Dietary Supplements Containing Ephedra
Health Risks and FDA's Oversight Gao ID: GAO-03-1042T July 23, 2003Dietary supplements containing ephedra have been associated with serious health-related adverse events, including heart attacks, strokes, seizures, and deaths. The Food and Drug Administration (FDA) regulates dietary supplements under the Dietary Supplement Health and Education Act of 1994 (DSHEA). Reports of adverse events have been received by FDA and others, including Metabolife International, the manufacturer of a dietary supplement containing ephedra, Metabolife 356. Because of concerns surrounding the safety of dietary supplements containing ephedra, GAO was asked to discuss and update some of the findings from its prior work on ephedra, including its examination of Metabolife International's records of health-related calls from consumers of Metabolife 356. Specifically, GAO examined (1) FDA's analysis of the adverse event reports it received for dietary supplements containing ephedra, (2) how the adverse events reported in the health-related call records collected by Metabolife International illustrate the health risks of dietary supplements containing ephedra, and (3) FDA's actions in the oversight of dietary supplements containing ephedra.
FDA has used the adverse event reports it has received to conclude that dietary supplements containing ephedra pose a significant public health hazard. Since February 1993, FDA has received 2,277 reports of adverse events associated with dietary supplements containing ephedra, 15 times more reports than it has received for the next most commonly reported herbal dietary supplement. The types of adverse events that GAO identified in the health-related call records from Metabolife International were consistent with the types of adverse events reported to FDA and with the documented physiological effects of ephedra. Although call records contained limited information for most of the reports, GAO identified 14,684 call records that had reports of at least one adverse event among consumers of Metabolife 356. GAO's count of 92 serious events--heart attacks, strokes, seizures, and deaths--was similar to that of other reviews of the call records, including counts by Metabolife International and its consultants. Many of the serious events were reported among relatively young consumers--more than one-third concerned consumers who reported an age under 30. In addition, for call records containing information on the amount of product consumed or length of product use, GAO found that most of the reported serious adverse events occurred among consumers who followed the usage guidelines on the Metabolife 356 label. As part of its oversight of dietary supplements, FDA has taken some actions specifically focused on dietary supplements containing ephedra. FDA has issued warnings that focus on improper labeling, issued warnings to consumers, and issued a proposed rule in 1997 that, among other things, would require a health warning on the label of dietary supplements containing ephedra and prohibit a dietary supplement from containing both ephedra and a stimulant. FDA subsequently banned the sale of certain classes of over-the-counter drugs containing ephedrine and related alkaloids--the active ingredient in ephedra--in combination with an analgesic or stimulant. As the 1997 proposed rule has not been finalized, there is no rule prohibiting the marketing of dietary supplements with similar ingredients, and many dietary supplements with ephedra, such as Metabolife 356, also include caffeine or other stimulants. To receive comments on new evidence, FDA recently reopened the comment period for the proposed rule, and FDA reported to GAO that the agency is in the process of reviewing comments it has received and has not reached a decision regarding further action.
GAO-03-1042T, Dietary Supplements Containing Ephedra: Health Risks and FDA's Oversight
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Testimony:
Before the Subcommittee on Oversight and Investigations, Committee on
Energy and Commerce, House of Representatives:
United States General Accounting Office:
GAO:
For Release on Delivery Expected at 10:00 a.m.
Wednesday, July 23, 2003:
Dietary Supplements Containing Ephedra:
Health Risks and FDA's Oversight:
Statement of Marcia Crosse :
Acting Director, Health Care--Public Health and Science Issues:
GAO-03-1042T:
GAO Highlights:
Highlights of GAO-03-1042T, testimony before the Subcommittee on
Oversight and Investigations, Committee on Energy and Commerce, House
of Representatives
Why GAO Did This Study:
Dietary supplements containing ephedra have been associated with
serious health-related adverse events, including heart attacks,
strokes, seizures, and deaths. The Food and Drug Administration (FDA)
regulates dietary supplements under the Dietary Supplement Health and
Education Act of 1994 (DSHEA). Reports of adverse events have been
received by FDA and others, including Metabolife International, the
manufacturer of a dietary supplement containing ephedra, Metabolife
356.
Because of concerns surrounding the safety of dietary supplements
containing ephedra, GAO was asked to discuss and update some of the
findings from its prior work on ephedra, including its examination of
Metabolife International‘s records of health-related calls from
consumers of Metabolife 356. Specifically, GAO examined (1) FDA‘s
analysis of the adverse event reports it received for dietary
supplements containing ephedra, (2) how the adverse events reported in
the health-related call records collected by Metabolife International
illustrate the health risks of dietary supplements containing ephedra,
and (3) FDA‘s actions in the oversight of dietary supplements
containing ephedra.
What GAO Found:
FDA has used the adverse event reports it has received to conclude
that dietary supplements containing ephedra pose a significant public
health hazard. Since February 1993, FDA has received 2,277 reports of
adverse events associated with dietary supplements containing ephedra,
15 times more reports than it has received for the next most commonly
reported herbal dietary supplement.
