[Federal Register: February 11, 2004 (Volume 69, Number 28)]
[Rules and Regulations]               
[Page 6787-6854]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr11fe04-40]                         
 
 
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Part III
 
Department of Health and Human Services
 
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Food and Drug Administration
 
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21 CFR Part 119
 
Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids 
Adulterated Because They Present an Unreasonable Risk; Final Rule
 
[[Page 6788]]
 
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
 
Food and Drug Administration
 
21 CFR Part 119
 
[Docket No. 1995N-0304]
RIN 0910-AA59
 
 
Final Rule Declaring Dietary Supplements Containing Ephedrine 
Alkaloids Adulterated Because They Present an Unreasonable Risk
 
AGENCY: Food and Drug Administration, HHS.
 
ACTION: Final rule.
 
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SUMMARY: The Food and Drug Administration (FDA, we, our) is issuing a 
final regulation declaring dietary supplements containing ephedrine 
alkaloids adulterated under the Federal Food, Drug, and Cosmetic Act 
(the act) because they present an unreasonable risk of illness or 
injury under the conditions of use recommended or suggested in 
labeling, or if no conditions of use are suggested or recommended in 
labeling, under ordinary conditions of use. We are taking this action 
based upon the well-known pharmacology of ephedrine alkaloids, the 
peer-reviewed scientific literature on the effects of ephedrine 
alkaloids, and the adverse events reported to have occurred in 
 
individuals following consumption of dietary supplements containing 
ephedrine alkaloids.
 
DATES: This rule is effective on April 12, 2004.
 
FOR FURTHER INFORMATION CONTACT: Wayne Amchin, Center for Food Safety 
and Applied Nutrition (HFS-007), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-6733.
 
SUPPLEMENTARY INFORMATION:
 
Table of Contents
 
I. Introduction
    A. Why Have We Concluded That Dietary Supplements Containing 
Ephedrine Alkaloids Present an Unreasonable Risk?
    B. What Are the Ephedrine Alkaloids and Where Do They Come From?
    C. What Regulatory Actions Have We Taken Regarding Dietary 
Supplements Containing Ephedrine Alkaloids?
    D. Petitions Received Relating to Dietary Supplement Containing 
Ephedrine Alkaloids
II. Summary of Letters and Comments
III. Finding of Adulteration
    A. What Does the Final Rule Do?
    B. What Products are Covered?
IV. Legal Issues
    A. What Is Our Legal Authority Under the Act?
    B. Do the Ephedrine Alkaloid-Containing Products Covered by this 
Rule Fall Within the Definition of Dietary Supplement Under the Act?
    C. Administrative Procedures
V. Scientific Evaluation
    A. How Did We Evaluate the Evidence?
    B. What Are the Known and Reasonably Likely Risks Presented by 
Dietary Supplements Containing Ephedrine Alkaloids?
    1. Pharmacology
    2. Other Safety Data
    3. Comparison with Drug Products Containing Ephedrine Alkaloids
    4. Abuse and Misuse
    5. Traditional Asian Medicine
    6. Adverse Events
    C. What Are the Known and Reasonably Likely Benefits of Dietary 
Supplements Containing Ephedrine Alkaloids?
    1. Weight Loss
    2. Enhancement of Athletic Performance
    3. Eased Breathing
    4. Other Uses
    D. Do Dietary Supplements Containing Ephedrine Alkaloids Present 
an Unreasonable Risk?
    1. What Does ``Unreasonable Risk'' Mean?
    2. Do Dietary Supplements Containing Ephedrine Alkaloids Present 
an Unreasonable Risk for Labeled or Ordinary Conditions of Use?
    3. Conclusion
VI. Why We Conclude that Other Restrictions Would Not Adequately 
Protect Consumers from the Risks Presented by Dietary Supplements 
Containing Ephedrine Alkaloids
    A. Warning Statement Alone
    B. Multiple Restrictions
    C. Self-Regulation
    D. More Education
    E. Nonbinding Guidance
    F. Targeted Enforcement Actions
VII. Miscellaneous Issues
    A. Freedom of Choice/FDA Bias
    B. Conduct of the Advisory Committee Meetings
VIII. Analysis of Impacts
    A. Benefit-Cost Analysis
    1. Introduction
    2. Regulatory Options
    3. Summary of Conclusions
    4. Option One--Take No New Regulatory Action
    5. Option Two--Remove Dietary Supplements Containing Ephedrine 
Alkaloids from the Market
    6. Option Three--Require the 2003 Proposed Warning Statement
    7. Option Four--Require the Proposed Warning Statement, But 
Modify it or Require it Only on Certain Products
    8. Option Five--Generate Additional Information or Take Some 
Action Other Than Removing Dietary Supplements Containing Ephedrine 
Alkaloids From the Market or Requiring Warning Statements
    9. Benefit-Cost Analysis: Summary
    B. Small Entity Analysis
IX. Environmental Impact
X. Paperwork Reduction Act
XI. Federalism
XII. References
 
I. Introduction
 
A. Why Have We Concluded That Dietary Supplements Containing Ephedrine 
Alkaloids Present an Unreasonable Risk?
 
    We conclude that dietary supplements containing ephedrine alkaloids 
are adulterated under section 402(f)(1)(A) (21 U.S.C. 342(f)(1)(A)) of 
the act because they present an unreasonable risk of illness or injury 
under the conditions of use recommended or suggested in labeling, or if 
no conditions of use are suggested or recommended in labeling, under 
ordinary conditions of use. Dietary supplements containing ephedrine 
alkaloids are most often used for weight loss, energy, or to enhance 
athletic performance.
    By its plain language, section 402(f)(1)(A) of the act requires 
evidence of ``significant or unreasonable risk'' of illness or injury. 
There is no requirement that there be evidence proving that the product 
has caused actual harm to specific individuals, only that scientific 
evidence supports the existence of risk. The Government's burden of 
proof for ``unreasonable risk'' is met when a product's risks outweigh 
its benefits in light of the claims and directions for use in the 
product's labeling or, if the labeling is silent, under ordinary 
conditions of use. ``Unreasonable risk,'' thus, represents a relative 
weighing of the product's known and reasonably likely risks against its 
known and reasonably likely benefits. In the absence of a sufficient 
benefit, the presence of even a relatively small risk of an important 
adverse health effect to a user may be unreasonable. Because it is not 
reasonable to conclude that a product is too risky in the absence of 
any significant evidence, some weight of evidence of risk is required 
to meet this standard. For example, isolated adverse events alone might 
not be expected to constitute substantiation of risk, but adverse event 
reports combined with pharmacological and other clinical evidence might 
be expected to do so.
    In considering whether dietary supplements containing ephedrine 
alkaloids present an unreasonable risk, we considered evidence from 
three principal sources: (1) The well-known, scientifically established 
pharmacology of ephedrine alkaloids; (2) peer-reviewed scientific 
literature on the effects of ephedrine alkaloids; and (3) the adverse 
events (including published case reports) reported to have occurred 
following consumption of dietary supplements containing ephedrine 
alkaloids.
 
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    Ephedrine alkaloids are members of a large family of 
pharmacological compounds called sympathomimetics. Sympathomimetics 
mimic the effects of epinephrine and norepinephrine, which occur 
naturally in the human body. Multiple studies demonstrate that dietary 
supplements containing ephedrine alkaloids, like other 
sympathomimetics, raise blood pressure and increase heart rate. These 
products expose users to several risks, including the consequences of 
increased blood pressure (e.g., serious adverse events such as stroke, 
heart attack, and death) and increased morbidity and mortality from 
worsened heart failure and pro-arrhythmic effects. Based on the best 
available scientific data and the known pharmacology of ephedrine 
alkaloids and similar compounds, we conclude that dietary supplements 
containing ephedrine alkaloids pose short-term and long-term risks. 
This is clearest in long-term use, where sustained increased blood 
pressure in any population will increase the risk of stroke, heart 
attack, and death, but there is also evidence of risk from shorter-term 
use in patients with heart failure or underlying coronary artery 
disease.
    The data do not indicate that these products provide a health 
benefit sufficient to outweigh these risks. The best clinical evidence 
for a benefit is for weight loss, but even there the evidence supports 
only a modest short-term weight loss, insufficient to positively affect 
cardiovascular risk factors or health conditions associated with being 
overweight or obese. Even if long-term weight loss could be achieved 
with the use of dietary supplements containing ephedrine alkaloids, we 
believe that the risks posed by these products when used continuously 
in the long term generally could not be adequately mitigated except 
through physician supervision. Other possible benefits, such as 
enhanced athletic performance, enhanced energy, or a feeling of 
alertness, lack scientific support and/or provide only temporary 
benefits that we consider trivial compared to the risks of these 
products, which may include long-term or permanent consequences like 
heart attack, stroke, and death. Therefore, we have determined that the 
risks of dietary supplements containing ephedrine alkaloids, when used 
for their labeled indications or under ordinary conditions of use, 
outweigh the benefits of these products. We do not believe these risks 
can be adequately mitigated through other regulatory measures available 
to FDA for dietary supplements, such as warnings in labeling.
    As with other sympathomimetics, we believe that the risks posed by 
dietary supplements containing ephedrine alkaloids, when used 
continuously over the long term, generally cannot be adequately 
mitigated except through physician supervision. Similar to over-the-
counter (OTC) single ingredient ephedrine and pseudoephedrine products, 
we expect that dietary supplements containing ephedrine alkaloids could 
be marketed without physician supervision for a very temporary, 
episodic use that provides a benefit that outweighs the known and 
reasonably likely risks of these products. However, we are currently 
unaware of any such use, and our experience with ephedrine alkaloid-
containing OTC drug products suggests that such benefits will be 
demonstrable only for disease uses.
 
B. What Are the Ephedrine Alkaloids and Where Do They Come From?
 
    The ephedrine alkaloids, including, among others, ephedrine, 
pseudoephedrine, norephedrine, methylephedrine, norpseudoephedrine, 
methylpseudoephedrine, are chemical stimulants that occur naturally in 
some botanicals (Refs. 1 through 5), but can be synthetically derived. 
The ingredient sources of the ephedrine alkaloids in dietary 
supplements include raw botanicals (i.e., plants) and extracts from 
botanicals. Ma huang, Ephedra, Chinese Ephedra, and epitonin are 
several names used for botanical ingredients, primarily from Ephedra 
sinica Stapf, Ephedra equisetina Bunge, Ephedra intermedia var. 
tibetica Stapf and Ephedra distachya L. (the Ephedras), that are 
sources of ephedrine alkaloids (Refs. 1, 6, and 7). Other plant sources 
that contain ephedrine alkaloids include Sida cordifolia L. and 
Pinellia ternata (Thunb.) Makino (Refs. 8 and 9). Common names that 
have been used for the various plants that contain ephedrine alkaloids 
include sea grape, yellow horse, joint fir, popotillo, and country 
mallow. The names desert herb, squaw tea, Brigham tea, and Mormon tea 
refer to North American species of Ephedra that do not contain 
ephedrine alkaloids but have been misused to identify ephedrine 
alkaloid containing ingredients. Although the proportions of the 
various ephedrine alkaloids in botanical species vary from one species 
to another, in most species used commercially, ephedrine is typically 
the predominant alkaloid in the raw material (Ref. 10).
    Dietary supplements containing ephedrine alkaloids are widely sold 
in the United States (Refs. 11 through 13).\1\ Over the last decade, 
dietary supplements containing ephedrine alkaloids have been labeled 
and used primarily for weight loss, energy, or to enhance athletic 
performance. Additional scientific evidence, and numerous reports of 
serious adverse events, including death, following consumption of 
dietary supplements containing ephedrine alkaloids, have raised 
concerns about their safety. Consequently, we have taken a number of 
actions in an attempt to protect the public from the risks of these 
products.
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    \1\ We use the term ``dietary supplements containing ephedrine 
alkaloids'' in this final rule to refer to dietary supplements 
containing botanical sources of ephedrine alkaloids. We use the term 
``ephedra'' to refer to botanical sources of ephedrine alkaloids, 
whether derived from a member of the Ephedra genus or another 
botanical, such as Sida cordifolia L. or Pinellia ternata (Thunb.) 
Makino. We use the term ``Ephedra'' to refer specifically to the 
Ephedra genus of plants.
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C. What Regulatory Actions Have We Taken Regarding Dietary Supplements 
Containing Ephedrine Alkaloids?
 
