Department of Health and Human Services 
OFFICE OF 
INSPECTOR GENERAL 
Adverse Event Reporting 
For Dietary Supplements 
An Inadequate Safety Valve 
APRIL  2001 
OEI-01-00-00180  OFFICE OF INSPECTOR GENERAL 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, is to 
protect the integrity of the Department of Health and Human Services programs as well as the 
health and welfare of beneficiaries served by them.  This statutory mission is carried out through a 
nationwide program of audits, investigations, inspections, sanctions, and fraud alerts.  The 
Inspector General informs the Secretary of program and management problems and recommends 
legislative, regulatory, and operational approaches to correct them. 
Office of Evaluation and Inspections 
The Office of Evaluation and Inspections (OEI) is one of several components of the Office of 
Inspector General.  It conducts short-term management and program evaluations (called 
inspections) that focus on issues of concern to the Department, the Congress, and the public.  The 
inspection reports provide findings and recommendations on the efficiency, vulnerability, and 
effectiveness of departmental programs. 
OEI's Boston Regional Office prepared this report under the direction of Mark R. Yessian, Ph.D., 
Regional Inspector General and Joyce M. Greenleaf, M.B.A., Assistant Regional Inspector 
General.  Principal OEI staff included: 
BOSTON  HEADQUARTERS 
Laura C. McBride, Lead Analyst  Elise Stein, Program Specialist

Aimee L. Kasenga, Program Analyst  Joseph Rutherford, Program Specialist

Nancy L. London, Program Analyst

Nicola Y. Pinson, Program Analyst

To obtain copies of this report, please call the Boston Regional Office at (617) 565-1050. 
Reports are also available on the World Wide Web at our home page address: 
http://www.dhhs.gov/oig/oei  E X E C U T I V E   S U M M A R Y  
PURPOSE 
To assess the effectiveness of the Food and Drug Administrations (FDA) adverse event 
reporting system for dietary supplements in protecting the American consumer. 
BACKGROUND 
Dietary supplements are increasingly popular.  Currently about 60 percent of Americans 
take some form of dietary supplement every day without any apparent problems. 
Supplements include substances such as vitamins, minerals, botanicals, and amino acids. 
Although many of these supplements can be beneficial, there are risks associated with 
some.  For example, ginkgo biloba may lead to excessive bleeding, vitamin A in high 
dosages during pregnancy may lead to birth defects, and St. Johns Wort may reduce the 
effectiveness of some antiviral drugs.  Unlike new prescription and over-the-counter 
drugs, FDA does not have the authority to require supplements to undergo premarket 
approval for safety and efficacy.  Instead, it relies mostly on its adverse event reporting 
system to identify safety problems. 
FDAs Adverse Event Reporting System for Dietary Supplements 
FDAs adverse event reporting system for dietary supplements includes (1) detecting 
adverse events, (2) generating signals of possible public health concerns, (3) assessing 
those signals, and (4) taking appropriate safety actions based on its assessment.  An 
adverse event is an incident of illness or injury that may be associated with a product or 
ingredient.  With further investigation, the association may or may not be confirmed. 
Reporting adverse events is entirely voluntary, and FDA receives reports from a variety of 
sources including consumers and health professionals. 
When a signal of a possible health problem is generated from the adverse event reporting 
system, FDA assesses whether it is an actual public health problem warranting attention. 
FDA can assess these signals by reviewing scientific literature, consulting with experts, 
reviewing clinical data, conducting its own laboratory tests, and/or commissioning studies. 
If FDA confirms that a public health problem exists it can take a range of safety actions, 
such as issuing warnings to consumers and health professionals, issuing import alerts, 
requesting product recalls, or seizing products. 
This Inquiry 
In this report, we evaluate how well FDAs adverse event reporting system for dietary 
supplements functions as a consumer protection tool.  We analyzed data from FDAs 
database; reviewed FDA laws, regulations, policies, and procedures; reviewed several 
adverse event reports; reviewed relevant literature; and interviewed FDA officials, industry 
representatives, and scientific experts.  We did not evaluate the internal 
i
Dietary Supplements: AER System   OEI-01-00-00180  operating procedures of the system. 
FINDINGS 
FDAs adverse event reporting system detects relatively few adverse events. 
Adverse event reporting systems typically detect only a small proportion of the events that 
actually occur.  This appears to be especially true of FDAs system for dietary 
supplements.  A recent FDA-commissioned study estimated that FDA receives less than 1 
percent of all adverse events associated with dietary supplements.  Among the factors that 
may contribute to under-reporting are that many consumers presume supplements to be 
safe, use these products without the supervision of a health care professional, and may be 
unaware that FDA regulates them.  FDAs limited outreach concerning this system 
contributes to this unawareness. 
It has difficulty generating signals of possible public health concerns. 
FDA lacks much of the information that is necessary to effectively analyze adverse event 
reports and to generate possible signals of concern.  Below we document the lack of 
information by presenting FDA data between 1994-1999. 
Limited medical information.  FDA did not receive the medical records for 58 percent 
(464 of 801) of the reports for which it requested them.  Only 20 percent (527 of 2,547) 
of adverse events reports received by FDA came from health professionals. 
Limited product information.  FDA was unable to determine the ingredients for 32 
percent (1,153 of 3,574) of the products mentioned in adverse event reports.  FDA does 
not have the product labels for 77 percent (2,752 of 3,574) of the products mentioned in 
reports.  FDA does not have product samples for 69 percent (130 of 188) of the products 
for which it requested them.  Product samples are especially helpful because dietary 
supplement ingredients are not standardized. 
Limited manufacturer information.  FDA reports that it has received fewer than 10 
adverse event reports directly from manufacturers.  FDA was unable to determine the 
manufacturer of dietary supplement products for 32 percent (1,153 of 3,574) of the 
products involved in reports.  FDA was unable to determine the city and State for 71 
percent (644 of 904) of the manufacturers. 
Limited information on the dietary supplement consumer.  FDA was unable to 
follow-up with 27 percent (214 of 801) of the reports it tagged for follow-up primarily 
because the reports lacked sufficient information to identify the alleged injured party. 
Limited ability to analyze trends.  FDA has difficulty analyzing trends of adverse event 
reports because its lacks an adequate computer database for routine analysis and receives 
relatively few reports. 
ii
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  FDA lacks vital information to adequately assess signals of possible public 
health concerns generated by the adverse event reporting system. 
In order to assess such signals, FDA must draw upon key information external to the 
system.  But FDA faces obstacles in obtaining such information.  For a recent case study 
that documents these obstacles see appendix A. 
Limited clinical information.  There is some clinical information available on dietary 
supplements and more is becoming available every day.  But, the current regulatory 
framework for dietary supplements permits manufacturers to market a supplement without 
premarket safety studies.  For this and other reasons, FDA has relatively little clinical 
information on particular products.  The law requires manufacturers of certain new dietary 
ingredients to notify FDA 75 days prior to market and include relevant safety 
information.  However, very few dietary ingredients are subject to this requirement, and 
FDA has issued no guidance on the type of safety information that should be submitted. 
Limited information on consumer use.  FDA lacks a mechanism to track the number of 
consumers using a particular supplement.  Such information can be helpful to determine 
the incidence of certain adverse events in the user population and thus, the extent of the 
public health problem that it poses. 
As a result, FDA rarely takes safety actions related to the adverse event reporting 
system. 
Safety actions can be of significant benefit to consumer safety.  For example, based on 
FDAs investigation of adverse event reports, it found products containing plantain were 
contaminated with Digitalis lanata, a plant that can cause heart attacks in certain 
individuals.  FDA issued a consumer warning against certain products containing plantain 
and asked supplement manufacturers to voluntarily recall their products contaminated with 
Digitalis lanata. 
But, between January 1994 and June 2000, we were able to document only 32 safety 
actions that FDA took based on the adverse event reporting systema period when more 
than 100 million people were taking supplements.  With limited information to draw upon 
to generate and assess signals, FDA rarely reaches the point of knowing whether taking a 
safety action is warranted. 
Public disclosure of adverse event reports can also be considered a type of safety action. 
FDA uses its website as its main vehicle for disclosure.  However, its website has 
significant limitations; for example, it provides no evaluation of the reports, contains 
misleading information, and is rarely updated. 
RECOMMENDATIONS 
Our evaluation of FDAs dietary supplement adverse event reporting system leads us to 
conclude that without further development of the overall regulatory framework for 
iii
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  dietary supplements, the potential of the system to serve as a consumer safeguard is 
inherently limited.  The program simply cannot serve as an adequate safety valve until 
other measures are taken that will allow FDA to generate and confirm signals of possible 
public health concerns. 
Below we offer our recommendations as a blueprint for actions that FDA can take over a 
reasonable period of time.  It has already called for some of them in its strategic plan for 
dietary supplements.  We recognize that some of our recommendations will call for 
legislative or regulatory changes.  We also recognize that resources are limited and that 
some of our recommendations may require additional resources. 
RECOMMENDATION 1:  Facilitate greater detection of adverse events. 
Require dietary supplement manufacturers to report serious adverse events to FDA 
for some products.  FDA should examine what types of products or ingredients should 
fall under this requirement.  FDA already requires pharmaceutical manufacturers to report 
adverse events for all prescription and some over-the-counter drugs. 
Contract with Poison Control Centers to obtain their adverse event reports on 
dietary supplements.  These centers hold information that may be useful to FDA. 
Reports from Poison Control Centers may provide additional data to help generate signals 
of possible public health concern. 
Inform health professionals and consumers about the adverse event reporting 
system for dietary supplements.  The main way FDA can accomplish this is by 
expanding its outreach to health professionals and including information about the safety 
actions it has taken.  Other possibilities include requiring manufacturers to provide a toll-
free number on their product labels or placing FDAs toll-free number on labels. 
RECOMMENDATION 2:  Obtain more information on adverse event reports in 
order to generate stronger signals of public health concerns. 
Educate health professionals about the importance of including medical information 
in adverse event reports.  Without medical information about the alleged injured parties, 
FDA lacks crucial information for determining the likelihood that an adverse event was 
related to the use of a dietary supplement.  When FDA conducts outreach it should 
encourage health processionals to obtain permission from their patients to release their 
medical records when appropriate. 
Require dietary supplement manufacturers to register their products with FDA. A 
complete product registry would allow FDA to instantly access a list of all of the 
ingredients in a particular product and determine the product manufacturers name as soon 
as it receives an adverse event report. 
Require dietary supplement manufacturers to register with FDA.  A registry of 
manufacturers would enable FDA to quickly and easily contact a manufacturer whose 
product was associated with an adverse event to obtain additional information. 
iv
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Notify manufacturers when FDA receives a serious adverse event report.  Alerting 
manufacturers of adverse events in which their products have been mentioned would give 
FDA the opportunity to obtain more product information from the manufacturer.  It 
would also allow manufacturers to reevaluate the safety profile of the product, including 
manufacturing procedures, in a timely manner. 
Emphasize to health professionals and consumers the importance of providing a way 
to identify the alleged injured party.  Without this information FDA may be unable to 
gather additional information excluded from the report. 
Develop a new computer database to track and analyze adverse event reports.  To 
help identify signals, FDA needs a database that allows for querying by ingredients as well 
as products and types of adverse events. 
RECOMMENDATION 3:  Obtain vital information to adequately assess signals 
generated by the adverse event reporting system. 
Issue guidance on the type of safety information that manufacturers should include 
in the 75-day premarket notification requirement for some new dietary supplement 
ingredients.  FDA should take full advantage of its existing authority to obtain as much 
safety information as possible prior to marketing. 
Explore the possibility of a monograph system for dietary supplements that would 
contain safety information on particular ingredients.  Monographs are point papers on 
particular ingredients that contain safety and efficacy information.  Such a system would 
allow FDA to have in a systematic fashion safety information that it could rely upon to 
help make decisions. 
Collaborate with the National Institutes of Health in setting a research agenda 
addressing safety issues.  Another way that FDA can gain clinical information is by 
collaborating with the National Institutes of Health that funds and conducts research 
related to dietary supplements. 
Assist industry and the United State Pharmacopeia in standardizing dietary 
supplement ingredients, particularly botanicals.  Standardized ingredients would allow 
FDA to have the confidence that in taking action against unsafe products or ingredients it 
is addressing all the products posing a health risk. 
Expedite the development and implementation of good manufacturing practices for 
dietary supplement manufacturers.  Standardized ingredients must be complemented by 
FDA enforcing those standards through good manufacturing practices.  These are essential 
for FDA to be assured of the precise contents of each batch of supplements that is 
manufactured. 
v
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  RECOMMENDATION 4:  Disclose more useful information to the public about 
dietary supplement adverse events. 
FDA should provide more useful data on its website so that consumers can, to some 
extent, evaluate the likelihood that the adverse event was related to the supplement. 
FDA could update the information on its website more regularly.  FDA could also 
accomplish this is by providing summary data on the numbers and types of reports 
received by product types or ingredients.  Over time, as resources become available it 
could consider indicating the likelihood the event was caused by a product. 
COMMENTS 
We received comments on our draft reports from the Food and Drug Administration.  We 
also solicited and received comments from three trade associations (Consumer Healthcare 
Products Association, American Herbal Products Association, and the Council for 
Responsible Nutrition) and two public interest organizations (Public Citizens Health 
Research Group and the Center for Science in the Public Interest.)  See appendix C for the 
comments in their entirety. 
On the basis of these comments we made several changes that are reflected in this final 
report.  Some involved minor technical changes, and others involved brief elaborations to 
clarify and add context.  In two instances we modified our recommendations to target 
them more effectively and to minimize regulatory burden.  We limited the scope of 
mandatory reporting of adverse event reports to events that are both serious in nature and 
fall under a certain subset of products to be determined by FDA.  Similarly, instead of 
calling for FDA to notify manufacturers of all adverse event reports it receives, we called 
for it to notify the manufacturers of serious reports only. 
Food and Drug Administration 
FDA reported that our findings were a fair assessment of the challenges it faces.  It also 
agreed with the majority of our recommendations.  As part of its comments, it categorized 
our recommendations into three areas: (1) tasks that it can currently accomplish, (2) tasks 
that require additional resources, and (3) tasks that require both legislative changes and 
additional resources.  FDA documented the progress it has made in each of these 
categories.  FDA indicated that the major difficulty it faces to improving the system is a 
lack of adequate resources. 
FDA is making progress toward improving the system along the lines we call for in our 
report.  Many of our recommendations are already included among FDAs top priorities 
for the year as well as in its 10-year strategic plan.  We also encourage FDA to seek the 
authority it needs to require manufacturer and product registration and mandatory 
manufacturer reporting of adverse events. 
vi
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Trade Associations 
The three trade associations provided some support for our recommendations, but for the 
most part, they were highly critical of both our findings and recommendations.  While we 
disagree with the thrust of their comments, they help sharpen the issues that need to be 
addressed as part of any reform. 
One of their major critiques was that we chose not to evaluate the internal operating 
procedures of FDAs adverse event reporting system, thereby leaving us with little basis 
for our broader recommendations.  We agree that there could be value to a procedural 
review.  FDA should be doing everything it can to make sure the current system operates 
as effectively as it possibly can.  However, we offer strong evidence that the current 
system is fundamentally flawed and cannot provide an adequate consumer safeguard 
unless FDA is given more tools to do the job. 
Another significant critique was that we failed to view dietary supplements in the context 
of a food-related system.  This failure, they claim, led us to call for more extensive 
oversight, similar to that for prescription drugs.  Our inquiry focused on how the current 
system was functioning and made us acutely aware of just how little information FDA has 
available to determine whether adverse events about dietary supplements (however 
characterized) present danger signs that should be addressed.  Without an improved 
capacity to obtain such information, FDAs adverse event reporting system will continue 
to fall short of its potential. 
Still another critique was that our report reflects a negative view of dietary supplements 
and fails to recognize their role as self-care products that so many consumers value.  We 
regret any implication of such a negative view.  If the kind of recommendations we call for 
are enacted, we suggest that consumers would have more extensive and useful information 
available to them on these self-care products and could have more confidence that an 
adverse event reporting system was providing them with a valuable measure of protection. 
Public Interest Organizations 
The two public interest organizations strongly supported our report.  Their main critique 
was that we did not go far enough.  One called for legislative changes that, over time, 
would significantly enhance FDA authorities.  The other called for FDA to support a 
systematic study of dietary supplement safety and efficacy.  While our evidence did not 
allow us to go as far as these organizations would like, it did lead us to emphasize that a 
comprehensive set of changes must be carried out if the adverse event reporting system is 
to provide an adequate consumer safety valve. 
vii
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  T A B L E   O F   C O N T E N T S  
PAGE

EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  i

INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

PRIMER ON FDAS ADVERSE EVENT REPORTING SYSTEM . . . . . . . . . . . . . . . . . . . 4

THE IMPORTANCE OF THE SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

FINDINGS

Few adverse events detected  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Difficulty generating signals of public health concern  . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Lacks vital information to assess signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Difficulty taking action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

RECOMMENDATIONS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  19

COMMENTS ON THE DRAFT REPORT  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  25

APPENDICES

A:  FDAs experiences in overseeing ephedrine alkaloids  . . . . . . . . . . . . . . . . . . . . . . . 28

B:  FDAs safety actions  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

C:  Comments on the draft report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

D:  Endnotes  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

viii
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  I N T R O D U C T I O N  
PURPOSE 
To assess the effectiveness of the Food and Drug Administrations (FDA) adverse event 
reporting system for dietary supplements in protecting the American consumer. 
BACKGROUND 
Dietary supplements are increasingly popular.  Currently about 60 percent of Americans 
take some form of dietary supplement every day without any apparent problems.  Dietary 
supplements include products such as vitamins, minerals, botanicals (herbal products), and 
amino acids.1  Healthy consumers use supplements to increase their energy, boost their 
immune systems, prevent memory loss, build muscle mass, or lose weight.  Ill people turn 
to supplements as an alternative to traditional treatments, to complement prescription 
drugs, to save money needed to buy more expensive prescription drugs, or in general to 
promote good health.  Research studies suggest some products are beneficial.  For 
example, glucosamine and chondroitin may relieve symptoms of osteoarthritis.2  Saw 
palmetto may improve the symptoms for men with benign prostatic hyperplasia.3  Folic 
acid may reduce the risk of  neural tube defects in newborns.4 
Although many of these supplements can be beneficial, risks are associated with some. 
For example, ginkgo biloba may lead to excessive bleeding, high dosages of vitamin A 
during pregnancy may lead to birth defects, and St. Johns Wort may compromise the 
effectiveness of some antiviral drugs.  Unlike new prescription and over-the-counter 
drugs, the law does not require supplements to undergo premarket approval for safety and 
efficacy.  Instead, FDA relies mainly on its adverse event reporting system to identify 
safety problems. 
FDAs Adverse Event System for Dietary Supplements 
In 1993 FDA created a system to collect and review adverse event reports on 
supplements.  An adverse event is an incident of illness or injury that may be associated 
with a product or ingredient.  FDAs adverse event reporting system for dietary 
supplements includes (1) detecting adverse events, (2) generating signals of possible public 
health concerns, (3) assessing those signals, and (4) taking appropriate safety actions 
based on its assessment.  The system for dietary supplements, according to the director of 
the Center for Food Safety and Applied Nutrition, provides an essential monitoring tool 
for identifying potential serious public health issues that may be associated with the use of 
a particular product or type of product already in the marketplace that needs to be 
investigated and critically evaluated.5 
Reporting adverse events associated with dietary supplements to FDA is entirely 
voluntary.  FDA receives adverse event reports on dietary supplements from consumers, 
health professionals, and manufacturers through a variety of sources, including State 
1
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  health departments, Poison Control Centers, direct communication with individuals, and 
MedWatch, a computerized reporting system used to monitor a variety of FDA-regulated 
products.  Reported events range in severity from nausea and dizziness to cardiac arrest or 
death. 
FDA relies on the adverse event reporting system to generate signals of possible public 
health concerns.  When signals are generated, FDA still needs to assess the signal to 
determine if a public health problem exists.  FDA can investigate the signal in many ways 
including examining clinical information and/or conducting laboratory tests.  If the signal is 
confirmed, FDA can take a variety of actions to protect the public depending on the 
seriousness of the problem.  FDA safety actions range from issuing warnings to consumers 
and health professionals to seizing products.  FDA can also take civil and enforcement 
actions.  (See the Primer on page 4 for additional information on the system.) 
Dietary Supplement Health and Education Act 
In 1994, Congress passed the Dietary Supplement Health and Education Act based on the 
premise that legislative action that protects the right of access of consumers to safe 
dietary supplements is necessary to promote wellness.6  The Act defined the term dietary 
supplement and legitimized it as a category of health care products.  It also created a new 
regulatory framework for dietary supplements while assuring consumers broad access. 
The Act generally classifies dietary supplements as a category of food.  As such, they fall 
under the authority of the FDA, in its Center for Food Safety and Applied Nutrition.  FDA 
has authority for dietary supplements for (1) product safety, (2) product labeling including 
claims, (3) notification of new dietary ingredients, and (4) good manufacturing practices. 
FDA has issued over 25 Federal Register notices regarding dietary supplements, mostly 
focused on labeling and product claims.  Although the Act is grounded on the presumption 
that dietary supplements are safe, it does provide FDA with the authority to take action 
against a dietary supplement or ingredient that presents a significant or unreasonable risk 
of illness or injury.7 
Our Inquiry 
FDAs adverse event reporting system for dietary supplements is a particularly important 
safety valve for consumers due to the lack of other complementary oversight systems, 
such as premarket approval, and the increased popularity of dietary supplements.  In this 
report, we examine how well the system (1) detects adverse events, (2) generates signals 
of public health concerns, (3) assesses these signals, and when necessary, (4) takes 
appropriate actions to protect consumers.  We do not evaluate the safety of dietary 
supplements themselves, nor do we evaluate the adequacy of other FDA activities related 
to dietary supplements, such as labeling requirements and product claims.8  Finally, we do 
not evaluate the internal operating procedures of the system. 
2
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  We analyzed data from FDA; reviewed FDA laws, regulations, policies, and procedures; 
reviewed several adverse event reports; examined the product labels and claims for 30 
dietary supplements; reviewed relevant literature; and interviewed relevant FDA officials, 
industry representatives, and scientific experts. 
We conducted this inspection in accordance with the Quality Standards for Inspections 
issued by the Presidents Council on Integrity and Efficiency. 
3
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  P R I M E R  O N  F D A  S   A D V E R S E  E V E N T  
R E P O R T I N G   S Y S T E M  
DETECTING ADVERSE EVENTS 
C  FDA receives adverse event reports through a variety of reporting mechanisms: MedWatch, Poison Control 
Centers, FDA District Offices, State Health Departments, and direct contact with individuals. 
C  Consumers, health professionals, and manufacturers are the three categories of reporters. 
GENERATING SIGNALS OF POSSIBLE PUBLIC HEALTH CONCERN 
C  FDA enters the adverse event report into its database and forwards it to its clinical staff for review. 
C	 FDA determines if follow-up to the report is needed to obtain more information based on whether FDA 
considers the event to be a high concern, serious, or clinically significant.9  If FDA does not request 
follow-up, it closes the file. In either case, FDA maintains the report in the database to be used for later 
analysis. 
C	 When FDA requests follow-up of an individual report, it may request one or more of the following: product 
label, product sample, consumers medical records, and information about how much was consumed and for 
how long. 
C	 The following criteria must be met for follow-up: adequate contact information of the reporter must exist, 
and the injured party must be identified in some way. 
C	 After follow-up, FDA reviews the information collected and determines whether it has enough information 
to evaluate the report. If it does, FDA makes an evaluation and closes the file. FDA maintains the report in 
a database. If FDA lacks enough information it may request information again. In cases where FDA 
cannot obtain the information the file is closed. 
C	 Adverse event reports in and of themselves do not lead to conclusive assessments of the safety of a product 
or ingredient. Rather, FDA uses adverse event reports to generate signals of possible public health 
concerns. Signals are most often generated when FDA identifies a trend, although one well-documented 
report may be enough to create a signal. 
ASSESSING SIGNALS 
C  FDA relies on its own evaluation as well as outside sources such as medical literature, clinical studies, and 
expert advisors to evaluate whether the signal signifies a public health problem warranting FDA action. 
C  FDA may also conduct its own laboratory testing of product samples to help assess and confirm signals. 
TAKING SAFETY ACTIONS 
C	 Once FDA has confirmed a signal, it can take a variety of actions to protect the public from risks associated 
with dietary supplements. These actions vary depending on the seriousness of the situation. FDA can issue 
warnings to consumers or health professionals, require more information on product labels, request a recall 
of the product, or seize the product. 
C  Depending on the action chosen, FDA may have to demonstrate that the product is adulterated, misbranded, 
or an unapproved new drug. 
C  FDA also publicly discloses some elements of its database on its public website. 
4
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  I M P O R T A N C E   O F  T H E   S Y S T E M  
Adverse event systems are typically used as ancillary risk identification systems.  Below 
we present several reasons specific to dietary supplements that underscore the need for 
FDAs system. 
Unique Role of the Adverse Event Reporting System for Dietary Supplements 
Adverse event reports in and of themselves typically cannot generate conclusive evidence 
about the safety of a product or ingredient.  Rather, the system can generate signals of 
possible public health problems.  FDA typically uncovers signals by analyzing trends of the 
reports, although one well-documented report can generate a signal as well.  FDA must 
assess these signals to confirm if in fact a public health problem exists related to a product 
or an ingredient.  In assessing a signal, it relies on a variety of sources, such as clinical 
research, scientific literature, and/or laboratory testing. 
In the case of dietary supplements, FDA has relatively little clinical data on ingredients and 
products.  Thus, FDA is inherently limited in its ability to investigate signals of public 
health problems generated by the system.  In contrast, manufacturers of new prescription 
drugs and over-the-counter drugs are required to submit safety data to FDA on their 
products prior to market (see table on the following page). 
Furthermore, unlike manufacturers of new prescription and over-the-counter drugs who 
shoulder the burden of demonstrating the safety of their products prior to market, the 
burden is placed on FDA to prove that the supplement is unsafe or adulterated after the 
product is already on the market.  And in some cases similar to other FDA products, FDA 
may have to prove that the product is unsafe when used as recommended by the 
manufacturer or suggested in the labeling; if the consumer suffers an adverse reaction after 
using a higher dosage than recommended or suggested in the labeling, the supplement may 
still be considered safe.10 
The law requires supplement manufacturers to notify FDA 75 days prior to marketing 
new dietary supplement ingredients.  However, this mechanism is only minimally effective 
at protecting consumers because so few ingredients are subject to this requirement.  The 
law defines a new dietary ingredient as a substance that was not present in the food 
supply as an article of food in a form in which the food has not been chemically altered in 
the United States before October 15, 1994.11  But, because FDA lacks documentation as 
to which dietary ingredients were marketed before 1994 and because there is a wide range 
of articles used for food, it is difficult for FDA to determine whether a dietary ingredient is 
subject to the 75-day notice requirement.  To date, FDA has received 97 premarket 
notifications, covering 114 ingredients, 102 of which were new dietary ingredients (the 
remaining products/ingredients were found to be drugs or biologics). 
Even when FDA receives a 75-day notification, FDA may disagree with the 
manufacturers assertion with respect to the safety of the ingredient, but FDA bears the 
5
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180   burden of showing that the data are inadequate to provide reasonable assurance that the 
ingredient does not present a significant or unreasonable risk of illness if an enforcement 
action becomes necessary.12 
A Comparison of FDAs Regulatory Mechanisms to Help Ensure the Safety of Products 
Product  Product  Manufac.  Premarke  Specific Good  Voluntary  Mandatory  Safety-
Class  Registration  Registration  t  Manufac.  Postmarket  Manufac.  Related 
Approval  Practices  Adverse  Reporting  Labeling 
of  Event  of Adverse  Requirements 
Products  Reporting  Event 
System  Reporting 
Dietary  under  U  some 
Supplement  development 
Conventional  U  U*  some 
Foods 
Food  U  U  U  some  U 
Additive 
Monograph  U  U  UU  U  U 
Drugs** 
New Drug  U  U  U  U  U  U  U 
Application 
Drugs*** 
Infant  U  U  proposed in  U  U  U 
Formula  1996 
*FDA does not collect or evaluate all adverse events on all conventional food. Excluded in this system are the 
investigations FDA conducts following food-borne illness outbreaks. 
**Monograph drugs are typically over-the-counter drugs that must adhere to specific safety standards set out for each 
ingredient and do not undergo clinical testing. 
***NDA is a new drug application that all prescription drugs and some over-the-counter drugs must submit to FDA prior to 
market. This application must include data that demonstrates the safety and efficacy of the product. 
Popularity of Dietary Supplements 
Since the early 1990s, consumer demand for supplements has sky-rocketed.  Estimated 
sales of dietary supplements increased nearly 100 percent between 1992 and 1996, from 
$3.7 billion to $6.5 billion.13  In 1999, the industry grossed an estimated $15.4 billion.14 
Today, dietary supplements are widely available in grocery stores, retail pharmacies, health 
food stores, and on the Internet.  According to a study commissioned by FDA, over 1,500 
manufacturers produce dietary supplements.15 
Currently, over 60 percent of the American population uses some form of dietary 
supplement every day.16  Vitamin and mineral supplements are the most commonly used.17 
An estimated 22.8 million consumers use herbal products in lieu of prescription medicine 
and 30 million use herbal products instead of over-the-counter drugs.18  The elderly are 
one of the largest consumer populations.19  In the words of the FDA 
6
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  commissioner, A small but disturbing number of these products have a potential for harm 
or bear unsupported claims.  In this context, a rapidly expanding industry and a changing 
demographic of consumers eager to manage their own health care needs provide a 
significant regulatory challenge.20 
Associated Risks With Some Dietary Supplements 
Many consumers use dietary supplements without apparent problems.  However, risks do 
exist.  In a recent survey, 12 percent of consumers of herbal products reported that they 
had experienced side effects.21  Possible health problems associated with dietary 
supplements fall into three major categories: direct toxicity, interactions with other drugs 
or supplements, and contamination of products.  Below we describe some recent study 
findings. 
Direct Toxicity.  Several clinical studies have identified serious side effects with dietary 
supplements.  For example, high dosages of vitamin A taken during pregnancy are 
associated with higher rates of cranial neural crest birth defects.22  Ginkgo biloba, a 
popular supplement taken to enhance memory, has been found to be a blood thinner.  It 
can lead to excessive bleeding and, in some cases, stroke.23 
Supplement-Drug Interactions.  A recent survey found that about 31 percent of 
respondents reported taking herbal products in conjunction with prescription drugs and 30 
percent took supplements with over-the-counter drugs.24  Several recent studies have 
identified potentially dangerous interactions between drugs and herbs that can include 
synergistic effects, poisoning, or inactivation of one of the substances.  In one recent 
study, researchers at the National Institutes of Health demonstrated that St. Johns Wort, 
typically used to enhance mood, could significantly compromise the effectiveness of 
antiviral drugs often prescribed to treat HIV infection.25 
Contamination of Products.  In 1989, FDA requested an urgent recall of products 
containing L-tryptophan, most often used as an aid for sleep.  The use of L-tryptophan 
was associated with an elevation of eosinophils, a particular type of white blood cell, and 
severe muscle pain, a syndrome referred to as the eosinophilia-mylagia syndrome.  These 
products were associated with over 1,500 cases of adverse events reported to the Center 
for Disease Control and Prevention.  In 1997, FDA found that certain dietary supplement 
products were contaminated with Digitalis lanata, a plant that contains powerful heart 
stimulants and under certain circumstances may lead to cardiac arrest.26  The California 
Department of Health reported that 32 percent of 260 Asian herbal products selected off 