The types of adverse events that GAO identified in the health-related
call records from Metabolife International were consistent with the
types of adverse events reported to FDA and with the documented
physiological effects of ephedra. Although call records contained
limited information for most of the reports, GAO identified 14,684
call records that had reports of at least one adverse event among
consumers of Metabolife 356. GAO‘s count of 92 serious events”heart
attacks, strokes, seizures, and deaths”was similar to that of other
reviews of the call records, including counts by Metabolife
International and its consultants. Many of the serious events were
reported among relatively young consumers”more than one-third
concerned consumers who reported an age under 30. In addition, for
call records containing information on the amount of product consumed
or length of product use, GAO found that most of the reported serious
adverse events occurred among consumers who followed the usage
guidelines on the Metabolife 356 label.
As part of its oversight of dietary supplements, FDA has taken some
actions specifically focused on dietary supplements containing
ephedra. FDA has issued warnings that focus on improper labeling,
issued warnings to consumers, and issued a proposed rule in 1997 that,
among other things, would require a health warning on the label of
dietary supplements containing ephedra and prohibit a dietary
supplement from containing both ephedra and a stimulant. FDA
subsequently banned the sale of certain classes of over-the-counter
drugs containing ephedrine and related alkaloids”the active ingredient
in ephedra”in combination with an analgesic or stimulant. As the 1997
proposed rule has not been finalized, there is no rule prohibiting the
marketing of dietary supplements with similar ingredients, and many
dietary supplements with ephedra, such as Metabolife 356, also include
caffeine or other stimulants. To receive comments on new evidence, FDA
recently reopened the comment period for the proposed rule, and FDA
reported to GAO that the agency is in the process of reviewing
comments it has received and has not reached a decision regarding
further action.
www.gao.gov/cgi-bin/getrpt?GAO-03-1042T.
To view the full product, including the scope and methodology, click
on the link above. For more information, contact Marcia Crosse, (202)
512-7119.
[End of section]
Mr. Chairman and Members of the Subcommittee:
I am pleased to be here today as the Subcommittee considers concerns
about the safety of dietary supplements containing ephedra. More than
half of U.S. adults are overweight or obese, and more than one-third
are trying to lose weight. Many Americans have turned to dietary
supplements to help them lose weight. The most widely used weight loss
supplement ingredient is ephedra, which is also referred to as ma
huang.[Footnote 1] The dietary supplement industry has estimated that
as many as 3 billion servings of dietary supplements containing ephedra
are consumed each year in the United States. Medical experts have
expressed concerns about the safety of dietary supplements containing
ephedra. Reports of adverse health events associated with such
supplements, including reports of heart attack, stroke, seizure, and
death, have been received by the Food and Drug Administration (FDA) and
others, including Metabolife International, the manufacturer of a
dietary supplement containing ephedra, Metabolife 356.
The Dietary Supplement Health and Education Act of 1994 (DSHEA) created
a framework for FDA's regulation of dietary supplements as part of its
oversight of food safety.[Footnote 2] Since dietary supplements are
generally marketed without prior FDA review of their safety, FDA relies
on voluntary reports of adverse events from consumers, health
professionals, manufacturers, and others in its effort to oversee the
safety of marketed dietary supplements.
Because of concerns surrounding the safety of dietary supplements
containing ephedra, you asked us to discuss some of the findings from
our prior work on ephedra. My remarks today will focus on (1) FDA's
analysis of adverse event reports it has received about dietary
supplements containing ephedra, (2) how the adverse events reported in
the call records received by Metabolife International illustrate the
health risks of dietary supplements containing ephedra, and (3) FDA's
actions in the oversight of dietary supplements containing ephedra.
This testimony is based primarily on our earlier reports on dietary
supplements, including our March 2003 review of health-related call
records received by Metabolife International.[Footnote 3] For this
testimony, we also conducted additional analyses of the data in the
Metabolife International call records, obtained updated information
from FDA about its oversight efforts and adverse event reports that it
has received concerning ephedra, and reviewed FDA analyses of the
safety of dietary supplements containing ephedra. We conducted our work
from June 2003 through July 2003 in accordance with generally accepted
government auditing standards.
In summary, FDA has determined that dietary supplements containing
ephedra pose a significant public health hazard based on the 2,277
adverse events reports it has received. The number of adverse event
reports FDA has received for dietary supplements containing ephedra is
15 times greater than the number it has received for the next most
commonly reported herbal dietary supplement. While it is difficult to
establish with certainty that a particular adverse event has been
caused by the use of ephedra, based on the pattern of adverse event
reports it has received and the scientific literature it has reviewed,
FDA has concluded that ephedra poses a risk of cardiovascular and
nervous system effects among consumers who are young to middle-aged.
The types of adverse events that we identified in the health-related
call records from Metabolife International were consistent with the
types of adverse events reported to FDA and with the documented
physiological effects of ephedra. Although the call records contained
limited information for most of the reports, we identified 14,684 call
records that contained reports of at least one adverse event among
consumers of Metabolife 356. Our count of 92 serious events--heart
attacks, strokes, seizures, and deaths--was similar to that of other
reviews of the call records, including counts by Metabolife
International and its consultants. Many of the serious events were
reported among relatively young consumers--more than one-third
concerned consumers who reported an age under 30. In addition, for the
call records containing information on the amount of product consumed
or length of product use, we found that most of the reported serious
adverse events occurred among consumers who followed the usage
guidelines on the Metabolife 356 label--the consumers reported that
they did not take more of the product or take it for a longer period
than the company recommended.