    In the Federal Register of June 4, 1997 (62 FR 30678) (June 1997 
proposal), we published a proposed rule on dietary supplements 
containing ephedrine alkaloids. In this document, we proposed to make a 
finding, with the force and effect of law, 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 in a 
6-hour period or a total daily intake of 24 mg or more of ephedrine 
alkaloids. The June 1997 proposal would also have required that the 
label of dietary supplements containing ephedrine alkaloids state that 
the product should not be used for more than 7 days. We also proposed 
to prohibit the use of ephedrine alkaloids in dietary supplements with 
other ingredients that have a known stimulant effect that 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 June 1997 proposal would have 
required a statement accompanying 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. We also proposed to require that the 
labels of all dietary supplements containing ephedrine alkaloids bear a 
statement warning consumers not to use the product if they are taking 
certain drugs;
 
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advising them to contact a health care professional before use if they 
have certain diseases or health conditions; and warning them to stop 
use and call a health care professional if they develop certain signs 
or symptoms. We proposed these actions in response to reports of 
serious illnesses and injuries, including a number of deaths, 
associated with the use of dietary supplements containing ephedrine 
alkaloids and our investigations and assessment of these illnesses and 
injuries. These actions were 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 what action FDA should take to address the serious health 
concerns associated with their use (Refs. 14 and 15).
    The comment period for the June 4, 1997, proposed rule ended on 
August 18, 1997. In a document published in the Federal Register of 
August 20, 1997 (62 FR 44247), we announced our intent to reopen the 
comment period after we corrected a number of inadvertent omissions in 
the administrative record. Subsequently on September 18, 1997 (62 FR 
48968), we reopened the comment period until December 2, 1997.
    During this second comment period, the Commission on Dietary 
Supplement Labels (the Commission) released its final report on 
November 24, 1997. The Commission, an independent agency established by 
section 12 of the Dietary Supplement Health and Education Act of 1994 
(DSHEA) (Public Law 103-417), was charged with conducting a study on, 
and providing recommendations for, the regulation of label claims and 
statements for dietary supplements. The Commission's members included 
several scientists from academia and industry. In its report, the 
Commission divided its conclusions into three categories: findings, 
guidance, and recommendations. The Commission Report defined 
``findings'' as conclusions reached by the Commission based on 
information and data it received during its deliberations. The 
Commission defined ``guidance'' that was directed to FDA as advice that 
we should consider as we developed or implemented activities related to 
the availability of dietary supplements in the marketplace. The 
Commission defined ``recommendations'' as suggested changes to FDA 
regulations or the development of new regulations governing dietary 
supplements.
    One guidance statement in the Commission Report pertains to the 
safety of dietary supplements containing ephedrine alkaloids. In the 
report, the Commission urges FDA to use its authority under DSHEA to 
take swift enforcement action to address potential safety issues such 
as those posed recently by products containing ephedrine alkaloids. 
While it is expected that a responsible industry will avoid marketing 
unsafe products and that the industry will react promptly to remove 
products shown to be associated with significant or serious adverse 
events, in the final analysis there must be a strong and reliable 
enforcement system to back up the safety provisions of DSHEA. Failure 
by FDA to act when strong enforcement is needed undermines public 
confidence in the ability of not only the Federal Government but also 
the dietary supplement industry to ensure safety and avoid harm to the 
public (Ref. 16 at p. VII of Executive Summary).
    In a notice published in the Federal Register on April 29, 1998 (63 
FR 23633), we announced our views on the recommendations and guidance 
of the Commission, as presented in the Commission's report. In this 
notice, we stated that we take seriously our public health protection 
mission and are committed to removing unsafe dietary supplements from 
the market (63 FR 23633 at 23634). The direction taken in the current 
rulemaking on dietary supplements containing ephedrine alkaloids is 
consistent with the Commission's advice.
    In September 1998, the U.S. General Accounting Office (GAO) began a 
study on FDA's June 1997 proposal. GAO's work culminated in the 
issuance of a July 1999 report (Ref. 17). GAO concluded that the 
evidence supported concern that ephedrine alkaloid-containing 
supplements can cause serious health problems and it recommended 
further data collection and review. At the same time, GAO criticized 
FDA's reliance on adverse event reports (AERs) as the basis for the 
proposed restrictions on dosage, frequency and duration of use.
    In the Federal Register of April 3, 2000 (65 FR 17474, April 3, 
2000), we withdrew parts of the June 1997 proposal. More specifically, 
we withdrew the proposed finding that a dietary supplement is 
adulterated if it contains 8 mg or more of ephedrine alkaloids per 
serving, or if its labeling suggests or recommends conditions of use 
that would result in the intake of 8 mg or more in a 6-hour period or a 
total daily intake of 24 mg or more of ephedrine alkaloids; the 
proposed compliance procedures (regarding the analytical method FDA 
would use to determine the level of ephedrine alkaloids in a dietary 
supplement); the proposed label statement ``Do not use this product for 
more than 7 days;'' the proposed prohibition on labeling claims for 
uses that encourage long-term intake; and the proposed label statement 
to accompany claims for short-term uses (``Taking more than the 
recommended serving may cause heart attack, stroke, seizure, or 
death.'').
    We stated in our 2000 partial withdrawal of the June 1997 proposal 
that we continued to have a public health concern about the use of 
dietary supplements containing ephedrine alkaloids and that we would 
continue to monitor and provide appropriate followup on adverse events 
associated with the use of these products. We also stated that 
withdrawal of certain provisions of the June 1997 proposal did not 
limit our discretion to initiate enforcement actions with respect to 
dietary supplements containing ephedrine alkaloids.
    On the same day as the 2000 partial withdrawal of the June 1997 
proposal, we announced the availability of certain documents to update 
the administrative docket of the proposed rule (65 FR 17509, April 3, 
2000). The documents consisted of additional information about some of 
the 270 adverse event reports (AERs) received by FDA between February 
and September 1997. In a separate Federal Register notice also issued 
on April 3, 2000, we announced the availability of additional AERs and 
related information received after publication of the proposed rule. 
The additional information included the analyses of these new AERs by 
experts both inside and outside the agency; review of labels of 
products associated with these adverse events; review of the use of 
Ephedra species in traditional Asian medicine; analysis of the 
likelihood and factors affecting the reporting of adverse events; and 
summaries of the known physiological, pharmacological, and toxic 
effects of ephedrine alkaloids (Ref. 18). This announcement was made in 
part to prepare for a meeting convened by the U.S. Department of Health 
and Human Services (HHS) Office of Women's Health (OWH) in August 2000 
to discuss information about the safety of dietary supplements 
containing ephedrine alkaloids. Shortly before that meeting, FDA 
announced (65 FR 46721, July 31, 2000) that it would again reopen the 
comment period for the June 1997
 
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proposal from August 10, 2000 (the day after the OWH meeting) until 
September 30, 2000. In that notice, we also announced the availability 
of a report on phenylpropanolomine and hemorrhagic stroke (Ref. 19).
    In April 2001, HHS's Office of the Inspector General issued a 
report entitled ``Adverse Event Reporting For Dietary Supplements: An 
Inadequate Safety Valve'' (Ref. 20) that assessed the effectiveness of 
FDA's Adverse Event Reporting System. This report found that adverse 
event reporting systems typically detect only a small proportion of the 
events that actually occur.
    In the Federal Register of March 5, 2003 (68 FR 10417), we 
published a notice making available new information about dietary 
supplements containing ephedrine alkaloids and requesting public 
comment on the new information and on regulation of these products (68 
FR 10417, March 5, 2003) (March 2003 notice). We specifically sought 
comments on whether, in light of current information, we should 
determine that dietary supplements containing ephedrine alkaloids are 
adulterated because they present a significant or unreasonable risk of 
illness or injury under the conditions of use recommended or suggested 
in labeling or under ordinary conditions of use if the labeling is 
silent. The notice also sought comment on a revised version of the 
warning statement first proposed on June 4, 1997. The revised warning 
statement had two components, a short warning that would be required to 
appear on the principal display panel (PDP) and a longer warning that 
could appear elsewhere in labeling. The proposed PDP warning stated 
that strokes, heart attacks, seizures, and death have been reported 
after consumption of dietary supplements containing ephedrine alkaloids 
and that the risks of adverse events increase with strenuous exercise 
and with use of other stimulants, including caffeine. The longer 
proposed warning included more detailed information about risks 
associated with the use of the product and recommended that consumers 
avoid using the product and/or consult a doctor under certain 
circumstances.
    In the March 2003 notice, we asked for public comment on all 
additional evidence developed since the publication of the June 1997 
proposal. One such study was a report by the Southern California 
Evidenced Based Practice Center (the RAND report, RAND, or RAND Corp.), 
commissioned by the National Institutes of Health (NIH) (Refs. 21 and 
22). RAND reviewed recent evidence on the risks and benefits of ephedra 
and ephedrine\2\ and found that dietary supplements containing 
ephedrine alkaloids are associated with higher risks of mild to 
moderate side effects such as heart palpitations, psychiatric effects, 
and upper gastrointestinal effects, and symptoms of autonomic 
hyperactivity such as tremor and insomnia, especially when they are 
taken with other stimulants. The RAND report identified 21 ``sentinel 
events'' among the adverse event reports it reviewed, including stroke, 
heart attack, and death.\3\ RAND also found limited evidence of an 
effect of ephedra on short-term weight loss. Furthermore, RAND found 
limited evidence that synthetic ephedrine and caffeine in combination 
have a short-term enhancement effect on athletic performance in certain 
physical activities. RAND concluded that the scientific literature does 
not support an effect of ephedrine alone on athletic performance, and 
there were no clinical trials on the effects of dietary supplements 
containing botanical ephedrine alkaloids on athletic performance. One 
of the studies reviewed by RAND, a study by Boozer, et al. (2002), 
though frequently relied on by the dietary supplement industry to 
demonstrate the safety of ephedrine alkaloids, raised additional 
concerns about the effects of dietary supplements containing ephedrine 
alkaloids on blood pressure. This evidence, discussed in section V.B of 
this document, added significantly to the evidence suggesting that 
dietary supplements containing ephedrine alkaloids as currently 
marketed are associated with unreasonable safety risks.
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    \2\ The RAND report uses the term ``ephedra'' to refer to 
ephedrine alkaloids from botanical sources, whether or not they are 
contained in dietary supplements. RAND uses the term ``ephedrine'' 
to refer to pharmaceutical sources of ephedrine.
    \3\ RAND defined a ``sentinel event'' as a case that met all 
three of the following criteria: (1) Documentation of an adverse 
event that met the selection criteria; (2) documentation that the 
person having the adverse event took an ephedra-containing 
supplement or ephedrine within 24 hours prior to the event (for 
cases of death, myocardial infarction [heart attack], stroke, or 
seizure); and, (3) documentation that alternative explanations for 
the adverse event were investigated and were excluded with 
reasonable certainty. These criteria were subject to procedures 
which included the following (among other procedures): medical 
record documentation that an adverse event had occurred; 
documentation that the subject had consumed ephedra or ephedrine 
within 24 hours prior to the adverse event, or that a toxicological 
examination revealed ephedrine or one of its associated products in 
the blood or urine. Cases with no such documentation were not 
reviewed further. For the Metabolife cases, ephedra was assumed to 
have been used within the prior 24 hours for all but psychiatric 
events. All cases of stroke that met the criterion of having 
consumed ephedra or ephedrine within 24 hours were reviewed in more 
detail; to be classified as a ``sentinel event,'' reports of 
thrombotic stroke needed to have an assessment for a hypercoagulable 
state and vasculitis, reports of embolic stroke needed to have an 
embolic evaluation performed, and reports of hemorrhagic stroke 
required an examination to assess structural problems with the 
circulatory system of the brain.
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    At about the same time as we published the March 2003 notice, we 
issued warning letters to 26 firms for making unsubstantiated claims 
concerning the use of dietary supplements containing ephedrine 
alkaloids to enhance athletic performance. We also issued warning 
letters to firms promoting dietary supplements containing ephedrine 
alkaloids as alternatives to illicit street drugs.
    In July 2003, GAO testified at a House Subcommittee hearing on 
issues relating to dietary supplements containing ephedrine alkaloids. 
GAO's testimony discussed and updated some of its findings from its 
prior 1999 report on dietary supplements containing ephedrine alkaloids 
(Ref. 23). The testimony provided new information, including an 
evaluation of Metabolife International's records of health-related 
calls from consumers of Metabolife 356 (Ref. 24). GAO noted that the 
types of adverse events identified in the health-related call records 
from Metabolife International were consistent with the types of adverse 
events reported to us, as well as with the scientifically documented 
physiological effects of ephedrine alkaloids. GAO also noted that 
despite the limited information contained in most of the call records, 
14,684 call records contained reports of at least one adverse event 
among consumers of Metabolife 356. The GAO testimony identified 92 
serious events that included heart attacks, strokes, seizures, and 
deaths and emphasized that these findings were similar to other reviews 
of the call records, including those done by Metabolife International 
and its consultants. The GAO testimony noted that, in those call 
records where age was documented, many of the serious adverse events 
occurred in relatively young consumers, with more than one-third being 
under the age of 30. Furthermore, for those call records in which 
quantity of use and/or frequency and duration of use were noted, most 
of the serious adverse events occurred among Metabolife 356 users who 
used the product within the recommended guidelines, i.e., they did not 
take more of the product nor consume it for a longer period of time 
than the product label recommended.
 
