Dietary Supplements Containing Ephedra: Health Risks and FDA's
Oversight (23-JUL-03, GAO-03-1042T).
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.
-------------------------Indexing Terms-------------------------
REPORTNUM: GAO-03-1042T
ACCNO: A07670
TITLE: Dietary Supplements Containing Ephedra: Health Risks and
FDA's Oversight
DATE: 07/23/2003
SUBJECT: Food and drug law
Food and drug legislation
Health hazards
Safety standards
Drugs
Consumer protection
Product safety
Safety regulation
Reporting requirements
******************************************************************
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GAO-03-1042T
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
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. 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 healthrelated 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 healthrelated 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.
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. Highlights of GAO-
03- 1042T, testimony
before the Subcommittee on Oversight and Investigations, Committee on
Energy and Commerce, House of Representatives July 23, 2003
DIETARY SUPPLEMENTS CONTAINING EPHEDRA
Health Risks and FDA*s Oversight
Page 1 GAO- 03- 1042T
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. 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. 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.
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.
Page 2 GAO- 03- 1042T
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. 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
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).
Page 3 GAO- 03- 1042T
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.
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.
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
Background FDA Oversight of Dietary
Supplements under DSHEA
Page 4 GAO- 03- 1042T
each ingredient in the product. 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, 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 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).
Page 5 GAO- 03- 1042T
from the market. 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.
Ephedra has been associated with numerous adverse health effects. As we
previously reported, 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.
6 *Adulterated* is the statutory term used to describe dietary supplements
and other FDAregulated products that are unsuitable for marketing. It is
illegal to market any adulterated product. 7 GAO/ HEHS/ GGD- 99- 90.
Health Concerns about
Ephedra
Page 6 GAO- 03- 1042T
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 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
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).
Page 7 GAO- 03- 1042T
manufacturers continue to offer dietary supplements containing ephedra
while also offering similar products that are ephedra- free. 9 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.
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. 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
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. Adverse Event
Reports Have Led FDA to Conclude That Dietary Supplements Containing
Ephedra Pose a Significant Public Health Hazard
More Adverse Events Have Been Reported for Products Containing Ephedra
Than for Any Other Dietary Supplement
Page 8 GAO- 03- 1042T
ingredients, in 2002, 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. 12 Neither the American Association of Poison Control Centers nor
Metabolife International is required to report these adverse events to
FDA.
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. 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.
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,
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). FDA Has
Determined That
the Adverse Event Reports and Scientific Literature Indicate That Dietary
Supplements Containing Ephedra Pose a Significant Public Health Hazard
Page 9 GAO- 03- 1042T
difficulties estimating population exposure, and poor report quality. 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. 16 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.
In our review of health- related call records for users of Metabolife 356,
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
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. Metabolife
International Call Records Contain Reports of Adverse Events That Are
Consistent with the Types of Adverse Events Reported to FDA
Consumer Information in the Metabolife International Call Records Was
Limited
Page 10 GAO- 03- 1042T
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.
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. 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). 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. 20 Table 1: Number of Reports of Heart Attack,
Stroke, Seizure, or Death in Metabolife
International Call Records Type of adverse event Number a
Heart attack 18 Stroke 26 Seizure 43 Death 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. 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).
Metabolife
International Call Records Contained Reports of Thousands of Adverse
Events, Some of Which Were Serious, among Consumers of Metabolife 356
Page 11 GAO- 03- 1042T
We also found 1,079 reports of other types of adverse events that FDA
identified as serious or potentially serious. 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. 22 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. 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. 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. Reports of
Serious Adverse
Events Involved Consumers Who Were Relatively Young
Page 12 GAO- 03- 1042T
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. 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. 25 This pattern is consistent with
findings from FDA*s review of adverse events associated with ephedra
products. 26 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. 27 For example, in
February 2003, FDA issued warning letters to 26 firms that sell dietary
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. Serious Adverse Events
Were Reported among Consumers Who Used Metabolife 356 within Recommended
Guidelines
FDA Has Taken Some Actions to Oversee Dietary Supplements Containing
Ephedra
Page 13 GAO- 03- 1042T
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 28 and
proposed good manufacturing practice (GMP) regulations 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. 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), 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).
Page 14 GAO- 03- 1042T
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. 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. 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. 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. 34 FDA sought comments on three areas: New evidence on health
risks associated with ephedra.
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).
Page 15 GAO- 03- 1042T
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. 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. Concluding
Observations
Page 16 GAO- 03- 1042T
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.
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. Contact
and
Acknowledgments
Page 17 GAO- 03- 1042T
Product class Product registration Manufacturer
registration Premarket
approval of products
Specific good manufacturing practices Voluntary
postmarket adverse event reporting system
Mandatory manufacturer reporting of adverse events
Safety- related labeling requirements Dietary supplements X a Proposed in
2003 b X Some Conventional foods X a X X c Some
Food additives X a X X X X Monograph drugs d X X X X X
New Drug Application drugs e X X X X X X X Infant formula X X Proposed in
1996 f X X X 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- thecounter
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.
Appendix I: Mechanisms for FDA Oversight of Different Types of Products
(290304)
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