the shelves of California retail stores were contaminated with lead, arsenic, or undeclared 
pharmaceuticals.27  Several reports have identified herbal products containing prescription 
drugs used to treat diabetes.28  In another case, a large supplement manufacturer was 
found guilty of defrauding the government by adding synthetic ingredients to a product 
labeled all natural and thus, misbranding the product.29 
7
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Concerns About Dietary Supplement Product Labels 
The law prevents manufacturers from marketing dietary supplement products with labeling 
that is false or misleading.  Labeling that omits a material fact is considered misleading 
under the law.  Many products that lack warnings may be misbranded under this provision, 
and FDA may not be adequately enforcing this requirement.  For example, we purchased 
three different brands of ginkgo biloba, a supplement that can act as an anticoagulant. 
Product A had no warning.  Product B warned, if you are using MAO inhibitors consult 
your healthcare practitioner prior to using this product.  Product C warned, if you are 
pregnant or breast-feeding, taking blood-thinning medications or regularly taking aspirin, 
consult your health care professional before using this product.  Some industry groups 
have established standard warnings for certain products, but manufacturers use of these 
standard warnings is voluntary.  FDA has issued a regulation requiring a warning label on 
dietary supplement that contain iron, but otherwise generally has not prescribed warnings 
or listings of side effects for particular ingredients or products. 
Even when consumers are aware of the risks associated with certain dietary supplement 
ingredients, the ingredients or the active constituent can be listed under a variety of names 
that may be unfamiliar to the consumer.  For example, products containing ephedrine 
alkaloids, a category of ingredients that act as stimulants, have several names.  In our 
review of botanical literature we found 25 common names for botanicals containing 
ephedrine alkaloids including Ma Huang, Ephedra, Chinese joint-fir, Country Mallow, and 
Brighams Tea.30  FDA labeling regulations for dietary supplements require that 
ingredients be listed under their Latin binomial names except when they are available in the 
Herbs of Commerce.31  FDA requires that manufacturers use common names consistent 
with the names standardized in the Herbs of Commerce to help limit the number of 
common names in use.  However, even the Herbs of Commerce contains multiple 
common names for plants that contain ephedrine alkaloids.32 
8
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  F I N D I N G S  
FDAs Adverse Event Reporting System Detects Relatively Few 
Adverse Events. 
Adverse event systems typically detect only a small proportion of events that actually 
occur.  They are passive systems that depend on someone linking an adverse event with 
the use of a product and then reporting that event.  FDAs adverse event reporting system 
for dietary supplements is no exception.  A recent study commissioned by FDA estimated 
that the adverse event reports FDA receives represent less than 1 percent of all of the 
adverse events associated with dietary supplements.33  We found that FDAs dietary 
supplement adverse event 
system received 2,547 adverse 
event reports related to 
Dietary Supplement Adverse Event Reports 
supplements from 1994 through  Received by FDA and Poison Control Centers 
1999a period when more than 
100 million people were taking 
supplements.  A survey found 
that 12 percent (11.9 million) of 
all consumers using herbal 
products reported that they have 
experienced side effects or 
adverse reactions.34 
Comparison to other adverse 
event reporting systems.  We 
recognize that no clear standard 
exists on how many reports 
FDA should receive.  While not 
directly comparable, other 
systems appear to be receiving 
more reports.  Most notably, 
Source: FDAs Adverse Event Reporting Database 
Poison Control Centersa 
and Poison Control Centers Data 
network of sites, predominantly 
hospitals and academic health 
centers, that respond to consumer calls about problems with productsreceived 
significantly more dietary supplement adverse event reports than FDA for the past several 
years.  For example, in 1999 these Centers received 13,000 reports related to dietary 
supplements while FDA received 460 reports (see figure).35,36  Similarly, since 1993, the 
Texas State Department of Health has received 1,400 reports involving dietary 
supplements; thus, a single State received more than half the number of reports that FDA 
received during that same time period.37 
9
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Manufacturers also have information on adverse events that they do not share with FDA. 
Dietary supplements manufacturers are not legally required to report adverse events.  In 
one legal proceeding, the manufacturer initially reported that it had no adverse event 
reports, but later released hundreds of refund requests that detailed many adverse 
events.38 
Certain characteristics of dietary supplements may contribute to under-reporting. 
Dietary supplements include natural ingredients and are self-care products.  These two 
factors may minimize a consumers readiness to link an adverse event with a dietary 
supplement productthe first step in the reporting process. 
Presumed safety.  The presumed safety of dietary supplements may limit consumers 
inclination to link an adverse event with a supplement product.  Many consumers believe 
that, due to the natural ingredients contained in dietary supplements, the products are 
inherently safe.  Congress, in establishing the current dietary supplement regulatory 
system, stated, dietary supplements are safe within a broad range of intake, and safety 
problems with the supplements are relatively rare.39 
Self-Care products.  Another factor that may contribute to under-reporting of supplement 
adverse events is that they are self-care products.  In some instances, consumers may turn 
to supplements instead of over-the-counter medications, despite the fact that most dietary 
supplements are intended to supplement the diet and cannot explicitly claim to affect 
disease.40  Consumers often use supplements without guidance from, or even the 
knowledge of, their physicians.  Health professionals are often unaware that their patients 
are taking dietary supplements.  They may not ask their patients whether they are taking a 
supplement and even when they do, patients may fail to inform them.  A recent study 
found that 7 in 10 surgery patients who were taking herbal supplements failed to tell their 
doctors when asked.41  Thus, health professionals may be unable to link a patients adverse 
event, should one arise, with supplement use. 
Perceived lack of Federal involvement.  Another potential cause of under-reporting to 
FDAs dietary supplement adverse event system is that the required disclaimer for  specific 
types of dietary supplement claims permitted without prior authorization may be 
misinterpreted to mean that FDA has no oversight over dietary supplements.  The required 
disclaimer, following a products claim states, this statement has not been evaluated by 
the Food and Drug Administration.  This product is not intended to diagnose, treat, cure 
or prevent any disease.  In fact a recent survey showed that 50 percent of Americans 
think the Federal government does not regulate supplements and 16 percent were 
uncertain.42  Therefore, consumers may not think that FDA is the appropriate body to 
which to report. 
FDA conducts little outreach.  While FDA does provide information on adverse event 
reporting for dietary supplements on its website, many consumers may be unaware of this. 
FDA has not conducted targeted outreach to health care professionals encouraging 
physicians and alternative health care providers to ask questions about supplements, nor 
10
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  has it conducted public awareness campaigns where consumers purchase supplements.  In 
recent years, FDA has made broad efforts to inform health professionals about reporting 
adverse events associated with FDA-regulated products through its Medwatch system but 
this had done little to help counteract under-reporting of dietary supplement adverse 
events. 
FDAs Adverse Event Reporting System Has Difficulty Generating 
Signals of Possible Public Health Concerns. 
FDAs adverse event reporting system for dietary supplements generates signals of 
possible public health risks.  As is the case for any database, if the data coming in are poor 
the analysis coming out will also be poor.  Below we present the key types of information 
that a system needs in order to generate strong signals and to assess the signals.  We will 
discuss the first four elements with regard to generating signals and the last two in the next 
section about assessing signals.  Where appropriate, we draw on our analysis of data from 
FDAs adverse event reporting database.43  Unless otherwise stated, the data are from the 
period 1994-1999. 
Key Information For An Adverse Event Reporting System 
Element  Description 
Medical  Information such as laboratory tests, medical diagnosis, medical history, preexisting 
Information  conditions, dose, frequency of use, and concurrent medications assist clinical staff in 
evaluating whether the product could have caused the adverse event. 
Product  FDA needs to know the identities and concentrations of ingredients contained in the 
Information  product to determine which ingredient may have caused the adverse event. It is also 
valuable for FDA to have some information about the products safety, recommended 
dosing, claims, and the products label. 
Manufacturer  Information such as address and contact person help FDA contact manufacturers to obtain 
Information  additional information. Often manufacturers have more clinical data and information 
that are not readily available to FDA. Also, manufacturers could provide FDA with 
product samples. 
Contact  Information on the consumer of the dietary supplement is important in order to conduct 
Information on the  follow up. A consumer can be identified through a variety of mechanisms that still 
Consumer  maintain confidentiality. 
Clinical  Information on the types of experiences in similar populations or in the past provide 
Information  contextual information that could help FDA triage reports. This information can be 
obtained from large scale clinical trials, small research studies, and epidemiological 
studies. 
Trend Analysis  A database with the capacity to conduct statistical analysis must be available and FDA 
needs to receive enough reports to conduct meaningful trend analyses. 
11
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Limited medical information.  FDA could not obtain the medical records for 58 percent 
(464 of 801) of the reports it followed up on.  To obtain medical records, FDA first must 
obtain the permission of the alleged injured party.  However, FDA told us that it often has 
difficulty locating or reaching consumers.  FDA may need to make repeated phone calls 
over weeks before contacting the consumer and securing access to medical information. 
And sometimes consumers refuse to release their medical records to FDA out of concern 
for their privacy.  According to the General Accounting Office, FDAs credibility in 
attempting to restrict the sale and use of dietary supplements containing ephedrine 
alkaloids was undermined, in part, because FDA lacked sufficient medical records to 
establish a causal relationship between these supplements and the reported adverse 
events.44 
At least half of the reports in FDAs database came from consumers.45  Consumers 
generally cannot provide as much medical detail or expertise as health professionals and 
therefore consumer reports tend to be less useful than those given by health 
professionals.46  Because supplements are generally self-care products, it is not surprising 
that FDA receives the majority of supplement adverse event reports from consumers. 
Twenty percent (527 of 2,547) of adverse events reports received by FDA came from 
health professionals.  Physicians and pharmacists are often in the best position to provide 
critical medical information as well as to assist FDA in determining the relationship 
between the product and the event. 
Limited product information.  FDA was unable to determine the ingredients for 32 
percent (1,153 of 3,574) of the products mentioned in adverse event reports.  Dietary 
supplement manufacturers do not have to register their products with the FDA, in contrast 
to drug manufacturers.  Therefore, FDA lacks a list of supplement products and their 
ingredients as a quick, easy reference when it receives a report.  In addition, because 
dietary supplement manufacturers are not required to prove the safety of their products 
prior to marketing them, FDA generally has relatively little information about the safety of 
that particular product when it receives an adverse event report. 
FDA lacks product labels for 77 percent (2,752 of 3,574) of the products associated with 
reports.  In order to determine the ingredients of dietary supplements, FDA often depends 
on obtaining a copy of the product label.  FDA officials told us that it is important that 
they obtain a photo of the actual label from the product consumed by the alleged injured 
party because dietary supplements sold under the same name often vary in the amount and 
type of ingredients they contain.  For this reason, FDA cannot always assume that the 
ingredients in a product that it locates are the same ingredients contained in the identically 
named product consumed by the alleged injured party.  In fact, we found a product with 
the same name and packaging in three different locations, yet each product listed different 
ingredients.  Furthermore, dietary supplement manufacturers can claim proprietary 
blends and choose to exclude the actual quantities of particular ingredients on the labels 
of dietary supplements.47 
12
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  FDA lacks product samples for 69 percent (130 of 188) of the products for which samples 
were requested.  Not only is it difficult for FDA to locate supplement consumers, but FDA 
also finds that supplement consumers often cannot or will not provide a product sample. 
Consumers may have discarded the remaining product, may want to hold on to it pending 
legal action, or may have sent it back to the manufacturer for a refund. 
Even when FDA has information about the ingredients contained in the consumed 
product, as stated on the label, a sample might need to be tested in order to determine the 
actual ingredients or the amount of each ingredient in the dose.  Several recent studies 
highlighted the wide variation in the quality of supplement products.48  One found that 
products contained varying amounts, ranging from 0 to 150 percent, of the labeled 
concentration of ingredients.49 
Another reason why FDA has difficulty determining the contents of dietary supplements is 
that it has not yet established good manufacturing practices for supplements,  regulations 
on processes for ensuring ingredient quality and quantity.  Although the Dietary 
Supplement Health and Education Act granted FDA the authority to establish good 
manufacturing practices for dietary supplements, it has not yet issued final regulations.50 
Without them, FDA lacks the explicit authority to examine manufacturer files that contain 
important information on how the product was made. 
Limited manufacturer information.  FDA receives few reports from manufacturers. 
Although we cannot confirm the number of reports FDA has received from manufacturers 
from FDAs database, FDA officials indicated that they have received fewer than 10 
reports from manufacturers since 1993.  Supplement manufacturers are not legally 
required to report adverse events.  In contrast, prescription drug manufacturers are legally 
required to report adverse events as well as have a system in place to evaluate them.51 
Thus, in 1999, FDAs Center for Drug Evaluation and Research, received 90 percent of its 
280,000 adverse event reports for drugs and biologics from the manufacturers of those 
products.  Pharmaceutical manufacturers must also do the investigative work that FDA 
sometimes does for dietary supplement reports. 
FDA could not determine the identity of the manufacturer for 32 percent (1,153 of 3,574) 
of the products involved in the reports.  FDA does not know the city and State where the 
manufacturer is located for 71 percent (644 of 904) of the manufacturers in its database. 
FDA does not routinely contact the supplement manufacturer when it receives an adverse 
event report on its product.  One of the reasons FDA gives for not contacting 
manufacturers is that it cannot locate many of them.  Manufacturers need to include only 
their name, city, and State on a product label if their phone number is listed in their local 
directory.52  If their phone numbers are not listed in the local directory, they must include 
their phone number on the label.  However, FDA reports that dietary supplement 
companies have often moved from the addresses listed on the labels or exclude required 
information from their labels.  In one instance, FDA received two reports of comas 
associated with a product, but when field inspectors tried to track down the manufacturer, 
they found a post office box belonging to an owner who had since moved and closed the 
13
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  account.  FDA was only able to locate the manufacturer after receiving more reports of 
adverse events and conducting further investigations. 
Another difficulty in tracking manufacturers is that many supplements are sold through 
multi-level organizations.53  In such a case, the consumer may know who the distributor is, 
but not the manufacturer.  Distributors can be several layers removed from the 
manufacturer, making it increasingly difficult to track the source of the product.  One 
inspector told us that he had resorted to searching State tax records to locate the 
manufacturer associated with a certain product. 
On the other hand, some manufacturers have complained about not learning of adverse 
event reports involving their products until the media contacted them after obtaining the 
report from FDAs website.  Unlike drug manufacturers, dietary supplement 
manufacturers are not required to register with FDA.  Without such a database, FDA 
cannot easily contact the manufacturers and notify them that it received a report. 
Limited contact information on the dietary supplement consumer.  FDA could not 
follow-up with 27 percent (214 of 801) of the reports it tagged for follow-up.  The 