[[Page 6792]]
 
D. Petitions Received Relating to Dietary Supplement Containing 
Ephedrine Alkaloids
 
    We received three petitions relating to dietary supplements 
containing ephedrine alkaloids. The first petition, dated August 27, 
1998, was submitted by the American Obesity Association and requested 
that we issue a final rule on dietary supplements containing ephedrine 
alkaloids that adopts the regulations in the June 1997 proposal. The 
second petition, dated October 25, 2000, was filed jointly by the 
American Herbal Products Association, the Consumer Healthcare Products 
Association, the National Nutritional Foods Association, and the Utah 
Natural Products Alliance and requested that we withdraw the remaining 
portions of our June 1997 proposal and adopt and implement in its place 
an industry-developed standard for the labeling and marketing of 
dietary supplements containing ephedrine alkaloids.
    The third petition, dated September 5, 2001, was submitted by 
Public Citizen. This petition requested that we declare dietary 
supplements containing ephedrine alkaloids adulterated because they 
present a significant or unreasonable risk of illness or injury under 
section 402(f) of the act and ban, all production and sales of these 
products under section 301(a) (21 U.S.C. 331(a)) of the act. The 
petition also requested that we issue an advisory to stop the use of 
dietary supplements containing ephedrine alkaloids due to the 
established risks of injury.
    The information cited in support of this petition included:
    <bullet> Summaries of the updated numbers and types of 
adverse events reported to us for ephedrine-alkaloid containing dietary 
supplements compared to the lower incidence of the same types of 
adverse events reported for all other dietary supplements;
    <bullet> An FDA preliminary analysis of data collected by 
and purchased from the American Association of Poison Control Centers 
(AAPCC) that showed an increase in the number of ephedrine alkaloid-
related AERS from 211 in 1997 to 407 in 1999; and
    <bullet> Adverse events reported to Public Citizen.
    The petition also cited the known pharmacological and toxicological 
properties of ephedrine alkaloids, recent published articles and case 
reports, the fact that adverse events are invariably underreported, and 
the lack of any evidence of long-term benefits for the products.
    We have considered the information submitted by these petitions, as 
well as the comments received in response to these petitions and all 
other information in the docket. For the reasons summarized in section 
I.A of this document, we have concluded that dietary supplements 
containing ephedrine alkaloids are adulterated.
 
II. Summary of Letters and Comments
 
    We have received more than 48,000 comments in three dockets 
pertaining to ephedrine alkaloids, Docket Nos. 1995N-0304, 2000N-1200, 
and 2001P-0396. These comments include all letters received prior to 
the June 1997 proposal, all comments received in response to Federal 
Register notices, and all submissions related to public meetings 
pertaining to dietary supplements containing ephedrine alkaloids. The 
48,000 comments include more than 41,000 form letters received in the 
1997 docket. Many comments submitted identical or nearly identical 
statements to more than one docket or in response to more than one 
Federal Register notice. Most of the comments were submitted by 
individual consumers who use dietary supplements containing ephedrine 
alkaloids or by independent distributors of these products. 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, medical or scientific associations, State or 
local health departments, Government agencies, members of Congress, 
dietary supplement manufacturers, traditional Asian medicine 
practitioners and associations, dietary supplement industry trade 
associations, public health associations, and consumer groups.
    The form letters, while not submitting substantive evidence or 
analyses, expressed strong views about our regulation of these 
products. Most of these letters opposed further federal regulation of 
dietary supplements containing ephedrine alkaloids. More than 13,000 
comments opposed a ban of these products and indicated that further 
restrictions on these products would infringe on personal choice. 
Thousands of comments requested that FDA not impose stricter 
regulations on dietary supplements containing ephedrine alkaloids than 
those imposed on OTC drugs that contain synthetic ephedrine alkaloids. 
Hundreds of comments requested that we not ban or reclassify ephedra as 
a prescription drug because, they claimed, such action would result in 
illegitimate profits for the pharmaceutical companies. Many expressed 
the view that we should only ban supplements containing excessive 
amounts of ephedrine alkaloids and those marketed to adolescents and 
children or to others who may abuse and misuse these products.
    Some form letters supported further regulation of these dietary 
supplement products. Several stated that dietary supplements containing 
ephedrine alkaloids are dangerous and asked us to ban them. Others 
requested that we impose more stringent requirements such as mandatory 
warning labels and maximum dosage levels. Thousands of form letters 
stated that DSHEA provides us with the necessary authority to protect 
the public health and that we do not need additional authority. 
Numerous comments criticized us for failing to exercise the enforcement 
powers authorized by DSHEA. Numerous form letters requested that 
ephedrine alkaloids be allowed for professional use by traditional 
Asian medicine practitioners and dispensed by licensed health care 
professionals.
    We have also received approximately 2,500 individual comments that, 
although not form letters, did not contain substantive information, 
analyses, or data. Many of these individual comments raised the same 
issues as raised in the form letters. Many comments were personal 
testimonials of how dietary supplements containing ephedrine alkaloids 
are effective for weight control, improving stamina, or treating 
medical conditions, and should not be banned or further restricted. 
Several comments stated that the June 1997 proposal lacked scientific 
basis and that there are many legitimate studies that support the 
responsible use of dietary supplements containing ephedrine alkaloids; 
however, these comments did not submit any additional scientific 
evidence. Others stated that dietary supplements containing ephedrine 
alkaloids are safe when used appropriately. Others were personal 
testimonials of adverse events related to these products that urged a 
ban or tighter restrictions of these products. Some comments criticized 
the proposed label warning as too long and ineffective.
    Other comments came from members of Congress, with many echoing the 
issues raised by the form letters. Several congressional 
representatives commented that Americans are increasingly turning to 
dietary supplements to improve their health and that Congress passed 
DSHEA to ensure that these products are regulated
 
[[Page 6793]]
 
as foods rather than drugs. They cited our own statements that DSHEA 
gives FDA sufficient authority to remove unsafe dietary supplements 
from the market. Many urged us to ensure that there was ample 
opportunity to submit scientific evidence related to dietary 
supplements containing ephedrine alkaloids. Many urged us to base our 
decisions on sound science and not rely too heavily on AERs. Some 
expressed concern about alleged FDA bias against dietary supplements 
containing ephedrine alkaloids. Others passed on concerns expressed by 
constituents about adverse health effects from these products. Several 
comments from members of Congress expressed concern about consumers' 
ability to read and properly use labels and warnings.
    Many of the substantive comments submitted data and other 
information regarding the use of ephedrine alkaloids. Some comments 
contained legal analyses of DSHEA and other provisions of the act. Many 
comments related to provisions of the June 1997 proposal that were 
withdrawn in 2000 or that have become moot as a result of the action 
taken in this final rule and, therefore, do not require a response. 
Examples of moot issues are the proposed prohibition on claims that 
encourage long-term use and the proposed label statement that the 
product should not be used for more than 7 days. Other comments 
addressed issues outside the scope of the rulemaking (e.g., comments 
about the diversion of ephedrine alkaloids for the illegal manufacture 
of methamphetamine and methcathinone) and will also not be addressed in 
this document.
    A summary of all relevant comments and our responses to those 
comments follow. To make it easier to identify comments and our 
responses, the word ``Comment,'' in parentheses, will appear before the 
comment summary and the word ``Response,'' in parentheses, will appear 
before our response. We have also numbered each comment summary to help 
distinguish between different comment summaries. The number assigned to 
each comment summary is purely for organizational purposes and does not 
signify the comments' value or importance or the order in which they 
were received.
 
III. Finding of Adulteration
 
A. What Does the Final Rule Do?
 
    This final rule declares dietary supplements containing ephedrine 
alkaloids to be adulterated under section 402(f)(1)(A) of the act. We 
have determined that these products present an unreasonable risk of 
illness or injury under the conditions of use recommended or suggested 
in labeling or, if no conditions of use are suggested or recommended in 
labeling, under ordinary conditions of use. We are taking this action 
based upon the well-known and scientifically established pharmacology 
of ephedrine alkaloids, the peer-reviewed scientific literature about 
the effects of ephedrine alkaloids, published case reports of adverse 
events, and the adverse events reported to us that have occurred in 
individuals using products containing ephedrine alkaloids, particularly 
dietary supplements. We have concluded that dietary supplements 
containing ephedrine alkaloids pose a risk of serious adverse events, 
including heart attack, stroke, and death, and that these risks are 
unreasonable in light of any benefits that may result from the use of 
these products under their labeled conditions of use, or under ordinary 
conditions of use if the labeling is silent. We are not addressing the 
issue of whether these products present a ``significant'' risk under 
section 402(f)(1)(A) of the act.
 
B. What Products are Covered?
 
    This final rule applies to dietary supplements containing ephedrine 
alkaloids, including, but not limited to, those from the botanical 
species Ephedra sinica Stapf, Ephedra equisetina Bunge, Ephedra 
intermedia var. tibetica Stapf, Ephedra distachya L., Sida cordifolia 
L. and Pinellia ternata (Thunb.) Makino or their extracts. The 
ingredient sources of the ephedrine alkaloids include raw botanicals 
and extracts from botanical sources. Although synthetic ephedrine (in 
the form of ephedrine hydrochloride) has been found in products labeled 
as dietary supplements, ephedrine hydrochloride was approved for use as 
a human drug as early as the late 1940s and, to the best of our 
knowledge there is no evidence that it was marketed prior to that time 
as a dietary supplement or food. Furthermore, ephedrine hydrochloride 
and other synthetic sources of ephedrine cannot be dietary ingredients 
because they are not constituents or extracts of a botanical, nor do 
they qualify as any other type of dietary ingredient. For these 
reasons, products containing synthetic ephedrine cannot be legally 
marketed as dietary supplements (See section 201(ff)(1) and 
201(ff)(3)(B) of the act (21 U.S.C. 321(ff)(1) and (ff)(3)(B))). In 
October 2001, we brought a seizure action against $2.8 million worth of 
finished drug products containing synthetic ephedrine hydrochloride 
that were labeled as dietary supplements (United States v. 1009 Cases * 
* * E'ola International AMP II), No. 2:01CV-820C (D. Utah filed October 
22, 2001)). As a result of this seizure, in 2002, the manufacturer 
signed a consent decree agreeing to the condemnation and destruction of 
the seized products and prohibiting it from manufacturing or 
distributing violative ephedrine hydrochloride products. In other 
actions, we have sent warning letters to multiple firms that were 
marketing products containing synthetic ephedrine alkaloids as dietary 
supplements, resulting in the removal of the illegal products from the 
market.
    The final rule does not apply to conventional food products that 
contain ephedrine alkaloids. Substances intentionally added to a 
conventional food are generally considered to be food additives under 
section 201(s) of the act. Ephedrine alkaloids contained in 
conventional foods would generally be considered unsafe food additives 
(see section 409 of the act (21 U.S.C. 348)). A food that contains an 
unsafe food additive is adulterated under section 402(a)(2)(C) of the 
act.
    This final rule also does not include OTC or prescription drugs 
that contain ephedrine alkaloids. The use of ephedrine or 
pseudoephedrine for the treatment of asthma, colds, allergies, or any 
other disease is beyond the scope of this final rule. Ephedrine is 
allowed as an active ingredient in oral OTC bronchodilator drugs for 
use in the treatment of medically diagnosed mild asthma (Sec. 341.16 
(21 CFR 341.16)), when used within the established dosage limits and 
when the product is labeled in accordance with the required statements 
of identity, indications, warnings, and directions for use found in 
Sec. 341.76. In the near future, we intend to propose revisions to Sec. 
341.76 to reflect current scientific information about the risks of 
ephedrine. Both ephedrine (topical) and pseudoephedrine (oral) are 
permitted as active ingredients for use as nasal decongestants (Sec. 
341.20), when they are used within the dosage limits established by and 
labeled in accordance with Sec. 341.80. The topical use of ephedrine 
will not be further discussed in this rule because it is not relevant 
to oral consumption of ephedrine in dietary supplements. The use of 
ephedrine alkaloids in drug products is discussed in more detail in 
section V.B.3 of this document.
    Several Ephedra species (including those known as ma huang) have a 
long history of use in traditional Asian medicine. These products are 
beyond the scope of this rule because they are
 
[[Page 6794]]
 
not marketed as dietary supplements. The use of ephedrine alkaloids in 
traditional Asian medicine is discussed in more detail in section V.B.5 
of this document. As we describe there, this rule does not change how 
these products are regulated under the act.
    (Comment 1) One comment stated that we coined the term ``ephedrine 
alkaloids'' to improperly broaden the scope of the published scientific 
literature and AERs cited in the June 1997 proposal. The comment 
pointed out that ephedrine, pseudoephedrine, and phenylpropanolamine 
(PPA) are all different chemical entities and stated the opinion that 
only data on ephedrine are relevant to the June 1997 proposal.
    (Response) Although we agree that the terms ephedrine, 
pseudoephedrine, and PPA refer to different chemical entities, we 
disagree with the rest of the comment and its conclusions. The term 
``ephedrine alkaloids'' refers to a class of naturally occurring 
compounds structurally related to ephedrine, and the term has been used 
in that manner in the scientific literature (Refs. 25 and 26). We chose 
this particular term, rather than several alternatives, such as 
``Ephedra bases'' and ``ephedrine type alkaloids,'' to limit the scope 
of the June 1997 proposal to those compounds that are natural 
constituents of the aerial parts of the Ephedra plant or other 
botanical sources of ephedrine and related alkaloids. We also defined 
the term by listing the six principal natural alkaloids in the June 
1997 proposal and other FDA documents (Refs. 6 and 27). The ephedrine 
alkaloids in botanicals include l-ephedrine, d-pseudoephedrine, l-
norephedrine, l-methylephedrine, d-norpseudoephedrine, d-
methylpseudoephedrine, and minor related alkaloids. All of these 
compounds are pharmacologically active substances in the plant. 
Therefore, we considered all of them in our evaluation of the risks 
associated with the use of the botanical or extracts from the 
botanical. However, as discussed in the response to comment 24 in 
section VI.B.1 of this document, we recognize that there are some 
differences between ephedrine and PPA.
    (Comment 2) Several comments asked whether North American species 
of Ephedra (e.g., Mormon Tea) are covered in this rulemaking.
    (Response) Most North American species of Ephedra (e.g., Mormon 
tea) do not contain ephedrine alkaloids (Refs. 2 and 26). Nonetheless, 
any dietary supplement that contains ephedrine alkaloids from any 
botanical source, including from a North American species of Ephedra, 
is subject to this rulemaking.
 