As part of its oversight of dietary supplements, FDA has taken some
actions specifically focused on dietary supplements containing ephedra.
FDA has issued warnings to manufacturers that focus on improper product
labeling, issued warnings to consumers, and issued a proposed rule in
1997 that, among other things, would require a health warning on the
label of dietary supplements containing ephedra and prohibit a dietary
supplement from containing both ephedrine alkaloids--the active
ingredient in ephedra--and a stimulant. FDA subsequently banned the
sale of certain classes of over-the-counter drugs containing ephedrine
and related alkaloids in combination with an analgesic or stimulant. As
the 1997 proposed rule has not been finalized, there is no rule
prohibiting the marketing of dietary supplements with similar
ingredients, and many dietary supplements with ephedra, such as
Metabolife 356, also include caffeine or other stimulants. To receive
comments on new evidence, FDA recently reopened the comment period for
the proposed rule, and FDA reported to us that the agency is in the
process of reviewing comments it has received and has not reached a
decision regarding further action.
Background:
Ephedra, the most widely used ingredient in dietary supplements for
weight loss, is a powerful stimulant that can affect the nervous and
cardiovascular systems. Adverse events among consumers of dietary
supplements containing ephedra have been described in scientific
literature and in detailed adverse event reports. Because of concerns
about the risks of ephedra, medical organizations, states, and athletic
associations have sought to reduce the use of dietary supplements
containing ephedra.
FDA Oversight of Dietary Supplements under DSHEA:
Under DSHEA, FDA regulates dietary supplements, including vitamins,
minerals, herbs and other botanicals, amino acids, certain other
dietary substances, and derivatives of these items. DSHEA requires that
dietary supplement labels include a complete list of ingredients and
the amount of each ingredient in the product.[Footnote 4] Dietary
supplements may not contain synthetic active ingredients that are sold
in over-the-counter drugs and prescription medications and cannot be
promoted as a treatment, prevention, or cure for a specific disease or
condition.
Under DSHEA, manufacturers are responsible for ensuring the safety of
dietary supplements they sell. Dietary supplements do not need approval
from FDA before they are marketed; thus FDA generally addresses safety
concerns only after dietary supplements are marketed. DSHEA does not
require manufacturers to register with FDA,[Footnote 5] identify the
products they manufacture, or provide reports of adverse events to FDA.
Mechanisms that FDA uses to oversee dietary supplements and other
products it regulates differ (see app. I for more details).
Since manufacturers of dietary supplements are not required to provide
reports of adverse events to FDA, the agency relies on voluntary
postmarket reporting of adverse events to better understand the safety
of dietary supplements. Some individual adverse event reports are
especially valuable to FDA because they include enough information to
help FDA determine if the adverse event was likely caused by the
supplement. These reports include information about the receipt of
medical care, health care professionals' attribution of adverse events
to the consumption of dietary supplements, the consumer's appropriate
use of the products, the consumer's use of other products, underlying
health conditions and other alternative explanations for the adverse
event, and the consistency of symptoms with the documented effects of
the dietary supplement.
FDA, through the Department of Justice, can take enforcement action in
court against dietary supplements that are adulterated to remove them
from the market.[Footnote 6] A dietary supplement is considered
adulterated under a number of circumstances, including when it:
* presents a "significant or unreasonable risk of illness or injury"
under the conditions of use recommended or suggested in its labeling,
or under ordinary conditions of use if there are no suggestions or
recommendations in the labeling, or:
* bears or contains any "poisonous or deleterious substance" which may
render it injurious to health under the conditions of use recommended
or suggested in its labeling.
Instead of going to court, FDA may choose to take administrative action
to prohibit the sale of dietary supplements it considers to be
adulterated. FDA can promulgate a regulation declaring a particular
dietary supplement to be adulterated. FDA has not taken this action
with any dietary supplement. FDA can also issue an advisory letter
explaining why it considers the dietary supplement to be adulterated.
The advisory letter provides guidance to the industry regarding FDA's
opinion and notifies the public that FDA may take legal action against
firms or individuals that do not follow the letter's advice. FDA has
done this for two dietary supplement ingredients, comfrey and
aristolochic acid.
In addition, although it has never been done, the Secretary of Health
and Human Services (HHS) may declare that a dietary supplement is
adulterated because it poses an "imminent hazard" to public health or
safety. In doing so, the Secretary must initiate an administrative
hearing to affirm or withdraw the declaration.
