine, yohimbine) may be included in a dietary
supplement that contains ephedrine alkaloids. FDA proposed this
provision in response to the many adverse events that had been reported
to the agency. These adverse events involved the use of dietary
supplements that contain ephedrine alkaloids in combination with other
ingredients, some with known physiological or pharmacological effects,
including kola nut, yohimbe, willow bark, senna, and Uva ursi (see Ref.
164 of the proposed rule (Docket No. 95N-0304)). These adverse events
suggested that the other ingredients may act in combination with the
ephedrine alkaloids to produce more frequent, more severe, or
potentially different patterns of adverse effects than those noted with
the use of ephedrine alkaloids alone.
In the ephedrine alkaloids proposal, FDA also tentatively concluded
that a warning statement on the labels of dietary supplements
containing ephedrine alkaloids is necessary, in conjunction with
dietary ingredient limitations and other requirements proposed in that
document, to protect the public health. The warning statements proposed
in Sec. 111.100(g) contained several elements, including cautions that
consumers not use the product if they have certain diseases or health
conditions or are using certain drugs, and to stop the use of the
product if they develop certain signs or symptoms. As noted in the
preamble to the ephedrine alkaloids proposal, persons having certain
diseases or taking specific medications known to interact with
ephedrine alkaloids are at risk of suffering adverse events with the
use of dietary supplements containing ephedrine alkaloids. Generally,
use of ephedrine alkaloids at any intake level by these persons is
contraindicated. For these persons a warning label statement can be a
useful means of alerting them to potential consequences that can result
from the use of the product. In addition, many consumers who are
unaware that they are sensitive to the effect of ephedrine alkaloids
may not recognize the significance of early warning signs and symptoms
as potential indicators of more serious side effects (e.g., dizziness
or severe headache may be early symptoms of hypertension or stroke).
Under these circumstances, a warning statement could provide
information on what actions the consumer should take if certain
symptoms occur (62 FR 30678 at 30700).
The agency has not at this time concluded that it will finalize the
provisions in Sec. 111.100(d) and (g). Rather, the agency intends to
consider whether to finalize these provisions, or take additional or
alternative regulatory action, after it receives public input on the
significance of new information collected by the agency about the
safety of dietary supplements containing ephedrine alkaloids.
IV. Continued Monitoring and Followup
Although FDA is withdrawing certain provisions of the ephedrine
alkaloids proposal, FDA continues to have a public health concern with
respect to the use of dietary supplements containing ephedrine
alkaloids. The agency will continue to monitor and provide appropriate
followup on adverse events associated with the use of these products.
In a notice of availability published elsewhere in this issue of the
Federal Register, FDA is seeking public input about the significance of
new information collected by the agency about the safety of dietary
supplements containing ephedrine alkaloids. The agency is also
requesting the submission of any other information that the submitters
believe is relevant to such a safety assessment. Should additional
information suggest that additional action is necessary, FDA will
consider what action is appropriate, and take appropriate steps to
protect consumers and the public health.
V. Enforcement
Withdrawal of certain provisions of the ephedrine alkaloids
proposal does not limit the agency's discretion to initiate enforcement
actions with respect to ephedrine alkaloids containing dietary
supplements. For example, circumstances may warrant enforcement action
against a dietary supplement containing ephedrine alkaloids if an
evaluation of the relevant facts show a health hazard or that the
product is otherwise adulterated or misbranded.
FDA maintains its street drug alternative policy, as articulated in
the preamble to the ephedrine alkaloids proposal, which states that
because alternatives to illicit street drugs are not intended to
supplement the diet, products that purport to be or that are
represented, either expressly or implicitly, for use as alternatives to
street drugs are not dietary supplements within the meaning of section
201(ff) of
[[Page 17477]]
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(ff)).
(See 62 FR 30678 at 30699 and 30700). FDA is publishing elsewhere in
this issue of the Federal Register a notice announcing the availability
of a guidance entitled ``Street Drug Alternatives.'' The guidance is
intended to inform industry and the public that FDA considers any
product that is promoted as a street drug alternative to be an
unapproved new drug and a misbranded drug in violation of the act. To
date, the agency has taken action against several products marketed as
alternatives to illicit street drugs, and it may do so in the future,
as well.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, the proposed
rule published on June 4, 1997 (62 FR 30678), is withdrawn in part for
Sec. 111.100(a), (b), (c), (e), and (f).
Dated: March 28, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-8109 Filed 3-31-00; 8:45 am]
BILLING CODE 4160-01-F