IV. Legal Issues
 
A. What Is Our Legal Authority Under the Act?
 
    We are issuing this final regulation under sections 402(f)(1)(A) 
and 701(a) of the act (21 U.S.C. 371(a)). Section 402(f)(1)(A) of the 
act deems a food to be adulterated for the following reasons:
    If it is a dietary supplement or contains a dietary ingredient 
that--
    (A) presents a significant or unreasonable risk of illness or 
injury under--
    (i) conditions of use recommended or suggested in labeling, or
    (ii) if no conditions of use are suggested or recommended in the 
labeling, under ordinary conditions of use.
    This regulation makes a finding that dietary supplements containing 
ephedrine alkaloids are adulterated because they present an 
unreasonable risk within the meaning of section 402(f)(1)(A) of the 
act. This finding is based on our conclusion that the risks of these 
products outweigh their benefits. Our legal interpretation of 
``unreasonable risk'' is discussed in detail in section V.D.1 of this 
document. This regulation does not address the meaning of ``significant 
risk'' or whether dietary supplements containing ephedrine alkaloids 
present a significant risk under section 402(f)(1(A) of the act.
    Section 701(a) of the act gives FDA authority to issue regulations 
for the efficient enforcement of the act. We are using this rulemaking 
authority for dietary supplements containing ephedrine alkaloids 
because we are articulating a standard for unreasonable risk under 
402(f)(1)(A) of the act for the first time and because it is more 
efficient to declare these products adulterated as a category than to 
remove them from the market in individual enforcement actions in which 
we would have to establish, for each individual product, that they 
present a significant or unreasonable risk.
    The March 2003 notice asked about the adequacy of FDA's authority 
to regulate dietary supplements containing ephedrine alkaloids. More 
specifically, we sought comments on ``what additional legislative 
authorities, if any, would be necessary or appropriate to enable us to 
address this issue most effectively'' (68 FR 10417 at 10420).
    (Comment 3) Many comments expressed the view that we already have 
the authority we need to take action against dietary supplements 
containing ephedrine alkaloids. These comments cited our authority to 
declare these supplement products to be a significant or unreasonable 
risk or imminent hazard under section 402(f)(1) of the act or to 
regulate the products as containing a poisonous or deleterious 
substance that may render them injurious to health under section 
402(a). The comments differed as to whether we had the necessary 
evidence to utilize these provisions. Several comments opposed any 
additional authority and criticized us for allegedly not fully 
implementing the authority we already have.
    (Response) We agree that we have the authority to take action 
against dietary supplements that contain ephedrine alkaloids. All three 
authorities mentioned by the comments are available to us when 
circumstances warrant. In this instance, we have chosen to proceed 
under the adulteration standard in section 402(f)(1)(A) of the act. We 
believe that we have sufficient evidence to meet this standard.
    (Comment 4) In contrast, other comments stated that our legal 
authority should be strengthened. Several comments expressed the view 
that DSHEA needs to be amended because it cannot adequately protect 
public health. One public interest group noted that our delay in acting 
reflects the difficulty we encounter implementing DSHEA. Several 
comments offered suggestions for amendments that would strengthen our 
legal authority, including mandatory reporting of adverse events, 
certain sales restrictions (e.g., restricting sales to behind the 
counter only, prohibiting sales to individuals under the age of 18), 
special labeling requirements for dietary supplements containing 
ephedrine alkaloids, registration and listing, premarket approval for 
safety and efficacy (particularly for all new stimulants and steroid 
substitutes), and repeal of the de novo review provision so that we 
would receive judicial deference on adulteration issues. A few comments 
suggested that dietary supplements be regulated as drugs. One comment 
suggested new legislation to classify dietary supplements according to 
a risk-based regulatory scheme.
    (Response) We must regulate dietary supplements under our existing 
authority. Accordingly, we are unable to take action regarding 
suggestions for amendments to DSHEA because any such amendments must 
result from congressional action rather than rulemaking. Therefore, we 
are not addressing those suggestions in this rule.
    (Comment 5) One comment stated that conventional food safety 
standards, i.e., the generally recognized as safe (GRAS) standard or 
the standard for
 
[[Page 6795]]
 
FDA approval as a food additive, do not apply to dietary ingredients.
    (Response) We agree that the standards referred to in this comment 
do not apply to dietary ingredients. Premarket approval is required of 
substances that are food additives as defined in section 201(s) of the 
act. Substances that would otherwise fall under the food additive 
definition but are generally recognized as safe by experts are not food 
additives and do not require premarket approval. Dietary ingredients 
contained in, or intended for use in, a dietary supplement are 
explicitly excluded from the food additive definition in section 
201(s)(6) of the act. Therefore, neither the premarket approval regime 
for food additives nor the GRAS standard applies to dietary 
ingredients. We are instead basing this final rule on the dietary 
supplement adulteration standard set forth in section 402(f)(1)(A) of 
the act.
    (Comment 6) One comment stated we are violating the First Amendment 
of the U.S. Constitution and the Administrative Procedure Act (APA) by 
requiring a much higher standard of safety for dietary supplements than 
for conventional foods. Another comment also raised concerns about the 
First Amendment limits of FDA's authority to regulate dietary 
supplements containing ephedrine alkaloids.
    (Response) We disagree with these comments. There are a number of 
different safety standards for foods (see, e.g., section 402(a)(1) and 
section 402(a)(2)(C) of the act), and whether these standards are 
higher or lower than the ``significant or unreasonable risk'' standard 
for dietary supplements in section 402(f)(1)(A) of the act is not 
relevant to the legal sufficiency of this rule. To the extent that we 
regulate dietary supplements and conventional foods differently, these 
differences are justified by the differences in the statutory 
provisions that apply to these two categories of products. Although 
some parts of the act apply to both dietary supplements and 
conventional foods, other provisions apply only to one or the other. 
Where Congress expressly provided for dietary supplements to be subject 
to a requirement or standard that does not apply to conventional foods, 
we may implement that provision without violating the APA. Further, 
this final rule does not violate the First Amendment. This rule does 
not restrict speech; rather, it makes a finding of adulteration that 
results in a prohibition on the distribution and sale of a product that 
presents unreasonable health risks. Such restrictions on purely 
commercial, nonexpressive conduct are not subject to First Amendment 
scrutiny. See, e.g., United States v. O'Brien, 391 U.S. 367, 376 
(1968).
    (Comment 7) Several comments expressed the view that these products 
should be regulated as drugs under our existing authority. Some 
comments stated that we should make these products available only by 
prescription, arguing that the potential health hazards associated with 
dietary supplements containing ephedrine alkaloids are too serious for 
OTC use and that restricting access by requiring a prescription would 
insert trained medical professionals into a case-by-case decision on 
the appropriateness of these products to an individual consumer. 
Further, one comment recommended that if the frequency of adverse 
events under prescription status does not improve, more restrictive 
action should be implemented, including the withdrawal of all products 
containing ephedrine alkaloids from the market.
    (Response) We do not agree that all dietary supplements containing 
ephedrine alkaloids may be regulated as drugs under our existing 
authority. Products are drugs only if they meet the definition of drug 
in section 201(g)(1) of the act. Products containing ephedrine 
alkaloids are regulated as drugs if they are intended to be used in the 
diagnosis, cure, mitigation, treatment, or prevention of disease 
(section 201(g)(1)(B) of the act). Without evidence of intended use for 
such purposes, the product is not a drug under the act. Some dietary 
supplements containing ephedrine alkaloids are promoted for disease 
uses, e.g., to treat obesity. In such instances, we can and have taken 
action against certain dietary supplement products as drugs. Under the 
act, considerations such as potential risks to health, need for medical 
supervision, and pharmacology of a product that meets the dietary 
supplement definition are not by themselves sufficient to subject the 
product to regulation as a drug.
    To the extent that comments suggest that these products could 
somehow remain dietary supplements but be available only by 
prescription, we note that we do not have authority to take such 
action. The act gives us the authority to restrict drugs and devices to 
prescription use; it does not give us the authority to restrict dietary 
supplements to prescription use.
    (Comment 8) One comment stated that the generally accepted 
definition of safety for a drug, i.e., a low incidence of adverse 
reactions or significant side effects under appropriate conditions of 
use, and a low potential for harm, which might result from abuse 
situations, is equally applicable to dietary supplements or food.
    (Response) We do not agree that the safety standards for drugs 
apply to dietary supplements or other foods. As explained previously, 
dietary supplements are not drugs unless they meet the definition of 
drug in section 201(g)(1) of the act. The same is true for conventional 
foods. We are basing this final rule on the dietary supplement 
adulteration standard set forth in section 402(f)(1)(A) of the act. The 
adulteration standard for dietary supplements set forth in section 
402(f)(1)(A) of the act implies a risk-benefit calculus. While we also 
use a risk-benefit evaluation in the drug evaluation process (see Sec. 
312.21(c), Sec. 314.50(c)(5)(viii), and Sec. 330.10(a)(4) (21 CFR 
312.21(c), 314.50(c)(5)(viii), and 330.10(a)(4))), the act creates 
different evidentiary standards for dietary supplements and drugs. 
Therefore, we are not applying the drug safety standard to dietary 
supplements.
 
B. Do the Ephedrine Alkaloid-Containing Products Covered by this Rule 
Fall Within the Definition of Dietary Supplement Under the Act?
 
    A threshold issue is whether the products covered by this rule meet 
the definition of a dietary supplement under section 201(ff) of the 
act.
    (Comment 9) One comment from a State department of health stated 
the opinion that dietary supplements containing ephedrine alkaloids 
present significant risks when they are consumed as a regular part of 
the diet and do not fall within section 201(ff)(1) of the act. The 
comment explained that because these products cannot be used on a daily 
basis without presenting significant risks they cannot be ``intended to 
supplement the diet'' and are not dietary supplements within the 
meaning of the act. A related comment expressed the opinion that, for a 
substance to be a dietary supplement, it must be proven that the human 
body needs the substance to establish a need for supplementation.
    (Response) We agree with these comments in part and disagree in 
part. We agree that dietary supplements containing ephedrine alkaloids 
present a risk when consumed as a regular part of the diet; as 
discussed in section V.B of this document, they present a risk to some 
users even when consumed occasionally. We do not agree, however, that 
dietary supplements containing botanical ephedrine alkaloids do not 
fall within the definition of a dietary supplement in section 201(ff) 
of the act. Section 201(ff)(1) of the act, added by
 
[[Page 6796]]
 
DSHEA, provides, in part, that the term ``dietary supplement'' means a 
product ``intended to supplement the diet'' that bears or contains one 
or more dietary ingredients. Among the dietary ingredients listed in 
section 201(ff)(1) of the act are herbs and other botanicals. 
Therefore, botanical sources of ephedrine alkaloids, such as Ephedra 
sinica Stapf and the other botanicals described in section III.B. of 
this document, are dietary ingredients. Further, we do not agree that 
the phrase ``intended to supplement the diet'' authorizes the exclusion 
of a product from the dietary supplement definition solely on the basis 
of risk. Given the explicit references to risk in section 402 of the 
act and the inclusion of botanicals as a category of dietary 
ingredients in section 201(ff)(1) of the act, it seems clear that 
Congress intended us to regulate botanical products as dietary 
supplements (provided that they are not drugs and otherwise meet the 
dietary supplement definition) and to evaluate their risks under the 
adulteration provisions in section 402 of the act.
    We also do not agree that, under the dietary supplement definition, 
it must be proven that the human body needs a particular substance to 
establish a need for supplementation. Under DSHEA, a substance does not 
necessarily have to be shown to be essential to human nutrition to be 
marketed as a dietary supplement. Although no provision in the act or 
legislative history directly addresses this issue, section 201(ff) of 
the act lists classes of dietary ingredients (e.g., botanicals) that 
are not essential for growth or to maintain good health (Ref. 28). The 
fact that Congress classified such substances as dietary ingredients is 
clear evidence that Congress did not intend to limit dietary 
ingredients to substances that have been deemed to be essential in 
human nutrition.
    (Comment 10) Several comments, including one from an industry 
medical consultant, stated that herbal products should not be regulated 
under DSHEA because they have physiologic effects and significant 
potential for toxicity. The comment encouraged us to work with industry 
to establish an appropriate regulatory category for botanicals.
    (Response) Under the act (as amended by DSHEA), botanicals can be 
marketed as dietary supplements provided that they otherwise meet the 
dietary supplement definition, and are safe and properly labeled. If 
botanicals meet the drug definition in section 201(g) of the act, they 
are properly regulated as drugs. In this regard, we published a final 
rule entitled ``Additional Criteria and Procedures for Classifying 
Over-the-Counter Drugs as Generally Recognized as Safe and Effective 
and Not Misbranded'' (67 FR 3060, January 23, 2002). This rule defines 
 
the term ``botanical drug substance'' and explains how to submit a time 
and extent application to request that a botanical drug substance be 
included in an OTC drug monograph (see Sec. 330.14). In addition, we 
recognize, and are addressing, the current need for guidance for 
manufacturers seeking to develop botanicals as either OTC or 
prescription drug products under the applicable statutory and 
regulatory requirements. (See Guidance for Industry: Botanical Drug 
Products (Draft Guidance) (August 2000) (available at http://www.fda.gov/cder/guidance/1221dft.pdf
).)
 