Health Concerns about Ephedra:
Ephedra has been associated with numerous adverse health effects. As we
previously reported,[Footnote 7] case reports and scientific literature
have suggested that ephedrine alkaloids can increase blood pressure in
those with normal blood pressure, predispose certain individuals to
rapid heart rate, and cause stroke, among other things. We also
reported descriptions of adverse events associated with ephedrine
alkaloids that affected the central nervous system, such as seizures,
mania, and paranoid psychoses. FDA has received reports of adverse
events associated with dietary supplements containing ephedra,
including heart attack, stroke, seizure, psychosis, and death, that are
consistent with the scientific literature. In February 2003, the RAND
Corporation released a review of the scientific evidence on the safety
and efficacy of dietary supplements containing ephedra[Footnote 8] and
concluded that a sufficient number of cases of these same types of
events had occurred in young adults to warrant further scientific study
of the causal relationship between ephedra and these serious adverse
events. RAND also found that use of ephedra or ephedrine plus caffeine
is associated with a number of other adverse effects, including an
increased risk of nausea, vomiting, heart palpitations, and psychiatric
symptoms such as anxiety and change in mood.
Because of these health concerns, many organizations and jurisdictions
have taken actions aimed at reducing the use of dietary supplements
containing ephedra. The American Medical Association and the American
Heart Association have urged FDA to ban the sale of dietary supplements
containing ephedra. In January 2002, Health Canada issued a Health
Advisory for Canadians not to use certain products containing ephedra,
especially those that also contain caffeine and other stimulants. In
2003, Illinois banned the sale of products containing ephedra and other
states have similar bans under consideration. In addition, some states
have banned the sale of such products to minors or required label
warnings. Several sports organizations, including the NCAA, the
National Football League, the U.S. Olympic Committee, and the
International Olympic Committee, have banned the use of ephedra by
their athletes.
In 2003, General Nutrition Centers, the nation's largest specialty
retailer of nutritional supplements, discontinued the sale of products
containing ephedra, as have three other major retail outlets. Some
manufacturers have stopped producing dietary supplements containing
ephedra. Other manufacturers continue to offer dietary supplements
containing ephedra while also offering similar products that are
ephedra-free.[Footnote 9]
Adverse Event Reports Have Led FDA to Conclude That Dietary Supplements
Containing Ephedra Pose a Significant Public Health Hazard:
Using the adverse event reports it has received and evidence from the
scientific literature, FDA has concluded that dietary supplements
containing ephedra pose a "significant public health hazard." FDA and
others have received thousands of reports of adverse events among users
of dietary supplements containing ephedra, more than for any other
dietary supplement ingredient. Metabolife International also received
thousands of reports of adverse events.
More Adverse Events Have Been Reported for Products Containing Ephedra
Than for Any Other Dietary Supplement:
FDA has received more reports of adverse events for dietary supplements
containing ephedra than for any other dietary supplement ingredient. In
addition, poison control centers and one manufacturer, Metabolife
International, have received thousands of reports of adverse events
associated with dietary supplements containing ephedra. From February
22, 1993, through July 14, 2003, FDA received 2,277 reports of adverse
events associated with dietary supplements containing ephedra, which
was 15 times more reports than it received for the next most commonly
reported herbal dietary supplement, St. John's wort.[Footnote 10]
Other organizations also have received a large number of adverse event
reports for dietary supplements containing ephedra. The American
Association of Poison Control Centers received 1,428 reports of adverse
events associated with dietary supplements containing ephedra, either
alone or in combination with other botanical dietary supplement
ingredients, in 2002,[Footnote 11] nearly two-thirds as many as FDA
received over a 10-year period. The centers noted that there were more
reports of adverse events for ephedra-containing dietary supplements
than for others. Further, as we reported in March 2003, Metabolife
International had 14,684 health-related call records that contained
reports of adverse events associated with its product, Metabolife 356,
from May 1997 through July 2002.[Footnote 12] Neither the American
Association of Poison Control Centers nor Metabolife International is
required to report these adverse events to FDA.
FDA Has Determined That the Adverse Event Reports and Scientific
Literature Indicate That Dietary Supplements Containing Ephedra Pose a
Significant Public Health Hazard:
From the adverse event reports it has received and the scientific
literature it has reviewed, FDA concluded in March 2000 that dietary
supplements containing ephedra pose a significant public health hazard
that primarily involves consumers who are young to middle-aged and can
result in adverse cardiovascular and nervous system effects.[Footnote
13] It further concluded that many of the adverse events were serious,
resulting in morbidity and mortality that would not be expected in a
young population and that could further compromise the health of more
vulnerable older adults or those with underlying conditions.
A study commissioned by FDA estimated that the agency receives reports
for less than 1 percent of adverse events associated with dietary
supplements.[Footnote 14] Although causality cannot be determined based
on the individual adverse event reports FDA receives, the agency uses
these reports to identify possible risks to consumers from dietary
supplements. As we have previously reported, there are well-known
weaknesses in the current system of voluntary reporting of adverse
events, such as different interpretations in determining an adverse
event, underreporting, difficulties estimating population exposure,
and poor report quality.[Footnote 15] Despite these limitations, FDA
maintains that even isolated reports can be definitive in associating
products with an adverse effect if the report contains sufficient
evidence, such as supporting medical documents, a temporal relationship
between the product and effect, and evidence of dechallenge and
rechallenge.[Footnote 16]
Metabolife International Call Records Contain Reports of Adverse Events
That Are Consistent with the Types of Adverse Events Reported to FDA:
The types of adverse events that we identified in the Metabolife
International call records are consistent with the types of adverse
events reported to FDA and with the documented physiological effects of
ephedra. As we recently reported, most of the Metabolife International
call records contained limited information about the event and the
consumer. Nonetheless, the call records contribute to existing
knowledge about adverse events that have been associated with ephedra
use. In our review, we identified 14,684 call records that contained
reports of at least one adverse event among consumers of Metabolife
356. Within these call records, we found 92 reports of serious adverse
events--heart attacks, strokes, seizures, and deaths--a count that was
similar to that of other reviews of the call records. In addition, the
call records contain reports of serious adverse events in consumers who
were young and among those who used the product within the recommended
guidelines. These findings are consistent with reports FDA has received
regarding dietary supplements containing ephedra.