primary reason is lack of enough contact information or some type of identifier of the 
alleged injured party to enable follow-up.  Reporters may be reluctant to provide such 
information out of concern for privacy. 
Limited ability to analyze trends.  FDA has difficulty tracking and analyzing adverse 
event reports for three main reasons.  First, FDA receives so few reports that it is difficult 
to conduct rigorous statistical analysis of them.  As we have already pointed out, FDA 
received only 2,547 adverse event reports between 1994-1999. 
Second, report quality is poor.  As we have shown throughout the report, FDA is missing 
key information even after conducting follow-up.  Missing information further weakens 
FDAs analysis. 
Third, FDA has an inadequate computer database to track adverse event reports.  The 
existing database emerged from FDAs need to log the reports that it receives.  FDA did 
not design the database to analyze trends.  For example, many of the data fields are empty 
in the majority of reports because the fields were created recently and the staff has not had 
the time to enter data retrospectively from its paper files.  The database lacks  automatic 
data edits that would remove common data entry errors such as misspellings or illogical 
entries, making it difficult to query for a specific word or entry.  A number of the fields are 
defined poorly, complicating analysis.  For example, all the ingredients for a product are 
listed in the same data field making it difficult to search for trends by a specific ingredient. 
It is also difficult to analyze across reports when a report involves more than one product. 
14
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  FDA Lacks Vital Information to Adequately Assess Signals of Possible 
Public Health Concerns Generated by the Adverse Event Reporting 
System. 
Limited clinical information.  One key tool that FDA lacks in assessing signals is 
adequate clinical information.  Information on the types of experiences in similar 
populations or in the past provide contextual information that could help FDA assess 
signals.  This information can sometimes be obtained from large scale clinical trials, small 
research studies, and epidemiological studies.  However, the current regulatory framework 
for dietary supplements does not require manufacturers to conduct these studies pre- or 
post-marketing.  For this and other reasons, FDA has relatively little clinical information 
on particular products. 
Some manufacturers and researchers have conducted such studies, but these studies by no 
means cover all dietary supplement products or ingredients.  And the limited scientific 
literature on dietary supplements that does exist focuses almost exclusively on individual 
ingredients, such as certain botanicals or minerals.  However, dietary supplements tend to 
contain multiple ingredients.54 
FDA does obtain some clinical information from its 75-day premarket notification 
requirements.  But this applies only to dietary ingredients that were not marketed in the 
United States before October 15, 1994, and that have not been in the food supply as 
articles used as food without chemical alteration.  To date, FDA has received 97 
premarket notifications, covering 114 ingredients, 102 of which were new dietary 
ingredients (the remaining products/ingredients were found to be drugs or biologics). 
FDA has some clinical information from the history of use.  However, history of use 
information can be difficult to interpret as the information may be difficult to verify. 
Limited information on consumer use.  The size of the consumer population and the 
dosage taken by consumers helps FDA estimate the size of the potential threat to public 
health.  Although millions of supplements are sold in hundreds of forms in thousands of 
locations, little evidence is available on how many doses of a particular product or 
ingredient are consumed.  This dearth of information contrasts with the available 
information for prescription drugs for which the number of filled prescriptions is tracked 
and tabulated.  Without consumer use information, it is difficult for FDA to know what 
the denominator is when evaluating the adverse event reports it receives and thus, the 
incidence of adverse events relating to a particular product or ingredient within the user 
population.  This makes it difficult for FDA to determine the magnitude of safety 
concerns. 
In appendix A we present a case study involving ephedrine alkaloids that illustrates the 
information FDA lacks to assess signals of possible public health concerns generated by 
the adverse event reporting system. 
15
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  As a Result, FDA Rarely Takes Safety Actions Related to the Adverse 
Event Reporting System. 
With limited information to draw upon to generate and assess signals, it is not surprising 
that FDA rarely reaches the point of knowing whether an action is needed in order to 
protect consumers.  In our discussions with FDA officials and our review of available 
data, we sought to determine just how many safety actions FDA has taken that are 
attributable, at least in part, to the adverse event reporting system.  We could not arrive at 
an exact number because of limitations in FDAs data systems, because of a lack of clarity 
over whether a safety action is, in fact, associated with adverse events, and even because 
of problems associated with defining the term action.  After a careful review, we did 
document 32 safety actions taken between January 1994 and June 2000 that FDA officials 
indicate were associated with adverse events.  Depending on how one defines actions and 
with more information, there may well be more such actions in that time period.  But, it is 
quite clear that at a time when more than 100 million people were taking dietary 
supplements, the number of FDA safety actions was strikingly low.55  (See the table below 
and appendix B for additional information.) 
FDA Safety Actions Related to the Adverse Event Reporting System 
(January 1994-June 2000) 
Action  Description  Number 
Issue Consumer Warnings  FDA can alert the public in the form of press releases or  9 
discussion papers. FDA publishes these alerts on the Internet. 
Disseminate Dear  FDA can issue letters that provide advice and guidance on the  2 
Colleague Letter to Health  use and marketing of dietary supplements to health 
Professionals or  professionals, manufacturers, and industry groups. 
Manufacturers 
Require Additional Labeling  FDA can require supplement manufacturers to provide  1 
additional information on the product label, such as warnings, 
side effects, or dosage information. 
Import Alert  FDA can prevent certain products or ingredients that are  1 
adulterated from entering the country. 
Request Voluntary Product  FDA can ask product manufacturers to recall a product  15 
Recall  voluntarily in lieu of mandating a recall. 
Seizure of Products and  FDA can seize products that are illegal, such as products that  4 
Products that are Unapproved  FDA has concluded are unapproved new drugs rather than 
New Drugs  dietary supplements.  FDA seizes particular lots of products or 
a particular manufacturers products on a case-by-case basis. 
Note: Due to limitations in FDAs data system, lack of clarity over whether or not a safety action is, in fact, 
associated with an adverse event, and problems in defining the term action, there could be other actions that 
FDA has taken that are excluded from this table. 
16
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  It is important to recognize that just one action can have considerable impact on consumer 
safety.  For example, FDA investigated a product upon receiving a report from a 
consumer complaining of nausea and irregular heart rates after she ingested a dietary 
supplement that was labeled as containing plantain.  From its investigation, FDA 
determined that the product was contaminated with Digitalis lanata, a plant that contains 
heart stimulants, which under certain circumstances may lead to cardiac arrest.  FDA 
widened its investigation and found other products labeled as containing plantain that were 
potentially contaminated with Digitalis lanata.  This led FDA to issue a warning to 
consumers against certain products that were labeled as containing plantain. 
Simultaneously, FDA asked supplement manufacturers to recall these products. 
On the other hand, we found 
several instances where FDA 
was unable to seize all the 
Lack of enforcement? 
illegal products on the market 
(see box).  Enforcing regulatory  C	 In June, 2000, we purchased two self-described herbal 
actions and ongoing monitoring  Phen-Fen products in two national stores a few blocks 
are the responsibility of the  away from our offices in Boston. FDA concluded that 
herbal Phen-Fen is an unapproved new drug in 1997. 
FDAs Office of Regulatory 
Affairs, which coordinates 
C	 We found Internet sites selling the street drug alternative, 
enforcement and routine 
herbal ecstasy. These products were being marketed as 
monitoring for all of FDA.  safe alternatives to ecstasy, an illegal drug. One stated 
Supplement cases must compete  that its product is an herbal formulation that is designed 
to specifically mimic the stimulating and prosensual 
for enforcement resources with 
effects of MDMA aka ecstasy. Another site simply 
prescription drugs, medical 
stated Herbal Ecstasy: an online store for items to get 
devices, biologics, and food 
you high. FDA considers any product that is promoted 
inspections, as well as outbreaks  as a street drug alternative to be an unapproved new drug 
of food-borne illness.  Ensuring  and a misbranded drug. We recognize that enforcing 
compliance with actions taken  Internet sales may be difficult. 
against dietary supplements and 
routine monitoring of 
supplements are low priorities 
for FDAgenerally prioritized below other FDA-regulated products, 
according to some FDA officials. 
Public disclosure is ineffective.  FDAs public disclosure of adverse events reports can 
also be considered a type of action.  FDAs website is its main vehicle for providing 
information to consumers.  The website contains access, with searching capabilities, to a 
public database on dietary supplement adverse event reports.  However, this database has 
significant limitations: no evaluation of the listed adverse event reports, incorrect 
information among the reports, and the information is rarely updated.  As a result, the 
website does a poor job of informing the public. 
The public databases main limitation is that it fails to provide any FDA evaluation of the 
relatedness of the dietary supplement or a particular ingredient to the adverse event.  The 
reports are posted as reported and exclude any FDA assessment.  To illustrate this 
17
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  shortcoming, we typed lettuce, an ingredient sometimes contained in herbal products, 
into the public adverse event database to determine whether any adverse events were 
associated with this clearly innocuous ingredient; the search found four adverse events, 
including two deaths.  However the website made no mention of the fact that the event is 
unlikely associated with this ingredient.56 
Furthermore, some of the information in the database may be inaccurate because FDA was 
unable to contact the reporter to verify the information.  In one case, a manufacturer was 
contacted by a consumer who had seen a report of an adverse event attributed to the 
manufacturers product on the FDA website.  In fact, the manufacturer did not sell that 
product.  When the manufacturer alerted FDA about the problem, FDA made the 
correction.57 
Finally, FDA rarely updates the database.  As of October 2000, the most current 
information was from a October 20, 1998 report. 
Although FDAs website is its primary mode of disclosing public information, interested 
parties always have another option for obtaining information from government agencies 
through Freedom of Information Act requests.  However, even this form of public 
disclosure is problematic for retrieving information on dietary supplement adverse event 
reports.  FDA must maintain the confidentiality of personal medical information contained 
in the report file when processing such requests.  That information provides essential 
information about a supplements role in a particular event.  To avoid privacy violations, 
FDA removes any information that could identify an alleged injured party before releasing 
a file, a time-consuming and resource-intensive process.  Industry representatives 
complain that, as a result of this redaction process, FDA takes a long time to fill these 
requests, thereby preventing the timely release of adverse event information. 
18
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  R E C O M M E N D A T I O N S  
Our evaluation of FDAs dietary supplement adverse event reporting system leads us to 
conclude that without further development of the overall regulatory framework for dietary 
supplements, the potential of the adverse event reporting system as a consumer safeguard 
is inherently limited. 
FDA is aware of its limitations in terms of confirming signals generated from its system. 
In its dietary supplement strategic plan, it identified a number of measures that it expects 
to enact as soon as resources become available.58,59  Similarly, manufacturers 
acknowledging waning consumer confidence in the safety of products, have also called for 
changes.60  And finally, the 1997 White House Commission on Dietary Supplement Labels 
and the General Accounting Office have both issued reports that address these concerns.61 
In presenting our recommendations, we offer a blueprint for actions that can be taken over 
a reasonable period of time.  We recognize that some of our recommendations may call 
for legislative or regulatory changes.  We also recognize that FDAs resources are limited 
and that some of our recommendations may require additional resources. 
RECOMMENDATION 1:  Facilitate Greater Detection of Adverse Events. 
FDA must make efforts to facilitate the reporting of adverse event reports to the system. 
Even with the best quality information, too few reports will minimize FDAs capacity to 
detect signals among adverse events reports (even the tightly controlled premarket clinical 
trials for pharmaceuticals, which usually contain around 3,000 subjects, fail to detect 
relatively rare adverse events during clinical trials).  To increase the percentage of events 
reported, FDA should: 
Require dietary supplement manufacturers to report serious adverse events to FDA 
for some products.  Requiring supplement manufacturers to report serious adverse events 
would be valuable to FDA.  However, such a requirement may not be necessary for all 
dietary supplements.  FDA should determine the appropriate scope of this requirement. 
FDA already requires pharmaceutical manufacturers to report adverse events for all 
prescription and some over-the-counter drugs.  FDA should recognize that if 
manufacturers are going to adhere to such a requirement, FDA first needs to convince 
them of the importance and adequacy of the system. 
Contract with Poison Control Centers to obtain their adverse event reports on 
dietary supplements.  In 1999, these Centers collectively received far more dietary 
supplement reports than FDA did in that same year.  They clearly hold a wealth of reports 
that would be extremely useful.  However, before contracting with these centers, FDA will 
have to grapple with two main complications.  First, it will have to reconcile its 
19
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  database technology with that of the Centers.  Secondly, it will need to reconcile the two 
entities conflicting privacy policies.  The Centers consider product identity private 
information and, thus, have told FDA that they would remove any product codes from 
their reports unless FDA were to agree not to release product identities to the public. 
Inform health professionals and consumers about the adverse event reporting 
system for dietary supplements.  FDA should expand its outreach to health 
professionals by disseminating information about the supplement adverse event system, 
actions it has taken, and warnings about potentially harmful supplements.  It should target 
not only physician and nurse organizations, but also professional organizations for 
pharmacists and practitioners of alternative and complementary medicine.62 
FDA may also want to consider requiring manufacturers to list their toll-free number on 
product labels especially if they are required to report adverse events to FDA.  Another 
possibility is for FDA to require its toll-free number be placed on product labels. 
RECOMMENDATION 2:  Obtain More Information on Adverse Event 
Reports In Order to Generate Stronger Signals of Public Health 
Concerns. 
Medical Information 
Without the alleged injured partys medical records, FDA lacks crucial information for 
determining the likelihood that the adverse event was related to use of the dietary 
supplement.  Too often, these records are missing from reports.  To increase the 
probability of receiving medical records, FDA should: 
Educate health professionals about the importance of including medical information 
in adverse event reports.  When FDA conducts general outreach to health professionals 
about the dietary supplement adverse event reporting system, it should present information 
on the role that medical records play in assessing adverse events.  FDA should conduct 
further outreach to encourage health professionals to obtain consent from their patients to 
release their medical records to FDA. 
Product Information 
One of the main reasons FDA has difficulty determining which, if any, supplement 
ingredient or combination of ingredients is most likely to have caused the adverse event is 
that it is often unable to determine the precise ingredients contained in the supplement that 
was consumed.  To improve the quality and quantity of this product information, FDA 
should: 
Require dietary supplement manufacturers to register their products with FDA. 
FDA often has difficulty obtaining the product identified in the report.  A complete 
product registry would allow FDA to instantly access a list of all of the ingredients in a 
20
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  particular product and determine the product manufacturers name as soon as an adverse 
event report was received. 
Notify manufacturers when FDA receives a serious adverse event report.  Alerting 
manufacturers to adverse events in which their products have been mentioned would give 
FDA the opportunity to obtain more product information from the manufacturer and could 