 
C. Administrative Procedures
 
    (Comment 11) Several comments stated that it is premature to 
request comments on whether dietary supplements containing ephedrine 
alkaloids present a significant or unreasonable risk before we define 
that standard. These comments urged us to undertake a rulemaking, or a 
guidance document, on this new standard so that it can be applied in 
the future to all dietary supplements posing health concerns. One 
comment suggested that defining ``significant or unreasonable risk'' 
may require new legislation.
    (Response) We do not agree that we must define the term 
``unreasonable risk'' standard through regulation or guidance before 
taking action against dietary supplements containing ephedrine 
alkaloids based upon this standard. An agency may interpret a statutory 
provision through rulemaking or case-by-case adjudication (SEC v. 
Chenery, 332 U.S. 194 (1947)). We conclude, based upon available 
evidence discussed in section V of this document, that dietary 
supplements containing ephedrine alkaloids present an unreasonable risk 
of illness or injury because their risks outweigh their benefits, and 
that these products are therefore adulterated under section 
402(f)(1)(A) of the act. We are using our general rulemaking authority 
to issue regulations for the efficient enforcement of the act (section 
701(a) of the act) to issue a regulation applying the standard in the 
context of a particular category of dietary supplements--those that 
contain botanical ephedrine alkaloids. We are not required to issue a 
separate rule or guidance defining the 402(f)(1)(A) standard before 
issuing such a regulation. Similarly, lack of a regulation or guidance 
defining the standard neither prevents us from taking enforcement 
action against dietary supplements that present an ``unreasonable 
risk,'' nor is it new legislation necessary for us to interpret the 
meaning of ``unreasonable risk.'' If Congress has clearly spoken to a 
question of statutory interpretation, the agency charged with 
administering the statute must implement the unambiguous intent of 
Congress (``Chevron step one'') (Chevron U.S.A., Inc. v. Natural 
Resource Defense Council, 467 U.S. 837, 842-843 (1984)). If a statute 
is silent or ambiguous on the question, however, the agency may 
interpret the ambiguous provision (``Chevron step two'') Id. at 843-
844. When such administrative interpretations are made through 
rulemaking, they will be upheld as long as they are reasonable and 
consistent with the statute's purpose and legislative history 
(Christensen v. Harris County, 529 U.S. 576, 587 (2000); Chevron 
U.S.A., Inc. v. FERC, 193 F.Supp.2d 54, 68 (D.D.C. 2002)). As discussed 
in the response to comment 59 in section V.D.1 of this document, we 
have concluded under Chevron step one that the phrase ``unreasonable 
risk'' clearly directs FDA to conduct a risk-benefit analysis. Even if 
a court were to find that phrase ambiguous, however, our interpretation 
is reasonable under Chevron step two.
    (Comment 12) Several comments urged us not to act against all 
dietary supplements containing ephedrine alkaloids because all such 
products are different and must be considered individually. The 
comments cited differences in dosages, formulations, labeling, etc., 
across products and, thus, each product must be analyzed on its own 
merits. One industry comment argued that we exceeded our statutory 
authority in trying to regulate all dietary supplements containing 
ephedrine alkaloids through notice and comment rulemaking.
    (Response) We do not agree that we may not regulate the entire 
category of dietary supplements containing ephedrine alkaloids through 
rulemaking. We recognize that there are differences between different 
dietary supplements containing ephedrine alkaloids. However, we 
conclude, based on available science, that all dietary supplements 
containing ephedrine alkaloids present an unreasonable risk of illness 
or injury, regardless of how they are formulated or labeled, because 
the risks outweigh any benefits that may result from use of the 
products. Therefore, we may issue a rule finding the entire class of 
products adulterated.
    (Comment 13) A few comments noted that we bear the burden of proof 
to show
 
[[Page 6797]]
 
dietary supplements are adulterated under section 402(f)(1) of the act.
    (Response) We agree with this comment. Section 402(f)(1) of the act 
clearly states that in any proceeding under that provision, ``the 
United States shall bear the burden on each element to show that a 
dietary supplement is adulterated.'' We have met that burden in this 
rulemaking.
    (Comment 14) Several comments discussed our ability to declare 
dietary supplements containing ephedrine alkaloids an imminent hazard 
under section 402(f)(1)(C) of the act.
    (Response) We are not addressing these comments because we have 
chosen to proceed under section 402(f)(1)(A).
    (Comment 15) One industry comment stressed that comments to the 
June 1997 proposal may not be used to authorize other final 
regulations. The comment expressed concern that comments to a proposed 
warning statement would be used as a basis for another FDA action to 
regulate these supplements.
    (Response) We disagree with this comment. FDA may issue this final 
regulation based on a finding that dietary supplements containing 
ephedrine alkaloids are adulterated because they present an 
unreasonable risk under section 402(f)(1)(A) of the act. APA requires 
agencies to provide the public with notice and an opportunity for 
comment before issuing a new regulation (5 U.S.C. 553(b) and (c)). In 
keeping with this requirement, a final rule may differ from a proposed 
rule if the final rule is a ``logical outgrowth'' of a proposed rule 
(Small Refiner Lead Phase-Down Task Force v. EPA, 705 F.2d 506, 547 
(D.C. Cir. 1983)). The inquiry into whether a final rule is a logical 
outgrowth of the proposed rule is often stated as whether the regulated 
party ``should have anticipated that such a requirement might be 
imposed'' (Small Refiner, 705 F.2d at 549). Agencies ``undoubtedly have 
authority to promulgate a final rule that differs in some particulars 
from its proposed rule* * * `[a] contrary rule would lead to the 
absurdity that * * * the agency can learn from the comments on its 
proposals only at the peril of starting a new procedural round of 
commentary''' (Small Refiner, 705 F.2d at 546-547 (quoting 
International Harvester Co. v. Ruckelshaus, 478 F.2d 615, 632 n.51 
(D.C. Cir.1973))). The D.C. Circuit has also stated: ``The APA notice 
requirement is satisfied if the notice fairly apprises interested 
person of the subjects and issues the agency is considering; `the 
notice need not specifically identify ``every precise proposal which 
[the agency] may adopt as a final rule''' (Chemical Manufacturers 
Association Waste Mfrs. v. EPA, 870 F.2d 177, 203 (5th Cir. 1989) 
(quoting United Steelworkers of Am. v. Schuylkill Metals, 828 F.2d 314, 
317 (5th Cir. 1987) (internal citations omitted))).
    Our June 1997 proposal, along with our March 5, 2003 Federal 
Register notice, provided a sufficient basis to allow the public to 
anticipate our actions in this final rule. Through our proposed actions 
on dietary supplements containing ephedrine alkaloids, the public was 
properly notified of the possibility that we would find such products 
to be adulterated under section 402(f)(1)(A) of the act. In fact, our 
March 2003 notice specifically asked for comment on whether dietary 
supplements containing ephedrine alkaloids present a significant or 
unreasonable risk under section 402(f)(1)(A) of the act. We also sought 
comment on new evidence concerning the safety of dietary supplements 
containing ephedrine alkaloids (68 FR 10417 at 10420). In addition, the 
restriction on ephedrine alkaloid/stimulant combinations proposed in 
1997, which was unaffected by the 2000 partial withdrawal proposal, was 
based in part on a finding of adulteration under section 402(f)(1)(A) 
of the act (62 FR 30678 at 30696). Though we did not specifically 
propose to codify a finding of adulteration based on significant or 
unreasonable risk in the March 2003 notice, it was clear that we were 
contemplating the possibility that dietary supplements containing 
ephedrine alkaloids were adulterated under section 402(f)(1)(A) of the 
act. Courts have upheld final rules that contained new elements when 
the public was made aware that the agency was contemplating such a 
change (See Chem. Mfrs. Ass'n. , 870 F.2d 202-203). Furthermore, we 
received several comments regarding the possibility of a finding that 
all dietary supplements containing ephedrine alkaloids would be deemed 
adulterated under section 402(f)(1)(A) of the act. Though not 
determinative of logical outgrowth in and of themselves, comments on 
the issue are evidence that the public received adequate notice of our 
final rule (Shell Oil Co. v. EPA, 950 F.2d 741, 757 (D.C. Cir. 1991)). 
Based upon our explicit request for comments on the adulteration issue 
in our March 2003 notice, our reference to the section 402(f)(1)(A) of 
the act adulteration standard as a basis for our June 1997 proposal, 
and the fact that a number of parties commented on whether dietary 
supplements containing ephedrine alkaloids present a significant or 
unreasonable risk, there was adequate notice to the public of our 
actions in this final rule.
    (Comment 16) Several comments cited language in section 402(f)(1) 
of the act providing that courts must review any determination under 
section 402(f)(1) of the act de novo and further stated that we would 
not get judicial deference in any court review. The comments argued 
that, under this provision, it would make no difference whether we 
brought our case initially in court or whether we proceeded through 
rulemaking that was subsequently challenged in court. One trade 
association noted that such de novo review is a novel approach in that 
usually a court would just review the administrative record.
    (Response) Section 402(f)(1) of the act states that a court will 
decide any issue under that paragraph on a de novo basis. We agree that 
the de novo standard of review applies to our factual findings under 
section 402(f)(1) of the act, but do not agree that it applies to our 
conclusion under Chevron U.S.A., Inc., that ``unreasonable risk'' means 
a risk-benefit analysis (see section V.D.1 of this document). This 
interpretation of the de novo provision of section 402(f)(1) of the act 
is consistent with case law on the Toxic Substances Control Act (TSCA), 
which contains an unreasonable risk standard coupled with a 
``substantial evidence'' standard of review, analogous to the act's 
unreasonable risk standard coupled with a de novo standard of review. 
In Chem. Mfrs. Ass'n v. EPA, 859 F.2d 977 (D.C. Cir. 1988), the D.C. 
Circuit distinguished EPA's legal interpretation of unreasonable risk, 
which received deference under Chevron U.S.A., Inc. v. Natural 
Resources Defense Council, 467 U.S. 837 (1984), from its burden of 
showing with ``substantial evidence'' in the record that it has met the 
standard. The court stated: ``This fairly rigorous standard of record 
review should not * * * be confused with the substantive statutory 
standard * * * '' (859 F.2d at 992). Thus, the court in Chem. Mfrs. 
Ass'n. held that the ``substantial evidence'' standard of record review 
applied to the factual basis of EPA's decision but not to its 
interpretation of the statutory standard. In applying Chevron U.S.A., 
Inc., we have concluded that Congress unambiguously intended that 
unreasonable risk entails a risk-benefit calculus. If a court were to 
find the phrase ``unreasonable risk'' ambiguous, however, our 
interpretation of unreasonable risk as meaning a risk-benefit calculus 
should receive Chevron U.S.A., Inc. deference, like EPA's
 
[[Page 6798]]
 
interpretation of the statutory standard in Chem. Mfrs. Ass'n.. The 
requirement for de novo review should be applied only to the factual 
basis of FDA's determination.
    Regardless of which standard applies, however, our determination 
that dietary supplements containing ephedrine alkaloids present an 
unreasonable risk under section 402(f)(1)(A) of the act should be 
sustained by a court. Our conclusion that ``unreasonable risk'' entails 
a risk-benefit analysis is consistent with the express intent of 
Congress. The scientific evidence regarding the pharmacology of 
products containing ephedrine alkaloids, clinical studies showing that 
these products raise blood pressure, published case reports, and AERs, 
when compared with the evidence regarding the very modest benefits 
conferred by these supplements, forms a strong factual basis for 
finding that the known and reasonably likely risks of dietary 
supplements containing ephedrine alkaloids outweigh the known and 
reasonably likely benefits of these products. Therefore, dietary 
supplements containing ephedrine alkaloids present an unreasonable risk 
of injury or illness under section 402(f)(1)(A) of the act.
    (Comment 17) One comment submitted by a trade association noted 
that, before requesting the Department of Justice to take any civil 
action against dietary supplements containing ephedrine alkaloids, we 
must give appropriate notice and opportunity to present oral and 
written arguments at least 10 days prior to the request.
    (Response) We agree with this comment in part and disagree in part. 
Section 402(f)(2) of the act provides that ``the person against whom 
such proceeding would be initiated'' must be given notice and the 
opportunity to present views, orally and in writing, 10 days before we 
report a violation of section 402(f)(1)(A) of the act (the 
``significant or unreasonable risk'' provision) to the Department of 
Justice for a civil proceeding. By the plain language of this 
provision, it applies to proceedings against persons, not to 
proceedings against products. Thus, the requirement applies to 
injunction actions, which are brought against a corporate or individual 
person, but not to seizures, which are brought against a product. 
Therefore, if we were to refer a seizure of dietary supplements 
containing ephedrine alkaloids to the Department of Justice, the notice 
requirement would not apply. We further note that the current 
proceeding is a rulemaking, not a civil action being referred to the 
Department of Justice, and therefore the 10-day notice requirement does 
not apply.
    (Comment 18) One industry comment stated that the stringent 30-day 
timeframe allowed for comments in response to the March 2003 notice did 
not provide the industry with a fair opportunity to review the 
administrative record and fairly respond to ``any alleged new evidence 
and analyses'' by FDA. This comment urged us to allow for a comment 
period of 180 days. The comment stated that this procedural lapse would 
render the entire rulemaking process arbitrary and capricious.
    (Response) We disagree with this comment. We believe that the 30-
day comment period on the March 2003 notice provided interested persons 
with an adequate opportunity for review and comment. The information 
placed in the public docket at that time was limited, consisting of the 
RAND report plus six recent studies. APA requires only that an agency 
``give interested persons an opportunity to participate in the 
rulemaking through submission of written data, views, or arguments * * 
*'' This opportunity to participate is all that the APA requires. There 
is no statutory requirement concerning how many days we must allow for 
comment, nor is there a requirement that we extend the comment period 
at the request of an interested person (See Phillips Petroleum Co. v. 
EPA, 803 F.2d 545, 559 (10th Cir. 1986)). Moreover, given that we first 
opened a docket on the issue of dietary supplements containing 
ephedrine alkaloids in 1995 and sought comments on this issue several 
times between then and 2003 (see section I.C of this document), there 
has been ample opportunity for all those interested to submit 
information and views.
 