Consumer Information in the Metabolife International Call Records Was
Limited:
In our review of health-related call records for users of Metabolife
356,[Footnote 17] we found that the information in the call records was
limited. Call records were sometimes difficult to read and interpret,
and consumer information was not consistently recorded. In some cases,
the evidence for a report of an adverse event was limited to a single
word on a call record. In other cases, information was entered into a
form developed by Metabolife International with multiple boxes for
consumer-and event-related information. Most call records did not
document complete information about the consumer's age, sex, weight,
and height. Because the company did not systematically follow up on
calls reporting adverse events, and the adverse events were not
reported to FDA, it is not possible to gather more complete information
or medical records.
Metabolife International Call Records Contained Reports of Thousands of
Adverse Events, Some of Which Were Serious, among Consumers of
Metabolife 356:
As we reported in March 2003, we identified 14,684 call records that
contained at least one report of an adverse event among consumers of
Metabolife 356.[Footnote 18] The types of reported adverse events were
consistent with the cardiovascular and central nervous system effects
that have been associated with ephedra products in the literature,
adverse event reports received by FDA, other case reports, and RAND's
review. Within the call records, we identified 92 reports of heart
attack, stroke, seizure, and death (see table 1).[Footnote 19] Our
count of reports of these serious adverse events was similar to that of
other reviews of the Metabolife International call records, including
counts by Metabolife International and its consultants.[Footnote 20]
Table 1: Number of Reports of Heart Attack, Stroke, Seizure, or Death
in Metabolife International Call Records:
Type of adverse event: Heart attack; Number[A]: 18.
Type of adverse event: Stroke; Number[A]: 26.
Type of adverse event: Seizure; Number[A]: 43.
Type of adverse event: Death; Number[A]: 5.
Source: Metabolife International.
Note: GAO analysis of 14,684 health-related call records provided by
Metabolife International.
[A] The counts do not represent unique consumers because a single call
record may have more than one complaint and because some consumers
called the Metabolife health information phone line more than once.
[End of table]
We also found 1,079 reports of other types of adverse events that FDA
identified as serious or potentially serious.[Footnote 21] These
included chest pain, significant elevations in blood pressure, systemic
rash, and urinary infection. In addition to these 1,079 reports, we
found records that contained reports of a broad range of other types of
adverse events, including changes in heart rate such as palpitations
and increased heart rate; blood in stool; blood in urine; bruising;
hair loss; and menstrual irregularity.[Footnote 22]
Reports of Serious Adverse Events Involved Consumers Who Were
Relatively Young:
Within the subset of call records that contained information on age,
the distribution of ages suggests that a relatively young population
was experiencing the reported serious adverse events. Among the call
records that contained a report of a serious event, 44 percent included
information on age.[Footnote 23] For these call records, more than one-
third concerned consumers who reported an age under 30--the average
reported age was 38 (ranging from 17 to 65). As noted above, FDA has
also received reports of serious adverse events occurring in a
population of young adults. Because we do not know the age profile of
all Metabolife 356 consumers, we cannot determine if the age
distribution among those reporting serious adverse events in the
Metabolife International call records reflects that age profile.
Serious Adverse Events Were Reported among Consumers Who Used
Metabolife 356 within Recommended Guidelines:
Within the subset of Metabolife International call records that
contained information on how the product was used by the consumer, most
of the reported serious adverse events occurred among consumers who
reported using the product within the guidelines on the Metabolife 356
label--that is, who reported that they did not take more of the product
or take it for a longer period than recommended.[Footnote 24]
Information about product use, however, was incomplete--40 and 55
percent of the call records that reported a serious event contained
information about the amount of Metabolife 356 used and the duration of
use, respectively. Among the call records that reported a serious
adverse event and also contained information about product use, 97
percent of consumers reported using an amount of product within the
recommended guidelines. Similarly, 71 percent of those consumers
reported using the product for a length of time that was within the
recommended guidelines.[Footnote 25] This pattern is consistent with
findings from FDA's review of adverse events associated with ephedra
products.[Footnote 26]
FDA Has Taken Some Actions to Oversee Dietary Supplements Containing
Ephedra:
As part of its oversight of dietary supplements, FDA has taken some
actions specifically focused on dietary supplements containing ephedra.
FDA has issued warnings that focus on improper product labeling, issued
warnings to consumers, and issued a proposed rule in 1997 that, among
other things, would require a health warning on the label of dietary
supplements containing ephedra and prohibit a dietary supplement from
containing both ephedra and a stimulant. However, parts of this rule
remain under consideration 6 years after it was first proposed.