also improve FDA-industry relations.  FDA could use this interaction with the 
manufacturer to obtain a copy of the product label, information on the products 
ingredients, or information about any past adverse events that the manufacturer was aware 
of associated with that product.  If FDA notified manufacturers as soon as the adverse 
event was reported, manufacturers may be more helpful in sharing information about their 
products with FDA in a timely manner.  Manufacturers could also assess the products 
safety profile in a more timely fashion.  Clearly, it would be much easier for FDA to notify 
manufacturers if it had access to a complete registry of dietary supplement manufacturers. 
Manufacturer Information 
Require dietary supplement manufacturers to register with FDA.  A registry of 
manufacturers would enable FDA to quickly and easily contact a manufacturer whose 
product was associated with an adverse event.  It would also allow FDA to disseminate 
warnings, recalls, or other pertinent information to the manufacturers that might be 
affected by a particular action.  Registering with FDA could be a simple processa web-
based form, for exampleand would prevent FDA from wasting scarce resources while 
furthering its mission of protecting consumers. 
Contact Information on the Consumer 
FDA is often stymied in its efforts to contact the alleged injured party to gather more 
information about the product used, the circumstances under which it was used, and any 
preexisting conditions that the supplement consumer may have had.  It is essential that 
FDA confirm this information with the consumer of the supplement because, otherwise, 
the validity of the adverse event report may be called into question.  To ensure obtaining 
this contact information, FDA should: 
Emphasize to health professionals and consumers the importance of providing a way 
to identify the alleged injured party in reports.  Reporters to the adverse event 
reporting system must be aware that, without some type of identifier of the alleged injured 
party, FDA may be unable to take further action to investigate the report.  We recognize 
that confidentiality is a concern.  FDA must ensure that the reporter and the alleged 
injured party will be unidentifiable under any circumstances, including under a Freedom of 
Information Act request.  Once it is confident that it can ensure the confidentiality of this 
information, it should make this fact known to reporters of adverse events. 
21
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Trend Information 
Develop a new computer database to track and analyze adverse event reports.  The 
quality of each piece of information in the adverse event reporting system must be 
improved before FDA can effectively detect trends.  Beyond that, to improve its ability to 
generate signals from the system, FDA should reegineer its database.  The current 
database was designed for administrative purposes, not for analyzing trends.  FDA needs a 
new system that will allow it to rigorously analyze adverse event reports on an ongoing 
basis.  The system should allow for querying by ingredients as well as products and types 
of adverse event reaction.  It should also have automatic data edits so that queries will not 
be undermined due to misspelled or miskeyed entries.  FDA should work in partnership 
with the industry to redesign the system, as the industry has complained extensively about 
the current systems operations.  FDA has already called for this in its strategic plan. 
RECOMMENDATION 3:  Obtain Vital Information to Adequately Assess 
Signals Generated by the Adverse Event Reporting System. 
The central weakness we found is FDAs inability to adequately confirm signals that are 
generated from the system. 
Perhaps the largest problem that FDA faces is the paucity of scientifically robust research 
on dietary supplements that is available in the event that a particular supplement product 
or ingredient generates a signal of possible public health concern.  Below are some ways 
that FDA could increase the quality and quantity of clinical data available to them: 
Issue guidance on the type of safety information that manufacturers should include 
in the 75-day premarket notification requirement for new dietary supplement 
ingredients.  Because the 75-day requirement, though limited, represents the only 
premarket information that FDA is authorized to obtain on dietary supplements, it should 
take full advantage of its authority.  Yet no guidelines currently exist, undermining the 
usefulness of such a requirement.  We encourage FDA to collaborate with industry in 
developing these guidelines, another item on FDAs strategic plan. 
Explore the possibility of a monograph system for dietary supplements.  Monographs 
are point papers on particular products or ingredients that contain safety and efficacy 
information.  FDA has contracted with The National Academy of Sciences to describe a 
process for developing a monograph system for dietary supplements.63  Such a system 
would allow FDA to gather, in a systematic fashion, safety information that it could base 
safety decisions upon.  In addition, FDA could require manufacturers to adhere to the 
monographs in the future. 
Collaborate with the National Institutes of Health in setting a research agenda 
addressing safety issues.  Another way that FDA can gain clinical information on 
supplements is by collaborating with the National Institutes of Healths Center for 
22
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Alternative Medicine and Office of Dietary Supplements.  FDA and NIH already work 
with another through a trans-agency committee dedicated to supplements.  They should 
continue to work together and should begin to address specific safety issues that arise 
from the system. 
Assist industry and the United States Pharmacopeia in standardizing dietary 
supplement ingredients, particularly botanicals.  Standardized ingredients would allow 
FDA to recognize trends in adverse events associated with products containing common 
ingredients.  Ingredient names should also be standardized so that a particular ingredient 
cannot be listed under multiple names, adding to FDAs difficulty in conducting trend 
analysis.  FDA and industry have been working with the United States Pharmacopeia, a 
not-for-profit standard-setting body, to develop such quality standards.  Although it has 
been setting standards for vitamins and minerals for 10 years, its efforts in setting 
standards for botanical dietary supplements have been delayed due to the complexity of 
their ingredients.64  Nevertheless, it is currently considering a voluntary demonstration 
program for assuring the quality of botanical supplements in the marketplace through 
conformity testing of ingredient and product standards as well as performance standards 
for manufacturing.65  Such a program, though valuable, would be limited in its ability to 
protect consumers because it would be voluntary; it would not address botanicals health 
claims or safety issues, and United States Pharmacopeia would not enforce adherence to 
these standards.  Despite these limitations, we encourage FDA to continue working with 
this body on this effort.  Ultimately, FDA should work towards making adherence to 
quality standards mandatory for supplement manufacturers. 
Expedite the development and enactment of good manufacturing practices for 
dietary supplement manufacturers.  Standardized ingredients must be complemented by 
FDA enforcing those standards through good manufacturing practices.  These are essential 
for FDA to be assured of the precise contents of each batch of supplements that is 
manufactured.  Such information is crucial when an adverse event occurs following the 
use of a particular product because it allows FDA to verify the amount of each ingredient 
contained in the product and the possibility of contamination by another substance. 
Without them, FDA is hard-pressed to investigate supplement manufacturers because it 
has few standards to which to hold them accountable.  FDAs development of good 
manufacturing practices, which is in FDAs strategic plan for dietary supplements, is 
nearing completion and will be integrated, when possible, into United States 
Pharmacopeias aforementioned standardization efforts.66  As so much of FDAs capacity 
to oversee supplements rests on enforceable good manufacturing practices, we urge FDA 
to expedite developing and enacting of them. 
23
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  RECOMMENDATION 4:  Disclose More Useful Information to the Public 
about Dietary Supplement Adverse Events. 
FDA needs to provide data to the public so that the consumer can, to some extent, 
evaluate the likelihood that the adverse event was related to consuming the supplement. 
One way in which FDA can accomplish this is by placing summary data on it website.  For 
example, FDA could indicate the number of adverse events it has received with a 
particular product or ingredient.  FDA could also update the adverse event reporting 
information on its website more regularly.  Public disclosure loses its force as a consumer 
protection mechanism when the information is out-of-date.  Over time FDA may want to 
explore the possibility of indicating the likelihood that such events may or may not be 
associated with the product or ingredient. 
24
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  C O M M E N T S   O N  T H E  D R A F T  
R E P O R T  
We received comments on our draft report from the Food and Drug Administration 
(FDA).  We solicited and received comments from three trade associations: the Consumer 
Healthcare Products Association, the American Herbal Products Association, and the 
Council for Responsible Nutrition.  We also solicited and received comments from two 
public interest organizations: Public Citizens Health Research Group and the Center for 
Science in the Public Interest. 
On the basis of these comments we made several changes that are reflected in this final 
report.  Some involved minor technical changes, and others involved brief elaborations to 
clarify and add context.  In two instances we modified our recommendations to target 
them more effectively and to minimize regulatory burden.  We limited the scope of 
mandatory reporting of adverse event reports to events that are both serious in nature and 
fall under a certain subset of products to be determined by FDA.  Similarly, instead of 
calling for FDA to notify manufacturers of all adverse event reports it receives, we called 
for FDA to notify manufacturers of serious reports only. 
Below we summarize some of the larger issues raised in the comments and provide our 
response.  (See appendix C for the comments in their entirety.) 
Food and Drug Administration 
FDA thought that our findings were a fair assessment of the challenges it faces in using the 
adverse event reporting system.  FDA also agreed with the majority of our 
recommendations.  As part of its comments, it categorized our recommendations into 
three areas: (1) tasks that it can currently accomplish, (2) tasks that require additional 
resources, and (3) tasks that require legislative changes as well as additional resources. 
FDA pointed out that for many of those recommendations that fall into the first two 
categories, it already is taking steps to implement them.  FDA has included among its top 
priorities publishing good manufacturing practices and establishing a system for making 
adverse event reports available to manufacturers in a timely fashion.  In addition, FDA is 
working with the National Institutes of Health to highlight research areas and with the 
Institute of Medicine to categorize dietary ingredients based on safety concerns. 
FDA has not taken any steps to implement our recommendations that fall into the third 
category, requiring both legislative authority and additional resources.  This includes 
requiring manufacturers to report adverse events associated with dietary supplements and 
requiring manufacturers and their products to be registered with FDA.  In its comments, 
FDA took no position on these recommendations. 
25
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  FDA is making progress toward improving the system that is in line with the 
recommendations we call for in this report.  Many of our recommendations are already 
included among FDAs top priorities.  We encourage FDA to seek the authority it needs 
to require manufacturer and product registration and mandatory manufacturer reporting of 
adverse events. 
Trade Associations 
The three trade associations provide some support for a number of our recommendations, 
but, for the most part, they were highly critical of both our findings and recommendations. 
While we disagree with the thrust of their comments, we believe that they help sharpen the 
issues that need to be addressed as part of any reform. 
One of their major critiques was that we chose not to evaluate the internal operating 
procedures of FDAs adverse event reporting system.  This decision, the trade groups 
suggest, precluded us from making more practical recommendations on how the system 
could be improved.  As one respondent also noted, with little support for broader 
recommendations on how the system could be enhanced.  We recognize that there could 
be value to a procedural study.  FDA should be doing everything it can to make sure the 
current system operates as effectively as it possibly can.  But we strongly disagree with the 
comment that the current system could work adequately by simply improving internal 
operating procedures.  The adverse event reporting system, as we document extensively, 
cannot provide an adequate consumer safeguard without further development of the 
overall regulatory framework for dietary supplements. 
Another significant critique from the trade groups was that we failed to view dietary 
supplements in the context of a food-related system.  This failure, they claim, led us to call 
for more extensive regulatory interventions, similar to those for prescription drugs.  In 
response, our inquiry made us acutely aware of how little information FDA has available 
to identify whether adverse events about dietary supplements provide signals of possible 
public health concerns and to assess those signals.  Without an improved capacity to 
obtain such information, FDAs adverse event reporting system will continue to fall short 
of its potential. 
Still another critique is that our report reflects a negative view of dietary supplements and 
fails to recognize their role as self-care products that so many consumers value.  We regret 
any implication of such a negative view.  We have sought to focus strictly on how well the 
current system works and how it could work better.  If the kind of recommendations we 
call for are enacted, we suggest that consumers would have more extensive and useful 
information available to them on these self-care products.  Consumers also could have 
more confidence that an adverse event reporting system was providing them with a 
valuable measure of protection. 
26
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  Public Interest Organizations 
The two public interest organizations strongly supported our report.  Both expressed 
support for all of our recommendations.  Their main critique was that we did not go far 
enough.  One group called for legislative changes that, over time, would significantly 
enhance FDA authorities.  The other called for FDA to support a systematic study of 
dietary supplement safety and efficacy. 
While our evidence did not allow us to go as far as these organizations would like, it did 
lead us to emphasize that a comprehensive set of changes must be carried out if the 
adverse event reporting system is to provide an adequate consumer safety valve. 
27
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX A 
FDAs Experiences in Overseeing Ephedrine Alkaloids 
The purpose of this case study is not to judge the safety of botanical forms of ephedrine 
alkaloids.  Rather, we intend to use the example of dietary supplements that contain 
ephedrine alkaloids to illustrate that, even when FDA receives a strong warning signal 
from its adverse event reporting system, severe limitations inhibit FDAs ability to confirm 
the signal. Therefore, FDAs ability to take action is undermined.  FDAs attempted 
regulation of ephedrine alkaloids is, by no means, representative of other actions 
attempted by the agency.  We choose to highlight it because it exemplifies many of the 
shortcomings in the current adverse event reporting system for dietary supplements. 
After a brief background on the subject, we describe the key elements in FDAs oversight 
of ephedrine alkaloids and we discuss criticisms directed at FDA.  Finally, we provide our 
own commentary on the criticisms. 
Background 
Ephedrine alkaloids may be derived from plants (botanicals) or synthesized chemically. 
The botanical form is generally derived from Ephedra sinica, also known as ma huang, but 
it may come from other botanical sources.  The most common uses for supplements 
containing botanical ephedrine alkaloids are for losing weight and boosting energy.67 
Botanical forms of ephedrine have been used in traditional Chinese medicine for thousands 
of years to treat asthma, colds, coughs, fever, and nasal congestion.  FDA currently 
regulates synthetic forms of ephedrine as over-the-counter drugs to treat asthmatic 
symptoms.  Synthetic ephedrine (ephedrine HCl) is generally recognized as safe and 
effective for those 12 and older when used as a bronchodilator at doses up to 25 mg per 
dose not to exceed 150 mg a day. 
According to FDA, between 1993, when it began a new system to collect dietary 
supplement adverse event reports, and March, 2000, it received 1,173 adverse event 
reports associated with the use of products that contain, or were suspected to contain, 
ephedrine alkaloids.  Many of these reports involved serious events, including some 
deaths.  They also tended to involve young people; about 60 percent of the alleged injured 
parties were under the age of 40.68  The reports that FDA received containing ephedrine 
alkaloids comprised about half of the total reports that FDA received relating to all dietary 
supplements.  The size and severity of reports associated with botanical ephedrine 
alkaloids raised concerns within FDA about the safety of this ingredient and prompted 
FDA to learn more about potential health concerns relating to ephedrine alkaloids.  As of 
September, 2000, FDA had not taken any action to regulate ephedrine alkaloids, although 
during this time period many States and industry groups have taken safety measures 
related to these supplements. 69,70 
28
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX A 
Below we present the major events in FDAs attempt to ensure the safety of dietary