V. Scientific Evaluation
 
A. How Did We Evaluate the Evidence?
 
    To determine whether a dietary supplement presents an unreasonable 
risk of illness or injury, the agency performs a risk/benefit analysis 
to ascertain whether the risks of the product outweigh its benefits.
    The risks and benefits of a dietary supplement must be evaluated in 
light of the claims and directions for use in the product's labeling 
or, if the labeling is silent, under ordinary conditions of use 
(section 402(f)(1)(A) of the act). Labeling claims for dietary 
supplements must be substantiated. Unless the manufacturer has 
substantiation that a labeling claim promoting a dietary supplement for 
a purported benefit is truthful and non-misleading, the claim misbrands 
the product (See section 403(a)(1) and 403(r)(6) of the act. We note 
that the standards for substantiating the efficacy of a drug for a 
labeled indication (i.e., the generally recognized as effective (GRAE) 
standard for OTC monograph ingredients and the substantial evidence 
standard for new drugs) do not apply to dietary supplements.
    Substantiation of a benefit may not be necessary to lawfully market 
a dietary supplement if its labeling does not include a claim, and the 
product poses little or no risk. In weighing risks and benefits to 
determine whether dietary supplements containing ephedrine alkaloids 
present an unreasonable risk under section 402(f)(1)(A) of the act, we 
considered only known and reasonably likely benefits, not speculative 
benefits. A reasonably likely benefit is one that is supported by a 
meaningful totality of the evidence, given the current state of 
scientific knowledge, though the evidence need not necessarily meet the 
approval standard for a prescription drug.
    Although Congress placed the burden on FDA to show ``unreasonable 
risk,'' once a danger is identified, we do not believe that Congress 
intended us to delay action until double-blind, placebo-controlled 
clinical studies could be conducted or that no action be taken if such 
clinical studies are infeasible or unethical (see the response to 
comment 19 of this document). While such studies are the ``gold 
standard'' for determining effectiveness, they are not always available 
for dietary supplements because DSHEA does not require companies to 
conduct such studies before marketing a dietary supplement. DSHEA also 
does not require postmarketing safety and adverse event reporting from 
dietary supplement manufacturers. Accordingly, FDA is relying on the 
available scientific data and literature to support its conclusion that 
dietary supplements containing ephedrine alkaloids present an 
``unreasonable risk.'' The government's burden of proof for 
``unreasonable risk'' can be met with any science-based evidence of 
risk and does not require a showing that the substance has actually 
caused harm in particular cases.
    For example, there is clear scientific evidence that a sustained 
increase in blood pressure increases the risks of cardiovascular 
disease (Refs. 29, 29a, and 30). Thus, a dietary supplement that caused 
a sustained rise in blood pressure across the population would increase 
the risk of cardiovascular events including stroke, heart attack, or 
death to that population. Even risks that
 
[[Page 6799]]
 
may not be detectable in small studies or studies of short duration 
(which are not designed to detect such risks at a statistically 
significant level) could, over time, and on a population-wide basis, 
result in thousands of adverse health events.
    In making a determination, we consider studies using closely 
related products. In considering the risks of a product, such as 
dietary supplements containing ephedrine alkaloids, it is appropriate 
to consider the safety of closely related products, such as those with 
the same active ingredient (e.g., synthetic ephedrine products) or 
closely related ingredients (such as other sympathomimetics) because we 
would expect that dietary supplements containing ephedrine alkaloids 
will exhibit pharmacological effects similar to those other products 
and, therefore, pose similar risks. It is more difficult to extrapolate 
conclusions regarding the benefits between an ephedrine drug product 
and a dietary supplement containing ephedrine alkaloids since the 
ephedrine drug product is a well defined product with a known dose of 
ephedrine, while in the latter there is a complex mixture with, 
possibly, an unknown quantity of ephedrine plus other ephedrine 
alkaloids, and sometimes other active ingredients, many of which may 
not be fully characterized. We would need to know how the two products 
compare with regard to systemic delivery of ephedrine (e.g., the 
pharmacokinetics profile) to make any judgments about comparable 
benefits of the two products. If ephedrine pharmacokinetics were the 
same in a synthetic and plant-derived product and there were no 
ingredients or components other than ephedrine, one might conclude that 
the plant-derived and synthetic products would behave similarly. In 
actual fact, that is not the case because plant derived ephedra 
products contain other ephedrine alkaloids in addition to ephedrine 
itself (e.g. pseudoephedrine, methylephedrine, and others listed in 
section I.B of this document). Moreover, if there were other active and 
inactive ingredients in the plant-derived product, their properties 
would need to be explored.
    In evaluating whether dietary supplements containing ephedrine 
alkaloids present an unreasonable risk, we looked at the seriousness of 
the risks and the quality and persuasiveness of the totality of the 
evidence to support the presence of those risks. We then weighed the 
risks against the importance of the benefits and the quality and 
persuasiveness of the totality of the evidence to support the existence 
of those benefits. We give more weight to benefits that improve health 
outcomes, especially in the long term, than to benefits that are 
temporary or rely on subjective measures such as feeling or looking 
better. For example, sustained, long-term weight loss in an obese or 
overweight person is a much more important benefit than short-term 
weight loss because long-term weight loss in these individuals reduces 
the risk of serious morbidity and mortality (e.g., heart attacks and 
strokes), while short-term weight loss does not.
    In sections V.B, C, and D of this document, we describe the 
evidence FDA evaluated to reach its determination that dietary 
supplements containing ephedrine alkaloids present an unreasonable risk 
of illness or injury.
    (Comment 19) Many comments stated that any assessment of 
unreasonable risk must be based on sound science. Several comments 
stated that a conclusion about the safety and efficacy of dietary 
supplements containing ephedrine alkaloids is premature and that 
additional prospective or retrospective case controlled studies are 
needed to determine causality. A few comments recommended that FDA, 
NIH, or other parts of the federal government conduct such research to 
address unresolved issues of causation. Another trade association urged 
the government to collaborate with industry to design future controlled 
studies. Several of these comments cited RAND in support of the need 
for further research. Several comments noted that the National Center 
for Complementary and Alternative Medicine/NIH Working Group evaluated 
the RAND report and suggested a multi-site case-control study to assess 
the risks associated with these products, although it stated that such 
a study would take 4 to 8 years and cost $2 to $4 million per year 
(Ref. 31).
    In contrast, several comments asserted that conducting clinical 
trials of ephedrine alkaloids would be unethical in light of the risks 
to the human subjects. A professional association stated that FDA 
regulations that govern drug development and approval would not allow 
such research, given the absence of information to suggest a benefit 
that would outweigh the risks. A few comments suggested that any study 
that could be approved by a human subjects committee would be required 
to exclude patients at risk and therefore, would not be useful in 
evaluating risk when the products are taken by the general population 
without medical supervision. Other comments expressed concern that the 
additional research recommended by RAND would delay efforts or render 
it virtually impossible to safeguard public health.
    (Response) We recognize the value of properly conducted clinical 
trials to answer questions regarding the safety and effectiveness of 
FDA-regulated products. It is not clear, however, that clinical trials 
to evaluate the adverse effects of ephedrine alkaloids can be 
conducted. It would not be ethical to study the arrhythmogenic 
potential of ephedrine alkaloids in patients with coronary artery 
disease, the adverse effects of ephedrine alkaloids in people with 
heart failure, or the consequences of raising blood pressure in various 
populations. Moreover, there is now sufficient evidence, generated 
through multiple sources, including clinical trials, published 
literature, and other information, to reach the conclusion that dietary 
supplements containing ephedrine alkaloids have effects on blood 
pressure and other pharmacological risks that predict adverse effects 
in users. After considering the best available information, we conclude 
that these products present an unreasonable risk because the benefits 
that may result from use of these products are outweighed by the risks 
associated with such use (see discussion in section V.D of this 
document). Because of the nature of these risks, we do not believe it 
is appropriate to delay action until further clinical studies can be 
conducted to evaluate the safety of dietary supplements containing 
ephedrine alkaloids in the general population. We would, however, 
support the conduct of clinical investigations (carried out under the 
Investigational New Drug (IND) regulations with careful screening to 
exclude subjects at risk and careful safety monitoring during the 
trials) that examine the safety and efficacy of ephedrine alkaloids, 
with or without caffeine, as drugs such as for the treatment of obesity 
(see 21 CFR part 312).
    (Comment 20) Two comments stated that there is an accepted 
scientific methodology for determining whether, and at what level, a 
food additive, dietary ingredient, OTC or prescription drug, or 
biologic may be hazardous to human health. The stated components of 
this methodology include reviews of the following reports: (1) The 
existing scientific literature on the substance, to determine what is 
known about the substance's risk, particularly at the levels to be used 
in a product; (2) clinical studies involving the substance; (3) 
available animal studies on the substance and, if necessary, the 
conduct of additional studies; and (4) adverse event reports caused by 
the substance.
 
[[Page 6800]]
 
 In addition, the methodology includes a determination of whether 
individuals who consume the products suffer from a statistically 
significantly greater number of adverse (or beneficial) events than 
those who do not. One comment stated that the absence of premarket 
approval authority for dietary supplements does not preclude reliance 
on traditional methods of evaluating safety when making a decision 
about levels that are not safe.
    (Response) We do not agree with the comments stating that there is 
a single accepted method of evaluation to determine when a food 
ingredient or dietary ingredient in a dietary supplement presents a 
hazard to the public health. In any evaluation of the risks presented 
by a substance in a product in the marketplace, the method of 
evaluating the risk must be applied on a case-by-case basis that is 
based on the available data concerning the substance being evaluated. 
We believe that our method of evaluation for ephedrine alkaloids is, 
however, consistent with that used for other substances. The scientific 
methodology we used to evaluate the risks associated with the use of 
dietary supplements containing ephedrine alkaloids consisted of a 
review and evaluation of the available scientific literature (including 
literature on pharmacology), clinical studies, published case reports, 
and other data, including adverse event reports. This is the same type 
of scientific methodology that is applied in the evaluation of adverse 
effects associated with other FDA-regulated products (Ref. 32), and 
includes most of the steps listed in the comments summarized above.
    (Comment 21) A number of comments focused on FDA's obligation to 
ensure that its regulatory assessments are science-based. Two comments 
raised concern regarding our compliance with a statutory provision 
popularly known as the Data Quality Act (section 515 of the 
Consolidated Appropriations Act, 2001, Public Law 106-554, 44 U.S.C.A. 
3516 note). One comment stated that we are vulnerable to challenge 
under the Data Quality Act because there is a disconnect between our 
proposed actions and the conclusions of the RAND report. Another 
comment pointed to our related guidance entitled ``Guidelines for 
Ensuring the Quality of Information Disseminated to the Public'' 
(http://www.hhs.gov/infoquality/fda.html[numsign]i). FDA's guidance, 
 
which describes how we intend to meet our obligations under the Data 
Quality Act and the implementing Office of Management and Budget (OMB) 
guidelines, states that we are committed to ensuring that our 
regulatory decisions are based on objective information and notes our 
commitment to using the best available science conducted in accordance 
with sound and objective scientific practices, including peer reviewed 
science and supporting studies when available. This comment also cited 
the Center for Food Safety and Applied Nutrition's report ``Initiation 
and Conduct of All `Major' Risk Assessments within a Risk Analysis 
Framework'' (http://www.cfsan.fda.gov/dms/rafw-toc.html), which 
 
similarly stresses the importance of data quality and scientific 
objectivity in regulatory decisionmaking. Finally, this comment 
suggested that in evaluating the safety of dietary supplements 
containing ephedrine alkaloids, we should apply a rigorous scientific 
standard such as that used to evaluate whether a new drug application 
(NDA) should be approved or whether a health claim should be authorized 
under the significant scientific agreement standard (See Sec.Sec. 
314.125 and 314.126) (NDAs); Guidance for Industry: Significant 
Scientific Agreement in the Review of Health Claims for Conventional 
Foods and Dietary Supplements (http://www.cfsan.fda.gov/dms/ssaguide.html
) (health claims).
 