As we previously reported, FDA has focused its enforcement actions
regarding dietary supplements on improper labeling.[Footnote 27] For
example, in February 2003, FDA issued warning letters to 26 firms that
sell dietary supplements containing ephedra. All of these letters
advised marketers that label claims for enhancement of physical
performance were unsubstantiated and the products were therefore
misbranded.
FDA and HHS have also directly warned consumers about the safety of
dietary supplements containing ephedra. In February 1995, FDA issued a
press release warning consumers about a specific dietary supplement
product that contained both ephedra and caffeine, because it had
determined that the product represented a threat to public health.
Further, in February 2003, the Secretary of HHS issued a statement to
caution people against using dietary supplements containing ephedra and
indicated that FDA continues to have serious concerns about the risks
of these dietary supplements.
FDA has also taken actions in its oversight of dietary supplements in
general. Specifically, FDA has conducted facility inspections[Footnote
28] and proposed good manufacturing practice (GMP) regulations[Footnote
29] that focus on product quality in general, not the safety of an
individual ingredient.
FDA first issued a proposed rule to regulate dietary supplements
containing ephedrine alkaloids in 1997.[Footnote 30] The proposed rule
would:
* define the amount of ephedrine alkaloids in a serving of dietary
supplement at and above which the product would be deemed adulterated
(8 milligrams),
* establish labeling requirements regarding maximum frequency of use
and daily serving limits,
* require that labels on these supplements contain a statement warning
that the product should not be used for more than 7 days,
* prohibit the use of ephedrine alkaloids with ingredients that have a
known stimulant effect (e.g., caffeine),
* prohibit labeling claims that promote long-term intake of the
supplements to achieve the purported purpose,
* require a warning statement in conjunction with claims that encourage
short-term excessive intake to enhance the purported effect, and:
* require that specific warning statements appear on product labels.
Our 1999 report on the proposed rule was critical of the science FDA
used to support the serving size and duration of use limits in the
proposed rule.[Footnote 31] However, we did not conclude that dietary
supplements containing ephedra were safe, and we commented that the
adverse events reported to FDA were serious enough to warrant FDA's
further investigation of ephedra safety. Primarily, we were concerned
that FDA used only 13 adverse event reports to establish serving limits
and had weak support for proposed limits on duration of use. Partly as
a result of our review, FDA withdrew the sections of the proposed rule
on serving size and duration of use limits.[Footnote 32]
In the interim, FDA has taken action to regulate certain drugs that
contain ephedrine, the active ingredient in ephedra. In September 2001,
FDA issued a final rule stating that certain over-the-counter drugs
containing ephedrine and related alkaloids in combination with an
analgesic or stimulant could not be marketed as over-the-counter
drugs.[Footnote 33] There currently is no similar rule prohibiting the
marketing of dietary supplements containing ephedra in combination with
analgesics or stimulants, such as caffeine. As a result, dietary
supplements may contain ingredients that are prohibited in drugs. In
fact, many dietary supplements with ephedra, such as Metabolife 356,
also include caffeine. The proposed rule contains a provision that
would prohibit dietary supplements from containing both ephedra and
other stimulants.
In March 2003, almost 6 years after the initial proposal, FDA reopened
the comment period for the remaining provisions of this proposed rule
for 30 days.[Footnote 34] FDA sought comments on three areas:
* New evidence on health risks associated with ephedra.
* Whether the currently available evidence and medical literature
demonstrate that dietary supplements containing ephedra pose a
"significant or unreasonable risk of illness or injury" under the
conditions of use recommended or suggested in their labeling, or under
ordinary conditions of use if there are no suggestions in the labeling.
* A new warning label for ephedra products that warns about reports of
serious adverse events after the use of ephedra, including heart
attack, seizure, stroke, and death; cautions that the risk can increase
with the dose, with strenuous exercise, and with other stimulants such
as caffeine; specifies certain groups (such as women who are pregnant
or breast feeding and persons under 18) who should not use these
products; and lists other diseases, such as heart disease and high
blood pressure, that should rule out the use of ephedrine alkaloids.
On July 14, 2003, FDA reported to us that the agency is in the process
of reviewing the comments and has not reached a decision regarding
further action. While FDA has not attempted to ban the marketing of
dietary supplements containing ephedra, the agency has sought, in these
comments, additional information that would help it determine whether
or not such action would be warranted.
Concluding Observations:
Because the regulatory framework for dietary supplements is primarily a
postmarketing program and FDA does not review the safety of dietary
supplements before they are marketed, adverse event reports are
important sources of information about the health risks of dietary
supplements containing ephedra. It is often difficult to demonstrate
conclusively that a single reported adverse event was caused by
ephedra, but some individual reports, particularly when they are
complemented by follow-up investigation of the case, can be especially
informative. Although the information in the Metabolife International
call records we examined was limited, the types of adverse events we
observed were consistent with the known risks of ephedra, including
serious events such as five reports of death. Based on the pattern of
adverse event reports FDA has received and the consistency of those
reports with the known effects of ephedra from the scientific
literature, the agency concluded 3 years ago that dietary supplements
containing ephedra pose a "significant public health hazard." FDA is
currently reviewing information that will help the agency determine
what further actions are warranted.