supplements containing ephedrine alkaloids:

July, 1993:  FDA issued its first public warning of possible safety problems associated

with dietary supplements containing ephedrine alkaloids.  The received reports described

events such as hypertension, palpitation, neuropathy, myopathy, psychosis, stroke, and

memory loss.71

February, 1995:  FDA issued a press release warning consumers against a particular

dietary supplement, Formula One, which contained both ephedrine alkaloids and a

botanical containing caffeine.72

October, 1995:  FDA convened a working group of its Food Advisory Committee that

comprised medical and other scientific experts outside of FDA as well as consumer and

industry representatives, to consider public health concerns associated with the use of

dietary supplements containing ephedrine alkaloids.  The group agreed that these

supplements may cause consumers to experience serious adverse events, but could not

agree on a specific dosage limit or warning statement.73

April, 1996:  FDA warned consumers not to purchase or consume ephedrine-containing

dietary supplements with labels that portray the products as alternatives to illegal street

drugs, because they pose significant health risks.74

August, 1996:  FDA convened its full Food Advisory Committee to address safety

concerns about ephedrine alkaloid-containing dietary supplements.  Half of the committee

believed that no safe levels of ephedrine alkaloids in dietary supplements existed.  The

Committee did not reach a consensus on safety recommendations.75

June, 1997:  FDA published a  proposed rule on dietary supplements containing

ephedrine alkaloids.76  The rule contained the following provisions: 

<  Must contain less than 8 mg of ephedrine alkaloid per serving, and the recommended

use must not exceed 24 mg within 24 hours; 
<  Must carry a label stating that the product should not be used for more than 7 days; 
<  May not be combined with other known stimulants, such as caffeine; 
<  May not have a labeling claim that requires long-term intake to achieve purported 
effect; 
<  Must contain a statement in conjunction with claims that encourage short-term, 
excessive intake that ingesting more than the recommended serving may result in 
heart attack, stroke, seizure, or death; and 
<  Must contain a specific warning on the product label. 
29
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX A 
November, 1997:  FDA warned consumers against dietary supplements, most of which

contain ephedrine alkaloids, being promoted as natural herbal alternatives to the

prescription drug combination fen-phen (fenfluramine and phentermine).77

July, 1999:  The General Accounting Office (GAO) released the report, Dietary

Supplements: Uncertainties in Analyses Underlying FDAs Proposed Rule on Ephedrine

Alkaloids.78  Congress requested a report following challenges to FDAs Proposed Rule

by the supplement industry and the Small Business Association.  GAOs report criticized

the quality of information upon which the FDAs Proposed Rule was based.  Specifically,

it found that FDA relied almost exclusively on poorly documented adverse event reports

to write its Proposed Rule.  GAO pointed out that the majority of the adverse event

reports were incomplete; that FDA did not demonstrate the causality between ephedrine

alkaloids and the adverse event reports; and that the Rules recommended dosages and

duration of use were based solely on poorly documented adverse event reports.  However,

GAO stated that FDA was justified in determining that the number of adverse event

reports relating to dietary supplements containing ephedrine alkaloids warranted their

attention and consideration of steps to address safety concerns.79

April, 2000:  FDA formally withdrew many of the provisions from its Proposed Rule

about ephedrine alkaloids, pending further data collection and analysis.80  FDA withdrew

the following provisions:

<  Dosage limits and limits to maximum daily intake;

<  Method of ensuring manufacturer compliance with above provision;

<  Limits on duration of supplement use; and

<  Prohibition of claims about the supplement, such as those that would encourage use

that exceeds the proposed limits of individual dosages, daily intake, and duration of 
use. 
August, 2000:  The Department of Health and Human Services Office of Womens

Health convened a public meeting to discuss the ongoing safety assessment of dietary

supplements containing ephedrine alkaloids.  The meeting was not intended to deliberate

on possible regulatory actions.  FDA stated that these deliberations would not take place

until it believes that the available scientific information has been fully discussed.81 The

meeting set out to answer four main questions:

<  What positive and adverse physiological actions would be expected of botanical