    (Response) We agree that we have an obligation to base regulatory 
assessments, including our regulatory assessment of the safety of 
dietary supplements containing ephedrine alkaloids, on sound science. 
We have spent a great deal of time and effort compiling and evaluating 
the best available scientific evidence relevant to this rulemaking, and 
our decision is based on a careful, objective analysis of the most 
current information, including peer reviewed studies. In considering 
whether dietary supplements containing ephedrine alkaloids present an 
unreasonable risk, we considered evidence from three principal sources: 
(1) The well-known, scientifically established pharmacology of 
ephedrine alkaloids; (2) peer-reviewed scientific literature on the 
effects of ephedrine alkaloids; and (3) the adverse events (including 
published case reports) reported to have occurred following consumption 
of dietary supplements containing ephedrine alkaloids. We believe that 
this final rule, and the data considered, are consistent with the 
principles set forth in the Data Quality Act and related guidances 
cited in the comments. We do not agree, however, that we should apply 
the same standard of scientific proof to a determination of 
adulteration under section 402(f)(1)(A) of the act, the ``significant 
or unreasonable risk'' provision, as we would apply to a decision 
whether to approve an NDA or authorize a health claim under other 
provisions of the act. Although our decision on dietary supplements 
containing ephedrine alkaloids must be based on sound science, that 
decision is not subject to, and need not meet, the very specific 
evidentiary requirements set out in the new drug and health claim 
provisions of the act (See 21 U.S.C. 355(d) and 21 U.S.C. 
343(r)(3)(B)(i)).
 
B. What Are the Known and Reasonably Likely Risks Presented by Dietary 
Supplements Containing Ephedrine Alkaloids?
 
1. Pharmacology
    We have reviewed numerous studies and other data related to the 
safety of dietary supplements containing ephedrine alkaloids. Evidence 
about the pharmacology of ephedrine alkaloids--as well as other 
evidence in the docket--shows that these products present a risk of 
serious adverse health effects. Information submitted to the docket in 
an effort to establish the safety of these products is inadequate to 
rebut the evidence of risk.
    (Comment 22) Several comments focused on the known pharmacological 
and toxicological effects of ephedrine/ephedra on the cardiovascular 
and nervous systems, explaining that ephedra contains vasopressor 
amines that excite the heart and constrict the blood vessels, which in 
turn increases heart rate and raises blood pressure. The comments 
contended that, because of these effects, adverse events such as 
hypertensive episodes, arrhythmias (abnormal heart rhythms), heart 
attacks, seizures, and strokes can be anticipated and expected when 
millions of people are exposed to such products. Various comments 
maintained that dietary supplements containing ephedrine alkaloids have 
the same pharmacological and toxicological activity as prescription and 
OTC ephedrine alkaloid drugs and, thus, present the same risks. One 
comment emphasized that Chen and Middleton (Ref. 33) warned about 
ephedrine alkaloid-induced thromboembolism (blood clots that travel in 
the body) in 1927 and thereafter, reports of toxicity appeared in the 
medical literature, accompanied by warnings against indiscriminate use 
by doctors and sale to consumers. These early reports are relevant to 
current reports of myocardial infarctions (heart attacks) and stroke 
associated with products containing ephedrine alkaloids.
 
[[Page 6801]]
 
    One comment stated that ephedra presents a danger of prolonged 
bleeding in those who undergo surgery, and that patients and doctors 
may not be aware of this potential complication. Another comment cited 
a review article (Ref. 2) that described myocardial depression 
occurring with repeated dosing of ephedrine, and cited a reference from 
a pharmacological textbook documenting ephedrine's tendencies to cause 
atrial and ventricular arrhythmias. Another comment suggested that we 
should not ignore the other ingredients commonly found in dietary 
supplements containing ephedrine alkaloids, such as caffeine, 
laxatives, and diuretics, because these ingredients can alter 
electrolyte levels and increase the risk of arrhythmias. One comment, 
citing a study by Haller et al., contended that the apparent causal 
role of ephedrine alkaloids in severe adverse effects could be related 
to the additive stimulant effects of caffeine (Ref. 34). One comment 
submitted by a manufacturer attributed the good safety record of its 
product to, among other reasons, the absence of caffeine and other 
stimulants.
    (Response) We agree that dietary supplements containing ephedrine 
alkaloids present risks of adverse physiological and pharmacological 
effects. Based on the best available scientific data and the known 
pharmacology of ephedrine alkaloids and other sympathomimetics, 
ephedrine alkaloids--including dietary supplements containing ephedrine 
alkaloids--pose short-term and long-term risks. This is clearest in 
long-term use, where increased blood pressure in any population will 
clearly increase the risk of stroke, heart attack, and death, but there 
is also evidence of increased risk from shorter-term use in patients 
with heart failure or underlying coronary artery disease.
    Ephedrine alkaloids are members of a large family of 
sympathomimetic compounds that include dobutamine and amphetamine. 
Members of this family increase blood pressure and heart rate by 
binding to alpha- and beta-adrenergic receptors present in many parts 
of the body, including the heart and blood vessels (Refs. 35, 36, and 
37). These compounds are called sympathomimetics because they mimic the 
effects of epinephrine and norepinephrine, which occur naturally in the 
human body. In addition to their direct pharmacological effects, many 
of these compounds also stimulate the release of norepinephrine from 
nerve endings. The release of norepinephrine further increases the 
sympathomimetic effects of these compounds, at least transiently. 
Sympathomimetic effects raise three concerns. First, sympathomimetics 
can induce cardiac arrhythmias in susceptible people, such as those 
with underlying coronary artery disease. Second, increased mortality 
has been observed in patients with congestive heart failure who were 
treated with sympathomimetic drugs, such as beta-agonists (early 
studies using such drugs as albuterol led to adverse outcomes) and 
xamoterol (Ref. 38), as well as phosphodiesterase inhibitors, which 
potentiate (increase the effect of) the effects of beta-agonists, 
including milrinone (Ref. 39) and enoximone (Ref. 40). The studies that 
showed these adverse effects occurred in about 3 months of product use. 
Third, sympathomimetics can raise blood pressure (Ref. 41).
    Based on clinical data, the ephedrine alkaloids present in dietary 
supplements would be expected to have the same or similar effects as 
other sympathomimetics on heart rate and blood pressure. Controlled 
clinical trials using products containing ephedrine alkaloids confirm 
their typical sympathomimetic effects. Single-dose studies of dietary 
supplements containing ephedrine alkaloids show that these products 
cause increases in both heart rate and blood pressure in healthy 
subjects (Refs. 42, 43, and 44). In one such study of a dietary 
supplement containing ephedrine alkaloids, the peak increase in blood 
pressure following a single oral dose of ephedrine alkaloids and 
caffeine (20 mg/200 mg) was 14 millimeters of mercury (mm Hg) systolic 
and 6 mm Hg diastolic, occurring about 2 hours after the single dose 
was taken (Ref. 42).
    The findings from these studies are complicated by the presence of 
caffeine in the dietary supplements used because caffeine is also known 
to have acute effects on blood pressure and heart rate. However, the 
effect of caffeine on blood pressure is transient and is lost within 2 
weeks of continued use (Refs. 45 and 46). Evidence that ephedrine 
independently causes an increase in blood pressure when coadministered 
with caffeine comes from two sources. First, there are studies in which 
ephedrine and caffeine were tested separately so that their effects 
could be compared. In a study by Jacobs et al., a group of healthy 
subjects received ephedrine (E, 0.1 mg/kilogram (kg) orally), caffeine 
(C, 4 mg/kg orally), the combination, or a placebo (P) (Ref. 47). 
Although caffeine caused a small increase in systolic blood pressure 
(average 3 to 6 mm Hg), ephedrine alone gave a 12 mm Hg effect, and 
when added to caffeine, increased systolic blood pressure by an 
additional 15 mm Hg (C+E = 156 +/- 29 mm Hg; E = 150 +/- 14; C = 141 +/
- 16; P = 138 +/- 14) (Refs. 47 and 48). Second, ephedrine has been 
shown in a clinical study to increase blood pressure and heart rate 
acutely when administered intravenously to children to maintain blood 
pressure during surgery (Ref. 37). Therefore, these studies show a 
blood pressure effect from ephedrine itself, independent of any 
additional effect from caffeine.
    In a multiple-dose controlled trial, Boozer et al. (2002) compared 
the effects of a combination of ephedrine alkaloids (from Ephedra) and 
caffeine (from kola nut) with placebo over a 6-month period in a highly 
selected population of obese and overweight individuals, who were 
carefully screened by medical history and medical evaluation to 
eliminate cardiovascular and other acute or chronic disorders (Ref. 
49). The study measured sitting blood pressure in the clinic using the 
cuff method for all 6 months (at weeks 1, 2, 3, 4, and every 4 weeks 
thereafter) of the study; these cuff measurements were not taken 
throughout the day so they reflect only a snapshot of the blood 
pressure at the time of measurement. The study also measured changes in 
blood pressure throughout the day at weeks 1, 2 and 4 using an 
automated blood pressure monitoring device (ABPM); the ABPM method 
provides more frequent measurements of blood pressure and is, 
therefore, better able to evaluate blood pressure effects over time. 
The ephedrine alkaloids and caffeine-treated subjects did not show a 
difference in the blood pressure measurements taken at the clinic, but 
did show statistically significant higher average blood pressure 
measurements over 24 hours at week 4 measured by ABPM (approximately 4 
mm Hg for both systolic and diastolic blood pressure) when compared to 
placebo treated subjects. The ABPM results are shown in a table in the 
paper. The difference in blood pressure between the two groups 
represented the sum of small downward changes in the placebo group 
(compared to baseline) and small upward changes, or no change, in the 
ephedra group. Boozer et al. reported numerous breakdowns of these data 
(e.g., 6 a.m. to midnight and midnight to 6 a.m.) and characterized the 
difference between the ephedra and placebo groups as small (about 3 mm 
Hg) but for the most common ABPM measure, 24-hour value, the difference 
was 4/4 mm Hg. The observation that this difference (shown in table 2 
of the paper) (Ref. 49) reflected a fall in blood
 
[[Page 6802]]
 
pressure in the placebo group as much as a rise in blood pressure in 
the ephedra group is not relevant. The only controlled and, therefore, 
reliable observation is the comparison of the two groups. Small changes 
from baseline can occur for a wide variety of reasons and are commonly 
observed in placebo and treated groups. Therefore, the ABPM data are 
important because they demonstrate that the effect of the ephedrine 
alkaloids, including dietary supplements containing ephedrine 
alkaloids, on blood pressure is not transient, but is still evident 
after 1 month of continued exposure (when measured by ABPM) and, 
therefore, would be expected to persist long term. The effect reported 
in the Boozer, et al. (2002) study cannot be attributed to the caffeine 
because the effect of caffeine on blood pressure (discussed previously) 
is transient, and the acute effect of caffeine to increase blood 
pressure is lost within 2 weeks of continued use (Refs. 45 and 46). 
While some effects of sympathomimetics show tachyphylaxis (i.e., 
decrease in response following repetitive administration of a 
pharmacologically active substance http://www.stedmans.com/) 
 
tachyphylaxis usually occurs rapidly. (FDA has verified the Web site 
address, but FDA is not responsible for any subsequent changes to the 
nonFDA Web sites after this document publishes in the Federal 
Register.) Therefore, we believe, based upon these data and our 
experience, that the blood pressure effects of ephedrine alkaloids seen 
after 4 weeks of continued use will persist.
    The Boozer et al. (2002) study (Ref. 49) was reviewed at our 
request by three outside scientific experts, Norman M. Kaplan, M.D. 
(Ref. 50), Richard L. Atkinson, M.D. (Ref. 51), and Mark Espeland, 
Ph.D. (Ref. 52). These experts were asked to give their independent, 
scientific opinion of whether the study provides adequate data to 
assess safety of ephedrine alkaloids and caffeine for weight loss--
considering, among other things, the design and duration of the trial 
and subject selection--and whether further studies are needed. In 
general, the experts concluded that the safety of ephedrine alkaloid 
and caffeine containing products could not be established by this study 
because the study used a highly selected population (i.e., carefully 
screened by medical history and medical evaluation to eliminate 
cardiovascular and other acute or chronic disorders) and had relatively 
few subjects. One of the experts also concluded that the duration of 
the study was inadequate to establish safety. In general, the reviewers 
found that the results raised safety concerns. Dr. Kaplan, one of the 
reviewers, raised the concern that the size of the change in blood 
pressure observed with ABPM, when applied to a large population, could 
translate into a significant increase in the incidence of strokes and 
heart attacks. Dr. Kaplan's concern reflects the potential consequence 
of long-term use of ephedra (i.e., the consequence of a population 
increase in blood pressure). A short-term increase (e.g., 1 to 2 
months) would not be expected to have such an effect. Approximately one 
in four adults has high blood pressure. Of those with high blood 
pressure, 31 percent are unaware that they have it (Ref. 53). A 
relative increase in blood pressure in any population, even individuals 
with ``normal'' blood pressure, will increase the risk of heart attack, 
stroke, and death in that population (Refs. 29, 29a, and 54).
    The extremely high prevalence of diagnosed and undiagnosed 
hypertension in the U.S. population and the likelihood that blood 
pressure in obese patients is already elevated make the 4 mm Hg effect 
shown by the Boozer et al. (2002) study (Ref. 49) one of great concern. 
Reductions in blood pressure of this magnitude (i.e., around 4 mm Hg 
diastolic or systolic) are clearly associated with substantial long-
term reductions in the occurrence of heart attack, stroke and death, as 
seen in meta-analyses of antihypertensive drug trials (Refs. 55 and 
56). While these trials were conducted in patients with hypertension, 
increasing blood pressure in any population, even in individuals with 
``normal'' blood pressure, will increase the risk of cardiovascular 
disease (Ref. 29).
    Epidemiological studies support a graded and continuous 
relationship between increased blood pressure and risk of stroke, heart 
attack, and sudden death, even when the increase is within the normal 
range (i.e., less than 140 mm Hg systolic and less than 90 mm Hg 
diastolic) (Refs. 29 and 30). This indicates that many people would be 
at an increased risk with long-term use of dietary supplements 
containing ephedrine alkaloids. Studies of hypertension treatments 
suggest that this increase in risk would occur fairly quickly in 
hypertensive individuals. Anti-hypertensive drugs that lower blood 
pressure by 4 to 6 mm Hg have been shown to significantly decrease the 
occurrence of cardiovascular morbidity (stroke, heart attack) and 
mortality (Refs. 55, 57, and 58). This effect is evident within 6 to 12 
months in large outcome studies (Refs. 29 and 30). FDA is concerned 
about the adverse health effects that can occur with the use of agents 
that raise blood pressure, such as dietary supplements containing 
ephedrine alkaloids, for short- or long-term use. Even in the case of a 
controlled clinical trial of a possible hypertension treatment where 
subjects are closely monitored, we advise sponsors to limit the length 
of time subjects can be in a placebo/untreated group to about 8 weeks 
to minimize their exposure to cardiovascular risks from the absence of 
treatment.
    As noted previously, the pharmacological effects of ephedrine 
alkaloids also present increased short-term risks of adverse health 
events in susceptible populations. For example, there is evidence from 
peer-reviewed scientific literature that a wide range of drugs with 
sympathomimetic activity, including beta-agonists, phosphodiesterase 
inhibitors, and dobutamine, have adverse effects (increased mortality 
due to heart failure and sudden death) in patients studied with 
congestive heart failure. These effects have been seen in relatively 
short-term studies (Refs. 59, 60, and 61) Similarly, there are studies 
that document that people with coronary artery disease are more 
susceptible to the well-known pro-arrhythmic effects of 
sympathomimetics (Refs. 62, 63, and 64) The occurrence of such an 
arrhythmic event is not one that requires prolonged exposure but would 
represent a risk associated with each use, including the first. Many 
individuals are unaware that they have coronary artery disease or early 
heart failure because these conditions may not cause prominent symptoms 
until later in the course of these conditions. As a result, we are 
concerned that such individuals will not know that they are at an 
increased risk for developing significant cardiovascular adverse events 
from even short-term use of dietary supplements containing ephedrine 
alkaloids. Overweight and obese individuals are particularly prone to 
hypertension, coronary artery disease, and/or heart failure, as 
overweight and obesity are associated with these conditions (Refs. 65 
and 66). These conditions may not manifest clinically until later in 
the course of the condition and, therefore, individuals, including 
overweight and obese individuals, may be unaware they have these 
conditions. As a population, the overweight and obese are, thus, at a 
greater risk even from short-term use of sympathomimetics.
    As summarized previously, the comments cited certain literature 
suggesting the possibility of additional adverse effects of ephedrine 
alkaloids,
 