Mr. Chairman, this completes my prepared statement. I would be happy to
respond to any questions you or other Members of the Subcommittee may
have at this time.
Contact and Acknowledgments:
For more information regarding this testimony, please call Marcia
Crosse at (202) 512-7119. Key contributors include Martin T. Gahart,
Carolyn Feis Korman, Chad Davenport, Roseanne Price, and Julian
Klazkin.
[End of section]
Appendix I: Mechanisms for FDA Oversight of Different Types of
Products:
Table 2:
Product class: Dietary supplements; Product registration: No;
Manufacturer registration: Yes[A]; Premarket approval of products:
No; Specific good manufacturing practices: Proposed in 2003[B];
Voluntary postmarket adverse event reporting system: Yes; Mandatory
manufacturer reporting of adverse events: No; Safety-related
labeling requirements: Some.
Product class: Conventional foods; Product registration: No;
Manufacturer registration: Yes[A]; Premarket approval of products:
No; Specific good manufacturing practices: Yes; Voluntary postmarket
adverse event reporting system: Yes[C]; Mandatory manufacturer reporting
of adverse events: No; Safety-related labeling requirements: Some.
Product class: Food additives; Product registration: No;
Manufacturer registration: Yes[A]; Premarket approval of products: Yes;
Specific good manufacturing practices: Yes; Voluntary postmarket adverse
event reporting system: Yes; Mandatory manufacturer reporting of adverse
events: No; Safety-related labeling requirements: Yes.
Product class: Monograph drugs[D]; Product registration: Yes;
Manufacturer registration: Yes; Premarket approval of products: No;
Specific good manufacturing practices: Yes; Voluntary postmarket adverse
event reporting system: Yes; Mandatory manufacturer reporting of adverse
events: No; Safety-related labeling requirements: Yes.
Product class: New Drug Application drugs[E]; Product registration: Yes;
Manufacturer registration: Yes; Premarket approval of products: Yes;
Specific good manufacturing practices: Yes; Voluntary postmarket adverse
event reporting system: Yes; Mandatory manufacturer reporting of adverse
events: Yes; Safety-related labeling requirements: Yes.
Product class: Infant formula; Product registration: Yes; Manufacturer
registration: Yes; Premarket approval of products: No; Specific good
manufacturing practices: Proposed in 1996[F]; Voluntary postmarket
adverse event reporting system: Yes; Mandatory manufacturer reporting of
adverse events: Yes; Safety-related labeling requirements: Yes.
Source: GAO analysis of U.S Department of Health and Human Services,
Office of Inspector General, Adverse Event Reporting for Dietary
Supplements: An Inadequate Safety Valve.
[A] Under the Public Health Security and Bioterrorism Preparedness and
Response Act of 2002, Pub.L. No. 107-188, 116 Stat. 594, manufacturers
and distributors are required to registered with FDA no later than
December 13, 2003.
[B] FDA proposed good manufacturing practices in March 2003. Comments
are due to FDA by August 11, 2003. Regulations regarding the packaging
of dietary supplements containing iron were issued in 1997.
[C] FDA does not collect or evaluate all adverse event reports on all
conventional food. In addition, excluded from this system are the
investigations FDA conducts following food-borne illness outbreaks.
[D] Monograph drugs are typically over-the-counter drugs that must
adhere to specific safety standards set for each ingredient and do not
undergo clinical testing.
[E] New Drug Applications must be submitted to FDA for all prescription
drugs and some over-the-counter drugs prior to marketing. This
application must include data that demonstrate the safety and efficacy
of the product.
[F] The comment period for the proposed good manufacturing practices
regulation was reopened in June 2003, and closes August 26, 2003.
[End of table]
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FOOTNOTES
[1] The active ingredients in ephedra are ephedrine alkaloids.
Ephedrine alkaloids that are not from an herbal or botanical source (or
a derivative thereof), such as synthetic ephedrine alkaloids, may not
be marketed as dietary supplements.
[2] Pub. L. No. 103-417, 108 Stat. 4325.
[3] U.S. General Accounting Office, Dietary Supplements: Uncertainties
in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids, GAO/
HEHS/GGD-99-90 (Washington, D.C.: July 2, 1999); Health Products for
Seniors: "Anti-Aging" Products Pose Potential for Physical and Economic
Harm, GAO-01-1129 (Washington, D.C.: Sept. 7, 2001); Dietary
Supplements for Weight Loss: Limited Federal Oversight Has Focused More
on Marketing Than on Safety, GAO-02-985T (Washington, D.C.: July 31,
2002); and Dietary Supplements: Review of Health-Related Call Records
for Users of Metabolife 356, GAO-03-494 (Washington, D.C.: Mar. 31,
2003).
[4] Products may include "proprietary blends," which must list all
ingredients but do not need to list the amount of each ingredient.
[5] However, manufacturers and distributors of dietary supplements are
required to register with FDA no later than December 13, 2003, under
the Public Health Security and Bioterrorism Preparedness and Response
Act of 2002, Pub. L. No. 107-188, 116 Stat. 594. FDA issued a proposed
rule in February 2003 to implement the requirement. See 68 Fed. Reg.