ephedrine alkaloids based on their known constituents?  Does the available 
information show an association between the use of dietary supplements and adverse 
events? 
<	 Are there any circumstances for which there are well established indications for the 
use of dietary supplements containing ephedrine alkaloids?  What doses and durations 
are needed to address those indications? 
30
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX A 
<	 How would one characterize the seriousness or severity of the risks of ephedrine 
alkaloids labeled for weight loss and exercise enhancement taking into account issues 
such as user demographics, the amount consumed by the population, use with other 
stimulants, or the added stress of exercise or individual sensitivities? 
<	 Are the outcomes associated with these products affected by dosage, by user 
characteristics or behaviors (such as combining use with other stimulants or 
compounds)?  Are outcomes affected by duration of exposure?82 
Some Criticisms of FDAs Proposed Rule of Dietary Supplements Containing Ephedrine 
Alkaloids 
The following represent some of the criticisms directed towards FDA in response to its 
Proposed Rule on dietary supplements containing ephedrine alkaloids.  Many of the 
criticisms were voiced by industry representatives during Congressional hearings about the 
Rule.  Others appear in the 1999 GAO report.  They are not direct quotes and may be 
attributed to many individuals and groups.  We also provide our own commentary on how 
the criticism demonstrates shortcomings in the adverse event system as well as other 
regulatory mechanisms that have a direct impact on the adverse event reporting system. 
Criticism:  FDAs proposed serving size (8 mg) is based, in large part, on its analysis of a 
negligible number of product samples associated with adverse event reports. 
Commentary:  Dietary supplement manufacturers are not required to register the 
formulations of their products with FDA.  In addition, FDA has not yet established Good 
Manufacturing Practices for dietary supplements that may provide the agency with more 
confidence in assuming that products contain what is listed on their labels, and in the 
quantities listed.  Thus, FDA depends overwhelmingly on consumers to provide samples 
of the consumed products associated with reports.  We already pointed out that FDA has 
difficulty obtaining these samples. 
Criticism:  FDAs case for the safety actions on supplements containing ephedrine alkaloid 
relies almost entirely on its analysis of adverse event reports, rather than on controlled research. 
Commentary:  Under the Dietary Supplement Health and Education Act, supplement 
manufacturers may market certain ingredients without any premarket review by FDA. 
The Act does not require that manufacturers prove the safety of ingredients in a controlled 
clinical setting; the burden is on FDA to prove that the ingredient is adulterated.  Because 
manufacturers do not have to conduct preapproval studies to determine appropriate 
dosages, side effects, and incidence of adverse events, FDA does not have this information 
available when it has concerns about the safety of an ingredient or product.  Controlled 
clinical trials take years to conduct, a time frame that may seem 
31
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX A 
both excessive and untenable when an ingredient seems to pose serious health problems.83 
Criticism:  Many of the adverse event reports that FDA relies upon for its safety assessment of 
supplements containing ephedrine alkaloids lack adequate information on how the product was 
used. 
Commentary:  The GAO found that, of a sample of reports, 39 percent lacked 
information on the amount of product consumed, 41 percent lacked information on the 
frequency with which the product was consumed, and 28 percent lacked information on 
the duration for which the product was consumed.84  Such incomplete data undermine 
FDAs ability to properly analyze the adverse event reports that it does receive, precluding 
it from being able to conclusively determine a safe dosage, frequency, and duration.  For 
other FDA-regulated products, data on dosage, frequency, and duration of use are 
established by the manufacturer in controlled clinical settings prior to market as part of 
FDAs preapproval process. 
Criticism:  FDA lacks denominator data and, thus, data on the incidence of adverse events 
associated with supplements containing ephedrine alkaloid. 
Commentary:  Because the law does not require any registration of either dietary 
supplement manufacturers or products, FDA has no way of quickly gauging the number of 
products sold.  Also, because there may be hundreds of products containing a particular 
ingredient, any effort on FDAs part to estimate the consumed doses of a particular 
ingredient is riddled with difficulties.  In situations where FDA feels a sense of urgency to 
act, an attempt to obtain reasonably accurate denominator data is too burdensome and 
time consuming. 
Criticism:  Adverse event reports are unreliable because they predominantly come from 
consumers. 
Commentary:  Dietary supplements are self-care products.  Health care professionals 
often are not aware that their patients are taking dietary supplements.  Supplement 
manufacturers are not required to report adverse events associated with their products to 
FDA, as they must for prescription drugs, and they virtually never do.  Thus, FDA is 
largely dependent upon consumer reports to alert them of possible concerns with dietary 
supplements. 
32
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX B 
FDA Actions Spurred by the Adverse Event Reporting System 
January 1994 - June 2000 
Below is a list of FDA safety actions based on the AER system that we were able to 
document.  Due to limitations in FDAs data systems, lack of clarity over whether or not a 
safety action is in fact associated with an adverse event, and problems defining the term 
action, there could be other actions that FDA has taken that are not included below. 
Consumer Warnings 
Formula One:  In February 1995, FDA warned consumers not to purchase or consume 
the Formula One products.  These product were marketed for weight loss.  The 
products may cause irregular heart beats and heart attacks.  (See appendix A). 
Ephedrine:  In April 1996, FDA warned consumers not to purchase or consume 
supplements containing ephedrine that are portrayed as alternatives to street drugs. 
Ephedrine is a stimulant that may cause seizures, heart attacks, and strokes. 
Gamma hydroxybutyric acid (GHB):  In February 1997, FDA reissued its 1990 
warning that GHB is an unapproved new drug and as such cannot be marketed as a dietary 
supplement.  GHB typically is marketed as an alternative to steroids.  Problems associated 
with its use include vomiting, dizziness, seizures, and even death. 
Chomper:  In May 1997, FDA warned consumers not to purchase or consume the 
product Chomper marketed as an herbal laxative.  FDA determined that this product 
was contaminated with the plant Digitalis lanata, which can cause rapid heart rate and 
even heart attacks. 
Plantain:  In June 1997, FDA warned consumers not to purchase or consume certain 
products labeled as containing plantain, sometimes marketed as herbal laxatives.  FDA 
found that some of these products were contaminated with the plant Digitalis lanata, 
which can cause rapid heart rate and even heart attacks. 
5-hydroxy-L-Tryptophan (5-HTP):  In August 1998, FDA found impurities in (5-HTP) 
products which are marketed as sleep aids and mood enhancers.  One of the impurities, 
termed Peak X is similar to an impurity that was found in products containing L-
tryptophan in 1989.  The use of L-tryptophan products was associated with eosinophilia
myalgia syndrome.  This syndrome is characterized by elevations in a particular type of 
white blood cell and severe muscle pain.  FDA encouraged consumers to report any 
adverse events associated with these products. 
33
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX B 
Gamma Butyrolactone (GBL):  In January 1999, FDA alerted consumers not to 
purchase or buy products containing GBL.  These products tend to be marketed as muscle 
builders, stress relievers, and sleep aids.  When ingested, GBL is transformed in the body 
to gamma hydroxybutyrate (GHB), an unapproved new drug, which can lead to 
unconsciousness and sometimes death. 
Gamma Butyrolactone (GBL) related products:  In May 1999, FDA warned 
consumers not to purchase or ingest products labeled as containing 1,4 butanediol (BD), 
tetramethylene glycol, gamma butyrolactone, or 2(3H)-furanone di-hydro.  Products 
containing these ingredients are usually marketed as sleep aids.  These products may cause 
low respiratory rates, unconsciousness, seizures, and possibly death. 
Triax Metabolic Accelerator:  In November 1999, FDA warned consumers not to 
purchase or consume the product Triax Metabolic Accelerator, marketed as a weight loss 
product, because FDA determined it was an unapproved new drug that contained a potent 
thyroid hormone.  The hormone may cause heart attacks and strokes. 
Dear Colleague Letters 
Aristolochic Acid:  In May 2000, FDA issued a letter to the industry and health care 
professionals warning that several botanical products were found to contain aristolochic 
acid, which can cause nephropathy and end-stage renal disease. 
Gamma Butyrolactone (GBL):  In June 1999, FDA issued a letter to health care 
organizations asking them to disseminate information warning consumers not to purchase 
or consume GBL-related products.  (See prior listing.) 
Require Additional Labeling 
Iron:  In January 1997, FDA required the following warning on dietary supplements 
containing iron or iron salts.  WARNING: Accidental overdose of iron-containing 
products is a leading cause of fatal poisoning in children under 6.  Keep this product out 
of reach of children.  In case of accidental overdose, call a doctor or poison control center 
immediately.  21 C.F.R. 101.17. 
Voluntary Recalls 
Plantain:  In October 1997, FDA asked 12 manufacturers to recall plantain products 
suspected to be contaminated with Digitalis lanata.  In April 1998, FDA asked another 
manufacturer to recall its product contaminated with Digitalis lanata. (See prior listing.) 
34
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX B 
Gamma Butyrolactone (GBL): In March 1999, FDA asked a manufacturer to recall its 
product containing GBL.  In December 1999, FDA asked another manufacturer to also 
recall its product containing GBL. 
Import Alerts 
Aristolochic Acid: In May 2000, issued an import alert preventing botanical ingredients 
that contain aristolochic acid from entering the country.  (See prior listing.) 
Product Seizures and Products That are Unapproved New Drugs 
Herbal Phen-Fen:  In November 1997, FDA concluded that products promoted as 
natural or safe alternatives to the weight-loss drugs phentermine and fenfluramine are, 
because of their intended use, unapproved new drugs.  These products do not contain 
prescription drugs.  Instead, many contain ephedra, a stimulant that may cause strokes and 
heart attacks.  (See prior listing.) 
Gamma Butyrolactone (GBL):  In 1999, FDA concluded that GBL is an unapproved 
new drug because it is transformed in the body to gamma hydroxybutyrate (GHB).  FDA 
initiated a seizure action in April 1999 against these products.  FDA also brought criminal 
cases against people distributing GBL and GHB. 
Triax Metabolic Accelerator:  In November 1999, FDA concluded that it was an 
unapproved new drug.  (See prior listing.)  FDA initiated a seizure action against Triax in 
December 1999. 
Street Drug Alternatives:  In March 2000, FDA determined that any products 
marketed as an alternative to street drugs are not dietary supplements because they intend 
to alter mental states, not supplement the diet.  FDA considers these products unapproved 
new drugs and, as such, they cannot be marketed as a dietary supplement. 
35
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
Comments on the Draft Report 
In this appendix, we present the full comments of all parties that responded to our draft 
report.  In order, the comments are from the following parties: 
<  Food and Drug Administration 
<  Consumer Healthcare Products Association 
<  American Herbal Products Association 
<  Council for Responsible Nutrition 
<  Public Citizens Health Research Group 
<  Center for Science in the Public Interest 
36
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
37
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
38
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
39
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
40
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
41
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
42
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
43
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
44
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
45
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
46
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
47
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
48
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
49
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
50
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
51
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
52
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
53
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
54
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
55
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
56
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
57
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
58
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
59
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
60
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
61
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
62
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
63
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
64
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
65
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
66
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
67
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
68
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
69
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
70
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
71
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
72
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
73
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
74
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
75
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
76
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
77
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
78
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
79
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
80
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
81
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
82
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
83
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
84
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
85
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
86
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
87
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
88
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
89
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
90
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
91
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX C 
92
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
Endnotes 
1.  21 U.S.C. sec. 321 (1994). 
2.  T. E. McAlindon, et al., Glucosamine and Chondroitin for Treatment of Osteoarthritis, 
Journal of the American Medical Association 238 (March 15, 2000) 111: 1469-1475. 
3.  T. J. Wilt, et al., Saw Palmetto Extracts for Treatment of Benign Prostatic Hyperplasia, 
Journal of the America Medical Association 280 (November 11, 1998) 18: 1604-1609. 
4.  21 C.F.R. sec.101.79. 
5.  How Accurate is the FDAs Monitoring of Supplements Like Ephedra?: Before the House 
Comm. on Government Reform, 106th Cong., 1st Sess. (1999) (statement of Joseph A. Levitt, 
Director, Center for Food Safety and Applied Nutrition, Food and Drug Administration). 
6.  Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103.417 sec. 2. 
7.  21 U.S.C. sec. 342 (1994). 
8.  It is important to note that the Federal Trade Commission also has jurisdiction over dietary 
supplements.  It regulates any type of advertising of dietary supplements on television, in print, or 
on the Internet, to ensure that false claims are not made. 
9.  High concern list of products/ingredients: The criteria for inclusion on this list will minimally 
include: 1) Targeted high frequency occurrences from the database or 2) information from other 
sources (scientific literature or that submitted to FDA by interested parties [consumers, scientists, 
industry, etc.]) citing deaths or aggregate system failure, and from information of other sources. 