[[Page 6803]]
 
such as prolonged bleeding in those who undergo surgery. Given the 
clear scientific evidence of this cardiovascular risks presented by 
dietary supplements containing ephedrine alkaloids, we have not relied 
on these other possible adverse effects noted in the comments in our 
determination of unreasonable risk.
    (Comment 23) Various comments did not agree that there are risks 
with products containing ephedrine alkaloids and stated the opinion 
that cardiovascular side effects associated with products containing 
ephedrine alkaloids in several blinded studies were not significantly 
different in control and treatment groups. Several comments maintained 
that there is no evidence from clinical studies that ephedrine 
``supplementation'' increases peak heart rate, peak blood pressure, or 
the prevalence of cardiac arrhythmias. Another comment contended that 
``clinically relevant doses'' of ephedra have no clinically significant 
effect on pulse or blood pressure, and produce no measurable 
alterations in myocardial function. A number of comments noted that 
changes in heart rate and blood pressure are transient and similar to 
those produced by exercise. Several comments stated that the effects of 
ephedra combined with caffeine on blood pressure are modest and 
generally subside over the first few days of use. Other comments stated 
that, although dietary supplements containing ephedrine alkaloids have 
a relatively high incidence of subjective and cardiovascular side 
effects with first use, the side effects diminish with continued use 
due to tachyphylaxis. Several comments noted that the literature, 
including the obesity studies we cited in the June 1997 proposal (Refs. 
36 and 67 through 80), indicated that tachyphylaxis sets in within a 
few days, at the most a few weeks, and results in a dramatic decrease 
in the likelihood of adverse events. Another comment suggested that 
pharmacological studies showed that peak ephedrine levels are reached 
within 1 to 4 days and that no further accumulation occurs thereafter. 
Another comment suggested that this fact means ephedrine alkaloids pose 
no risk of long-term toxicity.
    One comment noted that ephedrine alkaloids are not toxic in the 
classic sense, that is, do not cause organ changes or damage to the 
metabolism. Other comments suggested that the available pathology data 
do not show any pattern consistent with ephedrine alkaloids as a cause 
of death.
    (Response) We do not agree that ephedrine alkaloids pose no risk of 
adverse consequences. The suggestion that the cardiovascular effects of 
ephedrine alkaloids persist for only a few days is not supported by the 
Boozer et al. (2002) study (Ref. 49), which demonstrated a higher blood 
pressure (compared with placebo) at the end of 1 month of therapy (Ref. 
80a). This difference was observed when blood pressure was measured 
throughout the day, using ABPM, but not with cuff blood pressure 
measurements (a less sensitive measure). This difference in results 
using different measurement methods may have confused some readers and 
led them to conclude that ephedrine alkaloids do not have a clinically 
meaningful effect on blood pressure. The fact that an effect on blood 
pressure (as measured using ABPM, which follows measurements throughout 
the day) was still present at 1 month strongly indicates that 
tachyphylaxis to the effects of ephedrine does not occur. As discussed 
in the response to comment 22 of this document, tachyphylaxis tends to 
occur rapidly, as with caffeine, whose blood pressure raising effect is 
lost within 2 weeks. Therefore, FDA does not agree with the comments 
expressing assurances that adverse effects will disappear with 
continued use of ephedrine alkaloids because of tachyphylaxis.
    Additionally, some of the studies cited by the comments apparently 
measured cuff blood pressure only around the time of dosing, when 
minimal serum concentrations of ephedrine alkaloids and effects on 
blood pressure would be expected. Absence of an effect at this time 
cannot be seen as evidence that ephedrine alkaloids do not increase 
blood pressure.
    The suggestion that ``clinically relevant'' or ``clinically 
significant'' doses of ephedrine have no effects on blood pressure is 
unsupported by the available data. What constitutes a ``clinically 
relevant or significant'' dose is undefined (and unlikely to be 
definable given the nature of the available efficacy data for ephedrine 
alkaloids). The difficulties in using the available clinical data to 
obtain such reassurance with regard to the safe use of ephedrine are 
discussed in the response to comment 26 of this document.
    We do not agree that the clinical studies establish that ephedrine 
does not have adverse pharmacological and clinical effects. The 
published controlled studies of the use of ephedrine alkaloid products 
for weight loss cited by these comments cannot establish the safety 
profile of these products. First, many of the most serious risks, such 
as strokes or heart attacks (consequences of elevated blood pressure), 
arrhythmias, or worsened heart failure, are relatively infrequent or 
are delayed and, therefore, will not be detected in studies using small 
populations (such as under 100 patients per group) as these studies 
did. Second, these studies often had other important design 
limitations, such as lack of adequate controls (including the absence 
of placebo groups in some studies), and inadequate information about 
the causes that led to participants dropping out of the trial. In 
addition, persons with known cardiovascular disease or cardiovascular 
risks were usually excluded. Thus, these studies were not designed to 
detect serious adverse effects in susceptible individuals, nor to 
detect adverse effects that occur infrequently. As discussed in the 
following paragraphs, these studies were also not adequately designed 
to assess blood pressure effects. Given these limitations, it is not 
surprising that these published studies do not report serious adverse 
events (Refs. 21, 22, 50, 52, and 81).
    These trials also would not have been able to detect effects on 
blood pressure because of other design limitations. For example, when 
sponsors of drug products seek to detect a drug-induced decrease in 
blood pressure in patients with hypertension, the trial is specifically 
designed to perform the following functions: (1) Assess the blood 
pressure effects at both peak and trough levels of the drug in the 
blood, and (2) measure blood pressure in a consistent and reproducible 
manner. This typically requires the enrollment of at least 100 patients 
to detect a difference from placebo of around 4 to 6 mm Hg systolic, 
multiple measures at each time point and careful attention to how blood 
pressure is measured. These design features are either lacking or not 
described in the publications cited by the comments summarized above, 
significantly limiting the trials' ability to detect any differences 
between the treatment and placebo groups with regard to blood pressure 
or heart rate. With regard to the timing of the measurement, the blood 
pressure measures appear to have been made at (or shortly after) the 
administration of the product containing ephedrine for almost all of 
the published trials. Absorption of the new dose would be minimal or 
incomplete and the dose taken the day before (8 to 12 hours earlier) 
would have been substantially removed from the circulation, given 
ephedrine's approximately 4-hour half-life. Blood levels of ephedrine 
would
 
[[Page 6804]]
 
thus be at or near their lowest values of the day (``trough level''), a 
time when minimal effects on blood pressure would be anticipated. 
Measurements made only at trough level might well miss a significant 
effect on blood pressure that would have been seen at or near peak 
concentrations of ephedrine. Thus, although some published studies on 
the cardiovascular effects of ephedrine (especially blood pressure) 
over a period of weeks or months have reported little or no effect of 
ephedrine on blood pressure and a variable effect on heart rate, these 
studies are severely limited in their ability to establish safety 
because of the clinical trial design limitations (Refs. 81a, 81b, and 
81c), such that the true effects of ephedrine on heart rate and blood 
pressure cannot have been adequately assessed.
    We do not agree with the comments that state that ephedrine 
alkaloids are not toxic because they do not induce specific organ 
pathology. Persistently elevated blood pressure can result in defined 
cardiovascular toxicity (Refs. 29, 29a, and 54), as can ephedrine's 
sympathomimetic effects in people with coronary artery disease or heart 
failure, but the kinds of damage seen in humans from these effects 
would look the same as similar damage that occurs from the underlying 
disease or from raised blood pressure or arrhythmia due to another 
cause.
    (Comment 24) A number of comments discussed the relevance of PPA to 
regulatory decisions on dietary supplements containing ephedrine 
alkaloids. Several comments stated that PPA is a metabolite of 
ephedrine. Various comments contended that ephedrine and PPA are both 
partial agonists and that adverse events associated with dietary 
supplements containing ephedrine alkaloids are of the same type and 
greater in number than those associated with PPA, which was voluntarily 
withdrawn from the U.S. market for safety reasons. Other comments 
maintained that we should not use PPA data to support the hazards of 
dietary supplements containing ephedrine alkaloids. Several such 
comments stated that because PPA differs in pharmacological, 
pharmacokinetic, and pharmacotoxic effects from ephedrine or 
pseudoephedrine, it is scientifically inappropriate for us to assume 
that all ephedrine alkaloids are equivalent. Other comments asserted 
that the various isomers of ephedrine alkaloids have different actions, 
different favorable and adverse effects, different activation of 
receptors, and different effects on human tissues. Several comments 
indicated that norephedrine (an ephedrine alkaloid that makes up one 
component of PPA) is a metabolite of ephedrine and that interactions of 
the multiple ephedrine alkaloids in Ephedra and other botanicals and 
their in vivo metabolites should be considered in a safety evaluation 
of these ingredients and products containing them.
    A few comments asserted that the Hemorrhagic Stroke Project (HSP) 
(Ref. 19) was not designed to assess ephedra exposure. These comments 
maintained that the HSP is limited by significant issues relating to 
observation bias, selection bias, and confounding. One comment 
complained that we reopened the ephedra docket requesting comment on 
the HSP, but we did not place in the docket, or request comment on, the 
many published and unpublished clinical studies submitted by one trade 
organization to support PPA's safety. The comment asserted that our 
review of the pharmacology of ephedrine alkaloids did not include most 
of the pivotal information on PPA submitted to us by the Consumer 
Healthcare Products Association (CHPA). Another comment expressed the 
view that, in our review of safety data related to ephedra, we should 
avoid relying on safety data concerning other ingredients.
    (Response) The substance, l-norephedrine, also known as (-)-
norephedrine, refers to the isomeric portion of PPA that occurs 
naturally in Ephedra and as a metabolite of ephedrine in the body. We 
agree that the l-norephedrine in racemic PPA is a metabolite of 
ephedrine, and further that ephedrine and its metabolites have potent 
vasoactive properties, reinforcing the view that dietary supplements 
containing ephedrine alkaloids have the pharmacological properties 
described in the response to comment 22 of this document. These 
properties, in turn, are linked to predictable adverse clinical 
outcomes both in the general population (e.g., increased blood 
pressure) and in susceptible populations (e.g., cardiac arrhythmias). 
Although there are some similarities between PPA and ephedrine, there 
are also differences. PPA shows tachyphylaxis to rises in blood 
pressure within approximately 24 hours and usage has been linked to 
hemorrhagic strokes (bleeding strokes due to a ruptured blood vessel). 
Ephedrine does not show such tachyphylaxis. In addition, use of 
ephedrine has been associated with ischemic strokes (a blood clot 
blocking off an artery causing a lack of oxygen to portions of the 
brain), but not hemorrhagic strokes. The major alkaloid in most dietary 
supplements containing ephedrine alkaloids is generally ephedrine,