5378 (Feb. 3, 2003).
[6] "Adulterated" is the statutory term used to describe dietary
supplements and other FDA-regulated products that are unsuitable for
marketing. It is illegal to market any adulterated product.
[7] GAO/HEHS/GGD-99-90.
[8] Paul Shekelle, et al., Ephedra and Ephedrine for Weight Loss and
Athletic Performance Enhancement: Clinical Efficacy and Side Effects.
Evidence Report/Technology Assessment No. 76 (prepared by Southern
California Evidence-based Practice Center, RAND, under Contract No.
290-97-0001, Task Order No. 9). AHRQ Publication No. 03-E022
(Rockville, Md.: Agency for Healthcare Research and Quality, February
2003).
[9] Some ephedra-free products include other herbal stimulants, such as
Citrus aurantium. Citrus aurantium contains synephrine, which is
chemically similar to the ephedrine and pseudoephedrine found in many
over-the-counter and allergy medicines and in dietary supplements
containing ephedra.
[10] In total, FDA received 5,574 adverse reports for dietary
supplements during that period. The total number of reports of adverse
events for ephedra products includes 135 reports from the Metabolife
International call records that FDA designated as serious adverse
events.
[11] William A. Watson, et al., "2002 Annual Report of the American
Association of Poison Control Centers Toxic Exposure Surveillance
System," American Journal of Emergency Medicine (in press). See also
Stephen Bent, et al., "The Relative Safety of Ephedra Compared with
Other Herbal Products," Annals of Internal Medicine, vol. 138 (2003),
468-471.
[12] GAO-03-494.
[13] Food and Drug Administration, Assessment of Public Health Risks
Associated with the Use of Ephedrine Alkaloid-containing Dietary
Supplements (Mar. 31, 2000) (Docket No. 00N-1200).
[14] U.S. Department of Health and Human Services, Office of Inspector
General, Adverse Event Reporting for Dietary Supplements: An Inadequate
Safety Valve, OEI-01-00-00180 (Washington, D.C.: Apr. 2001).
[15] GAO/HEHS/GGD-99-90.
[16] Dechallenge is evident when signs and symptoms resolve or improve
when a consumer stops using a product, and rechallenge is evident when
symptoms recur when the consumer resumes using the product.
[17] GAO-03-494.
[18] A single call record may have had more than one complaint.
[19] We highlighted these serious adverse events because they are
identified in FDA's proposed label warning for dietary supplements
containing ephedra. See 68 Fed. Reg. 10417 (Mar. 5, 2003).
[20] Metabolife International has not issued a report on its review of
the call records, but provided us with a list of the calls it believed
to report heart attack, stroke, seizure, and death. Metabolife
International also commissioned reviews by three consultants (see
GAO-03-494).
[21] In its 1997 proposed rule on dietary supplements containing
ephedra, FDA identified as serious or potentially serious some types of
adverse events for which the agency had received reports. See 62 Fed.
Reg. 30678 (June 4, 1997).
[22] Within the complete set of call records, we also found 332 reports
of visits to either an emergency department or a hospital. According to
FDA officials, unlike most adverse events related to foods, adverse
event reports it had received related to ephedra products commonly
involved a visit to a physician or an emergency room. FDA considers a
hospitalization or prolongation of an existing hospitalization to be a
serious adverse event. Metabolife International records did not
consistently distinguish between an actual hospitalization and "going
to the hospital," which may not have resulted in an actual
hospitalization.
[23] For the entire set of the Metabolife International call records,
42 percent contained information on the age of the consumer.
[24] The product label recommends that adults take one to two caplets
two to three times per day or every 4 hours, not to exceed eight
caplets per day. The label also recommends that persons should not use
the product for more than 12 weeks and that exceeding the recommended
amount may cause serious adverse health effects, including heart attack
or stroke.
[25] For all call records containing information on the amount of
product used or duration of use, 99 and 91 percent of consumers,
respectively, reported using the product within the guidelines
recommended on the label.
[26] Food and Drug Administration, March 2000.
[27] GAO-02-985T.
[28] Since 1999, FDA, its state partners, and state contractors have
inspected 6 percent of the known dietary supplement manufacturing and
repacking facilities annually. Inspections focus on sanitation,
buildings and facilities, equipment, production, and process controls.
[29] In March 2003, FDA issued proposed GMP regulations for dietary
ingredients and dietary supplements. See 68 Fed. Reg. 12158 (Mar. 13,
2003). The comment period for the proposed GMPs was extended until Aug.
11, 2003. See 68 Fed. Reg. 27008 (May 19, 2003). GMP regulations are
important in ensuring that the product is not contaminated and contains
what the label reports. They do not, however, address the safety of any
individual ingredient, such as ephedra.
[30] 62 Fed. Reg. 30678 (June 4, 1997).
[31] GAO/HEHS/GGD-99-90.
[32] 65 Fed. Reg. 17474 (Apr. 3, 2000).
[33] See 66 Fed. Reg. 49276 (Sept. 27, 2001).
[34] 68 Fed. Reg. 10417 (Mar. 5, 2003).