Serious event:  For the purpose of evaluation, a medically serious adverse event implies a 
diagnosis or condition that is dangerous, critical, or alarming.  At a minimum, a medically serious 
adverse event would include all the definitions under Medwatch.  (Medwatch definition of 
serious: When the outcome is death, life threatening (real risk of dying), hospitalization (initial or 
prolonged), disability (significant, persistent, or permanent), congenital anomaly, or required 
intervention to prevent permanent impairment or damage.)  Other medical events that may not be 
immediately life-threatening, but which require intervention to prevent one of the Medwatch 
definitions would be considered medically serious. 
Clinically significant: an event, when occurring in healthy general populations, requires minimal 
intervention or supportive care, but when occurring in vulnerable populations (infant, children, 
immunocompromised, elderly, or otherwise debilitated individuals), often results in increased 
morbidity and/or prominent sequelae.  FDA, Standard Operating Procedures, November 28, 
93
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
1999. 
10.  21 U.S.C. sec. 402(f)(1)(A) (1994) contains the standards for which a dietary supplement is 
adulterated.  The standards for adulterated food also apply to supplements in sec. 402 (a-e and g). 
11.  21 U.S.C. sec. 350 b (1994). 
12.  21 U.S.C. sec. 402(f)(1)(B) (1994). 
13.  P. Kurtzweil, An FDA Guide to Dietary Supplements, FDA Consumer (1999): Publication 
No. (FDA) 99-2323. 
14.  Annual Industry Overview 2000, Nutrition Business Journal  5 (2000) 7/8. 
15.  U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition, Economic 
Characterization of the Dietary Supplement Industry Final Report, March 1999. 
[http://vm.cfsan.fda.gov/~comm/ds-econt.html] 
16.  Consumer Use of Dietary Supplements, Prevention Magazine, 2000, 19. 
17.  Ibid., 15. 
18.  Ibid., 37. 
19.  A survey of 43,000 households found that the largest percentage of households (30 percent) 
with a member who used a supplement in the past 6 months was 60 years or older.  P. 
Wingate, Consumers Not Supplement Brand Savvy, Natural Food Merchandiser, March 1998. 
20.  Dietary Supplement Health and Education Act: Is the FDA Trying to Change the Intent of 
Congress?: Hearing Before the House Comm. On Government Reform, 106th Congr., 1st Sess. 
(1999) (statement of Jane E. Henney, Commissioner, Food and Drug Administration). 
21.  Consumer Use of Dietary Supplements, Prevention Magazine, 2000, 74. 
22.  K. J. Rothman et al., Teratogenicity of High Vitamin A Intake,  New England Journal of 
Medicine 333 (1995) 21: 1369-1373. 
23.  M. Rosenblatt et al., Spontaneous Hyphema Associated with Ingestion of Ginkgo Biloba 
Extract [Letter], New England Journal of Medicine 336 (1997) 15: 1108. 
24.  Consumer Use of Dietary Supplements, Prevention Magazine, 2000, 37 and 39. 
25.  S. C. Piscitelli et al., Indinavir Concentrations and St John's Wort [Letter], Lancet 355 
(February 12, 2000) 9203: 547-548. 
94
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
26.  N. R. Slifman, et al., Contamination of Botanical Dietary Supplements by Digitalis Lanata, 
New England Journal of Medicine 339 (September 17, 1998) 12: 806-811. 
27.  R. J. Ko, Adulterants in Asian Patent Medicines [Editorial], New England Journal of 
Medicine, 339 (September 17, 1998) 12: 847. 
28.  California Department of Health Services, State Health Director Warns Consumers About 
Prescription Drugs in Herbal Products,  Press Release No. 09-00, February 15, 2000. 
29.  G. Gugliotta, Diet Supplement Maker Given Jail Time, Washington Post, Saturday, 8 July, 
2000, section A5. 
30.  Other common names we found for ephedrine alkaloids include:  Aradian tea, Khat, Miraa, 
Katstrauch, te de Arabia, Broomweed, Teaplant, arrow-leaf sida, Cuban-jute, Paddys-Lucerne, 
Queensland-Hemp, Kubajute, Cha-Bravo, Escoba, Common Yew, Eibe, Ban-Xia, European 
Aconite, and MonkShood. 
31.  21 C.F.R. sec. 104(h). 
32.  American Herbal Products Association, Herbs of Commerce (1992), 26. 
33.  A. Walker, The Relation between Voluntary Notification and Material Risk in Dietary 
Supplement Safety, FDA Commissioned Paper, March 9, 2000. 
34.  Consumer Use of Dietary Supplements, Prevention Magazine, 2000, 74. 
35.  American Association of Poison Control Centers, 1999 Annual Report of the American 
Association of Poison Control Centers Toxic Exposure Surveillance System, 1999. 
36.  It is important to note that Poison Control Centers use a broader definition for adverse event 
reports than FDA so the 13,000 may be somewhat high.  For example, these reports may contain 
accidental ingestion by a toddler. 
37.  The Texas reports may also contain reports from Texas Poison Control Center. 
38.  Lawsuit of Texas vs. Alliance, Texas Docket #3:94CV1002J;  FDA Stops Tracking Herbal 
Remedies: Agency Says it Doesnt Have the Funding to Assess Adverse Reactions, San 
Francisco Chronicle, Monday, 14 February, 2000. 
39.  Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103.417 sec. 2. 
40.  A recent survey found that nearly half of consumers who were taking supplements to treat or 
prevent a common illness took herbal products instead of over-the-counter medications. 
Consumer Use of Dietary Supplements, Prevention Magazine, 2000, 39. 
95
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
41.  R. Davis, Patients Fail to Fess Up on Herbal Remedies, USA Today, 29 May, 2000. 
42.  Consumer Use of Dietary Supplements, Prevention Magazine, 2000, 71. 
43.  By FDAs database we mean the database that FDA uses internally for its operations.  We are 
not referring to the information that is publicly available on adverse event reports on the Internet. 
44.  In a random sample of adverse event reports associated with dietary supplements containing 
ephedrine alkaloids (92 out of 864 reports), GAO found that 62 percent of the sampled reports 
did not include medical records.  U.S. General Accounting Office, Dietary Supplements: 
Uncertainties in Analyses Underlying FDAs Proposed Rule on Ephedrine Alkaloids, 
GAO/HEHS/GGD-99-90, July 1999, 11. 
45.  The remaining 32 percent of reports came from various sources including Poison Control 
Centers, State health departments, and family members. 
46.  A. S. Mitchell et al., Patients as a Direct Source of Information on Adverse Drug 
Reactions, British Medical Journal 297 (Oct 8, 1988) 6653: 891-893. 
47.  21 C.F.R., sec 101.36 (c). 
48.  A report conducted by ConsumerLab.com in January 2000 found that out of 13 brands of 
SAM-e, a dietary supplement used to treat depression, that it tested only 7 contained the amount 
listed on the label.  ConsumerLab.com, Product Review: SAM-e, 2000. 
[http://consumerlab.com/results/same.html] 
Another report conducted by ConsumerLab.com in January 2000 found that of 25 brands of 
glucosamine, chondroitin, and the combination of the two, 6 products did not have the amount of 
chondroitin listed on the label.  ConsumerLab.Com, Product Review:  Glucosamine and 
Chondroitin, 2000.  [http://consumerlab.com/results/gluco.html] 
49.  B. J. Gurley et al.,  Content Versus Label Claims in Ephedra-Containing Dietary 
Supplements, American Journal of Health Systems Pharmacists (May 15, 2000) 57: 963-951. 
50.  Interestingly, The Dietary Supplement Health Education Act (DSHEA) stated that the good 
manufacturing practices (GMPs) regulations should be modeled after those in place for food 
products.  However, if this is true, some are concerned that necessary tests would be excluded 
from the GMP regulations.  For example, tests of active ingredient concentrations are not relevant 
for food products.  It is also important to note that FDA may be able to inspect firms currently 
under the food good manufacturing practices. 
51.  Manufacturers of drugs under new drug applications must report all adverse events they 
receive to FDA.  21 C.F.R., sec. 314.80 (c) and 21 C.F.R., sec. 600.80 (c). 
96
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
52.  21 C.F.R., sec. 101.5. 
53.  About 20 percent of supplement companies are multi-level.  Annual Industry Overview 
2000, Nutrition Business Journal, 5 (2000) 7/8. 
54.  FDA has requested that interested parties submit any clinical data that they may have on the 
safety of specific ingredients that it has identified as a potential concern, such as ephedra. 
55.  FDA does have the authority to take other enforcement actions such as criminal prosecutions 
but for the purposes of this report we did not examine these types of actions. 
56.  There is a disclaimer on the website that there is no certainty that a reported event can be 
attributed to a particular product or ingredient. 
57.  FDA added a link to its Corrections Page explaining that the product was not produced by 
the listed manufacturer.  However, a search of the website by manufacturer does not include that 
reference to the Corrections Page. 
58.  The Presidents Budget for Fiscal Year 2000 and Fiscal Year 2001 requested $2.5 million for 
FDAs adverse event reporting system for dietary supplements and both times it was rejected. 
59.  Committee Report House Report 106-619, Agriculture, Rural Development, Food and Drug 
Administration, and Related Agencies Appropriations Bill, 2001, The Committee instructs the 
Food and Drug Administration to report to the Committee, within 6 months of enactment of the 
bill, on the dollar cost to implement the Dietary Supplement Strategy 10 Year Plan. The 
Committee instructs the Food and Drug Administration to report to the Committee within 6 
months of enactment of the bill, a summary of the total dollar amount spent in fiscal year 2000 in 
assessing the safety of dietary supplements, and in meeting the legal statutory burden under the 
Dietary Supplement Health and Education Act of 1994 for demonstrating safety problems with 
dietary supplements. 
60.  Unfortunately, the realities in our industry today require that we focus on core problems and 
challenges not successes, agree on remedial tasks and swiftly implement Council for Responsible 
Nutritions problem solving action plan, not bask in the light of earlier achievements.  The core 
challenges to the dietary supplement industry rest upon the declining confidence in dietary 
supplements by consumer, health care professionals, policymakers, and the media, which feeds the 
information flow of concern.  Council for Responsible Nutrition (CRN), Agenda for Action: 
Strengthening Confidence in Dietary Supplements, State of the Industry Presentation, CRN 2000 
Annual Conference, Miami, FL, September 18, 2000, 4. 
Now the potential exists for negative backlash.  There is scant evidence to prove this for 1999, 
but consumer disappointment, the relative lack of science and several other factors are 
undermining demand in herbs...  Annual Industry Overview 2000, Nutrition Business Journal. 
97
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
5 (2000) 7/8, 3. 
61.  U.S. General Accounting Office, Food Safety: Improvements Needed in Oversight of Dietary 
Supplements and Functional Foods, GAO/RCED-00-156, July 2000.;  Report Of The 
Commission On Dietary Supplement Labels, Commission on Dietary Supplement Labels, 
November 1997. 
62.  Some pharmacies provide optional forms for customers to list all of the medications they are 
taking, including dietary supplements.  With this information, pharmacists would be particularly 
well-poised to detect drug-supplement interactions. 
63.  Examination of the Evolving Science for Dietary Supplements, contract between FDA and 
National Academy of Sciences, effective September 30, 2000, section C, 4. 
64.  As of September 2000, United States Pharmacopeia (USP) had finalized one or more sets of 
standards for eleven dietary supplement ingredients. Status of USP-NF and USP-DI Botanical 
Monograph Development. [http://www.usp.org] 
65.  Standardization of botanicals has three components: standardizing the part of the plant from 
which the extract derives, assuring that the botanical extract contains the amount listed on the 
label, and ensuring that the botanical is not adulterated by pesticides, heavy metals, or other 
contaminants. Because acceptance criteria, such as benefits, safety, or nutritional value, have 
not been established for dietary supplements, USP must base its content standards on ranges 
observed in currently marketed supplements deemed to be safe. United States Pharmacopoeia, 
Draft Proposal: USP Quality Demonstration Program for Dietary Supplements, August 2000. 
[http://www.usp.org]. 
66.  United States Pharmacopoeia, Draft Proposal: USP Quality Demonstration Program for 
Dietary Supplements, August 2000, 4-5.  [http://www.usp.org] 
67.  M. Blumenthal et al., FDA Hearing Portends Uncertain Future for Mahuang: Members of 
FDA Panel Divided on Fate of Controversial Herb, HerbalGram (1996) 38: 29. 
68.  Food and Drug Administration Center for Food Safety and Applied Nutrition, Docket # 
OON-1200, Assessment of Public Health Risks Associated with the Use of Ephedrine Alkaloid-
containing Dietary Supplements (March 31, 2000), 11. 
69.  As of July, 2000, seven States had enacted laws restricting the sale of dietary supplements 
containing ephedrine alkaloids in some way: Florida, Michigan, Nebraska, New York, Ohio, 
Texas, and Virginia. 
70.  The American Herbal Products Association (AHPA), a dietary supplement trade group, 
established guidance for the responsible sale of products containing ephedrine alkaloids in 1994. 
98
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
After several iterations, its current guidelines recommend serving limits of 25 mg; require labels to 
state the amount of ephedrine alkaloids in the product; require labels to caution against use by 
those under 18, those with certain pre-existing conditions, and use in excess of recommended 
dosages; and prohibit marketing of these supplements as street drug alternatives.  These 
guidelines are currently supported by other key dietary supplement trade groups.  Adherence to 
these guidelines is strictly voluntary and many manufacturers of these supplements do not belong 
to the trade groups supporting these guidelines.  AHPA, Statement of Michael McGuffin 
President AHPA before the DHHS, Public meeting on the safety of dietary supplements 
containing ephedrine alkaloids, August 8, 2000. [http://www.ahpa.org/ephedrafda8800.html] 
71.  Food and Drug Administration, Center for Food Safety and Applied Nutrition, Illnesses and 
Injuries Associated with the Use of Selected Dietary Supplements, 1993. 
[http://vm.cfsan.fda.gov/~dms/ds-ill.htm] 
72.  U. S. Department of Health and Human Services, FDA Warns Consumers Against Natures 
Nutrition Formula One, HHS News, February 28, 1995. [http://vm.cfsan.fda.gov/~lrd/form1.html] 
73.  Food and Drug Administration, Center for Food Safety and Applied Nutrition, Docket # 
OON-1200, Assessment of Public Health Risks Associated with the Use of Ephedrine Alkaloid-
containing Dietary Supplements, (March 31, 2000), 2.  Also, Minutes of the Special Working 
Group on Food Products Containing Ephedrine Alkaloids of the FDA Food Advisory 
Committee, October 11-12, 1995. 
74.  U. S. Department of Health and Human Services, FDA Statement on Street Drugs 
Containing Botanical Ephedrine, HHS News, April 10, 1996. 
[http://vm.cfsan.fda.gov/~lrd/hhsephe1.html] 
75.  Food and Drug Administration Center for Food Safety and Applied Nutrition, Docket # 
OON-1200, Assessment of Public Health Risks Associated with the Use of Ephedrine Alkaloid-
containing Dietary Supplements, (March 31, 2000), 3.  Also, Minutes of the FDA Food Advisory 
Committee Meeting on Dietary Supplements Containing Ephedrine Alkaloids, August 27-28, 
1996. 
76.  62 Fed. Reg. 30677-30724, June 4, 1997 Dietary Supplements Containing Ephedrine 
Alkaloids: Proposed Rule. 
77.  FDA Warns Against Drug Promotion of Herbal Fen-Phen, FDA Talk Paper, November 6, 
1999. [http://vm.cfsan.fda.gov/~lrd/tpfenphn.html] 
78.  General Accounting Office, Dietary Supplements: Uncertainties in Analyses Underlying 
FDAs Proposed Rule on Ephedrine Alkaloids, GAO/HEHS/GGD-99-90, July 1999. 
79.  Ibid., 23. 
99
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180  APPENDIX D 
80.  64 Fed. Reg. 17474-17477, April, 3, 2000 Dietary Supplements Containing Ephedrine 
Alkaloids; Withdrawal in Part. 
81.  FDA, Dear Colleague letter about August 8, 2000 public meeting concerning the safety of 
dietary supplements containing ephedrine alkaloids, June 8, 2000. [http://vm.cfsan.fda.gov/~dms/ds
ltr6.html] 
82.  From transcript of U. S. Department of Health and Human Services, Office of Womens 
Healths Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids, 
(August 8, 2000), 5-6. 
83.  For example, a controlled clinical trial on the safety and effectiveness of ephedrine alkaloids, 
conducted by Harvard Medical School and Columbia Presbyterian Hospital, was designed in 
1996.  As of September, 2000, results of this study were still not available. 
84.  General Accounting Office, Dietary Supplements: Uncertainties in Analyses Underlying 
FDAs Proposed Rule on Ephedrine Alkaloids, GAO/HEHS/GGD-99-90, July 1999, 11. 
100
Adverse Event Reporting System for Dietary Supplements   OEI-01-00-00180